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Sample records for trail gene-armed oncolytic

  1. Trails, Other - Trails

    Data.gov (United States)

    NSGIC State | GIS Inventory — This trails map layer represents off-road recreational trail features and important road connections that augment Utah’s recreational trail network. This map layer...

  2. Oncolytic viruses as anticancer vaccines

    Directory of Open Access Journals (Sweden)

    Norman eWoller

    2014-07-01

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

  3. Oncolytic Adenoviruses in Cancer Treatment

    Directory of Open Access Journals (Sweden)

    Ramon Alemany

    2014-02-01

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

  4. Designing herpes viruses as oncolytics

    Directory of Open Access Journals (Sweden)

    Cole Peters

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

  5. Designing herpes viruses as oncolytics

    Science.gov (United States)

    Peters, Cole; Rabkin, Samuel D

    2015-01-01

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

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

    Science.gov (United States)

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

    2017-06-27

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

  7. Greenway Trails

    Data.gov (United States)

    Town of Cary, North Carolina — View the Town’s current and proposed greenway system, including connectors and street side trails.A greenway is a linear parcel of land set aside to preserve open...

  8. Airbag Trails

    Science.gov (United States)

    2004-01-01

    This segment of the first color image from the panoramic camera on the Mars Exploration Rover Spirit shows the rover's airbag trails. These depressions in the soil were made when the airbags were deflated and retracted after landing.

  9. Oncolytic viral therapy: targeting cancer stem cells

    Directory of Open Access Journals (Sweden)

    Smith TT

    2014-02-01

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

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

    Science.gov (United States)

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

    2012-02-01

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

  11. Alaska State Trails Program

    Science.gov (United States)

    Recreation Search DNR State of Alaska Home Menu Parks Home Alaska State Trails Boating Safety Design and Home / Alaska State Trails Alaska State Trails Program Trails in the Spotlight Glacier Lake and Saddle Trails in Kachemak State Park Glacier Lake A Popular route joins the Saddle and Glacier Lake Trails. The

  12. Molecular imaging of oncolytic viral therapy

    Directory of Open Access Journals (Sweden)

    Dana Haddad

    2014-01-01

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

  13. The impact of hypoxia on oncolytic virotherapy

    Directory of Open Access Journals (Sweden)

    Guo ZS

    2011-11-01

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

  14. Superior Hiking Trail Facilities

    Data.gov (United States)

    Minnesota Department of Natural Resources — Superior Hiking Trail main trail, spurs, and camp spurs for completed trail throughout Cook, Lake, St. Louis and Carlton counties. These data were collected with...

  15. Superior Hiking Trail

    Data.gov (United States)

    Minnesota Department of Natural Resources — Superior Hiking Trail main trail, spurs, and camp spurs for completed trail throughout Cook, Lake, St. Louis and Carlton counties. These data were collected with...

  16. Oncolytic virotherapy in upper gastrointestinal tract cancers

    Directory of Open Access Journals (Sweden)

    Yokoda R

    2018-03-01

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

  17. Oncolytic viruses: a step into cancer immunotherapy

    Directory of Open Access Journals (Sweden)

    Pol JG

    2011-12-01

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

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

    Directory of Open Access Journals (Sweden)

    Yokoda R

    2017-11-01

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

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

    Science.gov (United States)

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

    2015-01-01

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

  20. Current Immunotherapeutic Strategies to Enhance Oncolytic Virotherapy

    Directory of Open Access Journals (Sweden)

    Daniel E. Meyers

    2017-06-01

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

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

    Directory of Open Access Journals (Sweden)

    Hanni Uusi-Kerttula

    2015-11-01

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

  2. Oncolytic vaccinia therapy of squamous cell carcinoma

    Directory of Open Access Journals (Sweden)

    Yu Yong A

    2009-07-01

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

  3. DIRBE Comet Trails

    Science.gov (United States)

    Arendt, Richard G.

    2015-01-01

    Re-examination of the COBE DIRBE data reveals the thermal emission of several comet dust trails.The dust trails of 1P/Halley, 169P/NEAT, and 3200 Phaethon have not been previously reported.The known trails of 2P/Encke, and 73P/Schwassmann-Wachmann 3 are also seen. The dust trails have 12 and 25 microns surface brightnesses of trails are very difficult to see in any single daily image of the sky, but are evident as rapidly moving linear features in movies of the DIRBE data. Some trails are clearest when crossing through the orbital plane of the parent comet, but others are best seen at high ecliptic latitudes as the Earth passes over or under the dust trail. All these comets have known associations with meteor showers. This re-examination also reveals one additional comet and 13 additional asteroids that had not previously been recognized in the DIRBE data.

  4. Promising oncolytic agents for metastatic breast cancer treatment

    Directory of Open Access Journals (Sweden)

    Cody JJ

    2015-06-01

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

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

    Directory of Open Access Journals (Sweden)

    Saga K

    2015-10-01

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

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

    Directory of Open Access Journals (Sweden)

    Nicholas L. Denton

    2016-07-01

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

  7. Oncolytic Viruses: Therapeutics With an Identity Crisis

    Directory of Open Access Journals (Sweden)

    Caroline J. Breitbach

    2016-07-01

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

  8. THE ARC TRAIL

    African Journals Online (AJOL)

    INTRODUCTION. The project, carried out by the 1985 Conservation. Team at Durban Girls1 High School, consisted of three main aims- Awareness, Recreation and conservation, which were incorporated into the naming of the ARC trail. The trail is situated in suburban Durban where it was felt that it was important to ...

  9. Improvement of oncolytic adenovirus vectors through genetic capsid modifications

    NARCIS (Netherlands)

    Vrij, Jeroen de

    2012-01-01

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

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

    Science.gov (United States)

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

    2016-06-01

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

  11. DRBE comet trails

    International Nuclear Information System (INIS)

    Arendt, Richard G.

    2014-01-01

    Re-examination of the Cosmic Background Explorer Diffuse Infrared Background Experiment (DIRBE) data reveals the thermal emission of several comet dust trails. The dust trails of 1P/Halley, 169P/NEAT, and 3200 Phaethon have not been previously reported. The known trails of 2P/Encke and 73P/Schwassmann–Wachmann 3 are also seen. The dust trails have 12 and 25 μm surface brightnesses of <0.1 and <0.15 MJy sr −1 , respectively, which is <1% of the zodiacal light intensity. The trails are very difficult to see in any single daily image of the sky, but are evident as rapidly moving linear features in movies of the DIRBE data. Some trails are clearest when crossing through the orbital plane of the parent comet, but others are best seen at high ecliptic latitudes as the Earth passes over or under the dust trail. All these comets have known associations with meteor showers. This re-examination also reveals 1 additional comet and 13 additional asteroids that had not previously been recognized in the DIRBE data.

  12. DRBE comet trails

    Energy Technology Data Exchange (ETDEWEB)

    Arendt, Richard G., E-mail: Richard.G.Arendt@nasa.gov [CREST/UMBC, Code 665, NASA/GSFC, Greenbelt, MD 20771 (United States)

    2014-12-01

    Re-examination of the Cosmic Background Explorer Diffuse Infrared Background Experiment (DIRBE) data reveals the thermal emission of several comet dust trails. The dust trails of 1P/Halley, 169P/NEAT, and 3200 Phaethon have not been previously reported. The known trails of 2P/Encke and 73P/Schwassmann–Wachmann 3 are also seen. The dust trails have 12 and 25 μm surface brightnesses of <0.1 and <0.15 MJy sr{sup −1}, respectively, which is <1% of the zodiacal light intensity. The trails are very difficult to see in any single daily image of the sky, but are evident as rapidly moving linear features in movies of the DIRBE data. Some trails are clearest when crossing through the orbital plane of the parent comet, but others are best seen at high ecliptic latitudes as the Earth passes over or under the dust trail. All these comets have known associations with meteor showers. This re-examination also reveals 1 additional comet and 13 additional asteroids that had not previously been recognized in the DIRBE data.

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

    Directory of Open Access Journals (Sweden)

    Eisenstein S

    2014-11-01

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

  14. Taking Care of our Trails

    Science.gov (United States)

    our Trails Obeying Environmental Laws Protecting Wildlife Environmental Sustainability Sustainability Protection » Trails Taking Care of our Trails Continued access and use of Los Alamos National Laboratory trails is contingent upon being good stewards of these federal lands. June 7, 2017 Hikers walk along the

  15. Continental Divide Trail

    Data.gov (United States)

    Earth Data Analysis Center, University of New Mexico — This shapefile was created to show the proximity of the Continental Divide to the Continental Divide National Scenic Trail in New Mexico. This work was done as part...

  16. Minnesota Water Trails

    Data.gov (United States)

    Minnesota Department of Natural Resources — This shapefile describes water trails in the State of Minnesota as designated through legislation and recognized by the Department of Natural Resources. The...

  17. State Park Trails

    Data.gov (United States)

    Minnesota Department of Natural Resources — This data set is a collection of ArcView shapefiles (by park) of trails within statutory boundaries of individual MN State Parks, State Recreation Areas and State...

  18. Airbag Trails-2

    Science.gov (United States)

    2004-01-01

    This segment of the first color image from the panoramic camera on the Mars Exploration Rover Spirit shows the rover's airbag trails (upper left). These depressions in the soil were made when the airbags were deflated and retracted after landing.

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

    Science.gov (United States)

    Campbell, Stephanie A; Gromeier, Matthias

    2005-04-01

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

  20. Certification trails for data structures

    Science.gov (United States)

    Sullivan, Gregory F.; Masson, Gerald M.

    1993-01-01

    Certification trails are a recently introduced and promising approach to fault detection and fault tolerance. The applicability of the certification trail technique is significantly generalized. Previously, certification trails had to be customized to each algorithm application; trails appropriate to wide classes of algorithms were developed. These certification trails are based on common data-structure operations such as those carried out using these sets of operations such as those carried out using balanced binary trees and heaps. Any algorithms using these sets of operations can therefore employ the certification trail method to achieve software fault tolerance. To exemplify the scope of the generalization of the certification trail technique provided, constructions of trails for abstract data types such as priority queues and union-find structures are given. These trails are applicable to any data-structure implementation of the abstract data type. It is also shown that these ideals lead naturally to monitors for data-structure operations.

  1. Immunostimulatory Gene Therapy Using Oncolytic Viruses as Vehicles

    Directory of Open Access Journals (Sweden)

    Angelica Loskog

    2015-11-01

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

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

    Directory of Open Access Journals (Sweden)

    Sarah Aref

    2016-10-01

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

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

    Directory of Open Access Journals (Sweden)

    Hutzen B

    2015-08-01

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

  4. Oncolytic Replication of E1b-Deleted Adenoviruses

    Directory of Open Access Journals (Sweden)

    Pei-Hsin Cheng

    2015-11-01

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

  5. The confining trailing string

    CERN Document Server

    Kiritsis, E; Nitti, F

    2014-01-01

    We extend the holographic trailing string picture of a heavy quark to the case of a bulk geometry dual to a confining gauge theory. We compute the classical trailing confining string solution for a static as well as a uniformly moving quark. The trailing string is infinitely extended and approaches a confining horizon, situated at a critical value of the radial coordinate, along one of the space-time directions, breaking boundary rotational invariance. We compute the equations for the fluctuations around the classical solutions, which are used to obtain boundary force correlators controlling the Langevin dynamics of the quark. The imaginary part of the correlators has a non-trivial low-frequency limit, which gives rise to a viscous friction coefficient induced by the confining vacuum. The vacuum correlators are used to define finite-temperature dressed Langevin correlators with an appropriate high-frequency behavior.

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

    Directory of Open Access Journals (Sweden)

    Patil Sandeep S

    2012-01-01

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

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

    Science.gov (United States)

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

    2018-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Lundstrom K

    2018-02-01

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

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

    Directory of Open Access Journals (Sweden)

    Braidwood L

    2013-12-01

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

  10. Allegheny County Blazed Trails Locations

    Data.gov (United States)

    Allegheny County / City of Pittsburgh / Western PA Regional Data Center — Shows the location of blazed trails in all Allegheny County parks. This is the same data used in the Allegheny County Parks Trails Mobile App, available for Apple...

  11. Oncolytic adenovirus Ad657 for systemic virotherapy against prostate cancer

    Directory of Open Access Journals (Sweden)

    Nguyen TV

    2018-05-01

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

  12. Thigmotaxis Mediates Trail Odour Disruption.

    Science.gov (United States)

    Stringer, Lloyd D; Corn, Joshua E; Sik Roh, Hyun; Jiménez-Pérez, Alfredo; Manning, Lee-Anne M; Harper, Aimee R; Suckling, David M

    2017-05-10

    Disruption of foraging using oversupply of ant trail pheromones is a novel pest management application under investigation. It presents an opportunity to investigate the interaction of sensory modalities by removal of one of the modes. Superficially similar to sex pheromone-based mating disruption in moths, ant trail pheromone disruption lacks an equivalent mechanistic understanding of how the ants respond to an oversupply of their trail pheromone. Since significant compromise of one sensory modality essential for trail following (chemotaxis) has been demonstrated, we hypothesised that other sensory modalities such as thigmotaxis could act to reduce the impact on olfactory disruption of foraging behaviour. To test this, we provided a physical stimulus of thread to aid trailing by Argentine ants otherwise under disruptive pheromone concentrations. Trail following success was higher using a physical cue. While trail integrity reduced under continuous over-supply of trail pheromone delivered directly on the thread, provision of a physical cue in the form of thread slightly improved trail following and mediated trail disruption from high concentrations upwind. Our results indicate that ants are able to use physical structures to reduce but not eliminate the effects of trail pheromone disruption.

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

    Science.gov (United States)

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

    2017-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Matthew O. Old

    2016-06-01

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

  15. Tracking Online Trails

    Science.gov (United States)

    Qi, Man; Edgar-Nevill, Denis; Wang, Yongquan; Xu, Rongsheng

    Traceability is a key to the investigation of the internet criminal and a cornerstone of internet research. It is impossible to prevent all internet misuse but may be possible to identify and trace the users, and then take appropriate action. This paper presents the value of traceability within the email/-newsposting utilities, the technologies being using to hide identities, the difficulties in locating the traceable data and the challenges in tracking online trails.

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

    Directory of Open Access Journals (Sweden)

    Shashi Ashok Gujar

    2014-04-01

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

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

    Directory of Open Access Journals (Sweden)

    Gregory K Friedman

    2013-02-01

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

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

    Science.gov (United States)

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

    2017-09-15

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

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

    Science.gov (United States)

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

    2007-04-01

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

  20. BCDC Bay Trail Alignment 2009

    Data.gov (United States)

    California Natural Resource Agency — The Bay Trail provides easily accessible recreational opportunities for outdoor enthusiasts, including hikers, joggers, bicyclists and skaters. It also offers a...

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

    National Research Council Canada - National Science Library

    Zhang, Xiaoliu

    2004-01-01

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

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

    National Research Council Canada - National Science Library

    Zhang, Xiaoliu

    2005-01-01

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

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

    National Research Council Canada - National Science Library

    Zhang, Xiaoliu

    2006-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Marijke van Rikxoort

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

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

    Directory of Open Access Journals (Sweden)

    Jing Li Huang

    2016-09-01

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

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

    Science.gov (United States)

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

    2016-09-19

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

  7. The policy trail methodology

    DEFF Research Database (Denmark)

    Holford, John; Larson, Anne; Melo, Susana

    of ‘policy trail’, arguing that it can overcome ‘methodological nationalism’ and link structure and agency in research on the ‘European educational space’. The ‘trail’ metaphor, she suggests, captures the intentionality and the erratic character of policy. The trail connects sites and brings about change......, but – although policy may be intended to be linear, with specific outcomes – policy often has to bend, and sometimes meets insurmountable obstacles. This symposium outlines and develops the methodology, but also reports on research undertaken within a major FP7 project (LLLIght’in’Europe, 2012-15) which made use......In recent years, the “policy trail” has been proposed as a methodology appropriate to the shifting and fluid governance of lifelong learning in the late modern world (Holford et al. 2013, Holford et al. 2013, Cort 2014). The contemporary environment is marked by multi-level governance (global...

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

    Science.gov (United States)

    Tai, Lee-Hwa; Auer, Rebecca

    2014-01-01

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

  9. High-throughput screening to enhance oncolytic virus immunotherapy

    Directory of Open Access Journals (Sweden)

    Allan KJ

    2016-04-01

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

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

    Directory of Open Access Journals (Sweden)

    Janice Kim

    2015-11-01

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

  11. VT Green Mountain National Forest - Long Trail and Appalachian Trail

    Data.gov (United States)

    Vermont Center for Geographic Information — (Link to Metadata) GMNFTRAILS contains minor Forest Service roads and all trails within the proclamation boundary of the Green Mountain National Forest and many of...

  12. Reduction of airfoil trailing edge noise by trailing edge blowing

    International Nuclear Information System (INIS)

    Gerhard, T; Carolus, T; Erbslöh, S

    2014-01-01

    The paper deals with airfoil trailing edge noise and its reduction by trailing edge blowing. A Somers S834 airfoil section which originally was designed for small wind turbines is investigated. To mimic realistic Reynolds numbers the boundary layer is tripped on pressure and suction side. The chordwise position of the blowing slot is varied. The acoustic sources, i.e. the unsteady flow quantities in the turbulent boundary layer in the vicinity of the trailing edge, are quantified for the airfoil without and with trailing edge blowing by means of a large eddy simulation and complementary measurements. Eventually the far field airfoil noise is measured by a two-microphone filtering and correlation and a 40 microphone array technique. Both, LES-prediction and measurements showed that a suitable blowing jet on the airfoil suction side is able to reduce significantly the turbulence intensity and the induced surface pressure fluctuations in the trailing edge region. As a consequence, trailing edge noise associated with a spectral hump around 500 Hz could be reduced by 3 dB. For that a jet velocity of 50% of the free field velocity was sufficient. The most favourable slot position was at 90% chord length

  13. Tarague Interpretive Trail Mitigation Plan

    National Research Council Canada - National Science Library

    Welch, David

    2001-01-01

    ...), International Archaeological Research Institute, Inc. (lARfI) has prepared a mitigation plan for development of an interpretive trail at Tarague Beach, located on the north coast of the island of Guam (Fig. 1...

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

    Directory of Open Access Journals (Sweden)

    Andrew eNguyen

    2014-06-01

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

  15. Efficacy of combining ING4 and TRAIL genes in cancer-targeting gene virotherapy strategy: first evidence in preclinical hepatocellular carcinoma.

    Science.gov (United States)

    Galal El-Shemi, A; Mohammed Ashshi, A; Oh, E; Jung, B-K; Basalamah, M; Alsaegh, A; Yun, C-O

    2018-01-01

    Current treatments of hepatocellular carcinoma (HCC) are ineffective and unsatisfactory in many aspects. Cancer-targeting gene virotherapy using oncolytic adenoviruses (OAds) armed with anticancer genes has shown efficacy and safety in clinical trials. Nowadays, both inhibitor of growth 4 (ING4), as a multimodal tumor suppressor gene, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), as a potent apoptosis-inducing gene, are experiencing a renaissance in cancer gene therapy. Herein we investigated the antitumor activity and safety of mono- and combined therapy with OAds armed with ING4 (Ad-ΔB/ING4) and TRAIL (Ad-ΔB/TRAIL) gene, respectively, on preclinical models of human HCC. OAd-mediated expression of ING4 or TRAIL transgene was confirmed. Ad-ΔB/TRAIL and/or Ad-ΔB/ING4 exhibited potent killing effect on human HCC cells (HuH7 and Hep3B) but not on normal liver cells. Most importantly, systemic therapy with Ad-ΔB/ING4 plus Ad-ΔB/TRAIL elicited more eradicative effect on an orthotopic mouse model of human HCC than their monotherapy, without causing obvious overlapping toxicity. Mechanistically, Ad-ΔB/ING4 and Ad-ΔB/TRAIL were remarkably cooperated to induce antitumor apoptosis and immune response, and to repress tumor angiogenesis. This is the first study showing that concomitant therapy with Ad-ΔB/ING4 and Ad-ΔB/TRAIL may provide a potential strategy for HCC therapy and merits further investigations to realize its possible clinical translation.

  16. On the Appetite Trail

    Directory of Open Access Journals (Sweden)

    Grażyna Ewa Karpińska

    2015-12-01

    Full Text Available The article recounts actions oriented at experiencing and reliving culinary traditions, undertaken by the Local Action Group of the “Mroga” Society for the Local Community Development. The Society operates in five communes: Koluszki, Brzeziny, Dmosin, Jeżów and Rogów, located in the north-eastern part of the current Łódź voivodeship, east of the city of Łódź. In the past, this area, which bordered regions whose characteristic features indicated their distinct regional identities (the Łęczyca Land and the Łowicz Principality from the north, the Rawa Land from the east, the Opoczno and Piotrków Lands from the south, and Łódź from the west, was devoid of definite features typical to folk culture. Currently it is still an area which, due to the absence of a consistent and enduring cultural foundation to refer to, cannot be described in the categories of an ethnographic or geographic region. By following the tourist trail laid by the Society, known as the “Appetite Trail”, I reconstruct the vision of what the community resident in the five communes covered by the activity of the “Mroga” Local Action Group defines as the region’s culinary tradition, and I deconstruct the Group’s actions that reduce the tradition to the level of a tourist attraction.

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

    Directory of Open Access Journals (Sweden)

    Sokolowski NAS

    2015-11-01

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

  18. Trail Pheromone Disruption of Argentine Ant Trail Formation and Foraging

    Science.gov (United States)

    Suckling, D.M.; Peck, R.W.; Stringer, L.D.; Snook, K.; Banko, P.C.

    2010-01-01

    Trail pheromone disruption of invasive ants is a novel tactic that builds on the development of pheromone-based pest management in other insects. Argentine ant trail pheromone, (Z)-9-hexadecenal, was formulated as a micro-encapsulated sprayable particle and applied against Argentine ant populations in 400 m2 field plots in Hawai'i Volcanoes National Park. A widely dispersed point source strategy for trail pheromone disruption was used. Traffic rates of ants in bioassays of treated filter paper, protected from rainfall and sunlight, indicated the presence of behaviorally significant quantities of pheromone being released from the formulation for up to 59 days. The proportion of plots, under trade wind conditions (2-3 m s-1), with visible trails was reduced for up to 14 days following treatment, and the number of foraging ants at randomly placed tuna-bait cards was similarly reduced. The success of these trail pheromone disruption trials in a natural ecosystem highlights the potential of this method for control of invasive ant species in this and other environments. ?? Springer Science+Business Media, LLC 2010.

  19. Association between thyroid hormones and TRAIL.

    Science.gov (United States)

    Bernardi, Stella; Bossi, Fleur; Toffoli, Barbara; Giudici, Fabiola; Bramante, Alessandra; Furlanis, Giulia; Stenner, Elisabetta; Secchiero, Paola; Zauli, Giorgio; Carretta, Renzo; Fabris, Bruno

    2017-11-01

    Recent studies suggest that a circulating protein called TRAIL (TNF-related apoptosis-inducing ligand) might have a role in the regulation of body weight and metabolism. Interestingly, thyroid hormones seem to increase TRAIL tissue expression. This study aimed at evaluating whether overt thyroid disorders affected circulating TRAIL levels. TRAIL circulating levels were measured in euthyroid, hyperthyroid, and hypothyroid patients before and after thyroid function normalization. Univariate and multivariate analyses were performed to evaluate the correlation between thyroid hormones and TRAIL. Then, the stimulatory effect of both triiodothyronine (T3) and thyroxine (T4) on TRAIL was evaluated in vitro on peripheral blood mononuclear cells. Circulating levels of TRAIL significantly increased in hyperthyroid and decreased in hypothyroid patients as compared to controls. Once thyroid function was restored, TRAIL levels normalized. There was an independent association between TRAIL and both fT3 and fT4. Consistent with these findings, T3 and T4 stimulated TRAIL release in vitro. Here we show that thyroid hormones are associated with TRAIL expression in vivo and stimulate TRAIL expression in vitro. Given the overlap between the metabolic effects of thyroid hormones and TRAIL, this work sheds light on the possibility that TRAIL might be one of the molecules mediating thyroid hormones peripheral effects. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  20. Combining Oncolytic Virotherapy with p53 Tumor Suppressor Gene Therapy

    Directory of Open Access Journals (Sweden)

    Christian Bressy

    2017-06-01

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

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

    Directory of Open Access Journals (Sweden)

    Zong Sheng Guo

    2017-05-01

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

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

    Directory of Open Access Journals (Sweden)

    Guy Ungerechts

    2016-01-01

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

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

    Science.gov (United States)

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

    2016-01-01

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

  4. Recreational Trails in the State of Iowa

    Data.gov (United States)

    Iowa State University GIS Support and Research Facility — This file represents the locations of trails in Iowa. The original trail file was created by the Iowa Department of Transportation (IDOT), and included developed...

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

    International Nuclear Information System (INIS)

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

    2015-01-01

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

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

    Science.gov (United States)

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

    2015-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Yonatan Y Mahller

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

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

    Science.gov (United States)

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

    2011-12-01

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

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

    Directory of Open Access Journals (Sweden)

    Yoshiaki Yura

    2017-05-01

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

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

    Directory of Open Access Journals (Sweden)

    Timothy P Cripe

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

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

    Science.gov (United States)

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

    2016-02-01

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

  12. 77 FR 22333 - Prospective Grant of Exclusive License: Development of Oncolytic Viral Cancer Therapies

    Science.gov (United States)

    2012-04-13

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

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

    Science.gov (United States)

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

    2018-04-03

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

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

    Directory of Open Access Journals (Sweden)

    Tien V. Nguyen

    2017-08-01

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

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

    African Journals Online (AJOL)

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

  16. 77 FR 45721 - Consolidated Audit Trail

    Science.gov (United States)

    2012-08-01

    ... maintain a consolidated order tracking system, or consolidated audit trail, with respect to the trading of... With a Consolidated Audit Trail 3. Large Trader Reporting System Rule B. Summary of Proposed Rule 613 C... Authority (``FINRA'') and some of the exchanges currently maintain their own separate audit trail systems...

  17. 75 FR 32555 - Consolidated Audit Trail

    Science.gov (United States)

    2010-06-08

    ... Part II Securities and Exchange Commission 17 CFR Part 242 Consolidated Audit Trail; Proposed Rule... 3235-AK51 Consolidated Audit Trail AGENCY: Securities and Exchange Commission. ACTION: Proposed rule... a consolidated order tracking system, or consolidated audit trail, with respect to the trading of...

  18. Global variation of meteor trail plasma turbulence

    Directory of Open Access Journals (Sweden)

    L. P. Dyrud

    2011-12-01

    Full Text Available We present the first global simulations on the occurrence of meteor trail plasma irregularities. These results seek to answer the following questions: when a meteoroid disintegrates in the atmosphere, will the resulting trail become plasma turbulent? What are the factors influencing the development of turbulence? and how do these trails vary on a global scale? Understanding meteor trail plasma turbulence is important because turbulent meteor trails are visible as non-specular trails to coherent radars. Turbulence also influences the evolution of specular radar meteor trails; this fact is important for the inference of mesospheric temperatures from the trail diffusion rates, and their usage for meteor burst communication. We provide evidence of the significant effect that neutral atmospheric winds and ionospheric plasma density have on the variability of meteor trail evolution and on the observation of non-specular meteor trails. We demonstrate that trails are far less likely to become and remain turbulent in daylight, explaining several observational trends for non-specular and specular meteor trails.

  19. Trails and physical activity: a review.

    Science.gov (United States)

    Starnes, Heather A; Troped, Philip J; Klenosky, David B; Doehring, Angela M

    2011-11-01

    To provide a synthesis of research on trails and physical activity from the public health, leisure sciences, urban planning, and transportation literatures. A search of databases was conducted to identify studies published between 1980 and 2008. 52 studies were identified. The majority were cross-sectional (92%) and published after 1999 (77%). The evidence for the effects of trails on physical activity was mixed among 3 intervention and 5 correlational studies. Correlates of trail use were examined in 13 studies. Several demographic (eg, race, education, income) and environmental factors (eg, land-use mix and distance to trail) were related to trail use. Evidence from 31 descriptive studies identified several facilitators and barriers to trail use. Economic studies (n = 5) examining trails in terms of health or recreational outcomes found trails are cost-effective and produce significant economic benefits. There is a growing body of evidence demonstrating important factors that should be considered in promoting trail use, yet the evidence for positive effects of trails on physical activity is limited. Further research is needed to evaluate the effects of trails on physical activity. In addition, trail studies that include children and youth, older adults, and racial and ethnic minorities are a research priority.

  20. Carving a New Assessment Trail

    Science.gov (United States)

    Morriston, Terry

    2007-01-01

    TRAILS (Tool for Real-Time Assessment of Information Literacy Skills), is a free online test of student information-handling skills. It was formulated by the Institute for Library and Information Literacy Education and Kent State University Libraries. Based on the Ohio Academic Content Standards and the philosophy of Information Power, it assesses…

  1. A Mathematics and Science Trail

    Science.gov (United States)

    Smith, Kathy Horak; Fuentes, Sarah Quebec

    2012-01-01

    In an attempt to engage primary-school students in a hands-on, real-world problem-solving context, a large urban district, a mathematics and science institute housed in a college of education, and a corporate sponsor in the southwest United States, joined forces to create a mathematics and science trail for fourth- and fifth-grade students. A…

  2. Tissue distribution of the death ligand TRAIL and its receptors

    NARCIS (Netherlands)

    Spierings, DC; de Vries, EG; Vellenga, E; van den Heuvel, FA; Koornstra, JJ; Wesseling, J; Hollema, H; de Jong, S

    Recombinant human (rh) TNF-related apoptosis-inducing ligand (TRAIL) harbors potential as an anticancer agent. RhTRAIL induces apoptosis via the TRAIL receptors TRAIL-R1 and TRAIL-R2 in tumors and is non-toxic to nonhuman primates. Because limited data are available about TRAIL receptor

  3. Existence of spanning and dominating trails and circuits

    NARCIS (Netherlands)

    Veldman, H.J.

    1986-01-01

    Let T be a trail of a graph G. T is a spanning trail (S-trail) if T contains all vertices of G. T is a dominating trail (D-trail) if every edge of G is incident with at least one vertex of T. A circuit is a nontrivial closed trail. Sufficient conditions involving lower bounds on the degree-sum of

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

    International Nuclear Information System (INIS)

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

    2014-01-01

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

  5. Correlates of Trail Use for Recreation and Transportation on 5 Massachusetts Trails.

    Science.gov (United States)

    Orstad, Stephanie L; McDonough, Meghan H; Klenosky, David B; Mattson, Marifran; Troped, Philip J

    2016-08-01

    Promoting use of community trails is a recommended strategy for increasing population levels of physical activity. Correlates of walking and cycling for recreation or transportation differ, though few studies have compared correlates of trail-based physical activity for recreation and transportation purposes. This study examined associations of demographic, social, and perceived built environmental factors with trail use for recreation and transportation and whether associations were moderated by age, gender, and prior trail use. Adults (N = 1195) using 1 of 5 trails in Massachusetts responded to an intercept survey. We used multiple linear and logistic regression models to examine associations with trail use. Respondents' mean age was 44.9 years (standard deviation = 12.5), 55.3% were female, and 82.0% were white. Age (longer-term users only), trail use with others, travel time to the trail, and trail design were significantly associated with use for recreation (P trail safety (longer-term users only), travel time to the trail, trail design (younger users only), and trail beauty were associated with use for transportation (P trail use, whereas some variables were uniquely associated with use for 1 purpose. Tailored strategies are suggested to promote trail use for recreation and transportation.

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

    Directory of Open Access Journals (Sweden)

    Mari Hirvinen

    2016-01-01

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

  7. Exploring the TRAILs less travelled: TRAIL in cancer biology and therapy.

    Science.gov (United States)

    von Karstedt, Silvia; Montinaro, Antonella; Walczak, Henning

    2017-05-24

    The discovery that the tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce apoptosis of cancer cells without causing toxicity in mice has led to the in-depth study of pro-apoptotic TRAIL receptor (TRAIL-R) signalling and the development of biotherapeutic drug candidates that activate TRAIL-Rs. The outcome of clinical trials with these TRAIL-R agonists has, however, been disappointing so far. Recent evidence indicates that many cancers, in addition to being TRAIL resistant, use the endogenous TRAIL-TRAIL-R system to their own advantage. However, novel insight on two fronts - how resistance of cancer cells to TRAIL-based pro-apoptotic therapies might be overcome, and how the pro-tumorigenic effects of endogenous TRAIL might be countered - gives reasonable hope that the TRAIL system can be harnessed to treat cancer. In this Review we assess the status quo of our understanding of the biology of the TRAIL-TRAIL-R system - as well as the gaps therein - and discuss the opportunities and challenges in effectively targeting this pathway.

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

    Science.gov (United States)

    Liang, Min

    2018-01-01

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

  9. Happy trails: the effect of a media campaign on urban trail use in southern Nevada.

    Science.gov (United States)

    Clark, Sheila; Bungum, Tim J; Meacham, Mindy; Coker, Lisa

    2015-01-01

    Many Americans do not meet recommendations for physical activity (PA). Communities are building trail networks to encourage PA, but the relationship between trails and PA is not well understood. We monitored usage of urban trails (N = 10) in Las Vegas, NV, before and after a promotional marketing campaign (October 2011 and April 2012). The media campaign featured print, online, and radio ads, as well as billboards and signage on gas pumps. Data were collected with infrared monitors that were placed on the trails for periods of 7 days. We compared preintervention and postintervention usage rates. Mean usage increased (P trails, significant declines at 2 trails, and no change at 1 trail. Promotional campaigns may be an effective way to increase trail usage and encourage PA.

  10. Study of airfoil trailing edge bluntness noise

    DEFF Research Database (Denmark)

    Zhu, Wei Jun; Shen, Wen Zhong; Sørensen, Jens Nørkær

    2010-01-01

    This paper deals with airfoil trailing edge noise with special focus on airfoils with blunt trailing edges. Two methods are employed to calculate airfoil noise: The flow/acoustic splitting method and the semi-empirical method. The flow/acoustic splitting method is derived from compressible Navier...... design or optimization. Calculations from both methods are compared with exist experiments. The airfoil blunt noise is found as a function of trailing edge bluntness, Reynolds number, angle of attack, etc....

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

    Directory of Open Access Journals (Sweden)

    Fabrice Le Boeuf

    2017-09-01

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

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

    Science.gov (United States)

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

    2016-10-01

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

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

    OpenAIRE

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

    2018-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Irina Kuznetsova

    2017-12-01

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

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

    Directory of Open Access Journals (Sweden)

    Kaname Nosaki

    2016-01-01

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

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

    Science.gov (United States)

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

    2017-01-01

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

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

    Science.gov (United States)

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

    2014-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Ivaylo Gentschev

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

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

    Directory of Open Access Journals (Sweden)

    Hannah Burgess

    2018-03-01

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

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

    Directory of Open Access Journals (Sweden)

    Sampath P

    2015-06-01

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

  1. Trails

    Data.gov (United States)

    Vermont Center for Geographic Information — Data was hand drawn on USGS Topographic quads by foresters of the Vermont Department of Forests, Parks, & Recreation using orthophotos, survey data, and personal...

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

    Directory of Open Access Journals (Sweden)

    Mitsuhiro Machitani

    2017-12-01

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

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

    Science.gov (United States)

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

    2014-02-01

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

  4. LES tests on airfoil trailing edge serration

    DEFF Research Database (Denmark)

    Zhu, Wei Jun; Shen, Wen Zhong

    2016-01-01

    In the present study, a large number of acoustic simulations are carried out for a low noise airfoil with different Trailing Edge Serrations (TES). The Ffowcs Williams-Hawkings (FWH) acoustic analogy is used for noise prediction at trailing edge. The acoustic solver is running on the platform...

  5. Appalachian National Scenic Trail pilot survey

    Science.gov (United States)

    Stan Zarnoch; Michael Bowker; Ken Cordell; Matt Owens; Gary T. Green; Allison Ginn

    2011-01-01

    Visitation statistics on the Appalachian National Scenic Trail (AT) are important for management and Federal Government reporting purposes. However, no survey methodology has been developed to obtain accurate trailwide estimates over linear trails that traverse many hundreds of back-country miles. This research develops a stratified random survey design which utilizes...

  6. 49 CFR 236.776 - Movement, trailing.

    Science.gov (United States)

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false Movement, trailing. 236.776 Section 236.776 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... Movement, trailing. The movement of a train over the points of a switch which face in the direction in...

  7. Back in Time on a Mathematics Trail

    Science.gov (United States)

    Moffett, Pamela

    2010-01-01

    The recently revised "Northern Ireland Primary Curriculum" recommends that teachers make use of the environment to extend children's understanding of mathematics. One approach to using the environment in mathematics is to take children on a mathematics trail. A mathematics trail uses the resources and features within the environment as a…

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

    Directory of Open Access Journals (Sweden)

    Ramírez M

    2015-10-01

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

  9. Trail impacts and trail impact management related to ecotourism visitation at Torres del Paine National Park, Chile

    Science.gov (United States)

    Farrell, T.A.; Marion, J.L.

    2002-01-01

    Ecotourism and protected area visitation in Central and South America are largely dependent upon a relatively undisturbed quality of natural resources. However, visitation may impact vegetation, soil, water and wildlife resources, and degrade visitor facilities such as recreation sites and trails. Findings are reported from trail impact research conducted at Torres del Paine National Park in Patagonia, Chile. The frequency and magnitude of selected trail impacts and the relative effect of the amount of use, vegetation type, trail position and trail grade are investigated. Findings differed from previous studies in that amount of use was significantly related to both trail width increases and trail erosion. Management actions to minimize trail impacts are offered.

  10. Snails and their trails: the multiple functions of trail-following in gastropods.

    Science.gov (United States)

    Ng, Terence P T; Saltin, Sara H; Davies, Mark S; Johannesson, Kerstin; Stafford, Richard; Williams, Gray A

    2013-08-01

    Snails are highly unusual among multicellular animals in that they move on a layer of costly mucus, leaving behind a trail that can be followed and utilized for various purposes by themselves or by other animals. Here we review more than 40 years of experimental and theoretical research to try to understand the ecological and evolutionary rationales for trail-following in gastropods. Data from over 30 genera are currently available, representing a broad taxonomic range living in both aquatic and terrestrial environments. The emerging picture is that the production of mucus trails, which initially was an adaptation to facilitate locomotion and/or habitat extension, has evolved to facilitate a multitude of additional functions. Trail-following supports homing behaviours, and provides simple mechanisms for self-organisation in groups of snails, promoting aggregation and thus relieving desiccation and predation pressures. In gastropods that copulate, trail-following is an important component in mate-searching, either as an alternative, or in addition to the release of water- or air-borne pheromones. In some species, this includes a capacity of males not only to identify trails of conspecifics but also to discriminate between trails laid by females and males. Notably, trail discrimination seems important as a pre-zygotic barrier to mating in some snail species. As production of a mucus trail is the most costly component of snail locomotion, it is also tempting to speculate that evolution has given rise to various ways to compensate for energy losses. Some snails, for example, increase energy intake by eating particles attached to the mucus of trails that they follow, whereas others save energy through reducing the production of their own mucus by moving over previously laid mucus trails. Trail-following to locate a prey item or a mate is also a way to save energy. While the rationale for trail-following in many cases appears clear, the basic mechanisms of trail

  11. Automatic dirt trail analysis in dermoscopy images.

    Science.gov (United States)

    Cheng, Beibei; Joe Stanley, R; Stoecker, William V; Osterwise, Christopher T P; Stricklin, Sherea M; Hinton, Kristen A; Moss, Randy H; Oliviero, Margaret; Rabinovitz, Harold S

    2013-02-01

    Basal cell carcinoma (BCC) is the most common cancer in the US. Dermatoscopes are devices used by physicians to facilitate the early detection of these cancers based on the identification of skin lesion structures often specific to BCCs. One new lesion structure, referred to as dirt trails, has the appearance of dark gray, brown or black dots and clods of varying sizes distributed in elongated clusters with indistinct borders, often appearing as curvilinear trails. In this research, we explore a dirt trail detection and analysis algorithm for extracting, measuring, and characterizing dirt trails based on size, distribution, and color in dermoscopic skin lesion images. These dirt trails are then used to automatically discriminate BCC from benign skin lesions. For an experimental data set of 35 BCC images with dirt trails and 79 benign lesion images, a neural network-based classifier achieved a 0.902 are under a receiver operating characteristic curve using a leave-one-out approach. Results obtained from this study show that automatic detection of dirt trails in dermoscopic images of BCC is feasible. This is important because of the large number of these skin cancers seen every year and the challenge of discovering these earlier with instrumentation. © 2011 John Wiley & Sons A/S.

  12. TRAIL death receptors and cancer therapeutics

    International Nuclear Information System (INIS)

    Huang Ying; Sheikh, M. Saeed

    2007-01-01

    Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) also known as Apo2L is an apoptotic molecule that belongs to the tumor necrosis factor superfamily of cytokines. It mediates its apoptotic effects via its cognate death receptors including DR4 and DR5. Agonistic monoclonal antibodies have also been developed that selectively activate TRAIL death receptors to mediate apoptosis. Multiple clinically relevant agents also upregulate the expression of TRAIL death receptors, and cooperate with TRAIL as well as DR4 and DR5-specific agonistic antibodies to exhibit tumor cell killing. TRAIL is currently in phase I clinical trials, whereas DR4 and DR5-specific agonistic antibodies have been tested in phase I and II studies. Thus, TRAIL has clearly distinguished itself from the other family members including TNF-alpha and FasL both of which could not make it to the clinic due to their toxic nature. It is therefore, evident that the future of TRAIL-based therapeutic approaches looks brighter

  13. Pheromone disruption of Argentine ant trail integrity

    Science.gov (United States)

    Suckling, D.M.; Peck, R.W.; Manning, L.M.; Stringer, L.D.; Cappadonna, J.; El-Sayed, A. M.

    2008-01-01

    Disruption of Argentine ant trail following and reduced ability to forage (measured by bait location success) was achieved after presentation of an oversupply of trail pheromone, (Z)-9-hexadecenal. Experiments tested single pheromone point sources and dispersion of a formulation in small field plots. Ant walking behavior was recorded and digitized by using video tracking, before and after presentation of trail pheromone. Ants showed changes in three parameters within seconds of treatment: (1) Ants on trails normally showed a unimodal frequency distribution of walking track angles, but this pattern disappeared after presentation of the trail pheromone; (2) ants showed initial high trail integrity on a range of untreated substrates from painted walls to wooden or concrete floors, but this was significantly reduced following presentation of a point source of pheromone; (3) the number of ants in the pheromone-treated area increased over time, as recruitment apparently exceeded departures. To test trail disruption in small outdoor plots, the trail pheromone was formulated with carnuba wax-coated quartz laboratory sand (1 g quartz sand/0.2 g wax/1 mg pheromone). The pheromone formulation, with a half-life of 30 h, was applied by rotary spreader at four rates (0, 2.5, 7.5, and 25 mg pheromone/m2) to 1- and 4-m2 plots in Volcanoes National Park, Hawaii. Ant counts at bait cards in treated plots were significantly reduced compared to controls on the day of treatment, and there was a significant reduction in ant foraging for 2 days. These results show that trail pheromone disruption of Argentine ants is possible, but a much more durable formulation is needed before nest-level impacts can be expected. ?? 2008 Springer Science+Business Media, LLC.

  14. Audit trails in an online accountability system

    International Nuclear Information System (INIS)

    Jamison, C.

    1985-01-01

    The Safeguards Accountability Network (SAN) is an online computer system that was developed by Rockwell International to track the accounting and processing of nuclear materials from the time it arrives at Rocky Flats Plant through its life cycle. A major contributor to the success of SAN is the use of audit trails. They have proven to be invaluable for the management and safeguarding of these sensitive materials at Rocky Flats. Producing effective audit trails requires the recording of all pertinent transactions and the capability to access and report the information in a timely fashion. This paper discusses the implementation and application of these audit trails on the Rocky Flats SAN system

  15. Surface TRAIL decoy receptor-4 expression is correlated with TRAIL resistance in MCF7 breast cancer cells

    International Nuclear Information System (INIS)

    Sanlioglu, Ahter D; Dirice, Ercument; Aydin, Cigdem; Erin, Nuray; Koksoy, Sadi; Sanlioglu, Salih

    2005-01-01

    Tumor Necrosis Factor (TNF)-Related Apoptosis-Inducing Ligand (TRAIL) selectively induces apoptosis in cancer cells but not in normal cells. Despite this promising feature, TRAIL resistance observed in cancer cells seriously challenged the use of TRAIL as a death ligand in gene therapy. The current dispute concerns whether or not TRAIL receptor expression pattern is the primary determinant of TRAIL sensitivity in cancer cells. This study investigates TRAIL receptor expression pattern and its connection to TRAIL resistance in breast cancer cells. In addition, a DcR2 siRNA approach and a complementary gene therapy modality involving IKK inhibition (AdIKKβKA) were also tested to verify if these approaches could sensitize MCF7 breast cancer cells to adenovirus delivery of TRAIL (Ad5hTRAIL). TRAIL sensitivity assays were conducted using Molecular Probe's Live/Dead Cellular Viability/Cytotoxicity Kit following the infection of breast cancer cells with Ad5hTRAIL. The molecular mechanism of TRAIL induced cell death under the setting of IKK inhibition was revealed by Annexin V binding. Novel quantitative Real Time RT-PCR and flow cytometry analysis were performed to disclose TRAIL receptor composition in breast cancer cells. MCF7 but not MDA-MB-231 breast cancer cells displayed strong resistance to adenovirus delivery of TRAIL. Only the combinatorial use of Ad5hTRAIL and AdIKKβKA infection sensitized MCF7 breast cancer cells to TRAIL induced cell death. Moreover, novel quantitative Real Time RT-PCR assays suggested that while the level of TRAIL Decoy Receptor-4 (TRAIL-R4) expression was the highest in MCF7 cells, it was the lowest TRAIL receptor expressed in MDA-MB-231 cells. In addition, conventional flow cytometry analysis demonstrated that TRAIL resistant MCF7 cells exhibited substantial levels of TRAIL-R4 expression but not TRAIL decoy receptor-3 (TRAIL-R3) on surface. On the contrary, TRAIL sensitive MDA-MB-231 cells displayed very low levels of surface TRAIL-R4

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

    Directory of Open Access Journals (Sweden)

    Erkko Ylösmäki

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

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

    Science.gov (United States)

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

    2011-12-01

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

  18. Assessing soil erosion on trails: A comparison of techniques

    Science.gov (United States)

    Mark C. Jewell; William E. Hammitt

    2000-01-01

    Reports of trail degradation have been increasing in different wildernesses. This impact has become a common concern among managers. Deteriorating tread conditions of trails are increasing, as is concern at protected areas worldwide. In order to make objective and timely trail resource decisions, managers need to have effective and efficient methods of assessing trail...

  19. 36 CFR 261.55 - National Forest System trails.

    Science.gov (United States)

    2010-07-01

    ... 36 Parks, Forests, and Public Property 2 2010-07-01 2010-07-01 false National Forest System trails... PROHIBITIONS Prohibitions in Areas Designated by Order § 261.55 National Forest System trails. When provided by... National Forest System trail: (a) Being on a trail. (b) Using any type of vehicle prohibited by the order...

  20. VT Green Mountain National Forest - Trails

    Data.gov (United States)

    Vermont Center for Geographic Information — (Link to Metadata) GMNFTRAILS contains minor Forest Service roads and all trails within the proclamation boundary of the Green Mountain National Forest and many of...

  1. Minnesota State Park Trails and Roads

    Data.gov (United States)

    Minnesota Department of Natural Resources — This shapefile covers the trails in the State of Minnesota Parks, Recreation Areas, and Waysides as designated through legislation and recognized by the Department...

  2. Estimating the economic value and impacts of recreational trails: a case study of the Virginia creeper rail trail

    Science.gov (United States)

    J. Michael Bowker; John C. Bergstrom; Joshua Gill

    2007-01-01

    Many communities are interested in developing and maintaining recreational trails to benefit trail users and as tourist attractions to stimulate economic growth. In this paper, a study is described which estimates the net economic value to trail users and the local economic impacts of the Virginia Creeper Rail Trail in south-western Virginia, USA. The monetary...

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

    Directory of Open Access Journals (Sweden)

    Catherine Dold

    2016-01-01

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

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

    NARCIS (Netherlands)

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

    2006-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Gregory K Friedman

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

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

    NARCIS (Netherlands)

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

    2017-01-01

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

  7. TRAIL-receptor preferences in pancreatic cancer cells revisited: Both TRAIL-R1 and TRAIL-R2 have a licence to kill

    International Nuclear Information System (INIS)

    Mohr, Andrea; Yu, Rui; Zwacka, Ralf M.

    2015-01-01

    TRAIL is a potent and specific inducer of apoptosis in tumour cells and therefore is a possible new cancer treatment. It triggers apoptosis by binding to its cognate, death-inducing receptors, TRAIL-R1 and TRAIL-R2. In order to increase its activity, receptor-specific ligands and agonistic antibodies have been developed and some cancer types, including pancreatic cancer, have been reported to respond preferentially to TRAIL-R1 triggering. The aim of the present study was to examine an array of TRAIL-receptor specific variants on a number of pancreatic cancer cells and test the generality of the concept of TRAIL-R1 preference in these cells. TRAIL-R1 and TRAIL-R2 specific sTRAIL variants were designed and tested on a number of pancreatic cancer cells for their TRAIL-receptor preference. These sTRAIL variants were produced in HEK293 cells and were secreted into the medium. After having measured and normalised the different sTRAIL variant concentrations, they were applied to pancreatic and control cancer cells. Twenty-four hours later apoptosis was measured by DNA hypodiploidy assays. Furthermore, the specificities of the sTRAIL variants were validated in HCT116 cells that were silenced either for TRAIL-R1 or TRAIL-R2. Our results show that some pancreatic cancer cells use TRAIL-R1 to induce cell death, whereas other pancreatic carcinoma cells such as AsPC-1 and BxPC-3 cells trigger apoptosis via TRAIL-R2. This observation extended to cells that were naturally TRAIL-resistant and had to be sensitised by silencing of XIAP (Panc1 cells). The measurement of TRAIL-receptor expression by FACS revealed no correlation between receptor preferences and the relative levels of TRAIL-R1 and TRAIL-R2 on the cellular surface. These results demonstrate that TRAIL-receptor preferences in pancreatic cancer cells are variable and that predictions according to cancer type are difficult and that determining factors to inform the optimal TRAIL-based treatments still have to be identified

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

    Science.gov (United States)

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

    2017-09-08

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

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

    Science.gov (United States)

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

    2016-05-01

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

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

    Science.gov (United States)

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

    2017-10-20

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

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

    Science.gov (United States)

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

    2012-10-01

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

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

    International Nuclear Information System (INIS)

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

    2009-01-01

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

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

    Science.gov (United States)

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

    2018-05-01

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

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

    International Nuclear Information System (INIS)

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

    2011-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Eric K. Ring

    2017-12-01

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

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

    Science.gov (United States)

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

    2018-01-01

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

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

    Science.gov (United States)

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

    2018-01-01

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

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

    Science.gov (United States)

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

    2014-01-01

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

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

    International Nuclear Information System (INIS)

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

    2010-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2010-07-15

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

  1. Expression of TRAIL-splice variants in gastric carcinomas: identification of TRAIL-γ as a prognostic marker

    International Nuclear Information System (INIS)

    Krieg, Andreas; Mahotka, Csaba; Mersch, Sabrina; Wolf, Nadine; Stoecklein, Nikolas H; Verde, Pablo E; Schulte am Esch, Jan; Heikaus, Sebastian; Gabbert, Helmut E; Knoefel, Wolfram T

    2013-01-01

    TNF-related apoptosis inducing ligand (TRAIL) belongs to the TNF-superfamily that induces apoptotic cell death in a wide range of neoplastic cells in vivo as well as in vitro. We identified two alternative TRAIL-splice variants, i.e. TRAIL-β and TRAIL-γ that are characterized by the loss of their proapoptotic properties. Herein, we investigated the expression and the prognostic values of the TRAIL-splice variants in gastric carcinomas. Real time PCR for amplification of the TRAIL-splice variants was performed in tumour tissue specimens and corresponding normal tissues of 41 consecutive patients with gastric carcinoma. Differences on mRNA-expression levels of the TRAIL-isoforms were compared to histo-pathological variables and correlated with survival data. All three TRAIL-splice variants could be detected in both non-malignant and malignant tissues, irrespective of their histological staging, grading or tumour types. However, TRAIL-β exhibited a higher expression in normal gastric tissue. The proapoptotic TRAIL-α expression was increased in gastric carcinomas when compared to TRAIL-β and TRAIL-γ. In addition, overexpression of TRAIL-γ was associated with a significant higher survival rate. This is the first study that investigated the expression of TRAIL-splice variants in gastric carcinoma tissue samples. Thus, we provide first data that indicate a prognostic value for TRAIL-γ overexpression in this tumour entity

  2. Nature Trails, Braille Trails, Foot Paths, Fragrance Gardens, Touch Museums for the Blind; Policy Statement.

    Science.gov (United States)

    American Foundation for the Blind, New York, NY.

    The policy statement by the American Foundation for the Blind deals with nature trails, braille trails, foot paths, fragrance gardens, and touch museums for the blind. It is stated that the foundation approves of services such as provision of tape recorded guides and planting of fragrant shrubs which would benefit all users while recognizing…

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

    International Nuclear Information System (INIS)

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

    2010-01-01

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

  4. Comparing impacts between formal and informal recreational trails.

    Science.gov (United States)

    Pickering, Catherine Marina; Norman, Patrick

    2017-05-15

    Globally there are hundreds of thousands of kilometres of recreational trails traversing natural areas of high conservation value: but what are their impacts and do impacts differ among trails? We compared the effects of four common types of recreational trails [(1) narrow and (2) medium width informal bare earth trails and (3) gravel and (4) tarmac/concrete formal trails] on vegetation adjacent to trails in a high conservation value plant community that is popular for mountain biking and hiking in Australia. Plant species composition was recorded in quadrats along the edge of the four types of trails and in control sites away from trails. Vegetation cover, the cover of individual growth forms, and species richness along the edges of all four types of trails were similar to the controls, although the wider trails affected plant composition, with the tarmac and gravel trails favouring different species. With very few comparative studies, more research is required to allow managers and researchers to directly compare differences in the severity and types of impacts on vegetation among trails. In the meantime, limiting damage to vegetation on the edge of hardened trails during construction, use and maintenance is important, and hardening trails may not always be appropriate. Copyright © 2016. Published by Elsevier Ltd.

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

    Science.gov (United States)

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

    2010-12-15

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

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

    Science.gov (United States)

    Fox, Candace R; Parks, Griffith D

    2018-04-01

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

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

    Directory of Open Access Journals (Sweden)

    Prestwich Robin

    2011-06-01

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

  8. Audit trails in an online accountability system

    International Nuclear Information System (INIS)

    Jamison, C.

    1985-01-01

    The Safeguards Accountability Network (SAN) is an online computer system that was developed by Rockwell International to track the accounting and processing of nuclear materials from the time it arrives at Rocky Flats Plant through its life cycle. A major contributor to the success of SAN is the use of audit trails. They have proven to be invaluable for the management and safeguarding of these sensitive materials at Rocky Flats. Producing effective audit trails requires the recording of all pertinent transactions and the capability to access and report the information in a timely fashion. This paper discusses the implementation and application of these audit trials on the Rocky Flats SAN system. 1 fig

  9. Is the color trails culture free?

    Science.gov (United States)

    Fasfous, Ahmed F; Puente, Antonio E; Pérez-Marfil, María Nieves; Cruz-Quintana, Francisco; Peralta-Ramirez, Isabel; Pérez-García, Miguel

    2013-11-01

    Increasingly clinical neuropsychology has been addressing the effects of culture on neuropsychological functioning. However, that focus has been on comparing performance on standardized tests across two or more groups, often Hispanic. In this study, Arabic children were tested in Morocco using a "culture-free test," Children's Color Trails. Children of different ages and living in rural and urban centers were tested. The results suggest that the Color Trails Test scores from Arab children differed from U.S. norms available. Furthermore, the location of testing and the age of the child were of significance. The role of culture-specific tests was considered.

  10. Inhibition of TRAIL-induced apoptosis and forced internalization of TRAIL receptor 1 by adenovirus proteins.

    Science.gov (United States)

    Tollefson, A E; Toth, K; Doronin, K; Kuppuswamy, M; Doronina, O A; Lichtenstein, D L; Hermiston, T W; Smith, C A; Wold, W S

    2001-10-01

    Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induces apoptosis through two receptors, TRAIL-R1 (also known as death receptor 4) and TRAIL-R2 (also known as death receptor 5), that are members of the TNF receptor superfamily of death domain-containing receptors. We show that human adenovirus type 5 encodes three proteins, named RID (previously named E3-10.4K/14.5K), E3-14.7K, and E1B-19K, that independently inhibit TRAIL-induced apoptosis of infected human cells. This conclusion was derived from studies using wild-type adenovirus, adenovirus replication-competent mutants that lack one or more of the RID, E3-14.7K, and E1B-19K genes, and adenovirus E1-minus replication-defective vectors that express all E3 genes, RID plus E3-14.7K only, RID only, or E3-14.7K only. RID inhibits TRAIL-induced apoptosis when cells are sensitized to TRAIL either by adenovirus infection or treatment with cycloheximide. RID induces the internalization of TRAIL-R1 from the cell surface, as shown by flow cytometry and indirect immunofluorescence for TRAIL-R1. TRAIL-R1 was internalized in distinct vesicles which are very likely to be endosomes and lysosomes. TRAIL-R1 is degraded, as indicated by the disappearance of the TRAIL-R1 immunofluorescence signal. Degradation was inhibited by bafilomycin A1, a drug that prevents acidification of vesicles and the sorting of receptors from late endosomes to lysosomes, implying that degradation occurs in lysosomes. RID was also shown previously to internalize and degrade another death domain receptor, Fas, and to prevent apoptosis through Fas and the TNF receptor. RID was shown previously to force the internalization and degradation of the epidermal growth factor receptor. E1B-19K was shown previously to block apoptosis through Fas, and both E1B-19K and E3-14.7K were found to prevent apoptosis through the TNF receptor. These findings suggest that the receptors for TRAIL, Fas ligand, and TNF play a role in limiting virus

  11. TRAIL: A Novel Therapeutic Agent for Prostate Cancer

    National Research Council Canada - National Science Library

    Li, Honglin

    2002-01-01

    This study aims to elucidate the signaling pathway of TRAIL-mediated apoptosis in prostate cancer cells, and to examine the therapeutic effect of TRAIL on prostate cancer cells in vitro and in vivo...

  12. TRAIL: A Novel Therapeutic Agent for Prostate Cancer

    National Research Council Canada - National Science Library

    Li, Honglin

    2004-01-01

    This study aims to elucidate the signaling pathway of TRAIL-mediated apoptosis in prostate cancer cells, and to examine the therapeutic effect of TRAIL on prostate cancer cells in vitro and in vivo...

  13. TRAIL: A Novel Therapeutic Agent for Prostate Cancer

    National Research Council Canada - National Science Library

    Li, Honglin

    2003-01-01

    This study aims to elucidate the signaling pathway of TRAIL-mediated apoptosis in prostate cancer cells, and to examine the therapeutic effect of TRAIL on prostate cancer cells in vitro and in vivo...

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

    International Nuclear Information System (INIS)

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

    2008-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Beatriz Vera

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

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

    Science.gov (United States)

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

    2018-02-07

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

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

    Directory of Open Access Journals (Sweden)

    Lockley Michelle

    2010-07-01

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

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

    Science.gov (United States)

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

    2015-12-28

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

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

    Science.gov (United States)

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

    2011-02-01

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

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

    Science.gov (United States)

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

    2011-04-01

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

  1. Cuticular lipids as trail pheromone in a social wasp.

    OpenAIRE

    Steinmetz, Inge; Schmolz, Erik; Ruther, Joachim

    2003-01-01

    We investigated the origin and composition of the chemical trail of the common yellow jacket Vespula vulgaris L. (Vespidae) and found that an artificial trail made from an extract of cuticular lipids from V. vulgaris foragers was biologically as active as a trail laid naturally by the foragers. Chemical analysis of natural trail extracts and the behaviourally active cuticular extracts by coupled gas chromatography-mass spectrometry revealed that the majority of cuticular hydrocarbons were als...

  2. 21 CFR 1311.215 - Internal audit trail.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 9 2010-04-01 2010-04-01 false Internal audit trail. 1311.215 Section 1311.215... ORDERS AND PRESCRIPTIONS (Eff. 6-1-10) Electronic Prescriptions § 1311.215 Internal audit trail. (a) The... with audit trail functions. (6) For application service providers, attempted or successful annotation...

  3. A cellular automata model for ant trails

    Indian Academy of Sciences (India)

    In this study, the unidirectional ant traffic flow with U-turn in an ant trail was investigated using one-dimensional cellular automata model. It is known that ants communicate with each other by dropping a chemical, called pheromone, on the substrate. Apart from the studies in the literature, it was considered in the model that ...

  4. Certification trails and software design for testability

    Science.gov (United States)

    Sullivan, Gregory F.; Wilson, Dwight S.; Masson, Gerald M.

    1993-01-01

    Design techniques which may be applied to make program testing easier were investigated. Methods for modifying a program to generate additional data which we refer to as a certification trail are presented. This additional data is designed to allow the program output to be checked more quickly and effectively. Certification trails were described primarily from a theoretical perspective. A comprehensive attempt to assess experimentally the performance and overall value of the certification trail method is reported. The method was applied to nine fundamental, well-known algorithms for the following problems: convex hull, sorting, huffman tree, shortest path, closest pair, line segment intersection, longest increasing subsequence, skyline, and voronoi diagram. Run-time performance data for each of these problems is given, and selected problems are described in more detail. Our results indicate that there are many cases in which certification trails allow for significantly faster overall program execution time than a 2-version programming approach, and also give further evidence of the breadth of applicability of this method.

  5. Influence of hiking trails on montane birds

    Science.gov (United States)

    William V. Deluca; David I. King

    2014-01-01

    Montane forests contribute significantly to regional biodiversity. Long-term monitoring data, often located along hiking trails, suggests that several indicator species of this ecosystem have declined in recent decades. Declining montane bird populations have been attributed to anthropogenic stressors such as climate change and atmospheric deposition. Several studies...

  6. A cellular automata model for ant trails

    Indian Academy of Sciences (India)

    In this study, the unidirectional ant traffic flow with U-turn in an ant trail was inves- tigated using ... the literature, it was considered in the model that (i) ant colony consists of two kinds of ants, good- ... ponents without a central controller [8].

  7. Interpreter's Guide to Blackbird Marsh Nature Trail.

    Science.gov (United States)

    Environmental Studies Center, Pensacola, FL.

    This booklet was prepared to help the user interpret the natural history of Blackbird Marsh Nature Trail in Escambia County, Florida, and serves as a guide to the animal and plant life. The publication is part of a series of illustrated guides designed for use by teachers and students of all levels in conjunction with field trips to the 1200-acre…

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

    Science.gov (United States)

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

    2009-01-01

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

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

    Science.gov (United States)

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

    2009-03-01

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

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

    OpenAIRE

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

    2010-01-01

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

  11. Novel TRAIL sensitizer Taraxacum officinale F.H. Wigg enhances TRAIL-induced apoptosis in Huh7 cells.

    Science.gov (United States)

    Yoon, Ji-Yong; Cho, Hyun-Soo; Lee, Jeong-Ju; Lee, Hyo-Jung; Jun, Soo Young; Lee, Jae-Hye; Song, Hyuk-Hwan; Choi, SangHo; Saloura, Vassiliki; Park, Choon Gil; Kim, Cheol-Hee; Kim, Nam-Soon

    2016-04-01

    TRAIL (TNF-related apoptosis inducing ligand) is a promising anti-cancer drug target that selectively induces apoptosis in cancer cells. However, many cancer cells are resistant to TRAIL-induced apoptosis. Therefore, reversing TRAIL resistance is an important step for the development of effective TRAIL-based anti-cancer therapies. We previously reported that knockdown of the TOR signaling pathway regulator-like (TIPRL) protein caused TRAIL-induced apoptosis by activation of the MKK7-c-Jun N-terminal Kinase (JNK) pathway through disruption of the MKK7-TIPRL interaction. Here, we identified Taraxacum officinale F.H. Wigg (TO) as a novel TRAIL sensitizer from a set of 500 natural products using an ELISA system and validated its activity by GST pull-down analysis. Furthermore, combination treatment of Huh7 cells with TRAIL and TO resulted in TRAIL-induced apoptosis mediated through inhibition of the MKK7-TIPRL interaction and subsequent activation of MKK7-JNK phosphorylation. Interestingly, HPLC analysis identified chicoric acid as a major component of the TO extract, and combination treatment with chicoric acid and TRAIL induced TRAIL-induced cell apoptosis via JNK activation due to inhibition of the MKK7-TIPRL interaction. Our results suggest that TO plays an important role in TRAIL-induced apoptosis, and further functional studies are warranted to confirm the importance of TO as a novel TRAIL sensitizer for cancer therapy. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

  12. A mixed-modes approach for estimating hiking on trails through diverse forest landscapes: the case of the Appalachian Trail

    Science.gov (United States)

    Stanley J. Zarnoch; J.M. Bowker; H. Ken. Cordell

    2011-01-01

    Many hiking trails traverse the forests and public lands across North America. It has therefore become important for federal management to gain an understanding of total use on these trails. However, there has never been a formal attempt to estimate hiking on these long, backcountry trails. This paper presents an approach that utilizes two survey instruments (exit-site...

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

    Science.gov (United States)

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

    2015-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Anne Kleijn

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

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

    Directory of Open Access Journals (Sweden)

    Jan RH Hanauer

    2016-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Michael Karl Melzer

    2017-02-01

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

  17. Trailing Vortex-Induced Loads During Close Encounters in Cruise

    Science.gov (United States)

    Mendenhall, Michael R.; Lesieutre, Daniel J; Kelly, Michael J.

    2015-01-01

    The trailing vortex induced aerodynamic loads on a Falcon 20G business jet flying in the wake of a DC-8 are predicted to provide a preflight estimate of safe trail distances during flight test measurements in the wake. Static and dynamic loads on the airframe flying in the near wake are shown at a matrix of locations, and the dynamic motion of the Falcon 20G during traverses of the DC-8 primary trailing vortex is simulated. Safe trailing distances for the test flights are determined, and optimum vortex traverse schemes are identified to moderate the motion of the trailing aircraft during close encounters with the vortex wake.

  18. Possible novel therapy for malignant gliomas with secretable trimeric TRAIL.

    Directory of Open Access Journals (Sweden)

    Moonsup Jeong

    Full Text Available Malignant gliomas are the most common primary brain tumors. Despite intensive clinical investigation and many novel therapeutic approaches, average survival for the patients with malignant gliomas is only about 1 year. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL has shown potent and cancer-selective killing activity and drawn considerable attention as a promising therapy for cancers, but concerns over delivery and toxicity have limited progress. We have developed a secretable trimeric TRAIL (stTRAIL and here evaluated the therapeutic potential of this stTRAIL-based gene therapy in brain tumors. An adenovirus (Ad-stTRAIL delivering stTRAIL was injected into intra-cranial human glioma tumors established in nude mice and tumor growth monitored using the magnetic resonance imaging (MRI. Ad-stTRAIL gene therapy showed potent tumor suppressor activity with no toxic side effects at therapeutically effective doses. When compared with 1, 3-bis(2-chloroethyl-1-nitrosourea (BCNU, a conventional therapy for malignant gliomas, Ad-stTRAIL suppressed tumor growth more potently. The combination of Ad-stTRAIL and BCNU significantly increased survival compared to the control mice or mice receiving Ad-stTRAIL alone. Our data indicate that Ad-stTRAIL, either alone or combined with BCNU, has promise as a novel therapy for malignant gliomas.

  19. Aerodynamic Analysis of Trailing Edge Enlarged Wind Turbine Airfoils

    DEFF Research Database (Denmark)

    Xu, Haoran; Shen, Wen Zhong; Zhu, Wei Jun

    2014-01-01

    characteristics of blunt trailing edge airfoils are caused by blunt body vortices at low angles of attack, and by the combined effect of separation and blunt body vortices at large angles of attack. With the increase of thickness of blunt trailing edge, the vibration amplitudes of lift and drag curves increase......The aerodynamic performance of blunt trailing edge airfoils generated from the DU- 91-W2-250, DU-97-W-300 and DU-96-W-350 airfoils by enlarging the thickness of trailing edge symmetrically from the location of maximum thickness to chord to the trailing edge were analyzed by using CFD and RFOIL...... methods at a chord Reynolds number of 3 × 106. The goal of this study is to analyze the aerodynamic performance of blunt trailing edge airfoils with different thicknesses of trailing edge and maximum thicknesses to chord. The steady results calculated by the fully turbulent k-ω SST, transitional k-ω SST...

  20. Heavy water at Trail, British Columbia

    Energy Technology Data Exchange (ETDEWEB)

    Arsenault, J.E. [Ontario (Canada)

    2006-09-15

    Today Canada stands on the threshold of a nuclear renaissance, based on the CANDU reactor family, which depends on heavy water as a moderator and for cooling. Canada has a long history with heavy water, with commercial interests beginning in 1934, a mere two years after its discovery. At one time Canada was the world's largest producer of heavy water. The Second World War stimulated interest in this rather rare substance, such that the worlds largest supply (185 kg) ended up in Canada in 1942 to support nuclear research work at the Montreal Laboratories of the National Research Council. A year later commercial production began at Trail, British Columbia, to support work that later became known as the P-9 project, associated with the Manhattan Project. The Trail plant produced heavy water from 1943 until 1956, when it was shut down. During the war years the project was so secret that Lesslie Thomson, Special Liaison Officer reporting on nuclear matters to C.D. Howe, Minister of Munitions and Supply, was discouraged from visiting Trail operations. Thomson never did visit the Trail facility during the war. In 2005 the remaining large, tall concrete exchange tower was demolished at a cost of about $2.4 million, about the same as it cost to construct the facility about 60 years ago. Thus no physical evidence remains of this historic facility and another important artifact from Canada's nuclear history has disappeared forever. It is planned to place a plaque at the site at some point in the future. (author)

  1. Heavy water at Trail, British Columbia

    International Nuclear Information System (INIS)

    Arsenault, J.E.

    2006-01-01

    Today Canada stands on the threshold of a nuclear renaissance, based on the CANDU reactor family, which depends on heavy water as a moderator and for cooling. Canada has a long history with heavy water, with commercial interests beginning in 1934, a mere two years after its discovery. At one time Canada was the world's largest producer of heavy water. The Second World War stimulated interest in this rather rare substance, such that the worlds largest supply (185 kg) ended up in Canada in 1942 to support nuclear research work at the Montreal Laboratories of the National Research Council. A year later commercial production began at Trail, British Columbia, to support work that later became known as the P-9 project, associated with the Manhattan Project. The Trail plant produced heavy water from 1943 until 1956, when it was shut down. During the war years the project was so secret that Lesslie Thomson, Special Liaison Officer reporting on nuclear matters to C.D. Howe, Minister of Munitions and Supply, was discouraged from visiting Trail operations. Thomson never did visit the Trail facility during the war. In 2005 the remaining large, tall concrete exchange tower was demolished at a cost of about $2.4 million, about the same as it cost to construct the facility about 60 years ago. Thus no physical evidence remains of this historic facility and another important artifact from Canada's nuclear history has disappeared forever. It is planned to place a plaque at the site at some point in the future. (author)

  2. Prevalence of Injury in Ultra Trail Running

    Directory of Open Access Journals (Sweden)

    Malliaropoulos Nikolaos

    2015-06-01

    Full Text Available Purpose. The purpose of the study was to find the rate of musculoskeletal injuries in ultra-trail runners, investigate the most sensitive anatomical areas, and discover associated predicting factors to aid in the effective prevention and rapid rehabilitation of trail running injuries. Methods. Forty ultra trail runners responded to an epidemiological questionnaire. Results. At least one running injury was reported by 90% of the sample, with a total of 135 injuries were reported (111 overuse injuries, 24 appeared during competing. Lower back pain was the most common source of injury (42.5%. Running in the mountains (p = 0.0004 and following a personalized training schedule (p = 0.0995 were found to be protective factors. Runners involved in physical labor are associated with more injuries (p = 0.058. Higher-level runners are associated with more injuries than lower-level cohorts (p = 0.067, with symptoms most commonly arising in the lower back (p = 0.091, hip joint (p = 0.083, and the plantar surface of the foot (p = 0.054. Experienced runners (> 6 years are at greater risk of developing injuries (p = 0.001, especially in the lower back (p = 0.012, tibia (p = 0.049, and the plantar surface of the foot (p = 0 .028. Double training sessions could cause hip joint injury (p = 0.060. Conclusions. In order to avoid injury, it is recommended to train mostly on mountain trails and have a training program designed by professionals.

  3. TRAIL-coated lipid-nanoparticles overcome resistance to soluble recombinant TRAIL in non-small cell lung cancer cells

    International Nuclear Information System (INIS)

    De Miguel, Diego; Gallego-Lleyda, Ana; Erviti-Ardanaz, Sandra; Anel, Alberto; Martinez-Lostao, Luis; Ayuso, José María; Fernández, Luis José; Ochoa, Ignacio; Pazo-Cid, Roberto; Del Agua, Celia

    2016-01-01

    Purpose. Non-small cell lung cancer (NSCLC) is one the types of cancer with higher prevalence and mortality. Apo2-Ligand/TRAIL is a TNF family member able to induce apoptosis in tumor cells but not in normal cells. It has been tested in clinical trials against different types of human cancer including NSCLC. However, results of clinical trials have shown a limited efficacy of TRAIL-based therapies. Recently we have demonstrated that artificial lipid nanoparticles coated with bioactive Apo2L/TRAIL (LUV-TRAIL) greatly improved TRAIL cytotoxic ability being capable of killing chemoresistant hematological cancer cells. In the present work we have extended the study to NSCLC. Methods/patients. LUV-TRAIL-induced cytotoxicity was assessed on different NSCLC cell lines with different sensitivity to soluble TRAIL and on primary human tumor cells from three patients suffering from NSCLC cancer. We also tested LUV-TRAIL-cytotoxic ability in combination with several anti-tumor agents. Results. LUV-TRAIL exhibited a greater cytotoxic effect compared to soluble TRAIL both in A549 cells and primary human NSCLC cells. LUV-TRAIL-induced cell death was dependent on caspase-8 and caspase-3 activation. Moreover, combination of LUV-TRAIL with other anti-tumor agents such as flavopiridol, and SNS-032 clearly enhanced LUV-TRAIL-induced cytotoxicity against NSCLC cancer cells. Conclusion. The novel formulation of TRAIL based on displaying it on the surface of lipid nanoparticles greatly increases its anti-tumor activity and has clinical potential in cancer treatment. (paper)

  4. Decay times of transitionally dense specularly reflecting meteor trails and potential chemical impact on trail lifetimes

    Directory of Open Access Journals (Sweden)

    W. K. Hocking

    2016-12-01

    Full Text Available Studies of transitionally dense meteor trails using radars which employ specularly reflecting interferometric techniques are used to show that measurable high-temperature chemistry exists at timescales of a few tenths of a second after the formation of these trails. This is a process which is distinct from the ambient-temperature chemistry that is already known to exist at timescales of tens of seconds and longer in long-lived trails. As a consequence, these transitionally dense trails have smaller lifetimes than might be expected if diffusion were the only mechanism for reducing the mean trail electron density. The process has been studied with four SKiYMET radars at latitudes varying from 10 to 75° N, over a period of more than 10 years, 24 h per day. In this paper we present the best parameters to use to represent this behaviour and demonstrate the characteristics of the temporal and latitudinal variability in these parameters. The seasonal, day–night and latitudinal variations correlate reasonably closely with the corresponding variations of ozone in the upper mesosphere. Possible reasons for these effects are discussed, but further investigations of any causative relation are still the subject of ongoing studies.

  5. Access Control Based on Trail Inference

    Directory of Open Access Journals (Sweden)

    ALBARELO, P. C.

    2015-06-01

    Full Text Available Professionals are constantly seeking qualification and consequently increasing their knowledge in their area of expertise. Thus, it is interesting to develop a computer system that knows its users and their work history. Using this information, even in the case of professional role change, the system could allow the renewed authorization for activities, based on previously authorized use. This article proposes a model for user access control that is embedded in a context-aware environment. The model applies the concept of trails to manage access control, recording activities usage in contexts and applying this history as a criterion to grant new accesses. Despite the fact that previous related research works consider contexts, none of them uses the concept of trails. Hence, the main contribution of this work is the use of a new access control criterion, namely, the history of previous accesses (trails. A prototype was implemented and applied in an evaluation based on scenarios. The results demonstrate the feasibility of the proposal, allowing for access control systems to use an alternative way to support access rights.

  6. Reusable Reinforcement Learning via Shallow Trails.

    Science.gov (United States)

    Yu, Yang; Chen, Shi-Yong; Da, Qing; Zhou, Zhi-Hua

    2018-06-01

    Reinforcement learning has shown great success in helping learning agents accomplish tasks autonomously from environment interactions. Meanwhile in many real-world applications, an agent needs to accomplish not only a fixed task but also a range of tasks. For this goal, an agent can learn a metapolicy over a set of training tasks that are drawn from an underlying distribution. By maximizing the total reward summed over all the training tasks, the metapolicy can then be reused in accomplishing test tasks from the same distribution. However, in practice, we face two major obstacles to train and reuse metapolicies well. First, how to identify tasks that are unrelated or even opposite with each other, in order to avoid their mutual interference in the training. Second, how to characterize task features, according to which a metapolicy can be reused. In this paper, we propose the MetA-Policy LEarning (MAPLE) approach that overcomes the two difficulties by introducing the shallow trail. It probes a task by running a roughly trained policy. Using the rewards of the shallow trail, MAPLE automatically groups similar tasks. Moreover, when the task parameters are unknown, the rewards of the shallow trail also serve as task features. Empirical studies on several controlling tasks verify that MAPLE can train metapolicies well and receives high reward on test tasks.

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

    Directory of Open Access Journals (Sweden)

    Dominik Wodarz

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

  8. Blockade of Death Ligand TRAIL Inhibits Renal Ischemia Reperfusion Injury

    International Nuclear Information System (INIS)

    Adachi, Takaomi; Sugiyama, Noriyuki; Gondai, Tatsuro; Yagita, Hideo; Yokoyama, Takahiko

    2013-01-01

    Renal ischemia-reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI). Many investigators have reported that cell death via apoptosis significantly contributed to the pathophysiology of renal IRI. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor superfamily, and induces apoptosis and inflammation. However, the role of TRAIL in renal IRI is unclear. Here, we investigated whether TRAIL contributes to renal IRI and whether TRAIL blockade could attenuate renal IRI. AKI was induced by unilateral clamping of the renal pedicle for 60 min in male FVB/N mice. We found that the expression of TRAIL and its receptors were highly upregulated in renal tubular cells in renal IRI. Neutralizing anti-TRAIL antibody or its control IgG was given 24 hr before ischemia and a half-dose booster injection was administered into the peritoneal cavity immediately after reperfusion. We found that TRAIL blockade inhibited tubular apoptosis and reduced the accumulation of neutrophils and macrophages. Furthermore, TRAIL blockade attenuated renal fibrosis and atrophy after IRI. In conclusion, our study suggests that TRAIL is a critical pathogenic factor in renal IRI, and that TRAIL could be a new therapeutic target for the prevention of renal IRI

  9. An analysis of state legislation on community trails.

    Science.gov (United States)

    Eyler, Amy; Lankford, Tina; Chriqui, Jamie; Evenson, Kelly R; Kruger, Judy; Tompkins, Nancy; Voorhees, Carolyn; Zieff, Susan; Aytur, Semra; Brownson, Ross

    2010-03-01

    Trails provide opportunities for recreation, transportation and activity. The purpose of this article is to describe state legislation related to community trails, to analyze legislation content, and to evaluate legislation on inclusion of evidence-informed elements. State trail legislation from 2001 to 2008 was identified using online legislative databases. An analysis of evidence-informed elements included in the legislation was conducted. These elements included: funding, liability, accessibility, connectivity, and maintenance. Of the total 991 trail bills, 516 (52.0%) were appropriations bills, of which 167 (32.2%) were enacted. We analyzed 475 (48%) nonappropriation trail bills of which 139 (29.3%) were enacted. The percentage of enactment of appropriations bills decreased over time while enactment of nonappropriations trail bills increased. Over half of the nonappropriations trail bills included at least 1 evidence-informed element, most commonly funding. Few bills contained liability, connectivity, accessibility, or maintenance. There is opportunity for providing evidence-informed information to policy-makers to potentially influence bill content. The number of bills with a funding element demonstrates that fiscal support for trails is an important policy lever that state legislatures may use to support trails. Lastly, trails should be considered in over-all state-level physical activity legislation to provide opportunities for communities to be active.

  10. Travel to, and use of, twenty-one Michigan trails.

    Science.gov (United States)

    Price, Anna E; Reed, Julian A; Grost, Lisa; Harvey, Christina; Mantinan, Karah

    2013-03-01

    This study examined trail use among 857 trail users on 21 trails in Michigan from 2008 to 2011 using a valid and reliable intercept survey. Most of the 857 participants traveled to the trail from their home (92.6%), lived within 15 min of the trails (74.8%), and used active transport to travel to the trails 69.7%. The odds of active transport to the trails were greater among those who had not graduated high school (OR=3.49; 95% CI=1.02, 11.99) and high school graduates (OR=7.432; 95% CI=2.02, 27.30) compared to college graduates. Whites and adults also had greater odds of active transport than non-Whites (OR=3.160, 95% CI: 1.65, 6.05), and older adults (OR=1.75; 95% CI: 1.20, 2.54). The majority of respondents (89.7%) reported using trails for recreational purposes. A significantly greater proportion of females (73.3%) compared to males (64.7%) reported using the trail with others. The findings from this study might enable health and parks and recreation professionals to better promote physical activity on trails. Copyright © 2013 Elsevier Inc. All rights reserved.

  11. Modeling of Airfoil Trailing Edge Flap with Immersed Boundary Method

    DEFF Research Database (Denmark)

    Zhu, Wei Jun; Shen, Wen Zhong; Sørensen, Jens Nørkær

    2011-01-01

    The present work considers incompressible flow over a 2D airfoil with a deformable trailing edge. The aerodynamic characteristics of an airfoil with a trailing edge flap is numerically investigated using computational fluid dynamics. A novel hybrid immersed boundary (IB) technique is applied...... to simulate the moving part of the trailing edge. Over the main fixed part of the airfoil the Navier-Stokes (NS) equations are solved using a standard body-fitted finite volume technique whereas the moving trailing edge flap is simulated with the immersed boundary method on a curvilinear mesh. The obtained...... results show that the hybrid approach is an efficient and accurate method for solving turbulent flows past airfoils with a trailing edge flap and flow control using trailing edge flap is an efficient way to regulate the aerodynamic loading on airfoils....

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

    Science.gov (United States)

    Kumar, Varun; Radin, Daniel; Leonardi, Donna

    2017-11-01

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

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

    Science.gov (United States)

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

    2017-12-15

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

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

    Directory of Open Access Journals (Sweden)

    Sam Illingworth

    2017-06-01

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

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

    Directory of Open Access Journals (Sweden)

    Zong Sheng eGuo

    2014-04-01

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

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

    Directory of Open Access Journals (Sweden)

    James J Cody

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

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

    Science.gov (United States)

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

    2013-07-10

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

  18. A new concept in trail grooming. `The KRC groomer`

    Energy Technology Data Exchange (ETDEWEB)

    Alger, R G [Michigan Technological Univ., Houghton, MI (United States)

    1994-12-31

    A groomer developed for maintaining snow roads in Arctic regions was described. The KRC groomer was initially designed for use on snowmobile trails. The device resulted from research into the problem of mogul formation on trails and how to improve on present techniques to make trail surfaces more durable. Studies were conducted both in the laboratory and in the field in an attempt to better understand this bump formation. The device and studies of its design were discussed. 9 figs., 7 refs.

  19. Ambient Air Conditions and Variation in Urban Trail Use

    OpenAIRE

    Holmes, Ann M.; Lindsey, Greg; Qiu, Chenchen

    2009-01-01

    This study examines the effect of air quality and administrative policies on use of urban trails in Indianapolis, IN. Attention is focused on two policy variables: (1) issuance of air pollution advisories and (2) the adoption of Daylight Savings Time. Results suggest that while trail use varies with air quality, current public advisories regarding air pollution may be of limited effectiveness in reducing trail users’ exposures to hazardous pollutants. In contrast, the adoption of Daylight Sav...

  20. The role of trails in the creation of tourist space

    OpenAIRE

    MacLeod, Nicola

    2017-01-01

    Trails and routes are increasingly ubiquitous features within the tourism landscape and although their role and usefulness as applied tourism products has been analysed, they remain under-theorised within the academic literature. This article addresses this gap by exploring the role of trails within the socio-cultural construction of space. In particular, the potential function of trails in creating themed, static spaces is analysed and the concept of museumisation is employed to further illu...

  1. 77 FR 25910 - National Trails System Act and Railroad Rights-of-Way

    Science.gov (United States)

    2012-05-02

    ...] National Trails System Act and Railroad Rights-of-Way AGENCY: Surface Transportation Board, DOT. ACTION...) for rail banking and interim trail use under the National Trails System Act (Trails Act). New rules are adopted that require the parties jointly to notify the Board when an interim trail use/rail...

  2. A Tale of Two Trails: Exploring Different Paths to Success

    Science.gov (United States)

    Walker, Jennifer G.; Evenson, Kelly R.; Davis, William J.; Bors, Philip; Rodríguez, Daniel A.

    2016-01-01

    Background This comparative case study investigates 2 successful community trail initiatives, using the Active Living By Design (ALBD) Community Action Model as an analytical framework. The model includes 5 strategies: preparation, promotion, programs, policy, and physical projects. Methods Key stakeholders at 2 sites participated in in-depth interviews (N = 14). Data were analyzed for content using Atlas Ti and grouped according to the 5 strategies. Results Preparation Securing trail resources was challenging, but shared responsibilities facilitated trail development. Promotions The initiatives demonstrated minimal physical activity encouragement strategies. Programs Community stakeholders did not coordinate programmatic opportunities for routine physical activity. Policy Trails’ inclusion in regional greenway master plans contributed to trail funding and development. Policies that were formally institutionalized and enforced led to more consistent trail construction and safer conditions for users. Physical Projects Consistent standards for way finding signage and design safety features enhanced trail usability and safety. Conclusions Communities with different levels of government support contributed unique lessons to inform best practices of trail initiatives. This study revealed a disparity between trail development and use-encouragement strategies, which may limit trails’ impact on physical activity. The ALBD Community Action Model provided a viable framework to structure cross-disciplinary community trail initiatives. PMID:21597125

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

    Science.gov (United States)

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

    2013-12-01

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

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

    International Nuclear Information System (INIS)

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

    2011-01-01

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

  5. Doxorubicin potentiates TRAIL cytotoxicity and apoptosis and can overcome TRAIL-resistance in rhabdomyosarcoma cells

    NARCIS (Netherlands)

    Komdeur, R; Meijer, C; Van Zweeden, M; De Jong, S; Wesseling, J; Hoekstra, HJ; van der Graaf, WTA

    Doxorubicin (DOX) and ifosfamide (IFO) are the most active single agents in soft tissue sarcomas (STS). Tumour necrosis factor-alpha (TNF-alpha) is used for STS in the setting of isolated limb perfusions. Like TNF-alpha, TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis. In contrast to

  6. Computer simulation of trails on a square lattice. I. Trails at infinite temperature

    International Nuclear Information System (INIS)

    Lim, H.A.; Meirovitch, H.

    1989-01-01

    A trail is a random walk on a lattice for which two bonds are not allowed to overlap. However, the chain may cross itself and one may associate with each such intersection an attractive energy epsilon-c. We study trails at infinite temperature T = ∞ (i.e., trails without attractions) on a square lattice using the scanning simulation method. Our results for the radius of gyration and the end-to-end distance strongly suggest (as do previous studies) that the shape exponent is ν = 0.75, similar to that for self-avoiding walks (SAW's). We obtain significantly more accurate estimates than have been obtained before for the entropy exponent γ = 1.350 +- 0.012 and for the effective growth parameter μ = 2.720 58 +- 0.000 20 (95% confidence limit). The persistence length is found to increase with increasing chain length N and the data fit slightly better an exponential function N/sup w/ where w = 0.047 +- 0.009 than a logarithmic one. Guttmann [J. Phys. A 18, 567 (1985)] has shown exactly that trails and SAW's on the hexagonal lattice at T = ∞ have the same exponents. Our results suggest that this is true also for the square lattice

  7. From Ant Trails to Pedestrian Dynamics

    Directory of Open Access Journals (Sweden)

    Andreas Schadschneider

    2003-01-01

    Full Text Available This paper presents a model for the simulation of pedestrian dynamics inspired by the behaviour of ants in ant trails. Ants communicate by producing a pheromone that can be smelled by other ants. In this model, pedestrians produce a virtual pheromone that influences the motion of others. In this way all interactions are strictly local, and so even large crowds can be simulated very efficiently. Nevertheless, the model is able to reproduce the collective effects observed empirically, eg the formation of lanes in counterflow. As an application, we reproduce a surprising result found in experiments of evacuation from an aircraft.

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

    OpenAIRE

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

    2017-01-01

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

  9. LES tests on airfoil trailing edge serration

    International Nuclear Information System (INIS)

    Zhu, Wei Jun; Shen, Wen Zhong

    2016-01-01

    In the present study, a large number of acoustic simulations are carried out for a low noise airfoil with different Trailing Edge Serrations (TES). The Ffowcs Williams-Hawkings (FWH) acoustic analogy is used for noise prediction at trailing edge. The acoustic solver is running on the platform of our in-house incompressible flow solver EllipSys3D. The flow solution is first obtained from the Large Eddy Simulation (LES), the acoustic part is then carried out based on the instantaneous hydrodynamic pressure and velocity field. To obtain the time history data of sound pressure, the flow quantities are integrated around the airfoil surface through the FWH approach. For all the simulations, the chord based Reynolds number is around 1.5x10 6 . In the test matrix, the effects from angle of attack, the TE flap angle, the length/width of the TES are investigated. Even though the airfoil under investigation is already optimized for low noise emission, most numerical simulations and wind tunnel experiments show that the noise level is further decreased by adding the TES device. (paper)

  10. Use and users of the Appalachian Trail: a geographic study

    Science.gov (United States)

    Robert E. Manning; William Valliere; Jim Bacon; Alan Graefe; Gerard Kyle; Rita Hennessy

    2001-01-01

    The Appalachian National Scenic Trail (AT) is a public footpath that spans 2,160 miles of Appalachian Mountain ridgelines from Maine to Georgia. This paper describes the first comprehensive study of recreational use and users of the AT. The primary study method was a survey of visitors to the AT. The Trail was divided into 22 relatively homogeneous sections within four...

  11. Trail Crews: Developing a Service Component to Your Program.

    Science.gov (United States)

    Boehringer, Brad; Merrill, Kurt

    Through wilderness stewardship programs, service projects, or trail crews, college outdoor programs can help land management agencies with their maintenance needs and provide student participants with rewarding service learning opportunities. Trail crews are usually composed of volunteer outdoor enthusiasts who take part in a multitude of…

  12. Discussion on "The Trail" from the Perspective of Christianism Theology

    Science.gov (United States)

    Wang, Jing

    2008-01-01

    Kafka is a writer of strong religious complex. In "The Trail," he illustrates his religious thoughts by probing into the alienation of modern human beings from the God and also shows his pursuit and befuddlement of beliefs. This paper analyzes the crimes and punishment in "The Trail" through three parts, the accusation of…

  13. Audit Trail Management System in Community Health Care Information Network.

    Science.gov (United States)

    Nakamura, Naoki; Nakayama, Masaharu; Nakaya, Jun; Tominaga, Teiji; Suganuma, Takuo; Shiratori, Norio

    2015-01-01

    After the Great East Japan Earthquake we constructed a community health care information network system. Focusing on the authentication server and portal server capable of SAML&ID-WSF, we proposed an audit trail management system to look over audit events in a comprehensive manner. Through implementation and experimentation, we verified the effectiveness of our proposed audit trail management system.

  14. 30 CFR 75.600 - Trailing cables; flame resistance.

    Science.gov (United States)

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Trailing cables; flame resistance. 75.600 Section 75.600 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR COAL MINE... cables; flame resistance. [Statutory Provisions] Trailing cables used in coal mines shall meet the...

  15. Pupil initiatives in urban nature trail development: PMB MOSS and ...

    African Journals Online (AJOL)

    A brief background to Greenbelt and urban nature trail development in Pietermaritzburg is provided. Negotiations and procedures initiated by standard 9 pupils in stimulating authorities and the public to recognise the need for urban trail development and metropolitan open space (MOSS) are outlined. long-term ...

  16. Go West: Imagining the Oregon Trail. [Lesson Plan].

    Science.gov (United States)

    National Endowment for the Humanities (NFAH), Washington, DC.

    In this lesson plan, students in grades 3-5 compare imagined travel experiences of their own with the actual experiences of 19th-century pioneers on the Oregon Trail. After the 4 lessons students will have: (1) learned about the pioneer experience on the Oregon Trail; (2) compared and contrasted modern-day travel experiences with those of the 19th…

  17. Rail Trails and Property Values: Is There an Association?

    Science.gov (United States)

    Hartenian, Ella; Horton, Nicholas J.

    2015-01-01

    The Rail Trail and Property Values dataset includes information on a set of n = 104 homes which sold in Northampton, Massachusetts in 2007. The dataset provides house information (square footage, acreage, number of bedrooms, etc.), price estimates (from Zillow.com) at four time points, location, distance from a rail trail in the community, biking…

  18. Hydrodynamic trails produced by Daphnia: size and energetics.

    Science.gov (United States)

    Wickramarathna, Lalith N; Noss, Christian; Lorke, Andreas

    2014-01-01

    This study focuses on quantifying hydrodynamic trails produced by freely swimming zooplankton. We combined volumetric tracking of swimming trajectories with planar observations of the flow field induced by Daphnia of different size and swimming in different patterns. Spatial extension of the planar flow field along the trajectories was used to interrogate the dimensions (length and volume) and energetics (dissipation rate of kinetic energy and total dissipated power) of the trails. Our findings demonstrate that neither swimming pattern nor size of the organisms affect the trail width or the dissipation rate. However, we found that the trail volume increases with increasing organism size and swimming velocity, more precisely the trail volume is proportional to the third power of Reynolds number. This increase furthermore results in significantly enhanced total dissipated power at higher Reynolds number. The biggest trail volume observed corresponds to about 500 times the body volume of the largest daphnids. Trail-averaged viscous dissipation rate of the swimming daphnids vary in the range of 1.8 x 10(-6) W/kg to 3.4 x 10(-6) W/kg and the observed magnitudes of total dissipated power between 1.3 x 10(-9) W and 1 x 10(-8) W, respectively. Among other zooplankton species, daphnids display the highest total dissipated power in their trails. These findings are discussed in the context of fluid mixing and transport by organisms swimming at intermediate Reynolds numbers.

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

    Science.gov (United States)

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

    2016-10-27

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

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

    Science.gov (United States)

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

    2017-08-15

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

  1. Fast and flexible: argentine ants recruit from nearby trails.

    Directory of Open Access Journals (Sweden)

    Tatiana P Flanagan

    Full Text Available Argentine ants (Linepithema humile live in groups of nests connected by trails to each other and to stable food sources. In a field study, we investigated whether some ants recruit directly from established, persistent trails to food sources, thus accelerating food collection. Our results indicate that Argentine ants recruit nestmates to food directly from persistent trails, and that the exponential increase in the arrival rate of ants at baits is faster than would be possible if recruited ants traveled from distant nests. Once ants find a new food source, they walk back and forth between the bait and sometimes share food by trophallaxis with nestmates on the trail. Recruiting ants from nearby persistent trails creates a dynamic circuit, like those found in other distributed systems, which facilitates a quick response to changes in available resources.

  2. Fast and flexible: argentine ants recruit from nearby trails.

    Science.gov (United States)

    Flanagan, Tatiana P; Pinter-Wollman, Noa M; Moses, Melanie E; Gordon, Deborah M

    2013-01-01

    Argentine ants (Linepithema humile) live in groups of nests connected by trails to each other and to stable food sources. In a field study, we investigated whether some ants recruit directly from established, persistent trails to food sources, thus accelerating food collection. Our results indicate that Argentine ants recruit nestmates to food directly from persistent trails, and that the exponential increase in the arrival rate of ants at baits is faster than would be possible if recruited ants traveled from distant nests. Once ants find a new food source, they walk back and forth between the bait and sometimes share food by trophallaxis with nestmates on the trail. Recruiting ants from nearby persistent trails creates a dynamic circuit, like those found in other distributed systems, which facilitates a quick response to changes in available resources.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-07-10

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

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

    Directory of Open Access Journals (Sweden)

    Ji Young Yoo

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

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

    International Nuclear Information System (INIS)

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

    2015-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Donald Bastin

    2016-08-01

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

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

    Science.gov (United States)

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

    2014-05-01

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

  8. Down-regulation of HSP27 sensitizes TRAIL-resistant tumor cell to TRAIL-induced apoptosis

    DEFF Research Database (Denmark)

    Zhuang, Hongqin; Jiang, Weiwei; Cheng, Wei

    2010-01-01

    Tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL) has recently emerged as a cancer therapeutic agent because it preferentially induces apoptosis in human cancer over normal cells. Most tumor cells, including lung cancer cell line A549, unfortunately, are resistant to TRAIL tre...

  9. Equivalence of the Color Trails Test and Trail Making Test in nonnative English-speakers.

    Science.gov (United States)

    Dugbartey, A T; Townes, B D; Mahurin, R K

    2000-07-01

    The Color Trails Test (CTT) has been described as a culture-fair test of visual attention, graphomotor sequencing, and effortful executive processing abilities relative to the Trail Making Test (TMT). In this study, the equivalence of the TMT and the CTT among a group of 64 bilingual Turkish university students was examined. No difference in performance on the CTT-1 and TMT Part A was found, suggesting functionally equivalent performance across both tasks. In contrast, the statistically significant differences in performance on CTT-2 and TMT Part B, as well as the interference indices for both tests, were interpreted as providing evidence for task nonequivalence of the CTT-2 and TMT Part B. Results have implications for both psychometric test development and clinical cultural neuropsychology.

  10. TRAIL: a tokamak rail gun limiter

    International Nuclear Information System (INIS)

    Yu, W.S.; Powell, J.R.; Usher, J.L.

    1980-01-01

    An attractive new limiter concept is investigated. The TRAIL (Tokamak Rail Gun Limiter) system impacts a stream of moderate velocity pellets (100 to 200 m/sec through the plasma edge region to absorb energy and define the plasma boundary. The pellets are recycled after cooling, to the injector of an E-M mass accelerator. Heat fluxes of approx. 30,000 W/cm 2 can be readily accommodated by the pellets, with very low recirculating power requirements (approx. 0.1%) for the accelerator. The mass accelerator velocity requirements are well within the present state of the art (several Km/sec). Accelerators injecting pellets at approx. 1 Km/sec can be used to control local plasma temperature and current profiles and to act as energy absorbers to shut down the plasma without damage to the first wall if a plasma disruption occurs

  11. Personal reflections on a galvanizing trail.

    Science.gov (United States)

    O'Dell, B L

    1998-01-01

    This article encompasses my perception of, and experience in, an exciting segment of the trace element era in nutrition research: the role of zinc in the nutrition of animals and humans. Zinc has been a major player on the stage of trace element research, and it has left a trail that galvanized the attention of many researchers, including myself. It is ubiquitous in biological systems, and it plays a multitude of physiologic and biochemical functions. A brief historical overview is followed by a discussion of the contributions the work done in my laboratory has made toward understanding the physiological and biochemical functions of zinc. The effort of 40 years has led to the belief that one of zinc's major roles, and perhaps its first limiting role, is to preserve plasma-membrane function as regards ion channels and signal transduction. Although substantial knowledge has been gained relating to the importance of zinc in nutrition, much remains to be discovered.

  12. Trailing vortices from low speed flyers

    Science.gov (United States)

    Waldman, Rye; Kudo, Jun; Breuer, Kenneth

    2009-11-01

    The structure and strength of the vortex wake behind a airplane or animal flying with a fixed or flapping wing contains valuable information about the aerodynamic load history. However, the amount of vorticity measured in the trailing vortex is not always in agreement with the known lift generated, and the behavior of these vortices at relatively low Reynolds numbers is also not well-understood. We present the results from a series of wind tunnel PIV experiments conducted behind a low-aspect ratio rectangular wing at a chord-Reynolds numbers of 30,000. In addition to wake PIV measurements measured in the cross-stream (Trefftz) plane, we measure the lift and drag directly using a six-axis force-torque transducer. We discuss how vortex size, shape, strength and position vary in time and downstream location, as well as the challenges associated with the use of PIV wake measurements to accurate determine aerodynamic forces.

  13. On the Trail of Joan of Arc

    Directory of Open Access Journals (Sweden)

    Linda Joyce Forristal

    2013-12-01

    Full Text Available The year 2012 marked the 600th anniversary of the birthday of Joan of Arc (Fr., Jeanne d’Arc (1412–1431. Tributes to this national heroine can be found all over France. There are literally countless statues, streets and restaurants named after her and many sites dedicated to her life. However, despite widespread social and mechanical reproduction and cultural naming in relation to the Maid of Orléans, there is no official network or integrated signage in France to promote cultural heritage tourism to the numerous Joan of Arc sites and festivals, even though her life and death, by any measure, were seminal events in the country’s history. Unfortunately, the pilgrim who wants to follow or intersect with Joan of Arc’s trail through France, for cultural, historical or religious reasons, must do so without much help. Using Actor Network Theory and Site Sacralization Theory as framing devices, this paper explores human actors and tangible and intangible non-human factors that may have contributed to the lack of a unified tourism product despite the existence of an adequate Joan of Arc tourismscape. Insights gleaned from this research include Joan’s conflicted status as both/either saint and/or patriot, the existence of no cooperation or linkage between Joan of Arc sites, and cautious French tourism development policies. Several possible scenarios are suggested as suitable means to help implement or foster the creation of an on-the-ground or virtual Joan of Arc trail or tour.

  14. Aerodynamic Analysis of Trailing Edge Enlarged Wind Turbine Airfoils

    International Nuclear Information System (INIS)

    Xu, Haoran; Yang, Hua; Liu, Chao; Shen, Wenzhong; Zhu, Weijun

    2014-01-01

    The aerodynamic performance of blunt trailing edge airfoils generated from the DU- 91-W2-250, DU-97-W-300 and DU-96-W-350 airfoils by enlarging the thickness of trailing edge symmetrically from the location of maximum thickness to chord to the trailing edge were analyzed by using CFD and RFOIL methods at a chord Reynolds number of 3 × 10 6 . The goal of this study is to analyze the aerodynamic performance of blunt trailing edge airfoils with different thicknesses of trailing edge and maximum thicknesses to chord. The steady results calculated by the fully turbulent k-ω SST, transitional k-ω SST model and RFOIL all show that with the increase of thickness of trailing edge, the linear region of lift is extended and the maximum lift also increases, the increase rate and amount of lift become limited gradually at low angles of attack, while the drag increases dramatically. For thicker airfoils with larger maximum thickness to chord length, the increment of lift is larger than that of relatively thinner airfoils when the thickness of blunt trailing edge is increased from 5% to 10% chord length. But too large lift can cause abrupt stall which is profitless for power output. The transient characteristics of blunt trailing edge airfoils are caused by blunt body vortices at low angles of attack, and by the combined effect of separation and blunt body vortices at large angles of attack. With the increase of thickness of blunt trailing edge, the vibration amplitudes of lift and drag curves increase. The transient calculations over-predict the lift at large angles of attack and drag at all angles of attack than the steady calculations which is likely to be caused by the artificial restriction of the flow in two dimensions

  15. Difference between age-related macular degeneration and polypoidal choroidal vasculopathy in the hereditary contribution of the A69S variant of the age-related maculopathy susceptibility 2 gene (ARMS2).

    Science.gov (United States)

    Yanagisawa, Suiho; Kondo, Naoshi; Miki, Akiko; Matsumiya, Wataru; Kusuhara, Sentaro; Tsukahara, Yasutomo; Honda, Shigeru; Negi, Akira

    2011-01-01

    To investigate whether the A69S variant of the age-related maculopathy susceptibility 2 gene (ARMS2) has a different hereditary contribution in neovascular age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV). We initially conducted a comparative genetic analysis of neovascular AMD and PCV, genotyping the ARMS2 A69S variant in 181 subjects with neovascular AMD, 198 subjects with PCV, and 203 controls in a Japanese population. Genotyping was conducted using TaqMan technology. Results were then integrated into a meta-analysis of previous studies representing an assessment of the association between the ARMS2 A69S variant and neovascular AMD and/or PCV, comprising a total of 3,828 subjects of Asian descent. The Q-statistic test was used to assess between-study heterogeneity. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using a fixed effects model. The genetic effect of the A69S variant was stronger in neovascular AMD (allelic summary OR=3.09 [95% CI, 2.71-3.51], fixed effects parchitecture of this phenotypically heterogeneous disorder.

  16. Ambient air conditions and variation in urban trail use.

    Science.gov (United States)

    Holmes, Ann M; Lindsey, Greg; Qiu, Chenchen

    2009-11-01

    This study examines the effect of air quality and administrative policies on use of urban trails in Indianapolis, IN. Attention is focused on two policy variables: (1) issuance of air pollution advisories and (2) the adoption of Daylight Savings Time. Results suggest that while trail use varies with air quality, current public advisories regarding air pollution may be of limited effectiveness in reducing trail users' exposures to hazardous pollutants. In contrast, the adoption of Daylight Savings Time was associated with a statistically significant increase in traffic levels.

  17. Modulation of TRAIL resistance in colon carcinoma cells : Different contributions of DR4 and DR5

    NARCIS (Netherlands)

    van Geelen, Caroline M. M.; Pennarun, Bodvael; Le, Phuong T. K.; de Vries, Elisabeth G. E.; de Jong, Steven

    2011-01-01

    Background: rhTRAIL is a therapeutic agent, derived from the TRAIL cytokine, which induces apoptosis in cancer cells by activating the membrane death receptors 4 and 5 (DR4 and DR5). Here, we investigated each receptor's contribution to rhTRAIL sensitivity and rhTRAIL resistance. We assessed whether

  18. IMPROVED TUMOR CELL KILLING BY TRAIL REQUIRES SELECTIVE AND HIGH AFFINITY RECEPTOR ACTIVATION

    NARCIS (Netherlands)

    Szegezdi, Eva; van der Sloot, Almer M.; Alessandro, Natoni; Mahalingam, Devalingam; Cool, Robbert H.; Munoz, Ines G.; Montoya, Guillermo; Quax, Wim J.; Luis Serrano, Steven de Jong; Samali, Afshin; Wallach, D; Kovalenko, A; Feldman, M

    2011-01-01

    Apoptosis can be activated by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in a wide range of tumor cells, but not in non-transformed cells. TRAIL interaction with receptors DR4 or DR5 induces apoptosis, whereas DcR1, DcR2 and osteoprotegerin are decoy receptors for TRAIL. TRAIL

  19. 30 CFR 77.600 - Trailing cables; short-circuit protection; disconnecting devices.

    Science.gov (United States)

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Trailing cables; short-circuit protection... AREAS OF UNDERGROUND COAL MINES Trailing Cables § 77.600 Trailing cables; short-circuit protection; disconnecting devices. Short-circuit protection for trailing cables shall be provided by an automatic circuit...

  20. 30 CFR 75.601 - Short circuit protection of trailing cables.

    Science.gov (United States)

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Short circuit protection of trailing cables. 75... MINE SAFETY AND HEALTH MANDATORY SAFETY STANDARDS-UNDERGROUND COAL MINES Trailing Cables § 75.601 Short circuit protection of trailing cables. [Statutory Provisions] Short circuit protection for trailing cables...

  1. 76 FR 8992 - National Trails System Act and Railroad Rights-of-Way

    Science.gov (United States)

    2011-02-16

    ...] National Trails System Act and Railroad Rights-of-Way AGENCY: Surface Transportation Board, DOT. ACTION... procedures regarding the use of railroad rights-of-way for railbanking and interim trail use under the National Trails System Act (Trails Act). DATES: Comments are due by April 12, 2011; replies are due by May...

  2. 36 CFR 212.56 - Identification of designated roads, trails, and areas.

    Science.gov (United States)

    2010-07-01

    ... roads, trails, and areas. 212.56 Section 212.56 Parks, Forests, and Public Property FOREST SERVICE, DEPARTMENT OF AGRICULTURE TRAVEL MANAGEMENT Designation of Roads, Trails, and Areas for Motor Vehicle Use § 212.56 Identification of designated roads, trails, and areas. Designated roads, trails, and areas...

  3. Indicators and protocols for monitoring impacts of formal and informal trails in protected areas

    Science.gov (United States)

    Marion, Jeffrey L.; Leung, Yu-Fai

    2011-01-01

    Trails are a common recreation infrastructure in protected areas and their conditions affect the quality of natural resources and visitor experiences. Various trail impact indicators and assessment protocols have been developed in support of monitoring programs, which are often used for management decision-making or as part of visitor capacity management frameworks. This paper reviews common indicators and assessment protocols for three types of trails, surfaced formal trails, unsurfaced formal trails, and informal (visitor-created) trails. Monitoring methods and selected data from three U.S. National Park Service units are presented to illustrate some common trail impact indicators and assessment options.

  4. Blazing the trail: Official Report : Singapore 2010 Youth Olympic Games

    OpenAIRE

    2012-01-01

    The official report of the 1st Youth Olympic Games, “Blazing the trail: Official Report: Singapore 2010 Youth Olympic Games” consisted of one volume, published in French and English. The French version was published only in electronic form

  5. Geomorphological hazard and tourist vulnerability along Portofino Park trails (Italy

    Directory of Open Access Journals (Sweden)

    P. Brandolini

    2006-01-01

    Full Text Available The many trails existing in the coastal area of Portofino Promontory are used by tourists for trekking or as pathways to small villages and beaches. The aim of this paper is to define geomorphological hazard and tourist vulnerability in this area, within the framework of the management and planning of hiking activities in Portofino Natural Park. In particular, processes triggered by gravity, running waters and wave motion, affecting the slopes and the cliff, are considered. The typology of the trails and trail maintenance are also taken into account in relation to weather conditions that can make the excursion routes dangerous for tourists. In conclusion, an operative model is applied for the definition of possible risk scenarios. This model is founded on an inventory and the quantification of geomorphological hazards and tourist vulnerability, in comparison with trail rescue data. The model can be applied to other environments and tourist areas.

  6. Geomorphological hazard and tourist vulnerability along Portofino Park trails (Italy)

    Science.gov (United States)

    Brandolini, P.; Faccini, F.; Piccazzo, M.

    2006-06-01

    The many trails existing in the coastal area of Portofino Promontory are used by tourists for trekking or as pathways to small villages and beaches. The aim of this paper is to define geomorphological hazard and tourist vulnerability in this area, within the framework of the management and planning of hiking activities in Portofino Natural Park. In particular, processes triggered by gravity, running waters and wave motion, affecting the slopes and the cliff, are considered. The typology of the trails and trail maintenance are also taken into account in relation to weather conditions that can make the excursion routes dangerous for tourists. In conclusion, an operative model is applied for the definition of possible risk scenarios. This model is founded on an inventory and the quantification of geomorphological hazards and tourist vulnerability, in comparison with trail rescue data. The model can be applied to other environments and tourist areas.

  7. DNR Division of Parks and Trails District Boundaries

    Data.gov (United States)

    Minnesota Department of Natural Resources — This data shows the DNR Division of Parks and Trails District Boundaries as of May 2010. The boundaries were created by the Division Leadership Team. Boundaries are...

  8. pupil initiatives in urban nature trail development: pmb moss

    African Journals Online (AJOL)

    .ritzburg is provided. Negotiations and procedures initiated by standard 9 pupils in stimulating authorities and the public to recog~ nise the need for urban trail development and metropolitan open space. (MOSS) are outlined. long-tenn ...

  9. The Paracrine Induction of TRAIL by Genotoxic Agents

    National Research Council Canada - National Science Library

    Spalding, Aaron

    2002-01-01

    TNF related apoptosis inducing ligand, TRAIL, is a recently cloned cytokine that has been shown to induce apoptosis in a synergistic fashion with chemotherapeutic agents on several cancer cell lines...

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

    Science.gov (United States)

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

    2010-05-15

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

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

    Science.gov (United States)

    Power, Anthony T; Bell, John C

    2007-04-01

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

  12. Trailing Edge Noise Model Validation and Application to Airfoil Optimization

    DEFF Research Database (Denmark)

    Bertagnolio, Franck; Aagaard Madsen, Helge; Bak, Christian

    2010-01-01

    The aim of this article is twofold. First, an existing trailing edge noise model is validated by comparing with airfoil surface pressure fluctuations and far field sound pressure levels measured in three different experiments. The agreement is satisfactory in one case but poor in two other cases...... across the boundary layer near the trailing edge and to a lesser extent by a smaller boundary layer displacement thickness. ©2010 American Society of Mechanical Engineers...

  13. Universality of collapsing two-dimensional self-avoiding trails

    International Nuclear Information System (INIS)

    Foster, D P

    2009-01-01

    Results of a numerically exact transfer matrix calculation for the model of interacting self-avoiding trails are presented. The results lead to the conclusion that at the collapse transition, self-avoiding trails are in the same universality class as the O(n = 0) model of Bloete and Nienhuis (or vertex-interacting self-avoiding walk), which has thermal exponent ν = 12/23, contrary to previous conjectures. (fast track communication)

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

    Directory of Open Access Journals (Sweden)

    Yuuri Hashimoto

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

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

    International Nuclear Information System (INIS)

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

    2012-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Braidwood L

    2014-10-01

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

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

    Science.gov (United States)

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

    2014-02-01

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

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

    Directory of Open Access Journals (Sweden)

    Hutzen Brian

    2012-11-01

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

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

    Science.gov (United States)

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

    2011-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Mittra Arjun

    2011-03-01

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

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

    Science.gov (United States)

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

    2017-09-16

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

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

    Science.gov (United States)

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

    2018-05-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-04-03

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

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

    International Nuclear Information System (INIS)

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

    2015-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Kristopher J. Kimball

    2009-09-01

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

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

    Directory of Open Access Journals (Sweden)

    Adam W. Studebaker

    2017-09-01

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

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

    Directory of Open Access Journals (Sweden)

    Zong Sheng Guo

    2017-12-01

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

  8. Sesquiterpenes with TRAIL-resistance overcoming activity from Xanthium strumarium.

    Science.gov (United States)

    Karmakar, Utpal K; Ishikawa, Naoki; Toume, Kazufumi; Arai, Midori A; Sadhu, Samir K; Ahmed, Firoj; Ishibashi, Masami

    2015-08-01

    The ability of TRAIL to selectively induce apoptosis in cancer cells while sparing normal cells makes it an attractive target for the development of new cancer therapy. In search of bioactive natural products for overcoming TRAIL-resistance from natural resources, we previously reported a number of active compounds. In our screening program on natural resources targeting overcoming TRAIL-resistance, activity-guided fractionations of the extract of Xanthium strumarium led to the isolation of five sesquiterpene compounds (1-5). 11α,13-dihydroxanthinin (2) and 11α,13-dihydroxanthuminol (3) were first isolated from natural resources and xanthinosin (1), desacetylxanthanol (4), and lasidiol p-methoxybenzoate (5) were known compounds. All compounds (1-5) showed potent TRAIL-resistance overcoming activity at 8, 20, 20, 16, and 16 μM, respectively, in TRAIL-resistant AGS cells. Compounds 1 and 5 enhanced the levels of apoptosis inducing proteins DR4, DR5, p53, CHOP, Bax, cleaved caspase-3, cleaved caspase-8, and cleaved caspase-9 and also decreased the levels of cell survival protein Bcl-2 in TRAIL-resistant AGS cells in a dose-dependent manner. Compound 1 also enhanced the levels of DR4 and DR5 proteins in a time-dependent manner. Thus, compounds 1 and 5 were found to induce both extrinsic and intrinsic apoptotic cell death. Compound 1 also exhibit TRAIL-resistance overcoming activity in DLD1, DU145, HeLa, and MCF7 cells but did not decrease viability in non-cancer HEK293 cells up to 8 μM. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. Improvement of airfoil trailing edge bluntness noise model

    Directory of Open Access Journals (Sweden)

    Wei Jun Zhu

    2016-02-01

    Full Text Available In this article, airfoil trailing edge bluntness noise is investigated using both computational aero-acoustic and semi-empirical approach. For engineering purposes, one of the most commonly used prediction tools for trailing edge noise are based on semi-empirical approaches, for example, the Brooks, Pope, and Marcolini airfoil noise prediction model developed by Brooks, Pope, and Marcolini (NASA Reference Publication 1218, 1989. It was found in previous study that the Brooks, Pope, and Marcolini model tends to over-predict noise at high frequencies. Furthermore, it was observed that this was caused by a lack in the model to predict accurately noise from blunt trailing edges. For more physical understanding of bluntness noise generation, in this study, we also use an advanced in-house developed high-order computational aero-acoustic technique to investigate the details associated with trailing edge bluntness noise. The results from the numerical model form the basis for an improved Brooks, Pope, and Marcolini trailing edge bluntness noise model.

  10. Leading and Trailing Anvil Clouds of West African Squall Lines

    Science.gov (United States)

    Centrone, Jasmine; Houze, Robert A.

    2011-01-01

    The anvil clouds of tropical squall-line systems over West Africa have been examined using cloud radar data and divided into those that appear ahead of the leading convective line and those on the trailing side of the system. The leading anvils are generally higher in altitude than the trailing anvil, likely because the hydrometeors in the leading anvil are directly connected to the convective updraft, while the trailing anvil generally extends out of the lower-topped stratiform precipitation region. When the anvils are subdivided into thick, medium, and thin portions, the thick leading anvil is seen to have systematically higher reflectivity than the thick trailing anvil, suggesting that the leading anvil contains numerous larger ice particles owing to its direct connection to the convective region. As the leading anvil ages and thins, it retains its top. The leading anvil appears to add hydrometeors at the highest altitudes, while the trailing anvil is able to moisten a deep layer of the atmosphere.

  11. Cohort Profile Update: The TRacking Adolescents’ Individual Lives Survey (TRAILS)

    Science.gov (United States)

    Oldehinkel, Albertine J; Rosmalen, Judith GM; Buitelaar, Jan K; Hoek, Hans W; Ormel, Johan; Raven, Dennis; Reijneveld, Sijmen A; Veenstra, René; Verhulst, Frank C; Vollebergh, Wilma AM; Hartman, Catharina A

    2015-01-01

    TRAILS consists of a population cohort (N = 2230) and a clinical cohort (N = 543), both of which were followed from about age 11 years onwards. To date, the population cohort has been assessed five times over a period of 11 years, with retention rates ranging between 80% and 96%. The clinical cohort has been assessed four times over a period of 8 years, with retention rates ranging between 77% and 85%. Since the IJE published a cohort profile on the TRAILS in 2008, the participants have matured from adolescents into young adults. The focus shifted from parents and school to entry into the labour market and family formation, including offspring. Furthermore, psychiatric diagnostic interviews were administered, the database was linked to a Psychiatric Case Registry, and the availability of genome-wide SNP variations opened the door to genome-wide association studies regarding a wide range of (endo)phenotypes. With some delay, TRAILS data are available to researchers outside the TRAILS consortium without costs; access can be obtained by submitting a publication proposal (see www.trails.nl). PMID:25431468

  12. Cohort Profile Update: the TRacking Adolescents' Individual Lives Survey (TRAILS).

    Science.gov (United States)

    Oldehinkel, Albertine J; Rosmalen, Judith Gm; Buitelaar, Jan K; Hoek, Hans W; Ormel, Johan; Raven, Dennis; Reijneveld, Sijmen A; Veenstra, René; Verhulst, Frank C; Vollebergh, Wilma Am; Hartman, Catharina A

    2015-02-01

    TRAILS consists of a population cohort (N=2230) and a clinical cohort (N=543), both of which were followed from about age 11 years onwards. To date, the population cohort has been assessed five times over a period of 11 years, with retention rates ranging between 80% and 96%. The clinical cohort has been assessed four times over a period of 8 years, with retention rates ranging between 77% and 85%. Since the IJE published a cohort profile on the TRAILS in 2008, the participants have matured from adolescents into young adults. The focus shifted from parents and school to entry into the labour market and family formation, including offspring. Furthermore, psychiatric diagnostic interviews were administered, the database was linked to a Psychiatric Case Registry, and the availability of genome-wide SNP variations opened the door to genome-wide association studies regarding a wide range of (endo)phenotypes. With some delay, TRAILS data are available to researchers outside the TRAILS consortium without costs; access can be obtained by submitting a publication proposal (see www.trails.nl). © The Author 2014; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.

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

    International Nuclear Information System (INIS)

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

    2011-01-01

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

  14. Identification of TRAIL-inducing compounds highlights small molecule ONC201/TIC10 as a unique anti-cancer agent that activates the TRAIL pathway.

    Science.gov (United States)

    Allen, Joshua E; Krigsfeld, Gabriel; Patel, Luv; Mayes, Patrick A; Dicker, David T; Wu, Gen Sheng; El-Deiry, Wafik S

    2015-05-01

    We previously reported the identification of ONC201/TIC10, a novel small molecule inducer of the human TRAIL gene that improves efficacy-limiting properties of recombinant TRAIL and is in clinical trials in advanced cancers based on its promising safety and antitumor efficacy in several preclinical models. We performed a high throughput luciferase reporter screen using the NCI Diversity Set II to identify TRAIL-inducing compounds. Small molecule-mediated induction of TRAIL reporter activity was relatively modest and the majority of the hit compounds induced low levels of TRAIL upregulation. Among the candidate TRAIL-inducing compounds, TIC9 and ONC201/TIC10 induced sustained TRAIL upregulation and apoptosis in tumor cells in vitro and in vivo. However, ONC201/TIC10 potentiated tumor cell death while sparing normal cells, unlike TIC9, and lacked genotoxicity in normal fibroblasts. Investigating the effects of TRAIL-inducing compounds on cell signaling pathways revealed that TIC9 and ONC201/TIC10, which are the most potent inducers of cell death, exclusively activate Foxo3a through inactivation of Akt/ERK to upregulate TRAIL and its pro-apoptotic death receptor DR5. These studies reveal the selective activity of ONC201/TIC10 that led to its selection as a lead compound for this novel class of antitumor agents and suggest that ONC201/TIC10 is a unique inducer of the TRAIL pathway through its concomitant regulation of the TRAIL ligand and its death receptor DR5.

  15. BITC Sensitizes Pancreatic Adenocarcinomas to TRAIL-induced Apoptosis

    Directory of Open Access Journals (Sweden)

    Christina A. Wicker

    2009-01-01

    Full Text Available Pancreatic adenocarcinoma is an aggressive cancer with a greater than 95% mortality rate and short survival after diagnosis. Chemotherapeutic resistance hinders successful treatment. This resistance is often associated with mutations in codon 12 of the K-Ras gene (K-Ras 12, which is present in over 90% of all pancreatic adenocarcinomas. Codon 12 mutations maintain Ras in a constitutively active state leading to continuous cellular proliferation. Our study determined if TRAIL resistance in pancreatic adenocarcinomas with K-Ras 12 mutations could be overcome by first sensitizing the cells with Benzyl isothiocyanate (BITC. BITC is a component of cruciferous vegetables and a cell cycle inhibitor. BxPC3, MiaPaCa2 and Panc-1 human pancreatic adenocarcinoma cell lines were examined for TRAIL resistance. Our studies show BITC induced TRAIL sensitization by dual activation of both the extrinsic and intrinsic apoptotic pathways.

  16. Continuous Fraud Detection in Enterprise Systems through Audit Trail Analysis

    Directory of Open Access Journals (Sweden)

    Peter J. Best

    2009-03-01

    Full Text Available Enterprise systems, real time recording and real time reporting pose new and significant challenges to the accounting and auditing professions. This includes developing methods and tools for continuous assurance and fraud detection. In this paper we propose a methodology for continuous fraud detection that exploits security audit logs, changes in master records and accounting audit trails in enterprise systems. The steps in this process are: (1 threat monitoring-surveillance of security audit logs for ‘red flags’, (2 automated extraction and analysis of data from audit trails, and (3 using forensic investigation techniques to determine whether a fraud has actually occurred. We demonstrate how mySAP, an enterprise system, can be used for audit trail analysis in detecting financial frauds; afterwards we use a case study of a suspected fraud to illustrate how to implement the methodology.

  17. A dynamic stall model for airfoils with deformable trailing edges

    DEFF Research Database (Denmark)

    Andersen, Peter Bjørn; Gaunaa, Mac; Bak, Christian

    2009-01-01

    , lead-lag, pitch, trailing-edge flapping. In the linear region, the model reduces to the inviscid model, which includes the aerodynamic effect of a thin airfoil with a deformable camberline in inviscid flow. Therefore, the proposed model can be considered a crossover between the work of Gaunaa......The present work contains an extension of the Beddoes-Leishman-type dynamic stall model. In this work, a deformable trailing-edge flap has been added to the dynamic stall model. The model predicts the unsteady aerodynamic forces and moments on an airfoil section undergoing arbitrary motion in heave...... for the attached flow region and Hansen et al. The model is compared qualitatively to wind tunnel measurements of a Riso/ B1-18 blade section equipped with deformable trailing-edge flap devices in the form of piezoelectric devices. Copyright © 2009 John Wiley & Sons, Ltd....

  18. Hiking trails and tourism impact assessment in protected area: Jiuzhaigou Biosphere Reserve, China.

    Science.gov (United States)

    Li, Wenjun; Ge, Xiaodong; Liu, Chunyan

    2005-09-01

    More and more visitors are attracted to protected areas nowadays, which not only bring about economic increase but also seriously adverse impacts on the ecological environment. In protected areas, trails are linkage between visitors and natural ecosystem, so they concentrate most of the adverse impacts caused by visitors. The trampling problems on the trails have been received attentions in the tremendous researches. However, few of them have correlated the environmental impacts to trail spatial patterns. In this project, the trails were selected as assessment objective, the trampling problems trail widening, multiple trail, and root exposure were taken as assessment indicators to assess ecological impacts in the case study area Jiuzhaigou Biosphere Reserve, and two spatial index, connectivity and circularity, were taken to indicate the trail network spatial patterns. The research results showed that the appearing frequency of the trampling problems had inverse correlation with the circularity and connectivity of the trail network, while the problem extent had no correlation with the spatial pattern. Comparing with the pristine trails, the artificial maintenance for the trails such as wooden trails and flagstone trails could prohibit vegetation root from exposure effectively. The research finds will be useful for the future trail design and tourism management.

  19. Andrographolide sensitizes prostate cancer cells to TRAIL-induced apoptosis

    Directory of Open Access Journals (Sweden)

    Ruo-Jing Wei

    2018-01-01

    Full Text Available Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL is a promising agent for anticancer therapy. The identification of small molecules that can establish the sensitivity of prostate cancer (PCa cells to TRAIL-induced apoptosis is crucial for the targeted treatment of PCa. PC3, DU145, JAC-1, TsuPr1, and LNCaP cells were treated with Andrographolide (Andro and TRAIL, and the apoptosis was measured using the Annexin V/PI double staining method. Real time-polymerase chain reaction (PCR and Western blot analysis were performed to measure the expression levels of target molecules. RNA interference technique was used to down-regulate the expression of the target protein. We established a nude mouse xenograft model of PCa, which was used to measure the caspase-3 activity in the tumor cells using flow cytometry. In this research study, our results demonstrated that Andro preferentially increased the sensitivity of PCa cells to TRAIL-induced apoptosis at subtoxic concentrations, and the regulation mechanism was related to the up-regulation of DR4. In addition, it also increased the p53 expression and led to the generation of reactive oxygen species (ROS in the cells. Further research revealed that the DR4 inhibition, p53 expression, and ROS generation can significantly reduce the apoptosis induced by the combination of TRAIL and Andro in PCa cells. In conclusion, Andro increases the sensitivity of PCa cells to TRAIL-induced apoptosis through the generation of ROS and up-regulation of p53 and then promotes PCa cell apoptosis associated with the activation of DR4.

  20. Trailing edge noise model applied to wind turbine airfoils

    Energy Technology Data Exchange (ETDEWEB)

    Bertagnolio, F.

    2008-01-15

    The aim of this work is firstly to provide a quick introduction to the theory of noise generation that are relevant to wind turbine technology with focus on trailing edge noise. Secondly, the socalled TNO trailing edge noise model developed by Parchen [1] is described in more details. The model is tested and validated by comparing with other results from the literature. Finally, this model is used in the optimization process of two reference airfoils in order to reduce their noise signature: the RISOE-B1-18 and the S809 airfoils. (au)

  1. A dynamic stall model for airfoils with deformable trailing edges

    DEFF Research Database (Denmark)

    Andersen, Peter Bjørn; Gaunaa, Mac; Bak, Dan Christian

    2007-01-01

    on an airfoil section undergoing arbitrary motion in heave, lead-lag, pitch, Trailing Edge (TE) flapping. In the linear region, the model reduces to the inviscid model of Gaunaa [4], which includes the aerodynamic effect of a thin airfoil with a deformable camberline in inviscid flow. Therefore, the proposed......The present work contains an extension of the Beddoes-Leishman (B-L) type dynamic stall model, as described by Hansen et al. [7]. In this work a Deformable Trailing Edge Geometry (DTEG) has been added to the dynamic stall model. The model predicts the unsteady aerodynamic forces and moments...

  2. Improvement of airfoil trailing edge bluntness noise model

    DEFF Research Database (Denmark)

    Zhu, Wei Jun; Shen, Wen Zhong; Sørensen, Jens Nørkær

    2016-01-01

    In this article, airfoil trailing edge bluntness noise is investigated using both computational aero-acoustic and semi-empirical approach. For engineering purposes, one of the most commonly used prediction tools for trailing edge noise are based on semi-empirical approaches, for example, the Brooks......, Pope, and Marcolini airfoil noise prediction model developed by Brooks, Pope, and Marcolini (NASA Reference Publication 1218, 1989). It was found in previous study that the Brooks, Pope, and Marcolini model tends to over-predict noise at high frequencies. Furthermore, it was observed...

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

    Directory of Open Access Journals (Sweden)

    Dana Haddad

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

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

    International Nuclear Information System (INIS)

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

    2011-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Coffey Matthew C

    2009-07-01

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

  6. Cloning and Characterization of Genes that Inhibit TRAIL-Induced Apoptosis of Breast Cancer Cells

    National Research Council Canada - National Science Library

    Shu, Hong-Bing

    2003-01-01

    ...). However, some cancer cells are resistant to TRAIL-induced apoptosis (3, 4, 6-13). The purpose of this proposed study is to clone and characterize such inhibitory genes of TRAIL-induced apoptosis...

  7. Modulators of Response to Tumor Necrosis-Related Apoptosis-Inducing Ligand (TRAIL) Therapy in Ovarian Cancer

    National Research Council Canada - National Science Library

    Behbakht, Kian

    2008-01-01

    .... TRAIL therapies are particularly exciting because TRAIL reverses chemoresistance to standard chemotherapy as well as having a direct growth inhibitory effect on ovarian cancer cells, while sparing normal...

  8. 3-Bromopyruvate enhances TRAIL-induced apoptosis in human nasopharyngeal carcinoma cells through CHOP-dependent upregulation of TRAIL-R2.

    Science.gov (United States)

    Can, Zhou; Lele, Song; Zhirui, Zhang; Qiong, Pan; Yuzhong, Chen; Lingling, Liu; Surong, Zhao; Yiming, Sun; Pei, Zhang; Chenchen, Jiang; Liu, Hao

    2017-08-01

    Past reports have shown that the sensitivity of cancer cells to TRAIL-induced apoptosis is related to their expression of TRAIL-death receptors on the cell surface. However, the level of TRAIL-death receptors expression on cancer cells is always low. Our previous research showed that nasopharyngeal carcinoma (NPC) cells have a poor sensitivity to low doses of TRAIL. Here, we evaluated combined treatment with the energy inhibitor 3-bromopyruvate (3BP) and TRAIL as a method to produce an increased apoptotic response in NPC cells. The results showed that 3BP and TRAIL together produced higher cytotoxicity and increased TRAIL-R2 expression in NPC cells compared with the effects of either 3BP or TRAIL alone. These findings led us to hypothesize that 3BP may sensitize NPC cells to TRAIL. 3BP is a metabolic blocker that inhibits hexokinase II activity, suppresses ATP production, and induces endoplasmic reticulum (ER) stress. Our results showed that 3BP also activated AMP-activated protein kinase, which we found to play an important role in the induction of ER stress by 3BP. Furthermore, the induction of TRAIL-R2 expression and the sensitization of the NPC cells to TRAIL by 3BP were reduced when we inhibited the expression of CHOP. Taken together, our results showed that a low dose of 3BP sensitized NPC cells to TRAIL-induced apoptosis by the upregulation of CHOP, which was mediated by the activation of AMP-activated protein kinase and ER stress. The results showed that 3BP is a promising candidate agent for enhancing the therapeutic response to TRAIL in NPC.

  9. Experimental Investigation of Aerodynamic Performance of Airfoils Fitted with Morphing Trailing Edges

    OpenAIRE

    Ai, Qing; Kamliya Jawahar, Hasan; Azarpeyvand, Mahdi

    2016-01-01

    The aerodynamic performance and wake development of a NACA 0012 airfoil fitted with morphing trailing edges were studied using experimental and computational techniques. The NACA 0012 airfoil was tested with morphing trailing edges having various camber profiles with the same trailing edge tip deflection. The aerodynamic force measurements for the airfoil were carried out for a wide range of chord-based Reynolds number and angles of attack with trailing edge deflection angle of β= 5◦ and 10◦....

  10. Irradiation specifically sensitises solid tumour cell lines to TRAIL mediated apoptosis

    International Nuclear Information System (INIS)

    Marini, Patrizia; Schmid, Angelika; Jendrossek, Verena; Faltin, Heidrun; Daniel, Peter T; Budach, Wilfried; Belka, Claus

    2005-01-01

    TRAIL (tumor necrosis factor related apoptosis inducing ligand) is an apoptosis inducing ligand with high specificity for malignant cell systems. Combined treatment modalities using TRAIL and cytotoxic drugs revealed highly additive effects in different tumour cell lines. Little is known about the efficacy and underlying mechanistic effects of a combined therapy using TRAIL and ionising radiation in solid tumour cell systems. Additionally, little is known about the effect of TRAIL combined with radiation on normal tissues. Tumour cell systems derived from breast- (MDA MB231), lung- (NCI H460) colorectal- (Colo 205, HCT-15) and head and neck cancer (FaDu, SCC-4) were treated with a combination of TRAIL and irradiation using two different time schedules. Normal tissue cultures from breast, prostate, renal and bronchial epithelia, small muscle cells, endothelial cells, hepatocytes and fibroblasts were tested accordingly. Apoptosis was determined by fluorescence microscopy and western blot determination of PARP processing. Upregulation of death receptors was quantified by flow cytometry. The combined treatment of TRAIL with irradiation strongly increased apoptosis induction in all treated tumour cell lines compared to treatment with TRAIL or irradiation alone. The synergistic effect was most prominent after sequential application of TRAIL after irradiation. Upregulation of TRAIL receptor DR5 after irradiation was observed in four of six tumour cell lines but did not correlate to tumour cell sensitisation to TRAIL. TRAIL did not show toxicity in normal tissue cell systems. In addition, pre-irradiation did not sensitise all nine tested human normal tissue cell cultures to TRAIL. Based on the in vitro data, TRAIL represents a very promising candidate for combination with radiotherapy. Sequential application of ionising radiation followed by TRAIL is associated with an synergistic induction of cell death in a large panel of solid tumour cell lines. However, TRAIL receptor

  11. 30 CFR 77.804 - High-voltage trailing cables; minimum design requirements.

    Science.gov (United States)

    2010-07-01

    ... OF UNDERGROUND COAL MINES Surface High-Voltage Distribution § 77.804 High-voltage trailing cables; minimum design requirements. (a) High-voltage trailing cables used in resistance grounded systems shall be... 30 Mineral Resources 1 2010-07-01 2010-07-01 false High-voltage trailing cables; minimum design...

  12. Comprehensive Trail Making Test Performance in Children and Adolescents with Traumatic Brain Injury

    Science.gov (United States)

    Allen, Daniel N.; Thaler, Nicholas S.; Ringdahl, Erik N.; Barney, Sally J.; Mayfield, Joan

    2012-01-01

    The sensitivity of the Trail Making Test to brain damage has been well-established over many years, making it one of the most commonly used tests in clinical neuropsychological evaluations. The current study examined the validity of scores from a newer version of the Trail Making Test, the Comprehensive Trail Making Test (CTMT), in children and…

  13. Home | Trails of Hope: Overland Diaries and Letters, 1846-1869 | Digital

    Science.gov (United States)

    Collections | HBLL BYU Harold B. Lee Library Collections Trails of Hope: Overland Diaries and Mormons--Religious Life Religious Life Women Browse Search Browse all Maps Interactive Maps These maps illustrations. Search Browse all Photographs and Illustrations Search Browse all Trail Guides Trails of Hope

  14. Initiation of trailing edge failure in full-scale wind turbine blade test

    DEFF Research Database (Denmark)

    Haselbach, Philipp Ulrich; Branner, Kim

    2016-01-01

    non-linear buckling effect of the trailing edge under combined loading, and how it affects the ultimate strength of a blade in a trailing-edge failure dominated load direction were investigated. The study details the interaction between trailing edge buckling on damage onset and sandwich panel failure...

  15. Students’ Use of Knowledge Resources in Environmental Interaction on an Outdoor Learning Trail

    NARCIS (Netherlands)

    Tan, Esther; So, Hyo-Jeong

    2016-01-01

    This study examined how students leveraged different types of knowledge resources on an outdoor learning trail. We positioned the learning trail as an integral part of the curriculum with a pre- and post-trail phase to scaffold and to support students’ meaning-making process. The study was conducted

  16. Promoting and developing a trail network across suburban, rural, and urban communities.

    Science.gov (United States)

    Schasberger, Michele G; Hussa, Carol S; Polgar, Michael F; McMonagle, Julie A; Burke, Sharon J; Gegaris, Andrew J

    2009-12-01

    The Wyoming Valley Wellness Trails Partnership received an Active Living by Design grant late in 2003 for a project centered on a growing trail network linking urban, suburban, and rural communities in northeast Pennsylvania, a former coal region, in order to increase physical activity among residents. The partnership conducted research, collected information, created promotional documents, worked with partners on events and programs, and participated in trail planning. Local trail organizations continued planning and construction toward developing a trail network. Other partners spearheaded policy change in schools and worksites and worked toward downtown revitalization. The partnership assisted these efforts by providing a forum in which organizations could meet. The partnership became a central resource for information about local parks, trails, and outdoor recreational activities. The partnership increased awareness and use of recreational facilities. Trail partners constructed 22 miles of walking and biking trails. The partnership took advantage of an allied effort that created organizational capacity for wellness in schools and worksites. Messages promoting social and entertainment benefits of physical activity were more successful than those promoting health benefits. The existence of multiple small, independent trail organizations can help advance trail development through concurrent development efforts. Urban, suburban, and rural residents' conceptions of walkability may differ. Trails provide options for recreational and transportation-related physical activity across urban, suburban, and rural landscapes that are supported by all constituents. Trail builders can be strong allies in bringing active living to suburban and rural places.

  17. 30 CFR 75.907 - Design of trailing cables for medium-voltage circuits.

    Science.gov (United States)

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Design of trailing cables for medium-voltage... Medium-Voltage Alternating Current Circuits § 75.907 Design of trailing cables for medium-voltage circuits. [Statutory Provisions] Trailing cables for medium-voltage circuits shall include grounding...

  18. 36 CFR 261.12 - National Forest System roads and trails.

    Science.gov (United States)

    2010-07-01

    ... and trails. 261.12 Section 261.12 Parks, Forests, and Public Property FOREST SERVICE, DEPARTMENT OF AGRICULTURE PROHIBITIONS General Prohibitions § 261.12 National Forest System roads and trails. The following... by a sign. (c) Damaging and leaving in a damaged condition any such road, trail, or segment thereof...

  19. 36 CFR 212.55 - Criteria for designation of roads, trails, and areas.

    Science.gov (United States)

    2010-07-01

    ... roads, trails, and areas. 212.55 Section 212.55 Parks, Forests, and Public Property FOREST SERVICE, DEPARTMENT OF AGRICULTURE TRAVEL MANAGEMENT Designation of Roads, Trails, and Areas for Motor Vehicle Use § 212.55 Criteria for designation of roads, trails, and areas. (a) General criteria for designation of...

  20. 36 CFR 212.51 - Designation of roads, trails, and areas.

    Science.gov (United States)

    2010-07-01

    ... 36 Parks, Forests, and Public Property 2 2010-07-01 2010-07-01 false Designation of roads, trails... AGRICULTURE TRAVEL MANAGEMENT Designation of Roads, Trails, and Areas for Motor Vehicle Use § 212.51 Designation of roads, trails, and areas. (a) General. Motor vehicle use on National Forest System roads, on...

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

    Science.gov (United States)

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

    2017-07-12

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

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

    Science.gov (United States)

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

    2012-03-01

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

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

    Science.gov (United States)

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

    2013-10-01

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

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

    Directory of Open Access Journals (Sweden)

    Karoliina Autio

    2014-01-01

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

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

    Science.gov (United States)

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

    2018-02-14

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

  6. National forest trail users: planning for recreation opportunities

    Science.gov (United States)

    John J. Daigle; Alan E. Watson; Glenn E. Haas

    1994-01-01

    National forest trail users in four geographical regions of the United States are described based on participation in clusters of recreation activities. Visitors are classified into day hiking, undeveloped recreation, and two developed camping and hiking activity clusters for the Appalachian, Pacific, Rocky Mountain, and Southwestern regions. Distance and time traveled...

  7. Double blind clinical trail comparing the safety and efficacy of ...

    African Journals Online (AJOL)

    Double blind clinical trail comparing the safety and efficacy of nimesulide (100g) and diclofenac in osteoarthrosis of the hip and knee joints. ... A significant proportion of the patients in the diclofenac group (50% vs 17.6%) had break through pain that warranted the use of at least two tablets of 500mg of paracetamol per week ...

  8. Photography of a lithium vapor trail during the daytime.

    Science.gov (United States)

    Bedinger, J. F.

    1973-01-01

    Barium and lithium vapors were released from sounding rockets in the thermosphere and observed from aboard a jet aircraft at an altitude of 40,000 ft. The purpose of the releases was to demonstrate the feasibility of an all-weather technique for observing chemical releases and to evaluate methods of observing daytime releases. The selected flight plan of the aircraft allowed a series of observations of the trail from two different straight line paths. Data were recorded photographically. The reduction in sky brightness at the 40,000-ft altitude as compared to the ground allows the use of a filter with a 10-A bandwidth for trail photography in the daytime. These photographs verified the calculation of the usable angular field of the narrow-band filters. Photographs of a 45-min-old trail of lithium vapor were obtained up to 20 min after sunrise at the aircraft. It is concluded that now vapor trail observations may be made during the daytime without regard to weather and logistic restrictions.

  9. The Clam Trail: Blending Science Education, Public Art, and Tourism

    Science.gov (United States)

    Muscio, Cara; Flimlin, Gef; Bushnell, Rick

    2011-01-01

    The Barnegat Bay Shellfish Restoration's Clam Trail is an award-winning scavenger hunt that combines science education, public art, and tourism. This family adventure has participants seeking out giant painted fiberglass clams, upweller clam nurseries, and points of interest in search of science facts to record on their forms. Upon returning these…

  10. Mobilizing coastal resources along a digitally facilitated pilgrim trail

    DEFF Research Database (Denmark)

    Meged, Jane Widtfeldt; Gyimóthy, Szilvia

    The recently opened pilgrim trail, Camønoen represents an adapted collaborative business model and as such an appropriate case to study new coastal value creation processes. Our paper will follow the consolidation of Camønoen by analyzing its business model, the institutionalisation of brokers...

  11. Endonucleases induced TRAIL-insensitive apoptosis in ovarian carcinoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Geel, Tessa M. [Department of Pathology and Medical Biology, Groningen University Institute for Drug Exploration (GUIDE), University Medical Center Groningen (UMCG), Hanzeplein 1, 9713 GZ, Groningen (Netherlands); Meiss, Gregor [Institute of Biochemistry, Justus-Liebig-University Giessen, D-35392 Giessen (Germany); Gun, Bernardina T. van der; Kroesen, Bart Jan; Leij, Lou F. de [Department of Pathology and Medical Biology, Groningen University Institute for Drug Exploration (GUIDE), University Medical Center Groningen (UMCG), Hanzeplein 1, 9713 GZ, Groningen (Netherlands); Zaremba, Mindaugas; Silanskas, Arunas [Institute of Biotechnology, Vilnius LT-02241 (Lithuania); Kokkinidis, Michael [IMBB/FORTH and University of Crete/Department of Biology, GR-71409 Heraklion/Crete (Greece); Pingoud, Alfred [Institute of Biochemistry, Justus-Liebig-University Giessen, D-35392 Giessen (Germany); Ruiters, Marcel H. [Department of Pathology and Medical Biology, Groningen University Institute for Drug Exploration (GUIDE), University Medical Center Groningen (UMCG), Hanzeplein 1, 9713 GZ, Groningen (Netherlands); Synvolux therapeutics, Groningen (Netherlands); McLaughlin, Pamela M. [Department of Pathology and Medical Biology, Groningen University Institute for Drug Exploration (GUIDE), University Medical Center Groningen (UMCG), Hanzeplein 1, 9713 GZ, Groningen (Netherlands); Rots, Marianne G., E-mail: m.g.rots@med.umcg.nl [Department of Pathology and Medical Biology, Groningen University Institute for Drug Exploration (GUIDE), University Medical Center Groningen (UMCG), Hanzeplein 1, 9713 GZ, Groningen (Netherlands)

    2009-09-10

    TRAIL induced apoptosis of tumor cells is currently entering phase II clinical settings, despite the fact that not all tumor types are sensitive to TRAIL. TRAIL resistance in ovarian carcinomas can be caused by a blockade upstream of the caspase 3 signaling cascade. We explored the ability of restriction endonucleases to directly digest DNA in vivo, thereby circumventing the caspase cascade. For this purpose, we delivered enzymatically active endonucleases via the cationic amphiphilic lipid SAINT-18{sup Registered-Sign }:DOPE to both TRAIL-sensitive and insensitive ovarian carcinoma cells (OVCAR and SKOV-3, respectively). Functional nuclear localization after delivery of various endonucleases (BfiI, PvuII and NucA) was indicated by confocal microscopy and genomic cleavage analysis. For PvuII, analysis of mitochondrial damage demonstrated extensive apoptosis both in SKOV-3 and OVCAR. This study clearly demonstrates that cellular delivery of restriction endonucleases holds promise to serve as a novel therapeutic tool for the treatment of resistant ovarian carcinomas.

  12. Mississippi National River and Recreation Area Water Trail Plan.

    Science.gov (United States)

    2017-05-05

    The Water Trail Plan describes the current conditions of and future plans for the Mississippi National River and Recreation Area (NRRA), a 72-mile stretch of the Mississippi River running through the Twin Cities region of Minnesota. In 2012, the NRRA...

  13. Physiological Responses of Senior Adults Running a Fit Trail.

    Science.gov (United States)

    Lundegren, Herberta; And Others

    In this 1977 study the heart rates of 51 men and women ranging in age from 22-72 were continuously monitored while the subjects walked or ran a modified parcour fitness trail. The length of the course, its gradient, the distance between exercise stations, and the elevation of the course were measured. Mean percentage max HR (Karvonen) values were…

  14. A morphing trailing edge flap system for wind turbine blades

    DEFF Research Database (Denmark)

    Aagaard Madsen, Helge; Barlas, Athanasios; Løgstrup Andersen, Tom

    2015-01-01

    system has been further developed in corporation with the industrial partners Hydratech Industries (DK) and Rehau (DE). A new trailing edge flap design with spanwise voids (channels) and with a chord of 15cm suitable for a 1m chord blade section was developed. It was then manufactured by extrusion...

  15. Estimating soil erosion on hiking trails in the Sierra Mariola Natural Park in southern Spain

    Science.gov (United States)

    Magdalena Warter, Maria; Peeters, Mattias; Kuppen, Emiel; Blok, Kas; Dilly, Lina

    2017-04-01

    Natural parks and protected natural areas provide excellent recreational opportunities for outdoor activities through the richness of the natural environment and the abundance of walking trails. Hiking, mountain biking and running have rapidly gained popularity over recent years increasing concerns about the erosion and degradation of hiking trails caused by (over)use. This is also the case in the Sierra Mariola Natural Park in southeast Spain, which is a popular destination for tourists due to its diverse fauna and flora. The increasing number of tourists together with the negative impacts of climate change necessitates a better understanding of the key soil erosion processes impacting hiking trails. There are 4 scenic trail routes in the Natural Park amounting to 21 km plus an additional network of unofficial trails. Apart from the heavy touristic traffic on the trails there are large trail running events with up to 1000 participants becoming increasingly popular, however local park authorities have voiced concerns about the impacts of these activities on the trails. Despite the popularity of walking trails around the world, there is a paucity of research exploring soil erosion from these features. Therefore, the aims of this study are: 1) to ascertain the amount of erosion that occurs on trails in the Sierra Mariola Natural Park, and 2) determine the key factors that influence soil erosion. Some 100 km of trails were evaluated (both official and unmarked trails), with route segments ranging between 2 and 10 km. A trail classification system was developed to group trail segments based on their surface characteristics (bedrock, gravel, mixed sediment, soil or man-made) and specific erosion features (rills, ditch-shaped, tilted). For each class, the average erosion rate was calculated which ranged from 262 t/ha for soil-based trails to 2006 t/ha for heavily eroded, ditch-shaped trails. The spatial distribution of the different erosion rates and trail types were

  16. Influence of Cattle Trails on Runoff Quantity and Quality.

    Science.gov (United States)

    Miller, Jim J; Curtis, Tony; Chanasyk, David S; Willms, Walter D

    2017-03-01

    Cattle trails in grazed pastures close to rivers may adversely affect surface water quality of the adjacent river by directing runoff to it. The objective of this 3-yr study (2013-2015) in southern Alberta, Canada, was to determine if cattle trails significantly increased the risk of runoff and contaminants (sediment, nutrients) compared with the adjacent grazed pasture (control). A portable rainfall simulator was used to generate artificial rainfall (140 mm h) and runoff. The runoff properties measured were time to runoff and initial abstraction (infiltration), total runoff depth and average runoff rates, as well as concentrations and mass loads of sediment, N, and P fractions. Cattle trails significantly ( ≤ 0.10) decreased time to runoff and initial abstraction (26-32%) in the 2 yr measured and increased total runoff depth, runoff coefficients, and average runoff rates (21-51%) in 2 of 3 yr. Concentrations of sediment, N, and P fractions in runoff were not significantly greater for cattle trails than for control areas. However, mass loads of total suspended solids (57-85% increase), NH-N (31-90%), and dissolved reactive P (DRP) (30-92%) were significantly greater because of increased runoff volumes. Overall, runoff quantity and loads of sediment, NH-N, and DRP were greater for cattle trails compared with the adjacent grazed pasture, and hydrologic connection with cattle-access sites on the riverbank suggests that this could adversely affect water quality in the adjacent river. Extrapolation of the study results should be tempered by the specific conditions represented by this rainfall simulation study. Copyright © by the American Society of Agronomy, Crop Science Society of America, and Soil Science Society of America, Inc.

  17. Irigenin sensitizes TRAIL-induced apoptosis via enhancing pro-apoptotic molecules in gastric cancer cells.

    Science.gov (United States)

    Xu, Ying; Gao, Cheng-Cheng; Pan, Zhen-Guo; Zhou, Chuan-Wen

    2018-02-12

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) holds promising value for cancer therapy due to its capacity to induce apoptosis in cancer cells. Nevertheless, TRAIL therapy is greatly hampered by its resistance. Irigenin (Iri), isoflavonoids, can be isolated from the rhizome of Belamcanda chinensis, and has been shown anti-cancer properties. In this study, we explored if Iri could enhance TRAIL-regulated apoptosis in TRAIL resistant gastric cancer cells. Iri significantly potentiated TRAIL-triggered cytotoxicity. Iri alone and TRAIL alone showed no effective role in apoptosis induction, whereas combined treatment with Iri and TRAIL markedly induced apoptosis in cancer cells, as evidenced by the up-regulation of cleaved Caspase-8/-9/-3 and PARP. Additionally, the sensitization to TRAIL was along with the enhancement of pro-apoptotic proteins, including FAS-associated protein with death domain (FADD), death receptor 5 (DR5) and Bax. And suppressing FADD, DR5 and Bax by si RNA significantly reduced the apoptosis and enhanced the cell viability induced by the co-application of Iri and TRAIL. Moreover, the sensitization to TRAIL was accompanied by the decrease of Cellular-FLICE inhibitory protein (c-FLIP), Bcl-2 and Survivin. Additionally, Iri could sensitize TRAIL to produce reactive oxygen species (ROS). Pre-treatment of N-acetyl-cysteine (NAC), ROS scavenger, attenuated Iri plus TRAIL-induced apoptosis and improved cell viability. Finally, combination of Iri and TRAIL inhibited tumor growth in the xenograft model. Collectively, our present study gave new insights into the effects of Iri on potentiating TRAIL-sensitivity, and suggested that Iri could be a potential candidate for sensitizer of TRAIL-resistant cancer cell treatment. Copyright © 2018. Published by Elsevier Inc.

  18. High susceptibility of metastatic cells derived from human prostate and colon cancer cells to TRAIL and sensitization of TRAIL-insensitive primary cells to TRAIL by 4,5-dimethoxy-2-nitrobenzaldehyde

    Directory of Open Access Journals (Sweden)

    Lee Jae-Won

    2011-04-01

    Full Text Available Abstract Background Tumor recurrence and metastasis develop as a result of tumors' acquisition of anti-apoptotic mechanisms and therefore, it is necessary to develop novel effective therapeutics against metastatic cancers. In this study, we showed the differential TRAIL responsiveness of human prostate adenocarcinoma PC3 and human colon carcinoma KM12 cells and their respective highly metastatic PC3-MM2 and KM12L4A sublines and investigated the mechanism underlying high susceptibility of human metastatic cancer cells to TRAIL. Results PC3-MM2 and KM12L4A cells with high level of c-Myc and DNA-PKcs were more susceptible to TRAIL than their poorly metastatic primary PC3 and KM12 cells, which was associated with down-regulation of c-FLIPL/S and Mcl-1 and up-regulation of the TRAIL receptor DR5 but not DR4 in both metastatic cells. Moreover, high susceptibility of these metastatic cells to TRAIL was resulted from TRAIL-induced potent activation of caspase-8, -9, and -3 in comparison with their primary cells, which led to cleavage and down-regulation of DNA-PKcs. Knockdown of c-Myc gene in TRAIL-treated PC3-MM2 cells prevented the increase of DR5 cell surface expression, caspase activation and DNA-PKcs cleavage and attenuated the apoptotic effects of TRAIL. Moreover, the suppression of DNA-PKcs level with siRNA in the cells induced the up-regulation of DR5 and active caspase-8, -9, and -3. We also found that 4,5-dimethoxy-2-nitrobenzaldehyde (DMNB, a specific inhibitor of DNA-PK, potentiated TRAIL-induced cytotoxicity and apoptosis in relatively TRAIL-insensitive PC3 and KM12 cells and therefore functioned as a TRAIL sensitizer. Conclusion This study showed the positive relationship between c-Myc expression in highly metastatic human prostate and colon cancer cells and susceptibility to TRAIL-induced apoptosis and therefore indicated that TRAIL might be used as an effective therapeutic modality for advanced metastatic cancers overexpressing c-Myc and

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

    Science.gov (United States)

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

    2018-06-03

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

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

    Science.gov (United States)

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

    2017-04-04

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

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

    Directory of Open Access Journals (Sweden)

    Jeannine Lacroix

    2018-06-01

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

  2. Recreational Trails Reduce the Density of Ground-Dwelling Birds in Protected Areas

    Science.gov (United States)

    Thompson, Bill

    2015-05-01

    Recreational disturbance associated with trails has been identified as one of the major factors causing a decline of native biodiversity within protected areas. However, despite the negative impacts that recreation can have on biodiversity, providing public access to nature is critical for the future of the conservation of biodiversity. As such, many protected area managers are looking for tools to help maintain a balance between public access and biodiversity conservation. The objectives of this study were to examine the impacts of recreational trails on forest-dwelling bird communities in eastern North America, identify functional guilds which are particularly sensitive to recreational trails, and derive guidelines for trail design to assist in managing the impacts of recreational trails on forest-dwelling birds. Trails within 24 publicly owned natural areas were mapped, and breeding bird communities were described with the use of point count surveys. The density of forest birds, particularly of those species which nest or forage on the ground, were significantly positively influenced by the amount of trail-free refuge habitat. Although management options to control trail use in non-staffed protected areas are limited, this study suggests that protected area managers could design and maintain a trail network that would minimize impacts on resident wildlife, while providing recreational opportunities for visitors, by designing their trail network to maximize the area of trail-free habitat.

  3. The dynamics of foraging trails in the tropical arboreal ant Cephalotes goniodontus.

    Directory of Open Access Journals (Sweden)

    Deborah M Gordon

    Full Text Available The foraging behavior of the arboreal turtle ant, Cephalotes goniodontus, was studied in the tropical dry forest of western Mexico. The ants collected mostly plant-derived food, including nectar and fluids collected from the edges of wounds on leaves, as well as caterpillar frass and lichen. Foraging trails are on small pieces of ephemeral vegetation, and persist in exactly the same place for 4-8 days, indicating that food sources may be used until they are depleted. The species is polydomous, occupying many nests which are abandoned cavities or ends of broken branches in dead wood. Foraging trails extend from trees with nests to trees with food sources. Observations of marked individuals show that each trail is travelled by a distinct group of foragers. This makes the entire foraging circuit more resilient if a path becomes impassable, since foraging in one trail can continue while a different group of ants forms a new trail. The colony's trails move around the forest from month to month; from one year to the next, only one colony out of five was found in the same location. There is continual searching in the vicinity of trails: ants recruited to bait within 3 bifurcations of a main foraging trail within 4 hours. When bait was offered on one trail, to which ants recruited, foraging activity increased on a different trail, with no bait, connected to the same nest. This suggests that the allocation of foragers to different trails is regulated by interactions at the nest.

  4. The Prognostic Value of TRAIL and its Death Receptors in Cervical Cancer

    International Nuclear Information System (INIS)

    Maduro, John H.; Noordhuis, Maartje G.; Hoor, Klaske A. ten; Pras, Elisabeth; Arts, Henriette J.G.; Eijsink, Jasper J.H.; Hollema, Harry; Mom, Constantijne H.; Jong, Steven de; Vries, Elisabeth G.E. de; Bock, Geertruida H. de; Zee, Ate G.J. van der

    2009-01-01

    Purpose: Preclinical data indicate a synergistic effect on apoptosis between irradiation and recombinant human (rh) tumor necrosis factor-related apoptosis inducing ligand (TRAIL), making the TRAIL death receptors (DR) interesting drug targets. The aim of our study was to analyze the expression of DR4, DR5, and TRAIL in cervical cancer and to determine their predictive and prognostic value. Methods and Materials: Tissue microarrays were constructed from tumors of 645 cervical cancer patients treated with surgery and/or (chemo-)radiation between 1980 and 2004. DR4, DR5, and TRAIL expression in the tumor was studied by immunohistochemistry and correlated to clinicopathological variables, response to radiotherapy, and disease-specific survival. Results: Cytoplasmatic DR4, DR5, and TRAIL immunostaining were observed in cervical tumors from 99%, 88%, and 81% of the patients, respectively. In patients treated primarily with radiotherapy, TRAIL-positive tumors less frequently obtained a pathological complete response than TRAIL-negative tumors (66.3% vs. 79.0 %; in multivariate analysis: odds ratio: 2.09, p ≤0.05). DR4, DR5, and TRAIL expression were not prognostic for disease-specific survival. Conclusions: Immunostaining for DR4, DR5, and TRAIL is frequently observed in the cytoplasm of tumor cells in cervical cancer patients. Absence of TRAIL expression was associated with a higher pathological complete response rate to radiotherapy. DR4, DR5, or TRAIL were not prognostic for disease-specific survival.

  5. Multiple effects of TRAIL in human carcinoma cells: Induction of apoptosis, senescence, proliferation, and cytokine production

    International Nuclear Information System (INIS)

    Levina, Vera; Marrangoni, Adele M.; DeMarco, Richard; Gorelik, Elieser; Lokshin, Anna E.

    2008-01-01

    TRAIL is a death ligand that induces apoptosis in malignant but not normal cells. Recently the ability of TRAIL to induce proliferation in apoptosis-resistant normal and malignant cells was reported. In this study, we analyzed TRAIL effects in apoptosis sensitive MCF7, OVCAR3 and H460 human tumor cell lines. TRAIL at low concentrations preferentially induced cell proliferation. At 100 ng/ml, apoptotic death was readily observed, however surviving cells acquired higher proliferative capacity. TRAIL-stimulated production of several cytokines, IL-8, RANTES, MCP-1 and bFGF, and activation of caspases 1 and 8 was essential for this effect. Antibodies to IL-8, RANTES, and bFGF blocked TRAIL-induced cell proliferation and further stimulated apoptosis. For the first time, we report that high TRAIL concentrations induced cell senescence as determined by the altered morphology and expression of several senescence markers: SA-β-gal, p21 Waf1/Cip1 , p16 INK4a , and HMGA. Caspase 9 inhibition protected TRAIL-treated cells from senescence, whereas inhibition of caspases 1 and 8 increased the yield of SLP cells. In conclusion, in cultured human carcinoma cells, TRAIL therapy results in three functional outcomes, apoptosis, proliferation and senescence. TRAIL-induced proapoptotic and prosurvival responses correlate with the strength of signaling. TRAIL-induced cytokine production is responsible for its proliferative and prosurvival effects

  6. The dynamics of foraging trails in the tropical arboreal ant Cephalotes goniodontus.

    Science.gov (United States)

    Gordon, Deborah M

    2012-01-01

    The foraging behavior of the arboreal turtle ant, Cephalotes goniodontus, was studied in the tropical dry forest of western Mexico. The ants collected mostly plant-derived food, including nectar and fluids collected from the edges of wounds on leaves, as well as caterpillar frass and lichen. Foraging trails are on small pieces of ephemeral vegetation, and persist in exactly the same place for 4-8 days, indicating that food sources may be used until they are depleted. The species is polydomous, occupying many nests which are abandoned cavities or ends of broken branches in dead wood. Foraging trails extend from trees with nests to trees with food sources. Observations of marked individuals show that each trail is travelled by a distinct group of foragers. This makes the entire foraging circuit more resilient if a path becomes impassable, since foraging in one trail can continue while a different group of ants forms a new trail. The colony's trails move around the forest from month to month; from one year to the next, only one colony out of five was found in the same location. There is continual searching in the vicinity of trails: ants recruited to bait within 3 bifurcations of a main foraging trail within 4 hours. When bait was offered on one trail, to which ants recruited, foraging activity increased on a different trail, with no bait, connected to the same nest. This suggests that the allocation of foragers to different trails is regulated by interactions at the nest.

  7. Recreational trails reduce the density of ground-dwelling birds in protected areas.

    Science.gov (United States)

    Thompson, Bill

    2015-05-01

    Recreational disturbance associated with trails has been identified as one of the major factors causing a decline of native biodiversity within protected areas. However, despite the negative impacts that recreation can have on biodiversity, providing public access to nature is critical for the future of the conservation of biodiversity. As such, many protected area managers are looking for tools to help maintain a balance between public access and biodiversity conservation. The objectives of this study were to examine the impacts of recreational trails on forest-dwelling bird communities in eastern North America, identify functional guilds which are particularly sensitive to recreational trails, and derive guidelines for trail design to assist in managing the impacts of recreational trails on forest-dwelling birds. Trails within 24 publicly owned natural areas were mapped, and breeding bird communities were described with the use of point count surveys. The density of forest birds, particularly of those species which nest or forage on the ground, were significantly positively influenced by the amount of trail-free refuge habitat. Although management options to control trail use in non-staffed protected areas are limited, this study suggests that protected area managers could design and maintain a trail network that would minimize impacts on resident wildlife, while providing recreational opportunities for visitors, by designing their trail network to maximize the area of trail-free habitat.

  8. Beneficial effect of TRAIL on HIV burden, without detectable immune consequences.

    Directory of Open Access Journals (Sweden)

    Brett D Shepard

    2008-08-01

    Full Text Available During uncontrolled HIV disease, both TNF-related apoptosis inducing ligand (TRAIL and TRAIL receptor expression are increased. Enhanced TRAIL sensitivity is due to TRAIL receptor up-regulation induced by gp120. As a result of successful antiretroviral therapy TRAIL is down-regulated, and there are fewer TRAIL-sensitive cells. In this setting, we hypothesized that all cells that contain virus, including those productively- and latently-infected, have necessarily been "primed" by gp120 and remain TRAIL-sensitive, whereas uninfected cells remain relatively TRAIL-resistant.We evaluated the immunologic and antiviral effects of TRAIL in peripheral blood lymphocytes collected from HIV-infected patients with suppressed viral replication. The peripheral blood lymphocytes were treated with recombinant TRAIL or an equivalent amount of bovine serum albumin as a negative control. Treated cells were then analyzed by quantitative flow cytometry, ELISPOT for CD4+ and CD8+ T-cell function, and limiting dilution microculture for viral burden. Alterations in the cytokine milieu of treated cells were assessed with a multiplex cytokine assay. Treatment with recombinant TRAIL in vitro reduced viral burden in lymphocytes collected from HIV-infected patients with suppressed viral load. TRAIL treatment did not alter the cytokine milieu of treated cells. Moreover, treatment with recombinant TRAIL had no adverse effect on either the quantity or function of immune cells from HIV-infected patients with suppressed viral replication.TRAIL treatment may be an important adjunct to antiretroviral therapy, even in patients with suppressed viral replication, perhaps by inducing apoptosis in cells with latent HIV reservoirs. The absence of adverse effect on the quantity or function of immune cells from HIV-infected patients suggests that there is not a significant level of "bystander death" in uninfected cells.

  9. The influence of use-related, environmental, and managerial factors on soil loss from recreational trails

    Science.gov (United States)

    Olive, Nathaniel D.; Marion, Jeffrey L.

    2009-01-01

    Recreational uses of unsurfaced trails inevitably result in their degradation, with the type and extent of resource impact influenced by factors such as soil texture, topography, climate, trail design and maintenance, and type and amount of use. Of particular concern, the loss of soil through erosion is generally considered a significant and irreversible form of trail impact. This research investigated the influence of several use-related, environmental, and managerial factors on soil loss on recreational trails and roads at Big South Fork National River and Recreation Area, a unit of the U.S. National Park Service. Regression modeling revealed that trail position, trail slope alignment angle, grade, water drainage, and type of use are significant determinants of soil loss. The introduction of individual and groups of variables into a series of regression models provides improved understanding and insights regarding the relative influence of these variables, informing the selection of more effective trail management actions. Study results suggest that trail erosion can be minimized by avoiding “fall-line” alignments, steep grades, and valley-bottom alignments near streams, installing and maintaining adequate densities of tread drainage features, applying gravel to harden treads, and reducing horse and all-terrain vehicle use or restricting them to more resistant routes.This research also sought to develop a more efficient Variable Cross-Sectional Area method for assessing soil loss on trails. This method permitted incorporation of CSA measures in a representative sampling scheme applied to a large (24%) sample of the park's 526 km trail system. The variety of soil loss measures derived from the Variable CSA method, including extrapolated trail-wide soil loss estimates, permit an objective quantification of soil erosion on recreational trails and roads. Such data support relational analyses to increase understanding of trail degradation, and long

  10. The influence of snowmobile trails on coyote movements during winter in high-elevation landscapes.

    Directory of Open Access Journals (Sweden)

    Eric M Gese

    Full Text Available Competition between sympatric carnivores has long been of interest to ecologists. Increased understanding of these interactions can be useful for conservation planning. Increased snowmobile traffic on public lands and in habitats used by Canada lynx (Lynx canadensis remains controversial due to the concern of coyote (Canis latrans use of snowmobile trails and potential competition with lynx. Determining the variables influencing coyote use of snowmobile trails has been a priority for managers attempting to conserve lynx and their critical habitat. During 2 winters in northwest Wyoming, we backtracked coyotes for 265 km to determine how varying snow characteristics influenced coyote movements; 278 km of random backtracking was conducted simultaneously for comparison. Despite deep snow (>1 m deep, radio-collared coyotes persisted at high elevations (>2,500 m year-round. All coyotes used snowmobile trails for some portion of their travel. Coyotes used snowmobile trails for 35% of their travel distance (random: 13% for a mean distance of 149 m (random: 59 m. Coyote use of snowmobile trails increased as snow depth and penetrability off trails increased. Essentially, snow characteristics were most influential on how much time coyotes spent on snowmobile trails. In the early months of winter, snow depth was low, yet the snow column remained dry and the coyotes traveled off trails. As winter progressed and snow depth increased and snow penetrability increased, coyotes spent more travel distance on snowmobile trails. As spring approached, the snow depth remained high but penetrability decreased, hence coyotes traveled less on snowmobile trails because the snow column off trail was more supportive. Additionally, coyotes traveled closer to snowmobile trails than randomly expected and selected shallower snow when traveling off trails. Coyotes also preferred using snowmobile trails to access ungulate kills. Snow compaction from winter recreation influenced

  11. The influence of snowmobile trails on coyote movements during winter in high-elevation landscapes.

    Science.gov (United States)

    Gese, Eric M; Dowd, Jennifer L B; Aubry, Lise M

    2013-01-01

    Competition between sympatric carnivores has long been of interest to ecologists. Increased understanding of these interactions can be useful for conservation planning. Increased snowmobile traffic on public lands and in habitats used by Canada lynx (Lynx canadensis) remains controversial due to the concern of coyote (Canis latrans) use of snowmobile trails and potential competition with lynx. Determining the variables influencing coyote use of snowmobile trails has been a priority for managers attempting to conserve lynx and their critical habitat. During 2 winters in northwest Wyoming, we backtracked coyotes for 265 km to determine how varying snow characteristics influenced coyote movements; 278 km of random backtracking was conducted simultaneously for comparison. Despite deep snow (>1 m deep), radio-collared coyotes persisted at high elevations (>2,500 m) year-round. All coyotes used snowmobile trails for some portion of their travel. Coyotes used snowmobile trails for 35% of their travel distance (random: 13%) for a mean distance of 149 m (random: 59 m). Coyote use of snowmobile trails increased as snow depth and penetrability off trails increased. Essentially, snow characteristics were most influential on how much time coyotes spent on snowmobile trails. In the early months of winter, snow depth was low, yet the snow column remained dry and the coyotes traveled off trails. As winter progressed and snow depth increased and snow penetrability increased, coyotes spent more travel distance on snowmobile trails. As spring approached, the snow depth remained high but penetrability decreased, hence coyotes traveled less on snowmobile trails because the snow column off trail was more supportive. Additionally, coyotes traveled closer to snowmobile trails than randomly expected and selected shallower snow when traveling off trails. Coyotes also preferred using snowmobile trails to access ungulate kills. Snow compaction from winter recreation influenced coyote

  12. The influence of use-related, environmental, and managerial factors on soil loss from recreational trails.

    Science.gov (United States)

    Olive, Nathaniel D; Marion, Jeffrey L

    2009-03-01

    Recreational uses of unsurfaced trails inevitably result in their degradation, with the type and extent of resource impact influenced by factors such as soil texture, topography, climate, trail design and maintenance, and type and amount of use. Of particular concern, the loss of soil through erosion is generally considered a significant and irreversible form of trail impact. This research investigated the influence of several use-related, environmental, and managerial factors on soil loss on recreational trails and roads at Big South Fork National River and Recreation Area, a unit of the U.S. National Park Service. Regression modeling revealed that trail position, trail slope alignment angle, grade, water drainage, and type of use are significant determinants of soil loss. The introduction of individual and groups of variables into a series of regression models provides improved understanding and insights regarding the relative influence of these variables, informing the selection of more effective trail management actions. Study results suggest that trail erosion can be minimized by avoiding "fall-line" alignments, steep grades, and valley-bottom alignments near streams, installing and maintaining adequate densities of tread drainage features, applying gravel to harden treads, and reducing horse and all-terrain vehicle use or restricting them to more resistant routes. This research also sought to develop a more efficient Variable Cross-Sectional Area method for assessing soil loss on trails. This method permitted incorporation of CSA measures in a representative sampling scheme applied to a large (24%) sample of the park's 526 km trail system. The variety of soil loss measures derived from the Variable CSA method, including extrapolated trail-wide soil loss estimates, permit an objective quantification of soil erosion on recreational trails and roads. Such data support relational analyses to increase understanding of trail degradation, and long-term monitoring of

  13. Validation of Walking Trails for the Urban Training™ of Chronic Obstructive Pulmonary Disease Patients.

    Directory of Open Access Journals (Sweden)

    Ane Arbillaga-Etxarri

    Full Text Available Accessible interventions to train patients with chronic obstructive pulmonary disease (COPD are needed. We designed urban trails of different intensities (low, moderate and high in different types of public spaces (boulevard, beach and park. We aimed to validate the trails' design by assessing the physiological response to unsupervised walking trails of: (1 different intensities in COPD patients, and (2 same intensity from different public spaces in healthy adults.On different days and under standardized conditions, 10 COPD patients walked the three intensity trails designed in a boulevard space, and 10 healthy subjects walked the three intensity trails in three different spaces. We measured physiological response and energy expenditure using a gas analyzer. We compared outcomes across trails intensity and/or spaces using mixed-effects linear regression.In COPD patients, physiological response and energy expenditure increased significantly according to the trails intensity: mean (SD peak V̇O2 15.9 (3.5, 17.4 (4.7, and 17.7 (4.4 mL/min/kg (p-trend = 0.02, and MET-min 60 (23, 64 (26, 72 (31 (p-trend<0.01 in low, moderate and high intensity trails, respectively. In healthy subjects there were no differences in physiological response to walking trails of the same intensity across different spaces.We validated the trails design for the training of COPD patients by showing that the physiological response to and energy expenditure on unsupervised walking these trails increased according to the predefined trails' intensity and did not change across trails of the same intensity in different public space. Walkable public spaces allow the design of trails that could be used for the training of COPD patients in the community.

  14. 78 FR 76176 - Notice of Availability of the Record of Decision for the Final Trail Management Plan...

    Science.gov (United States)

    2013-12-16

    ... paddling; and improved parking facilities. Alternative 2A emphasized the importance of enhancing the... 1, the no-action alternative, the trails, authorized uses, and facilities addressed in this Plan/EIS... system, adoption of the Sustainable Trail Guidelines, and the consideration of trail facilities. Trail...

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

    Science.gov (United States)

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

    2015-04-01

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

  16. Advanced Trailing Edge Blowing Concepts for Fan Noise Control

    Directory of Open Access Journals (Sweden)

    Cezar RIZEA

    2012-03-01

    Full Text Available This study documents trailing edge blowing research performed to reduce rotor / stator interaction noise in turbofan engines. The existing technique of filling every velocity deficit requires a large amount of air and is therefore impractical. The purpose of this research is to investigate new blowing configurations in order to achieve noise reduction with lesser amounts of air. Using the new configurations air is not injected into every fan blade, but is instead varied circumferentially. For example, blowing air may be applied to alternating fan blades. This type of blowing configuration both reduces the amount of air used and changes the spectral shape of the tonal interaction noise. The original tones at the blade passing frequency and its harmonics are reduced and new tones are introduced between them. This change in the tonal spectral shape increases the performance of acoustic liners used in conjunction with trailing edge blowing.

  17. The Global and Local Characters of Mars Perihelion Cloud Trails

    Science.gov (United States)

    Clancy, R. T.; Wolff, M. J.; Smith, M. D.; Cantor, B. A.; Spiga, A.

    2014-12-01

    We present the seasonal and spatial distribution of Mars perihelion cloud trails as mapped from Mars Reconnaissance Orbiter (MRO) MARCI (Mars Color Imager) imaging observations in 2 ultraviolet and 3 visible filters. The extended 2007-2013 period of MARCI daily global image maps reveals the widespread distribution of these high altitude clouds, which are somewhat paradoxically associated with specific surface regions. They appear as longitudinally extended (300-700 km) cloud trails with distinct leading plumes of substantial ice cloud optical depths (0.02-0.2) for such high altitudes of occurrence (40-50 km, from cloud surface shadow measurements). These plumes generate small ice particles (Reff~1 to reflect locally elevated mesospheric water ice formation that may impact the global expression of mesospheric water ice aerosols.

  18. A Dynamic Stall Model for Airfoils with Deformable Trailing Edges

    International Nuclear Information System (INIS)

    Andersen, Peter Bjoern; Gaunaa, Mac; Bak, Christian; Hansen, Morten Hartvig

    2007-01-01

    The present work contains an extension of the Beddoes-Leishman (B-L) type dynamic stall model, as described by Hansen et al. In this work a Deformable Trailing Edge Geometry (DTEG) has been added to the dynamic stall model. The model predicts the unsteady aerodynamic forces and moments on an airfoil section undergoing arbitrary motion in heave, lead-lag, pitch, Trailing Edge (TE) flapping. In the linear region, the model reduces to the inviscid model of Gaunaa, which includes the aerodynamic effect of a thin airfoil with a deformable camberline in inviscid flow. Therefore, the proposed model can be considered a crossover between the work of Gaunaa for the attached flow region and Hansen et al. The model will be compared to wind tunnel measurements from Velux described by Bak et al

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

    Science.gov (United States)

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

    2018-03-29

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

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

    Science.gov (United States)

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

    2017-10-17

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

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

    Directory of Open Access Journals (Sweden)

    Carsten Geiss

    2017-10-01

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

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

    Science.gov (United States)

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

    2012-01-30

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

  3. The Relationship between Trail Running Withdrawals and Race Topography

    Directory of Open Access Journals (Sweden)

    Antonini Philippe Roberta

    2017-12-01

    Full Text Available Context: A growing amount of recent research in sport psychology has focused on trying to understand withdrawals from ultra-races. However, according to the Four E approach, the studies underestimated the embedded components of these experiences and particularly how they were linked to the specific environmental conditions in which the experiences occurred. Objective: This study aimed to characterize trail running withdrawals in relationship to race topography. Design: Qualitative design, involving self-confrontation interviews and use of a race map. Setting: Use of the race map for description of the race activity and self-confrontation interviews took place 1–3 days after the races. Participants: Ten runners who withdrew during an ultra-trail race. Data Collection and Analysis: Data on past activity traces and experiences were elicited from self-confrontation interviews. Data were coded and compared to identify common sequences and then each type of sequence was counted with regard to race topography. Results: Results showed that each sequence was related to runners’ particular possibilities for acting, feeling, and thinking, which were in turn embedded in the race topography. These sequences allowed the unfolding of the activity and increased its overall effectiveness in relation to the constraints of this specific sport. Conclusion: This study allowed us to highlight important information on how ultra-trail runners manage their races in relationship to the race environment and more specifically to its topography. The result will also help us to recommend potential adjustments to ultra-trail runners’ performance-oriented training and preparation.

  4. Study on Trailing Edge Ramp of Supercritical Airfoil

    Science.gov (United States)

    2016-03-30

    China Abstract Trailing edge flow control method could improve the performance of supercritical airfoil with a small modification on the original...stall behaviour . As a result, the non-separation ramp could increase the thickness of airfoil, which benefits wing structure and aerodynamic...direction based on the original RAE2822 airfoil, which will thicken the airfoil. The interpolation is implemented as shown in Eqn. 1. This modification could

  5. Design methodology for wing trailing edge device mechanisms

    OpenAIRE

    Martins Pires, Rui Miguel

    2007-01-01

    Over the last few decades the design of high lift devices has become a very important part of the total aircraft design process. Reviews of the design process are performed on a regular basis, with the intent to improve and optimize the design process. This thesis describes a new and innovative methodology for the design and evaluation of mechanisms for Trailing Edge High-Lift devices. The initial research reviewed existing High-Lift device design methodologies and current f...

  6. Road Expansion and Its Influence on Trail Sustainability in Bhutan

    Directory of Open Access Journals (Sweden)

    Taiichi Ito

    2011-12-01

    Full Text Available Bhutan was an inhabited wilderness until 1961, when road construction started after the closure of the Tibetan border. Since then, the road network has expanded from the Indian boarder, often tracing traditional trails. This has accelerated commerce as well as movement of people from India, benefitting both the Bhutanese and foreign tourists. At the same time, dependence on imported automobiles and fossil fuel has risen, and roadless areas have begun to shrink. This brought an inevitable loss of traditional environmental knowledge, such as the care of mules for packing, and reduction in physical and mental health among the Bhutanese. People who lost jobs as horsemen moved into towns to find jobs. Road extension is also a double-edged sword for visitors. It has resulted in shrinking trekking areas and loss of traditional culture, both of which have been sacrificed for easy access. Protected areas often function as fortifications against mechanical civilization. However, protected-area status or its zoning does not guarantee that an area will remain roadless where there is considerable resident population. An analysis in Jigme Dorji National Park showed the gradual retreat of trailheads and increasing dependence on automobiles among residents and trekkers. B. MacKaye, a regional planner in the Eastern United States, proposed using trails as a tool to control such mechanical civilization. His philosophy of regional planning suggests two measures; one is consolidated trailheads as dams, and the other is confinement of roads by levees, consisting of new trails and wilderness belts. According to case studies, the author proposed six options for coexistence of trails with roads.

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

    Science.gov (United States)

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

    2017-07-01

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

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

    Directory of Open Access Journals (Sweden)

    Benjamin Ruf

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

  9. Using cognitive status to predict crash risk: blazing new trails?

    Science.gov (United States)

    Staplin, Loren; Gish, Kenneth W; Sifrit, Kathy J

    2014-02-01

    A computer-based version of an established neuropsychological paper-and-pencil assessment tool, the Trail-Making Test, was applied with approximately 700 drivers aged 70 years and older in offices of the Maryland Motor Vehicle Administration. This was a volunteer sample that received a small compensation for study participation, with an assurance that their license status would not be affected by the results. Analyses revealed that the study sample was representative of Maryland older drivers with respect to age and indices of prior driving safety. The relationship between drivers' scores on the Trail-Making Test and prospective crash experience was analyzed using a new outcome measure that explicitly takes into account error responses as well as correct responses, the error-compensated completion time. For the only reliable predictor of crash risk, Trail-Making Test Part B, this measure demonstrated a modest gain in specificity and was a more significant predictor of future safety risk than the simple time-to-completion measure. Improved specificity and the potential for autonomous test administration are particular advantages of this measure for use with large populations, in settings such as health care or driver licensing. © 2013.

  10. Asymptotic theory of two-dimensional trailing-edge flows

    Science.gov (United States)

    Melnik, R. E.; Chow, R.

    1975-01-01

    Problems of laminar and turbulent viscous interaction near trailing edges of streamlined bodies are considered. Asymptotic expansions of the Navier-Stokes equations in the limit of large Reynolds numbers are used to describe the local solution near the trailing edge of cusped or nearly cusped airfoils at small angles of attack in compressible flow. A complicated inverse iterative procedure, involving finite-difference solutions of the triple-deck equations coupled with asymptotic solutions of the boundary values, is used to accurately solve the viscous interaction problem. Results are given for the correction to the boundary-layer solution for drag of a finite flat plate at zero angle of attack and for the viscous correction to the lift of an airfoil at incidence. A rational asymptotic theory is developed for treating turbulent interactions near trailing edges and is shown to lead to a multilayer structure of turbulent boundary layers. The flow over most of the boundary layer is described by a Lighthill model of inviscid rotational flow. The main features of the model are discussed and a sample solution for the skin friction is obtained and compared with the data of Schubauer and Klebanoff for a turbulent flow in a moderately large adverse pressure gradient.

  11. User Manual for SAHM package for VisTrails

    Science.gov (United States)

    Talbert, C.B.; Talbert, M.K.

    2012-01-01

    The Software for Assisted Habitat I\\•1odeling (SAHM) has been created to both expedite habitat modeling and help maintain a record of the various input data, pre-and post-processing steps and modeling options incorporated in the construction of a species distribution model. The four main advantages to using the combined VisTrail: SAHM package for species distribution modeling are: 1. formalization and tractable recording of the entire modeling process 2. easier collaboration through a common modeling framework 3. a user-friendly graphical interface to manage file input, model runs, and output 4. extensibility to incorporate future and additional modeling routines and tools. This user manual provides detailed information on each module within the SAHM package, their input, output, common connections, optional arguments, and default settings. This information can also be accessed for individual modules by right clicking on the documentation button for any module in VisTrail or by right clicking on any input or output for a module and selecting view documentation. This user manual is intended to accompany the user guide which provides detailed instructions on how to install the SAHM package within VisTrails and then presents information on the use of the package.

  12. Vortex coupling in trailing vortex-wing interactions

    Science.gov (United States)

    Chen, C.; Wang, Z.; Gursul, I.

    2018-03-01

    The interaction of trailing vortices of an upstream wing with rigid and flexible downstream wings has been investigated experimentally in a wind tunnel, using particle image velocimetry, hot-wire, force, and deformation measurements. Counter-rotating upstream vortices exhibit increased meandering when they are close to the tip of the downstream wing. The upstream vortex forms a pair with the vortex shed from the downstream wing and then exhibits large displacements around the wing tip. This coupled motion of the pair has been found to cause large lift fluctuations on the downstream wing. The meandering of the vortex pair occurs at the natural meandering frequency of the isolated vortex, with a low Strouhal number, and is not affected by the frequency of the large-amplitude wing oscillations if the downstream wing is flexible. The displacement of the leading vortex is larger than that of the trailing vortex; however, it causes highly correlated variations of the core radius, core vorticity, and circulation of the trailing vortex with the coupled meandering motion. In contrast, co-rotating vortices do not exhibit any increased meandering.

  13. Analysis of the impact of recreational trail usage for prioritising management decisions: a regression tree approach

    Science.gov (United States)

    Tomczyk, Aleksandra; Ewertowski, Marek; White, Piran; Kasprzak, Leszek

    2016-04-01

    The dual role of many Protected Natural Areas in providing benefits for both conservation and recreation poses challenges for management. Although recreation-based damage to ecosystems can occur very quickly, restoration can take many years. The protection of conservation interests at the same as providing for recreation requires decisions to be made about how to prioritise and direct management actions. Trails are commonly used to divert visitors from the most important areas of a site, but high visitor pressure can lead to increases in trail width and a concomitant increase in soil erosion. Here we use detailed field data on condition of recreational trails in Gorce National Park, Poland, as the basis for a regression tree analysis to determine the factors influencing trail deterioration, and link specific trail impacts with environmental, use related and managerial factors. We distinguished 12 types of trails, characterised by four levels of degradation: (1) trails with an acceptable level of degradation; (2) threatened trails; (3) damaged trails; and (4) heavily damaged trails. Damaged trails were the most vulnerable of all trails and should be prioritised for appropriate conservation and restoration. We also proposed five types of monitoring of recreational trail conditions: (1) rapid inventory of negative impacts; (2) monitoring visitor numbers and variation in type of use; (3) change-oriented monitoring focusing on sections of trail which were subjected to changes in type or level of use or subjected to extreme weather events; (4) monitoring of dynamics of trail conditions; and (5) full assessment of trail conditions, to be carried out every 10-15 years. The application of the proposed framework can enhance the ability of Park managers to prioritise their trail management activities, enhancing trail conditions and visitor safety, while minimising adverse impacts on the conservation value of the ecosystem. A.M.T. was supported by the Polish Ministry of

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

    Science.gov (United States)

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

    2013-06-01

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

  15. Accurate Natural Trail Detection Using a Combination of a Deep Neural Network and Dynamic Programming.

    Science.gov (United States)

    Adhikari, Shyam Prasad; Yang, Changju; Slot, Krzysztof; Kim, Hyongsuk

    2018-01-10

    This paper presents a vision sensor-based solution to the challenging problem of detecting and following trails in highly unstructured natural environments like forests, rural areas and mountains, using a combination of a deep neural network and dynamic programming. The deep neural network (DNN) concept has recently emerged as a very effective tool for processing vision sensor signals. A patch-based DNN is trained with supervised data to classify fixed-size image patches into "trail" and "non-trail" categories, and reshaped to a fully convolutional architecture to produce trail segmentation map for arbitrary-sized input images. As trail and non-trail patches do not exhibit clearly defined shapes or forms, the patch-based classifier is prone to misclassification, and produces sub-optimal trail segmentation maps. Dynamic programming is introduced to find an optimal trail on the sub-optimal DNN output map. Experimental results showing accurate trail detection for real-world trail datasets captured with a head mounted vision system are presented.

  16. The impact of glide phases on the trackability of hydrodynamic trails in harbour seals (Phoca vitulina).

    Science.gov (United States)

    Wieskotten, S; Dehnhardt, G; Mauck, B; Miersch, L; Hanke, W

    2010-11-01

    The mystacial vibrissae of harbour seals (Phoca vitulina) constitute a highly sensitive hydrodynamic receptor system enabling the seals to detect and follow hydrodynamic trails. In the wild, hydrodynamic trails, as generated by swimming fish, consist of cyclic burst-and-glide phases, associated with various differences in the physical parameters of the trail. Here, we investigated the impact of glide phases on the trackability of differently aged hydrodynamic trails in a harbour seal. As fish are not easily trained to swim certain paths with predetermined burst-and-glide phases, the respective hydrodynamic trails were generated using a remote-controlled miniature submarine. Gliding phases in hydrodynamic trails had a negative impact on the trackability when trails were 15 s old. The seal lost the generated trails more often within the transition zones, when the submarine switched from a burst to a glide moving pattern. Hydrodynamic parameter analysis (particle image velocimetry) revealed that the smaller dimensions and faster decay of hydrodynamic trails generated by the gliding submarine are responsible for the impaired success of the seal tracking the gliding phase. Furthermore, the change of gross water flow generated by the submarine from a rearwards-directed stream in the burst phase to a water flow passively dragged behind the submarine during gliding might influence the ability of the seal to follow the trail as this might cause a weaker deflection of the vibrissae. The possible ecological implications of intermittent swimming behaviour in fish for piscivorous predators are discussed.

  17. Assessing and Predicting Erosion from Off Highway Vehicle Trails in Front-Range Rocky Mountain Watersheds.

    Science.gov (United States)

    Howard, M. J.; Silins, U.; Anderson, A.

    2016-12-01

    Off highway vehicle (OHV) trails have the potential to deliver sediment to sensitive headwater streams and increased OHV use is a growing watershed management concern in many Rocky Mountain regions. Predictive tools for estimating erosion and sediment inputs are needed to support assessment and management of erosion from OHV trail networks. The objective of this study was to a) assess erodibility (K factor) and total erosion from OHV trail networks in Rocky Mountain watersheds in south-west Alberta, Canada, and to b) evaluate the applicability of the Universal Soil Loss Equation (USLE) for predicting OHV trail erosion to support erosion management strategies. Measured erosion rates and erodibility (K) from rainfall simulation plots on OHV trails during the summers of 2014 and 2015 were compared to USLE predicted erosion from these same trails. Measured erodibility (K) from 23 rainfall simulation plots was highly variable (0.001-0.273 Mg*ha*hr/ha*MJ*mm) as was total seasonal erosion from 52 large trail sections (0.0595-43.3 Mg/ha) across trail segments of variable slope, stoniness, and trail use intensity. In particular, intensity of trail use had a large effect on both erodibility and total erosion that is not presently captured by erodibility indices (K) derived from soil characteristics. Results of this study suggest that while application of USLE for predicting erosion from OHV trail networks may be useful for initial coarse erosion assessment, a better understanding of the effect of factors such as road/trail use intensity on erodibility is needed to support use of USLE or associated erosion prediction tools for road/trail erosion management.

  18. Validation of Walking Trails for the Urban Training™ of Chronic Obstructive Pulmonary Disease Patients.

    Science.gov (United States)

    Arbillaga-Etxarri, Ane; Torrent-Pallicer, Jaume; Gimeno-Santos, Elena; Barberan-Garcia, Anael; Delgado, Anna; Balcells, Eva; Rodríguez, Diego A; Vilaró, Jordi; Vall-Casas, Pere; Irurtia, Alfredo; Rodriguez-Roisin, Robert; Garcia-Aymerich, Judith

    2016-01-01

    Accessible interventions to train patients with chronic obstructive pulmonary disease (COPD) are needed. We designed urban trails of different intensities (low, moderate and high) in different types of public spaces (boulevard, beach and park). We aimed to validate the trails' design by assessing the physiological response to unsupervised walking trails of: (1) different intensities in COPD patients, and (2) same intensity from different public spaces in healthy adults. On different days and under standardized conditions, 10 COPD patients walked the three intensity trails designed in a boulevard space, and 10 healthy subjects walked the three intensity trails in three different spaces. We measured physiological response and energy expenditure using a gas analyzer. We compared outcomes across trails intensity and/or spaces using mixed-effects linear regression. In COPD patients, physiological response and energy expenditure increased significantly according to the trails intensity: mean (SD) peak V̇O2 15.9 (3.5), 17.4 (4.7), and 17.7 (4.4) mL/min/kg (p-trend = 0.02), and MET-min 60 (23), 64 (26), 72 (31) (p-trendtrails, respectively. In healthy subjects there were no differences in physiological response to walking trails of the same intensity across different spaces. We validated the trails design for the training of COPD patients by showing that the physiological response to and energy expenditure on unsupervised walking these trails increased according to the predefined trails' intensity and did not change across trails of the same intensity in different public space. Walkable public spaces allow the design of trails that could be used for the training of COPD patients in the community.

  19. Human embryonic and induced pluripotent stem cells express TRAIL receptors and can be sensitized to TRAIL-Iiduced apoptosis

    Czech Academy of Sciences Publication Activity Database

    Vinarsky, V.; Krivanek, J.; Rankel, Liina; Nahácka, Zuzana; Barta, T.; Jaros, J.; Anděra, Ladislav; Hampl, A.

    2013-01-01

    Roč. 22, č. 22 (2013), s. 2964-2974 ISSN 1547-3287 R&D Projects: GA ČR GAP301/10/1971 Grant - others:GA MŠk(CZ) ED1.100/02/0123 Institutional research plan: CEZ:AV0Z50520514 Institutional support: RVO:68378050 Keywords : TRAIL * apoptosis * pluripotent stem cells Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.202, year: 2013

  20. Candidate Gene Study of TRAIL and TRAIL Receptors: Association with Response to Interferon Beta Therapy in Multiple Sclerosis Patients

    Science.gov (United States)

    Órpez-Zafra, Teresa; Pinto-Medel, María Jesús; Oliver-Martos, Begoña; Ortega-Pinazo, Jesús; Arnáiz, Carlos; Guijarro-Castro, Cristina; Varadé, Jezabel; Álvarez-Lafuente, Roberto; Urcelay, Elena; Sánchez-Jiménez, Francisca

    2013-01-01

    TRAIL and TRAIL Receptor genes have been implicated in Multiple Sclerosis pathology as well as in the response to IFN beta therapy. The objective of our study was to evaluate the association of these genes in relation to the age at disease onset (AAO) and to the clinical response upon IFN beta treatment in Spanish MS patients. We carried out a candidate gene study of TRAIL, TRAILR-1, TRAILR-2, TRAILR-3 and TRAILR-4 genes. A total of 54 SNPs were analysed in 509 MS patients under IFN beta treatment, and an additional cohort of 226 MS patients was used to validate the results. Associations of rs1047275 in TRAILR-2 and rs7011559 in TRAILR-4 genes with AAO under an additive model did not withstand Bonferroni correction. In contrast, patients with the TRAILR-1 rs20576-CC genotype showed a better clinical response to IFN beta therapy compared with patients carrying the A-allele (recessive model: p = 8.88×10−4, pc = 0.048, OR = 0.30). This SNP resulted in a non synonymous substitution of Glutamic acid to Alanine in position 228 (E228A), a change previously associated with susceptibility to different cancer types and risk of metastases, suggesting a lack of functionality of TRAILR-1. In order to unravel how this amino acid change in TRAILR-1 would affect to death signal, we performed a molecular modelling with both alleles. Neither TRAIL binding sites in the receptor nor the expression levels of TRAILR-1 in peripheral blood mononuclear cell subsets (monocytes, CD4+ and CD8+ T cells) were modified, suggesting that this SNP may be altering the death signal by some other mechanism. These findings show a role for TRAILR-1 gene variations in the clinical outcome of IFN beta therapy that might have relevance as a biomarker to predict the response to IFN beta in MS. PMID:23658636

  1. Inhibition of vacuolar ATPase attenuates the TRAIL-induced activation of caspase-8 and modulates the trafficking of TRAIL receptosomes

    Czech Academy of Sciences Publication Activity Database

    Horová, Vladimíra; Hradilová, Naďa; Jelínková, Iva; Koc, Michal; Švadlenka, Jan; Bražina, Jan; Klíma, Martin; Slavík, J.; Vaculová, Alena; Anděra, Ladislav

    2013-01-01

    Roč. 280, č. 14 (2013), s. 3436-3450 ISSN 1742-464X R&D Projects: GA ČR GAP301/10/1971; GA ČR(CZ) GAP301/11/1730; GA MŠk 1M0506 Institutional support: RVO:68378050 ; RVO:68081707 Keywords : acidification * apoptosis * caspase-8 * TRAIL * V- ATPase Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.986, year: 2013

  2. Inhibition of vacuolar ATPase attenuates the TRAIL-induced activation of caspase-8 and modulates the trafficking of TRAIL receptosomes

    Czech Academy of Sciences Publication Activity Database

    Horová, Vladimíra; Hradilová, Naďa; Jelínková, Iva; Koc, Michal; Švadlenka, Jan; Bražina, Jan; Klíma, Martin; Slavík, J.; Vaculová, Alena; Anděra, Ladislav

    2013-01-01

    Roč. 280, č. 14 (2013), s. 3436-3450 ISSN 1742-464X R&D Projects: GA ČR GAP301/10/1971; GA ČR(CZ) GAP301/11/1730; GA MŠk 1M0506 Institutional support: RVO:68378050 ; RVO:68081707 Keywords : acidification * apoptosis * caspase-8 * TRAIL * V-ATPase Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.986, year: 2013

  3. Candidate gene study of TRAIL and TRAIL receptors: association with response to interferon beta therapy in multiple sclerosis patients.

    Directory of Open Access Journals (Sweden)

    Carlos López-Gómez

    Full Text Available TRAIL and TRAIL Receptor genes have been implicated in Multiple Sclerosis pathology as well as in the response to IFN beta therapy. The objective of our study was to evaluate the association of these genes in relation to the age at disease onset (AAO and to the clinical response upon IFN beta treatment in Spanish MS patients. We carried out a candidate gene study of TRAIL, TRAILR-1, TRAILR-2, TRAILR-3 and TRAILR-4 genes. A total of 54 SNPs were analysed in 509 MS patients under IFN beta treatment, and an additional cohort of 226 MS patients was used to validate the results. Associations of rs1047275 in TRAILR-2 and rs7011559 in TRAILR-4 genes with AAO under an additive model did not withstand Bonferroni correction. In contrast, patients with the TRAILR-1 rs20576-CC genotype showed a better clinical response to IFN beta therapy compared with patients carrying the A-allele (recessive model: p = 8.88×10(-4, pc = 0.048, OR = 0.30. This SNP resulted in a non synonymous substitution of Glutamic acid to Alanine in position 228 (E228A, a change previously associated with susceptibility to different cancer types and risk of metastases, suggesting a lack of functionality of TRAILR-1. In order to unravel how this amino acid change in TRAILR-1 would affect to death signal, we performed a molecular modelling with both alleles. Neither TRAIL binding sites in the receptor nor the expression levels of TRAILR-1 in peripheral blood mononuclear cell subsets (monocytes, CD4+ and CD8+ T cells were modified, suggesting that this SNP may be altering the death signal by some other mechanism. These findings show a role for TRAILR-1 gene variations in the clinical outcome of IFN beta therapy that might have relevance as a biomarker to predict the response to IFN beta in MS.

  4. Use Deflected Trailing Edge to Improve the Aerodynamic Performance and Develop Low Solidity LPT Cascade

    Science.gov (United States)

    Chao, Li; Peigang, Yan; Xiangfeng, Wang; Wanjin, Han; Qingchao, Wang

    2017-08-01

    This paper investigates the feasibility of improving the aerodynamic performance of low pressure turbine (LPT) blade cascades and developing low solidity LPT blade cascades through deflected trailing edge. A deflected trailing edge improved aerodynamic performance of both LPT blade cascades and low solidity LPT blade cascades. For standard solidity LPT cascades, deflecting the trailing edge can decrease the energy loss coefficient by 20.61 % for a Reynolds number (Re) of 25,000 and freestream turbulence intensities (FSTI) of 1 %. For a low solidity LPT cascade, aerodynamic performance was also improved by deflecting the trailing edge. Solidity of the LPT cascade can be reduced by 12.5 % for blades with a deflected trailing edge without a drop in efficiency. Here, the flow control mechanism surrounding a deflected trailing edge was also revealed.

  5. The interplay between scent trails and group-mass recruitment systems in ants.

    Science.gov (United States)

    Planqué, Robert; van den Berg, Jan Bouwe; Franks, Nigel R

    2013-10-01

    Large ant colonies invariably use effective scent trails to guide copious ant numbers to food sources. The success of mass recruitment hinges on the involvement of many colony members to lay powerful trails. However, many ant colonies start off as single queens. How do these same colonies forage efficiently when small, thereby overcoming the hurdles to grow large? In this paper, we study the case of combined group and mass recruitment displayed by some ant species. Using mathematical models, we explore to what extent early group recruitment may aid deployment of scent trails, making such trails available at much smaller colony sizes. We show that a competition between group and mass recruitment may cause oscillatory behaviour mediated by scent trails. This results in a further reduction of colony size to establish trails successfully.

  6. Cryptolepine, isolated from Sida acuta, sensitizes human gastric adenocarcinoma cells to TRAIL-induced apoptosis.

    Science.gov (United States)

    Ahmed, Firoj; Toume, Kazufumi; Ohtsuki, Takashi; Rahman, Mahmudur; Sadhu, Samir Kumar; Ishibashi, Masami

    2011-01-01

    Bioassay guided separation of Sida acuta whole plants led to the isolation of an alkaloid, cryptolepine (1), along with two kaempferol glycosides (2-3). Compound 1 showed strong activity in overcoming TRAIL-resistance in human gastric adenocarcinoma (AGS) cells at 1.25, 2.5 and 5 μm. Combined treatment of 1 and TRAIL sensitized AGS cells to TRAIL-induced apoptosis at the aforementioned concentrations. Copyright © 2010 John Wiley & Sons, Ltd.

  7. Trail pheromone of the Argentine ant, Linepithema humile (Mayr (Hymenoptera: Formicidae.

    Directory of Open Access Journals (Sweden)

    Dong-Hwan Choe

    Full Text Available The Argentine ant (Linepithema humile is recognized as one of the world's most damaging invasive species. One reason for the ecological dominance of introduced Argentine ant populations is their ability to dominate food and habitat resources through the rapid mobilization and recruitment of thousands of workers. More than 30 years ago, studies showed that (Z-9-hexadecenal strongly attracted Argentine ant workers in a multi-choice olfactometer, suggesting that (Z-9-hexadecenal might be the trail pheromone, or a component of a trail pheromone mixture. Since then, numerous studies have considered (Z-9-hexadecenal as the key component of the Argentine ant trails. Here, we report the first chemical analyses of the trails laid by living Argentine ants and find that (Z-9-hexadecenal is not present in a detectible quantity. Instead, two iridoids, dolichodial and iridomyrmecin, appear to be the primary chemical constituents of the trails. Laboratory choice tests confirmed that Argentine ants were attracted to artificial trails comprised of these two chemicals significantly more often than control trails. Although (Z-9-hexadecenal was not detected in natural trails, supplementation of artificial dolichodial+iridomyrmecin trails with an extremely low concentraion of (Z-9-hexadecenal did increase the efficacy of the trail-following behavior. In stark contrast with previous dogma, our study suggests that dolichodial and iridomyrmecin are major components of the Argentine ant trail pheromone. (Z-9-hexadecenal may act in an additive manner with these iridoids, but it does not occur in detectable quantities in Argentine ant recruitment trails.

  8. Accelerometer and GPS Analysis of Trail Use and Associations With Physical Activity.

    Science.gov (United States)

    Tamura, Kosuke; Wilson, Jeffrey S; Puett, Robin C; Klenosky, David B; Harper, William A; Troped, Philip J

    2018-03-26

    Concurrent use of accelerometers and global positioning system (GPS) data can be used to quantify physical activity (PA) occurring on trails. This study examined associations of trail use with PA and sedentary behavior (SB) and quantified on trail PA using a combination of accelerometer and GPS data. Adults (N = 142) wore accelerometer and GPS units for 1-4 days. Trail use was defined as a minimum of 2 consecutive minutes occurring on a trail, based on GPS data. We examined associations between trail use and PA and SB. On trail minutes of light-intensity, moderate-intensity, and vigorous-intensity PA, and SB were quantified in 2 ways, using accelerometer counts only and with a combination of GPS speed and accelerometer data. Trail use was positively associated with total PA, moderate-intensity PA, and light-intensity PA (P GPS and accelerometer data for quantifying on trail activity may be more accurate than accelerometer data alone and is useful for classifying intensity of activities such as bicycling.

  9. Assessing the influence of sustainable trail design and maintenance on soil loss

    Science.gov (United States)

    Marion, Jeff; Wimpey, Jeremy

    2017-01-01

    Natural-surfaced trail systems are an important infrastructure component providing a means for accessing remote protected natural area destinations. The condition and usability of trails is a critical concern of land managers charged with providing recreational access while preserving natural conditions, and to visitors seeking high quality recreational opportunities and experiences. While an adequate number of trail management publications provide prescriptive guidance for designing, constructing, and maintaining natural-surfaced trails, surprisingly little research has been directed at providing a scientific basis for this guidance. Results from a review of the literature and three scientific studies are presented to model and clarify the influence of factors that substantially influence trail soil loss and that can be manipulated by trail professionals to sustain high traffic while minimizing soil loss over time. Key factors include trail grade, slope alignment angle, tread drainage features, and the amount of rock in tread substrates. A new Trail Sustainability Rating is developed and offered as a tool for evaluating or improving the sustainability of existing or new trails.

  10. CD25 targeted therapy of chemotherapy resistant leukemic stem cells using DR5 specific TRAIL peptide

    Directory of Open Access Journals (Sweden)

    Jayaprakasam Madhumathi

    2017-03-01

    Full Text Available Chemotherapy resistant leukemic stem cells (LSCs are being targeted as a modern therapeutic approach to prevent disease relapse. LSCs isolated from methotrexate resistant side population (SP of leukemic cell lines HL60 and MOLT4 exhibited high levels of CD25 and TRAIL R2/DR5 which are potential targets. Recombinant immunotoxin conjugating IL2α with TRAIL peptide mimetic was constructed for DR5 receptor specific targeting of LSCs and were tested in total cell population and LSCs. IL2-TRAIL peptide induced apoptosis in drug resistant SP cells from cell lines and showed potent cytotoxicity in PBMCs derived from leukemic patients with an efficacy of 81.25% in AML and 100% in CML, ALL and CLL. IL2-TRAIL peptide showed cytotoxicity in relapsed patient samples and was more effective than TRAIL or IL2-TRAIL proteins. Additionally, DR5 specific IL2-TRAIL peptide was effective in targeting and killing LSCs purified from cell lines [IC50: 952 nM in HL60, 714 nM in MOLT4] and relapsed patient blood samples with higher efficacy (85% than IL2-TRAIL protein (46%. Hence, CD25 and DR5 specific targeting by IL2-TRAIL peptide may be an effective strategy for targeting drug resistant leukemic cells and LSCs.

  11. Assessing the influence of sustainable trail design and maintenance on soil loss.

    Science.gov (United States)

    Marion, Jeffrey L; Wimpey, Jeremy

    2017-03-15

    Natural-surfaced trail systems are an important infrastructure component providing a means for accessing remote protected natural area destinations. The condition and usability of trails is a critical concern of land managers charged with providing recreational access while preserving natural conditions, and to visitors seeking high quality recreational opportunities and experiences. While an adequate number of trail management publications provide prescriptive guidance for designing, constructing, and maintaining natural-surfaced trails, surprisingly little research has been directed at providing a scientific basis for this guidance. Results from a review of the literature and three scientific studies are presented to model and clarify the influence of factors that substantially influence trail soil loss and that can be manipulated by trail professionals to sustain high traffic while minimizing soil loss over time. Key factors include trail grade, slope alignment angle, tread drainage features, and the amount of rock in tread substrates. A new Trail Sustainability Rating is developed and offered as a tool for evaluating or improving the sustainability of existing or new trails. Published by Elsevier Ltd.

  12. Frequency-Weighted Model Predictive Control of Trailing Edge Flaps on a Wind Turbine Blade

    DEFF Research Database (Denmark)

    Castaignet, Damien; Couchman, Ian; Poulsen, Niels Kjølstad

    2013-01-01

    flapwise blade root moment and trailing edge flap deflection. Frequency-weighted MPC is chosen for its ability to handle constraints on the trailing edge flaps deflection, and to target at loads with given frequencies only. The controller is first tested in servo-aeroelastic simulations, before being......This paper presents the load reduction achieved with trailing edge flaps during a full-scale test on a Vestas V27 wind turbine. The trailing edge flap controller is a frequency-weighted linear model predictive control (MPC) where the quadratic cost consists of costs on the zero-phase filtered...

  13. Effects of the built environment on childhood obesity: the case of urban recreational trails and crime.

    Science.gov (United States)

    Sandy, Robert; Tchernis, Rusty; Wilson, Jeffrey; Liu, Gilbert; Zhou, Xilin

    2013-01-01

    We study the effects of urban environment on childhood obesity by concentrating on the effects of walking trails and crime close to children's homes on their BMI and obesity status. We use a unique dataset, which combines information on recreational trails in Indianapolis with data on violent crimes and anthropomorphic and diagnostic data from children's clinic visits between 1996 and 2005. We find that having a trail near a home reduces children's weight. However, the effect depends on the amount of nearby violent crimes. Significant reductions occur only in low crime areas and trails could have opposite effects on weight in high crime areas. These effects are primarily among boys, older children, and children who live in higher income neighborhoods. Evaluated at the mean length of trails this effect for older children in no crime areas would be a reduction of 2 lb of the body weight. Falsification tests using planned trails instead of existing trails, show that trails are more likely to be located in areas with heavier children, suggesting that our results on effects of trails represent a lower bound. Published by Elsevier B.V.

  14. Female Sex Pheromone in Trails of the Minute Pirate Bug, Orius minutus (L).

    Science.gov (United States)

    Maeda, Taro; Fujiwara-Tsujii, Nao; Yasui, Hiroe; Matsuyama, Shigeru

    2016-05-01

    Orius minutus (L.) (Heteroptera: Anthocoridae) is a natural enemy of agricultural pests such as thrips, aphids, and various newly hatched insect juveniles. In this study, we conducted 1) behavioral assays for evidence of contact sex pheromone activity in trails of O. minutus, and 2) chemical analysis to identify the essential chemical components of the trails. Males showed arrestment to trails of mature virgin females but not to trails from either conspecific nymphs or immature females. Females also showed arrestment to trails from conspecific males, although the response was weaker than that exhibited by males. The activity of female trails lasted for at least 46 h after deposition. Males showed a response irrespective of mating experience. Following confirmation that a contact sex pheromone was present in the trails of female O. minutus, we used a bioassay-driven approach to isolate the active chemicals. After fractionation on silica gel, the n-hexane fraction was found to be biologically active to males. A major compound in the active fraction was (Z)-9-nonacosene; this compound was found only in trail extracts of mature virgin females. Synthetic (Z)-9-nonacosene arrested O. minutus males, indicating that it is the major active component of the contact sex pheromone in the trails of female O. minutus.

  15. Sodium arsenite accelerates TRAIL-mediated apoptosis in melanoma cells through upregulation of TRAIL-R1/R2 surface levels and downregulation of cFLIP expression

    International Nuclear Information System (INIS)

    Ivanov, Vladimir N.; Hei, Tom K.

    2006-01-01

    AP-1/cJun, NF-κB and STAT3 transcription factors control expression of numerous genes, which regulate critical cell functions including proliferation, survival and apoptosis. Sodium arsenite is known to suppress both the IKK-NF-κB and JAK2-STAT3 signaling pathways and to activate the MAPK/JNK-cJun pathways, thereby committing some cancers to undergo apoptosis. Indeed, sodium arsenite is an effective drug for the treatment of acute promyelocytic leukemia with little nonspecific toxicity. Malignant melanoma is highly refractory to conventional radio- and chemotherapy. In the present study, we observed strong effects of sodium arsenite treatment on upregulation of TRAIL-mediated apoptosis in human and mouse melanomas. Arsenite treatment upregulated surface levels of death receptors, TRAIL-R1 and TRAIL-R2, through increased translocation of these proteins from cytoplasm to the cell surface. Furthermore, activation of cJun and suppression of NF-κB by sodium arsenite resulted in upregulation of the endogenous TRAIL and downregulation of the cFLIP gene expression (which encodes one of the main anti-apoptotic proteins in melanomas) followed by cFLIP protein degradation and, finally, by acceleration of TRAIL-induced apoptosis. Direct suppression of cFLIP expression by cFLIP RNAi also accelerated TRAIL-induced apoptosis in these melanomas, while COX-2 suppression substantially increased levels of both TRAIL-induced and arsenite-induced apoptosis. In contrast, overexpression of permanently active AKTmyr inhibited TRAIL-mediated apoptosis via downregulation of TRAIL-R1 levels. Finally, AKT overactivation increased melanoma survival in cell culture and dramatically accelerated growth of melanoma transplant in vivo, highlighting a role of AKT suppression for effective anticancer treatment

  16. Analysis of the quality of hospital information systems Audit Trails.

    Science.gov (United States)

    Cruz-Correia, Ricardo; Boldt, Isabel; Lapão, Luís; Santos-Pereira, Cátia; Rodrigues, Pedro Pereira; Ferreira, Ana Margarida; Freitas, Alberto

    2013-08-06

    Audit Trails (AT) are fundamental to information security in order to guarantee access traceability but can also be used to improve Health information System's (HIS) quality namely to assess how they are used or misused. This paper aims at analysing the existence and quality of AT, describing scenarios in hospitals and making some recommendations to improve the quality of information. The responsibles of HIS for eight Portuguese hospitals were contacted in order to arrange an interview about the importance of AT and to collect audit trail data from their HIS. Five institutions agreed to participate in this study; four of them accepted to be interviewed, and four sent AT data. The interviews were performed in 2011 and audit trail data sent in 2011 and 2012. Each AT was evaluated and compared in relation to data quality standards, namely for completeness, comprehensibility, traceability among others. Only one of the AT had enough information for us to apply a consistency evaluation by modelling user behaviour. The interviewees in these hospitals only knew a few AT (average of 1 AT per hospital in an estimate of 21 existing HIS), although they all recognize some advantages of analysing AT. Four hospitals sent a total of 7 AT - 2 from Radiology Information System (RIS), 2 from Picture Archiving and Communication System (PACS), 3 from Patient Records. Three of the AT were understandable and three of the AT were complete. The AT from the patient records are better structured and more complete than the RIS/PACS. Existing AT do not have enough quality to guarantee traceability or be used in HIS improvement. Its quality reflects the importance given to them by the CIO of healthcare institutions. Existing standards (e.g. ASTM:E2147, ISO/TS 18308:2004, ISO/IEC 27001:2006) are still not broadly used in Portugal.

  17. Temperature limits trail following behaviour through pheromone decay in ants

    Science.gov (United States)

    van Oudenhove, Louise; Billoir, Elise; Boulay, Raphaël; Bernstein, Carlos; Cerdá, Xim

    2011-12-01

    In Mediterranean habitats, temperature affects both ant foraging behaviour and community structure. Many studies have shown that dominant species often forage at lower temperature than subordinates. Yet, the factors that constrain dominant species foraging activity in hot environments are still elusive. We used the dominant ant Tapinoma nigerrimum as a model species to test the hypothesis that high temperatures hinder trail following behaviour by accelerating pheromone degradation. First, field observations showed that high temperatures (> 30°C) reduce the foraging activity of T. nigerrimum independently of the daily and seasonal rhythms of this species. Second, we isolated the effect of high temperatures on pheromone trail efficacy from its effect on worker physiology. A marked substrate was heated during 10 min (five temperature treatments from 25°C to 60°C), cooled down to 25°C, and offered in a test choice to workers. At hot temperature treatments (>40°C), workers did not discriminate the previously marked substrate. High temperatures appeared therefore to accelerate pheromone degradation. Third, we assessed the pheromone decay dynamics by a mechanistic model fitted with Bayesian inference. The model predicted ant choice through the evolution of pheromone concentration on trails as a function of both temperature and time since pheromone deposition. Overall, our results highlighted that the effect of high temperatures on recruitment intensity was partly due to pheromone evaporation. In the Mediterranean ant communities, this might affect dominant species relying on chemical recruitment, more than subordinate ant species, less dependent on chemical communication and less sensitive to high temperatures.

  18. Ants can learn to forage on one-way trails.

    Directory of Open Access Journals (Sweden)

    Pedro Leite Ribeiro

    Full Text Available The trails formed by many ant species between nest and food source are two-way roads on which outgoing and returning workers meet and touch each other all along. The way to get back home, after grasping a food load, is to take the same route on which they have arrived from the nest. In many species such trails are chemically marked by pheromones providing orientation cues for the ants to find their way. Other species rely on their vision and use landmarks as cues. We have developed a method to stop foraging ants from shuttling on two-way trails. The only way to forage is to take two separate roads, as they cannot go back on their steps after arriving at the food or at the nest. The condition qualifies as a problem because all their orientation cues -- chemical, visual or any other -- are disrupted, as all of them cannot but lead the ants back to the route on which they arrived. We have found that workers of the leaf-cutting ant Atta sexdens rubropilosa can solve the problem. They could not only find the alternative way, but also used the unidirectional traffic system to forage effectively. We suggest that their ability is an evolutionary consequence of the need to deal with environmental irregularities that cannot be negotiated by means of excessively stereotyped behavior, and that it is but an example of a widespread phenomenon. We also suggest that our method can be adapted to other species, invertebrate and vertebrate, in the study of orientation, memory, perception, learning and communication.

  19. Water in the trail of the Chelyabinsk bolide

    Science.gov (United States)

    Gladysheva, O. G.

    2017-09-01

    At 03:20 UTC on February 15, 2013 a very bright bolide entered Earth's atmosphere. Fragments of the meteorite fell to the earth's surface. Examination of these fragments revealed that several of them were located directly on the surface of the celestial body [1], while the majority lay at a depth of less than 2.5 m from the surface [2, 3]. The stone meteorite's durability, >15 MPa, corresponded to Feng-Yun 2D discovered ice debris (water) in the bolide trail [6]. Here, we will demonstrate that the Chelyabinsk chondrite was delivered to the Earth by an ice-bearing celestial body.

  20. Airfoil Trailing Edge Noise Generation and Its Surface Pressure Fluctuation

    DEFF Research Database (Denmark)

    Zhu, Wei Jun; Shen, Wen Zhong

    2015-01-01

    In the present work, Large Eddy Simulation (LES) of turbulent flows over a NACA 0015 airfoil is performed. The purpose of such numerical study is to relate the aerodynamic surface pressure with the noise generation. The results from LES are validated against detailed surface pressure measurements...... where the time history pressure data are recorded by the surface pressure microphones. After the flow-field is stabilized, the generated noise from the airfoil Trailing Edge (TE) is predicted using the acoustic analogy solver, where the results from LES are the input. It is found that there is a strong...

  1. Blazing the trail essays by leading women in science

    CERN Document Server

    Ideal, Emma

    2013-01-01

    Name a famous scientist. Got one? Now name a famous physicist. Ok, now name a famous female physicist. Ok, now name a famous living female physicist. Stumped? In Blazing the Trail: Essays by Leading Women in Science, 35 highly successful physicists, engineers, and chemists share their personal histories, their passion for discovery, and their secrets for success with the next generation. Essayists candidly recount their experiences – both positive and negative – with an uplifting tone, focusing on lessons learned along the way. The combination of personal stories and advice sends a powerful message to all young women considering scientific careers: I did it, so can you. Here’s how.

  2. ONC201 demonstrates anti-tumor effects in both triple negative and non-triple negative breast cancers through TRAIL-dependent and TRAIL-independent mechanisms

    OpenAIRE

    Ralff, Marie D.; Kline, Christina L.B.; Küçükkase, Ozan C; Wagner, Jessica; Lim, Bora; Dicker, David T.; Prabhu, Varun V.; Oster, Wolfgang; El-Deiry, Wafik S.

    2017-01-01

    Breast cancer is a major cause of cancer-related death. TRAIL has been of interest as a cancer therapeutic, but only a subset of triple negative breast cancers (TNBC) is sensitive to TRAIL. The small molecule ONC201 induces expression of TRAIL and its receptor DR5. ONC201 has entered clinical trials in advanced cancers. Here we show that ONC201 is efficacious against both TNBC and non-TNBC cells (n=13). A subset of TNBC and non-TNBC cells succumb to ONC201-induced cell death. In 2/8 TNBC cell...

  3. SAHA-induced TRAIL-sensitisation of Multiple Myeloma cells is enhanced in 3D cell culture.

    Science.gov (United States)

    Arhoma, A; Chantry, A D; Haywood-Small, S L; Cross, N A

    2017-11-15

    Multiple Myeloma (MM) is currently incurable despite many novel therapies. Tumour Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) is a potential anti-tumour agent although effects as a single agent are limited. In this study, we investigated whether the Histone Deacetylase (HDAC) inhibitor SAHA can enhance TRAIL-induced apoptosis and target TRAIL resistance in both suspension culture, and 3D cell culture as a model of disseminated MM lesions that form in bone. The effects of SAHA and/or TRAIL in 6 Multiple Myeloma cell lines were assessed in both suspension cultures and in an Alginate-based 3D cell culture model. The effect of SAHA and/or TRAIL was assessed on apoptosis by assessment of nuclear morphology using Hoechst 33342/Propidium Iodide staining. Viable cell number was assessed by CellTiter-Glo luminescence assay, Caspase-8 and -9 activities were measured by Caspase-Glo™ assay kit. TRAIL-resistant cells were generated by culture of RPMI 8226 and NCI-H929 by acute exposure to TRAIL followed by selection of TRAIL-resistant cells. TRAIL significantly induced apoptosis in a dose-dependent manner in OPM-2, RPMI 8226, NCI-H929, U266, JJN-3 MM cell lines and ADC-1 plasma cell leukaemia cells. SAHA amplified TRAIL responses in all lines except OPM-2, and enhanced TRAIL responses were both via Caspase-8 and -9. SAHA treatment induced growth inhibition that further increased in the combination treatment with TRAIL in MM cells. The co-treatment of TRAIL and SAHA reduced viable cell numbers all cell lines. TRAIL responses were further potentiated by SAHA in 3D cell culture in NCI-H929, RPMI 8226 and U266 at lower TRAIL + SAHA doses than in suspension culture. However TRAIL responses in cells that had been selected for TRAIL resistance were not further enhanced by SAHA treatment. SAHA is a potent sensitizer of TRAIL responses in both TRAIL sensitive and resistant cell lines, in both suspension and 3D culture, however SAHA did not sensitise TRAIL-sensitive cell

  4. Differences in the impacts of formal and informal recreational trails on urban forest loss and tree structure.

    Science.gov (United States)

    Ballantyne, Mark; Pickering, Catherine Marina

    2015-08-15

    Recreational trails are one of the most common types of infrastructure used for nature-based activities such as hiking and mountain biking worldwide. Depending on their design, location, construction, maintenance and use, these trails differ in their environmental impacts. There are few studies, however, comparing the impacts of different trail types including between formal management-created trails and informal visitor-created trails. Although both types of trails can be found in remote natural areas, dense networks of them often occur in forests close to cities where they experience intense visitor use. To assess the relative impacts of different recreational trails in urban forests, we compared the condition of the trail surface, loss of forest strata and changes in tree structure caused by seven types of trails (total network 46.1 km) traversing 17 remnants of an endangered urban forest in Australia. After mapping and classifying all trails, we assessed their impact on the forest condition at 125 sites (15 sites per trail type, plus 15 control sites within undisturbed forest). On the trail sites, the condition of the trail surface, distance from the trail edge to four forest strata (litter, understory, midstorey and tree cover) and structure of the tree-line were assessed. Informal trails generally had poorer surface conditions and were poorly-designed and located. Per site, formal and informal trails resulted in similar loss of forest strata, with wider trails resulting in greater loss of forest. Because there were more informal trails, however, they accounted for the greatest cumulative forest loss. Structural impacts varied, with the widest informal trails and all formal hardened trails resulting in similar reductions in canopy cover and tree density but an increase in saplings. These structural impacts are likely a function of the unregulated and intense use of large informal trails, and disturbance from the construction and maintenance of formal trails

  5. How Networks of Informal Trails Cause Landscape Level Damage to Vegetation.

    Science.gov (United States)

    Barros, Agustina; Marina Pickering, Catherine

    2017-07-01

    When visitors are not constrained to remain on formal trails, informal trail networks can develop and damage plant communities in protected areas. These networks can form in areas with low growing vegetation, where formal trails are limited, where there is limited regulation and where vegetation is slow to recover once disturbed. To demonstrate the extent of impacts from unregulated recreational use, we assessed damage to alpine vegetation by hikers and pack animals in the highest protected area in the southern Hemisphere: Aconcagua Park, in the Andes. Within the 237 ha area surveyed in the Horcones Valley, over 19 km of trails were found, nearly all of which (94%) were informal. This network of trails resulted in the direct loss of 11.5 ha of vegetation and extensive fragmentation of alpine meadows (21 fragments) and steppe vegetation (68 fragments). When levels of disturbance off these trails were quantified using rapid visual assessments, 81% of 102 randomly located plots showed evidence of disturbance, with the severity of disturbance greatest close to trails. As a result, vegetation in 90% of the Valley has been damaged by visitor use, nearly all of it from unregulated use. These results highlight the extent to which informal trails and trampling off-trail can cause landscape damage to areas of high conservation value, and hence the importance of better regulation of visitor use. The methodology used for off-trail impact assessment can be easily applied or adapted for other popular protected areas where trampling off-trail is also an issue.

  6. Validation of Walking Trails for the Urban TrainingTM of Chronic Obstructive Pulmonary Disease Patients

    Science.gov (United States)

    Arbillaga-Etxarri, Ane; Torrent-Pallicer, Jaume; Gimeno-Santos, Elena; Barberan-Garcia, Anael; Delgado, Anna; Balcells, Eva; Rodríguez, Diego A.; Vilaró, Jordi; Vall-Casas, Pere; Irurtia, Alfredo; Rodriguez-Roisin, Robert; Garcia-Aymerich, Judith

    2016-01-01

    Purpose Accessible interventions to train patients with chronic obstructive pulmonary disease (COPD) are needed. We designed urban trails of different intensities (low, moderate and high) in different types of public spaces (boulevard, beach and park). We aimed to validate the trails’ design by assessing the physiological response to unsupervised walking trails of: (1) different intensities in COPD patients, and (2) same intensity from different public spaces in healthy adults. Methods On different days and under standardized conditions, 10 COPD patients walked the three intensity trails designed in a boulevard space, and 10 healthy subjects walked the three intensity trails in three different spaces. We measured physiological response and energy expenditure using a gas analyzer. We compared outcomes across trails intensity and/or spaces using mixed-effects linear regression. Results In COPD patients, physiological response and energy expenditure increased significantly according to the trails intensity: mean (SD) peak V˙O2 15.9 (3.5), 17.4 (4.7), and 17.7 (4.4) mL/min/kg (p-trend = 0.02), and MET-min 60 (23), 64 (26), 72 (31) (p-trendtrails, respectively. In healthy subjects there were no differences in physiological response to walking trails of the same intensity across different spaces. Conclusions We validated the trails design for the training of COPD patients by showing that the physiological response to and energy expenditure on unsupervised walking these trails increased according to the predefined trails’ intensity and did not change across trails of the same intensity in different public space. Walkable public spaces allow the design of trails that could be used for the training of COPD patients in the community. PMID:26766184

  7. Trail communication regulated by two trail pheromone components in the fungus-growing termite Odontotermes formosanus (Shiraki).

    Science.gov (United States)

    Wen, Ping; Ji, Bao-Zhong; Sillam-Dussès, David

    2014-01-01

    The eusocial termites are well accomplished in chemical communication, but how they achieve the communication using trace amount of no more than two pheromone components is mostly unknown. In this study, the foraging process and trail pheromones of the fungus-growing termite Odontotermes formosanus (Shiraki) were systematically studied and monitored in real-time using a combination of techniques, including video analysis, solid-phase microextraction, gas chromatography coupled with either mass spectrometry or an electroantennographic detector, and bioassays. The trail pheromone components in foraging workers were (3Z)-dodec-3-en-1-ol and (3Z,6Z)-dodeca-3,6-dien-1-ol secreted by their sternal glands. Interestingly, ratio of the two components changed according to the behaviors that the termites were displaying. This situation only occurs in termites whereas ratios of pheromone components are fixed and species-specific for other insect cuticular glands. Moreover, in bioassays, the active thresholds of the two components ranged from 1 fg/cm to 10 pg/cm according to the behavioral contexts or the pheromonal exposure of tested workers. The two components did not act in synergy. (3Z)-Dodec-3-en-1-ol induced orientation behavior of termites that explore their environment, whereas (3Z,6Z)-dodeca-3,6-dien-1-ol had both an orientation effect and a recruitment effect when food was discovered. The trail pheromone of O. formosanus was regulated both quantitatively by the increasing number of workers involved in the early phases of foraging process, and qualitatively by the change in ratio of the two pheromone components on sternal glandular cuticle in the food-collecting workers. In bioassays, the responses of workers to the pheromone were also affected by the variation in pheromone concentration and component ratio in the microenvironment. Thus, this termite could exchange more information with nestmates using the traces of the two trail pheromone components that can be easily

  8. Target Trailing With Safe Navigation for Maritime Autonomous Surface Vehicles

    Science.gov (United States)

    Wolf, Michael; Kuwata, Yoshiaki; Zarzhitsky, Dimitri V.

    2013-01-01

    This software implements a motion-planning module for a maritime autonomous surface vehicle (ASV). The module trails a given target while also avoiding static and dynamic surface hazards. When surface hazards are other moving boats, the motion planner must apply International Regulations for Avoiding Collisions at Sea (COLREGS). A key subset of these rules has been implemented in the software. In case contact with the target is lost, the software can receive and follow a "reacquisition route," provided by a complementary system, until the target is reacquired. The programmatic intention is that the trailed target is a submarine, although any mobile naval platform could serve as the target. The algorithmic approach to combining motion with a (possibly moving) goal location, while avoiding local hazards, may be applicable to robotic rovers, automated landing systems, and autonomous airships. The software operates in JPL s CARACaS (Control Architecture for Robotic Agent Command and Sensing) software architecture and relies on other modules for environmental perception data and information on the predicted detectability of the target, as well as the low-level interface to the boat controls.

  9. Semiflexible crossing-avoiding trails on plane-filling fractals

    International Nuclear Information System (INIS)

    Živić, I.; Elezović-Hadžić, S.; Milošević, S.

    2015-01-01

    We have studied the statistics of semiflexible polymer chains modeled by crossing-avoiding trails (CAT) situated on the family of plane-filling (PF) fractals. The fractals are compact, that is, their fractal dimension d_f is equal to 2 for all members of the fractal family. By applying the exact and Monte Carlo real-space renormalization group method we have calculated the critical exponent ν, which governs the scaling behavior of the end-to-end distance of the polymer, as well as the entropic critical exponent γ, for a large set of fractals, and various values of polymer flexibility. Our results, obtained for CAT model on PF fractals, show that both critical exponents depend on the polymer flexibility, in such a way that less flexible polymer chains display enlarged values of ν, and diminished values of γ. We have compared the obtained results for CAT model with the known results for the self-avoiding walk and self-avoiding trail models and discussed the influence of excluded volume effect on the values of semiflexible polymer critical exponents, for a large set of studied compact fractals.

  10. Current Interview Trail Metrics in the Otolaryngology Match.

    Science.gov (United States)

    Cabrera-Muffly, Cristina; Chang, C W David; Puscas, Liana

    2017-06-01

    Objectives To identify how applicants to otolaryngology residency determine how to apply to, interview with, and rank programs on the interview trail and to determine the extent of the financial burden of the otolaryngology interview trail. Study Design Web-based survey distributed in March and April 2016. Setting Otolaryngology residency applicants throughout the United States. Subjects and Methods Applicants to otolaryngology residency during the 2016 match cycle and current otolaryngology residents were surveyed. Results Median number of applications, interview offers, interviews attended, and programs ranked was not different during the 2016 match and the previous 5 match years. The most important factor affecting the number of applications was the need to apply widely to ensure sufficient interview offers. The most common reason for declining an interview offer was scheduling conflict. Applicants during the 2016 match spent a median of $5400 applying and interviewing for otolaryngology residency. Conclusions Median number of applications, interview offers, interviews attended, and programs ranked has not changed. The most cited reason for applying to many programs was to increase the chances of matching, but this is not statistically likely to increase match success. We advocate for continued attempts to make the otolaryngology match process more transparent for both applicants and resident selection committees, but recognize that applicants are likely to continue to overapply for otolaryngology residency positions.

  11. The influence of trailed vorticity on flutter speed estimations

    International Nuclear Information System (INIS)

    Pirrung, Georg R; Madsen, Helge Aa; Kim, Taeseong

    2014-01-01

    This paper briefly describes the implementation of a coupled near and far wake model for wind turbine rotor induction in the aeroelastic code HAWC2 and its application for flutter analysis of the NREL 5 MW wind turbine. The model consists of a far wake part based on Blade Element Momentum (BEM) theory, which is coupled with Beddoes' near wake model for trailed vorticity. The first part of this work outlines the implementation in HAWC2, with a focus on the interaction of the induction from the blade based near wake model with the induction from the polar grid based BEM model in HAWC2. The influence of the near wake model on the aeroelastic stability of the blades of the NREL 5 MW turbine in overspeed conditions is investigated in the second part of the paper. The analysis is based on a runaway case in which the turbine is free to speed up without generator torque and vibrations start building up at a critical rotor speed. Blades with modified torsional and flapwise stiffness are also investigated. A flutter analysis is often part of the stability investigations for new blades but is normally carried out with engineering models that do not include the influence of unsteady trailed vorticity. Including this influence results in a slightly increased safety margin against classical flutter in all simulated cases

  12. Experimental testing of spanwise morphing trailing edge concept

    Science.gov (United States)

    Pankonien, Alexander; Inman, Daniel J.

    2013-04-01

    Aircraft wings with smooth, hinge-less morphing ailerons exhibit increased chordwise aerodynamic efficiency over conventional hinged ailerons. Ideally, the wing would also use these morphing ailerons to smoothly vary its airfoil shape between spanwise stations to optimize the lift distribution and further increase aerodynamic efficiency. However, the mechanical complexity or added weight of achieving such a design has traditionally exceeded the potential aerodynamic gains. By expanding upon the previously developed cascading bimorph concept, this work uses embedded Macro-Fiber Composites and a flexure box mechanism, created using multi-material 3D printing, to achieve the Spanwise Morphing Trailing Edge (SMTE) concept. The morphing actuators are spaced spanwise along the wing with an elastomer spanning the gaps between them, which allows for optimization of the spanwise lift distribution while maintaining the continuity and efficiency of the morphing trailing edge. The concept is implemented in a representative section of a UAV wing with a 305 mm chord. A novel honeycomb skin is created from an elastomeric material using a 3D printer. The actuation capabilities of the concept are evaluated with and without spanning material on a test stand, free of aerodynamic loads. In addition, the actuation restrictions of the spanning elastomer, necessary in adapting the morphing concept from 2D to 3D, are characterized. Initial aerodynamic results from the 1'×1' wind-tunnel also show the effects of aerodynamic loading on the actuation range of the SMTE concept for uniform morphing.

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

    International Nuclear Information System (INIS)

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

    2013-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2013-12-13

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

  15. Sex-specific trail pheromone mediates complex mate finding behavior in Anoplophora glabripennis

    Science.gov (United States)

    Kelli Hoover; Melody Keena; Maya Nehme; Shifa Wang; Peter Meng; Aijun Zhang

    2014-01-01

    Anoplophora glabripennis (Motsch.) is a polyphagous member of the Cerambycidae, and is considered, worldwide, to be one of the most serious quarantine pests of deciduous trees. We isolated four chemicals from the trail of A. glabripennis virgin and mated females that were not present in trails of mature males. These compounds were...

  16. Comparative efficacy of multimodal digital methods in assessing trail/resource degradation

    Science.gov (United States)

    Logan O. Park

    2014-01-01

    Outdoor recreation can cause both positive and negative impacts on associated forest ecosystems. Forest recreation trails localize negative impacts to a controlled spatial extent while providing recreation access beyond developed areas and transportation networks. Current methods for assessing extent and severity of trail and proximal resource degradation require...

  17. Op het spoor van een 'multifunctionele' test: Over de geschiedenis van de Trail Making Test

    NARCIS (Netherlands)

    Eling, P.A.T.M.

    2013-01-01

    De Trail Making Test is een van de meest gebruikte tests in de neuropsychologische praktijk. Hij ziet er gemakkelijk uit en al snel scoren patiënten slechter dan gezonden, het lijkt dus ook een gevoelig instrument. Net als andere populaire tests is de Trail Making al behoorlijk oud en heeft hij in

  18. 77 FR 37438 - Draft Trail Management Plan and Environmental Impact Statement for Cuyahoga Valley National Park...

    Science.gov (United States)

    2012-06-21

    ... DEPARTMENT OF THE INTERIOR National Park Service [NPS-MWR-CUVA-10100; 6065-4000-409] Draft Trail... Park Service, Interior. ACTION: Notice of Availability. SUMMARY: The National Park Service (NPS... blueprint to guide the expansion, elimination, restoration, management, and use of the trail system and its...

  19. Why Individuals Hike the Appalachian Trail: A Qualitative Approach to Benefits

    Science.gov (United States)

    Goldenberg, Marni; Hill, Eddie; Freidt, Barbara

    2008-01-01

    The Appalachian Trail (AT) is a 2,175 mile-long National Scenic Trail extending from Maine to Georgia. Since its inception in the early 1920s, individuals, families, schools, and other organizations, just to name a few, have used the AT. Approximately 3 to 4 million visitors hike a portion of the AT each year (ATC, 2006). Throughout its 80-year…

  20. Changes in soil bulk density resulting from construction and conventional cable skidding using preplanned skid trails

    Science.gov (United States)

    Jingxin Wang; Chris B. LeDoux; Pam Edwards

    2007-01-01

    A harvesting system consisting of chainsaw felling and cable skidder extraction was studied to determine soil bulk density changes in a central Appalachian hardwood forest site. Soil bulk density was measured using a nuclear gauge preharvest and postharvest systematically across the harvest site, on transects across skid trails, and for a subset of skid trail transects...

  1. Path Tortuosity and the Permeability of Roads and Trails to Wolf Movement

    Directory of Open Access Journals (Sweden)

    Jesse Whittington

    2004-06-01

    Full Text Available Few studies have examined the effects of human development on fine-scale movement behavior, yet understanding animal movement through increasingly human-dominated landscapes is essential for the persistence of many wild populations, especially wary species. In mountainous areas, roads and trails may be particularly deserving of study because they are concentrated in the valley bottoms where they can impede animal movement both across and between valleys. In this study, we tracked wolf (Canis lupus movement in the snow for two winters in Jasper National Park, Alberta, Canada to examine how wolves navigate through or around human-use features. We quantified the effects of human development and topography on the tortuosity of wolf paths and then tested the permeability of roads, trails, and a railway line to wolf movement by comparing the frequency with which actual wolf paths and a null model of random paths crossed these features. Wolf path tortuosity increased near high-use trails, within areas of high-trail and road density, near predation sites, and in rugged terrain. Wolves crossed all roads, trails, and the railway line 9.7% less often than expected, but avoided crossing high-use roads more than low-use trails. Surprisingly, trails affected movement behavior of wolves equally, if not more, than roads. These results suggest that although roads and trails in this study were not absolute barriers to wolf movement, they altered wolf movements across their territories.

  2. 77 FR 1723 - Notice of Availability, Potomac Heritage National Scenic Trail

    Science.gov (United States)

    2012-01-11

    ... Availability of a ``Foundation for Planning, Administration, Management and Interpretation of Potomac Heritage... the availability of a ``Foundation for Planning, Administration, Management and Interpretation of... planned Trail segments for non-motorized travel. Communities have invested in the Trail concept for a...

  3. Model Predictive Control of Trailing Edge Flaps on a wind turbine blade

    DEFF Research Database (Denmark)

    Castaignet, Damien; Poulsen, Niels Kjølstad; Buhl, Thomas

    2011-01-01

    Trailing Edge Flaps on wind turbine blades have been studied in order to achieve fatigue load reduction on the turbine components. We show in this paper how Model Predictive Control can be used to do frequency weighted control of the trailing edge flaps in order to reduce fatigue damage on the bl...

  4. Gingerol sensitizes TRAIL-induced apoptotic cell death of glioblastoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Dae-Hee, E-mail: leedneo@gmail.com [Departments of Surgery and Pharmacology and Cell Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA (United States); Kim, Dong-Wook [Department of Microbiology, Immunology, and Cancer Biology, University of VA (United States); Jung, Chang-Hwa [Division of Metabolism and Functionality Research, Korea Food Research Institute (Korea, Republic of); Lee, Yong J. [Departments of Surgery and Pharmacology and Cell Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA (United States); Park, Daeho, E-mail: daehopark@gist.ac.kr [School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 500-712 (Korea, Republic of)

    2014-09-15

    Glioblastoma multiforme (GBM) is the most lethal and aggressive astrocytoma of primary brain tumors in adults. Although there are many clinical trials to induce the cell death of glioblastoma cells, most glioblastoma cells have been reported to be resistant to TRAIL-induced apoptosis. Here, we showed that gingerol as a major component of ginger can induce TRAIL-mediated apoptosis of glioblastoma. Gingerol increased death receptor (DR) 5 levels in a p53-dependent manner. Furthermore, gingerol decreased the expression level of anti-apoptotic proteins (survivin, c-FLIP, Bcl-2, and XIAP) and increased pro-apoptotic protein, Bax and truncate Bid, by generating reactive oxygen species (ROS). We also found that the sensitizing effects of gingerol in TRAIL-induced cell death were blocked by scavenging ROS or overexpressing anti-apoptotic protein (Bcl-2). Therefore, we showed the functions of gingerol as a sensitizing agent to induce cell death of TRAIL-resistant glioblastoma cells. This study gives rise to the possibility of applying gingerol as an anti-tumor agent that can be used for the purpose of combination treatment with TRAIL in TRAIL-resistant glioblastoma tumor therapy. - Highlights: • Most GBM cells have been reported to be resistant to TRAIL-induced apoptosis. • Gingerol enhances the expression level of anti-apoptotic proteins by ROS. • Gingerol enhances TRAIL-induced apoptosis through actions on the ROS–Bcl2 pathway.

  5. 30 CFR 77.601 - Trailing cables or portable cables; temporary splices.

    Science.gov (United States)

    2010-07-01

    ... LABOR COAL MINE SAFETY AND HEALTH MANDATORY SAFETY STANDARDS, SURFACE COAL MINES AND SURFACE WORK AREAS OF UNDERGROUND COAL MINES Trailing Cables § 77.601 Trailing cables or portable cables; temporary... or splices that heat or spark under load shall not be used. ...

  6. Managing outdoor recreation conflict on the Squamish, British Columbia Trail Network

    Science.gov (United States)

    Ana Elia Ramón Hidalgo; Howard. Harshaw

    2012-01-01

    Recreationists with high expectations of satisfaction from outdoor recreation activities are increasingly using trails networks near urban areas. But differences in expectations, behaviors and values of trail users may create conflicts resulting in unsatisfactory experiences. The objective of this study was to test the efficacy of management practices that may reduce...

  7. 76 FR 54730 - Rubicon Trail Easement, Eldorado National Forest, Pacific Ranger District

    Science.gov (United States)

    2011-09-02

    ... waters of the state, and address human waste management on the Rubicon Trail. Proposed Action The... through these low spots thereby accelerating trail erosion and sedimentation. In July 2004, the El Dorado... fecal waste littered around the Spider Lake area. The amount of fecal waste was determined to pose a...

  8. 76 FR 35468 - Star-Spangled Banner National Historic Trail Advisory Council

    Science.gov (United States)

    2011-06-17

    ... DEPARTMENT OF THE INTERIOR National Park Service Star-Spangled Banner National Historic Trail... the Advisory Committee on the Star-Spangled Banner National Historic Trail will hold a meeting... Council is John Maounis, Superintendent, Chesapeake Bay Office, telephone: (410) 260-2471. DATES: The Star...

  9. Dichotomous scoring of Trails B in patients referred for a dementia evaluation.

    Science.gov (United States)

    Schmitt, Andrew L; Livingston, Ronald B; Smernoff, Eric N; Waits, Bethany L; Harris, James B; Davis, Kent M

    2010-04-01

    The Trail Making Test is a popular neuropsychological test and its interpretation has traditionally used time-based scores. This study examined an alternative approach to scoring that is simply based on the examinees' ability to complete the test. If an examinee is able to complete Trails B successfully, they are coded as "completers"; if not, they are coded as "noncompleters." To assess this approach to scoring Trails B, the performance of 97 diagnostically heterogeneous individuals referred for a dementia evaluation was examined. In this sample, 55 individuals successfully completed Trails B and 42 individuals were unable to complete it. Point-biserial correlations indicated a moderate-to-strong association (r(pb)=.73) between the Trails B completion variable and the Total Scale score of the Repeatable Battery for the Assessment of Neurological Status (RBANS), which was larger than the correlation between the Trails B time-based score and the RBANS Total Scale score (r(pb)=.60). As a screen for dementia status, Trails B completion showed a sensitivity of 69% and a specificity of 100% in this sample. These results suggest that dichotomous scoring of Trails B might provide a brief and clinically useful measure of dementia status.

  10. Web-Based Museum Trails on PDAs for University-Level Design Students: Design and Evaluation

    Science.gov (United States)

    Reynolds, R.; Walker, K.; Speight, C.

    2010-01-01

    This paper describes the development and evaluation of web-based museum trails for university-level design students to access on handheld devices in the Victoria and Albert Museum (V&A) in London. The trails offered students a range of ways of exploring the museum environment and collections, some encouraging students to interpret objects and…

  11. 77 FR 32178 - Notification of Trails Act Agreement/Substitute Sponsorship

    Science.gov (United States)

    2012-05-31

    ... DEPARTMENT OF TRANSPORTATION Surface Transportation Board [STB Ex Parte No. 702] Notification of Trails Act Agreement/Substitute Sponsorship AGENCY: Surface Transportation Board. ACTION: Notice of OMB... Trails System Act and Railroad Rights-of-Way, STB Ex Parte No. 702 (STB served Apr. 30, 2012) (77 FR...

  12. Gingerol sensitizes TRAIL-induced apoptotic cell death of glioblastoma cells

    International Nuclear Information System (INIS)

    Lee, Dae-Hee; Kim, Dong-Wook; Jung, Chang-Hwa; Lee, Yong J.; Park, Daeho

    2014-01-01

    Glioblastoma multiforme (GBM) is the most lethal and aggressive astrocytoma of primary brain tumors in adults. Although there are many clinical trials to induce the cell death of glioblastoma cells, most glioblastoma cells have been reported to be resistant to TRAIL-induced apoptosis. Here, we showed that gingerol as a major component of ginger can induce TRAIL-mediated apoptosis of glioblastoma. Gingerol increased death receptor (DR) 5 levels in a p53-dependent manner. Furthermore, gingerol decreased the expression level of anti-apoptotic proteins (survivin, c-FLIP, Bcl-2, and XIAP) and increased pro-apoptotic protein, Bax and truncate Bid, by generating reactive oxygen species (ROS). We also found that the sensitizing effects of gingerol in TRAIL-induced cell death were blocked by scavenging ROS or overexpressing anti-apoptotic protein (Bcl-2). Therefore, we showed the functions of gingerol as a sensitizing agent to induce cell death of TRAIL-resistant glioblastoma cells. This study gives rise to the possibility of applying gingerol as an anti-tumor agent that can be used for the purpose of combination treatment with TRAIL in TRAIL-resistant glioblastoma tumor therapy. - Highlights: • Most GBM cells have been reported to be resistant to TRAIL-induced apoptosis. • Gingerol enhances the expression level of anti-apoptotic proteins by ROS. • Gingerol enhances TRAIL-induced apoptosis through actions on the ROS–Bcl2 pathway

  13. The interplay between scent trails and group-mass recruitment systems in ants

    NARCIS (Netherlands)

    Planque, R.; van den Berg, G.J.B.; Franks, N.R.

    2013-01-01

    Large ant colonies invariably use effective scent trails to guide copious ant numbers to food sources. The success of mass recruitment hinges on the involvement of many colony members to lay powerful trails. However, many ant colonies start off as single queens. How do these same colonies forage

  14. ONC201 Demonstrates Antitumor Effects in Both Triple-Negative and Non-Triple-Negative Breast Cancers through TRAIL-Dependent and TRAIL-Independent Mechanisms.

    Science.gov (United States)

    Ralff, Marie D; Kline, Christina L B; Küçükkase, Ozan C; Wagner, Jessica; Lim, Bora; Dicker, David T; Prabhu, Varun V; Oster, Wolfgang; El-Deiry, Wafik S

    2017-07-01

    Breast cancer is a major cause of cancer-related death. TNF-related apoptosis-inducing ligand (TRAIL) has been of interest as a cancer therapeutic, but only a subset of triple-negative breast cancers (TNBC) is sensitive to TRAIL. The small-molecule ONC201 induces expression of TRAIL and its receptor DR5. ONC201 has entered clinical trials in advanced cancers. Here, we show that ONC201 is efficacious against both TNBC and non-TNBC cells ( n = 13). A subset of TNBC and non-TNBC cells succumbs to ONC201-induced cell death. In 2 of 8 TNBC cell lines, ONC201 treatment induces caspase-8 cleavage and cell death that is blocked by TRAIL-neutralizing antibody RIK2. The proapoptotic effect of ONC201 translates to in vivo efficacy in the MDA-MB-468 xenograft model. In most TNBC lines tested (6/8), ONC201 has an antiproliferative effect but does not induce apoptosis. ONC201 decreases cyclin D1 expression and causes an accumulation of cells in the G 1 phase of the cell cycle. pRb expression is associated with sensitivity to the antiproliferative effects of ONC201, and the compound synergizes with taxanes in less sensitive cells. All non-TNBC cells ( n = 5) are growth inhibited following ONC201 treatment, and unlike what has been observed with TRAIL, a subset ( n = 2) shows PARP cleavage. In these cells, cell death induced by ONC201 is TRAIL independent. Our data demonstrate that ONC201 has potent antiproliferative and proapoptotic effects in a broad range of breast cancer subtypes, through TRAIL-dependent and TRAIL-independent mechanisms. These findings develop a preclinical rationale for developing ONC201 as a single agent and/or in combination with approved therapies in breast cancer. Mol Cancer Ther; 16(7); 1290-8. ©2017 AACR . ©2017 American Association for Cancer Research.

  15. ONC201 demonstrates anti-tumor effects in both triple negative and non-triple negative breast cancers through TRAIL-dependent and TRAIL-independent mechanisms

    Science.gov (United States)

    Ralff, Marie D.; Kline, Christina L.B.; Küçükkase, Ozan C; Wagner, Jessica; Lim, Bora; Dicker, David T.; Prabhu, Varun V.; Oster, Wolfgang; El-Deiry, Wafik S.

    2017-01-01

    Breast cancer is a major cause of cancer-related death. TRAIL has been of interest as a cancer therapeutic, but only a subset of triple negative breast cancers (TNBC) is sensitive to TRAIL. The small molecule ONC201 induces expression of TRAIL and its receptor DR5. ONC201 has entered clinical trials in advanced cancers. Here we show that ONC201 is efficacious against both TNBC and non-TNBC cells (n=13). A subset of TNBC and non-TNBC cells succumb to ONC201-induced cell death. In 2/8 TNBC cell lines, ONC201 treatment induces caspase-8 cleavage and cell death that is blocked by TRAIL-neutralizing antibody RIK2. The pro-apoptotic effect of ONC201 translates to in vivo efficacy in the MDA-MB-468 xenograft model. In most TNBC lines tested (6/8) ONC201 has an anti-proliferative effect but does not induce apoptosis. ONC201 decreases cyclin D1 expression and causes an accumulation of cells in the G1 phase of the cell cycle. pRb expression is associated with sensitivity to the anti-proliferative effects of ONC201, and the compound synergizes with taxanes in less sensitive cells. All non-TNBC cells (n=5) are growth inhibited following ONC201 treatment, and unlike what has been observed with TRAIL, a subset (n=2) show PARP cleavage. In these cells, cell death induced by ONC201 is TRAIL-independent. Our data demonstrate that ONC201 has potent anti-proliferative and pro-apoptotic effects in a broad range of breast cancer subtypes, through TRAIL-dependent and TRAIL-independent mechanisms. These findings develop a pre-clinical rationale for developing ONC201 as a single agent and/or in combination with approved therapies in breast cancer. PMID:28424227

  16. Sediment pathways in a tropical forest: effects of logging roads and skid trails

    Science.gov (United States)

    Sidle, Roy C.; Sasaki, Shozo; Otsuki, Mieko; Noguchi, Shoji; Rahim Nik, Abdul

    2004-03-01

    Significant erosion occurred from recently constructed forest logging roads and skid trails in a small headwater catchment in Peninsular Malaysia. Soil loss was estimated by measuring dimensions of all significant rills and gullies along the road, as well as by measuring height of preserved soil pedestals in sidecast and fill material and on skid trails. Estimates of surface erosion from logging roads and skid trails were 272 +/- 20 t ha-1 year-1 and 275 +/- 20 t ha-1 year-1 respectively. However, owing to lack of connectivity of skid trails to the stream, much of the sediment mobilized on skid trails was stored either on adjacent hillslopes or the trails themselves, rather than being transported to the stream system, as was the case for the road. Steeper skid trails (>20% gradient) had slightly higher erosion rates (320 +/- 24 t ha-1 year-1) than trails with gentler gradients (245-264 t ha-1 year-1). Some 60% of the soil loss on logging roads comes from erosion of the running surface. Disturbed cut and fill material along the road supplied the remaining 40% of the soil loss from roads. Roads and skid trails had no designed drainage systems; runoff discharged onto the hillslope at 25 major discharge nodes from the logging road (690 m total length) and at 34 nodes from skid trails (2300 m). Sediment pathways were either fully or moderately connected to headwater channels at 64% of the logging road nodes, but at only 26% of the nodes emanating from skid trails. A detailed sediment budget revealed that 78% of the soil loss from the road system (including log landings) was delivered to the stream in the first 16 months after logging began. Most (90%) of the deposition from skid trails occurred below just three discharge nodes. Runoff from and onto skid trails often exacerbated the sediment connectivity to channels. Clearly, sediment discharge from logging roads was more highly connected to the stream than discharge from skid trails. Once in the channel, much of this

  17. Model predictive control of trailing edge flaps on a wind turbine blade

    DEFF Research Database (Denmark)

    Castaignet, Damien Bruno

    of the wind turbine fatigue and extreme loads. This potential was confirmed with wind tunnel tests made on blade sections with trailing edge flaps and on a scaled two-bladed wind turbine in a wind tunnel. The work presented in this thesis includes a full-scale test run on a Vestas V27 wind turbine equipped...... fatigue loads by 23%, but also the main shaft and the tower fatigue loads by up to 32%. Extreme loads during normal production also benefit from the trailing edge flaps. At last, the same controller was run on the Vestas V27 wind turbine located at the Risø Campus of the Technical University of Denmark......Trailing edge flaps on wind turbine blades have been investigated for several years. Aero-servoelastic simulations carried out with different simulation tools, trailing edge flaps configurations and controller designs proved that trailing edge flaps are a suitable solution for reducing some...

  18. Attitudes and intentions of off-highway vehicle riders toward trail use: implications for forest managers

    Science.gov (United States)

    Kuehn, D.M.; D'Luhosch, P. D.; Luzadis, V.A.; Malmsheimer, R.W.; Schuster, R.M.

    2011-01-01

    Management of off-highway vehicles (OHV) in public forest areas requires up-to-date information about the attitudes and intentions of OHV riders toward trail use. A survey of 811 members of the New England Trail Riders Association was conducted in fall 2007; 380 questionnaires were completed and returned. Descriptive statistics and regressions were used to identify relationships between OHV rider attitudes, management preferences, and intentions toward two trail use-related behaviors (i.e., illegal use of trails by OHVs and the creation and/or use of unauthorized trails by OHV riders). Results reveal that the average responding association member has a negative attitude toward the two depreciative behaviors, intends to ride OHVs legally, and slightly prefers indirect over direct forms of management. Significant relationships between intentions and both attitudes and management preferences are identified. Policy and management implications and strategies are discussed. ?? 2011 by the Society of American Foresters.

  19. Trail marking by caterpillars of the silverspot butterfly Dione juno huascuma.

    Science.gov (United States)

    Pescador-Rubio, Alfonso; Stanford-Camargo, Sergio G; Páez-Gerardo, Luis E; Ramírez-Reyes, Alberto J; Ibarra-Jiménez, René A; Fitzgerald, Terrence D

    2011-01-01

    A pheromone is implicated in the trail marking behavior of caterpillars of the nymphalid silverspot butterfly, Dione juno huascuma (Reakirt) (Lepidoptera: Heliconiinae) that feed gregariously on Passiflora (Malpighiales: Passifloraceae) vines in Mexico. Although they mark pathways leading from one feeding site to another with silk, this study shows that the silk was neither adequate nor necessary to elicit trail following behavior. Caterpillars marked trails with a long-lived pheromone that was deposited when they brushed the ventral surfaces of the tips of their abdomens along branch pathways. The caterpillars distinguished between pathways deposited by different numbers of siblings and between trails of different ages. Caterpillars also preferentially followed the trails of conspecifics over those of another nymphalid, Nymphalis antiopa L., the mourning cloak butterfly.

  20. Expression and significance of TRAIL and NF-kB in osteosarcoma

    International Nuclear Information System (INIS)

    Du Xiumin; You Murong; Qi Falian; Hu Chengjin

    2005-01-01

    To investigate the relationship between expressions of TRAIL, NF-kB and cell proliferation in human osteosarcomas, the expressions of TRAIL and NF-kB in 16 cases of osteosarcoma, 5 cases of giant cell tumor of bone and 6 cases of chondrosarcoma were studied by flow cytometry. The expressions of TRAIL and NF-kB in osteosarcomas of different differentiation states were higher than those in other two kinds of tumors significantly in our study(P 0.05). The expressions of TRAIL and NF-kB in chondrosarcoma and giant cell tumor of bone were not different significantly(P>0.05). The higher expression of TRAIL in osteosarcoma with different differentiation states could not induce apoptosis because of the higher expression of NF-kB. NF-kB may restrain the apoptosis of tumor cells by regulating the NF-kB- induced apoptosis path way in osteosarcoma. (authors)

  1. TRAIL Death Receptor-4 Expression Positively Correlates With the Tumor Grade in Breast Cancer Patients With Invasive Ductal Carcinoma

    International Nuclear Information System (INIS)

    Sanlioglu, Ahter D.; Korcum, Aylin F.; Pestereli, Elif; Erdogan, Gulgun; Karaveli, Seyda; Savas, Burhan; Griffith, Thomas S.; Sanlioglu, Salih V.

    2007-01-01

    Purpose: Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) selectively induces apoptosis in cancer cells but not in normal cells, and a number of clinical trials have recently been initiated to test the safety and antitumoral potential of TRAIL in cancer patients. Four different receptors have been identified to interact with TRAIL: two are death-inducing receptors (TRAIL-R1 [DR4] and TRAIL-R2 [DR5]), whereas the other two (TRAIL-R3 [DcR1] and TRAIL-R4 [DcR2]) do not induce death upon ligation and are believed to counteract TRAIL-induced cytotoxicity. Because high levels of DcR2 expression have recently been correlated with carcinogenesis in the prostate and lung, this study investigated the importance of TRAIL and TRAIL receptor expression in breast cancer patients with invasive ductal carcinoma, taking various prognostic markers into consideration. Methods and Materials: Immunohistochemical analyses were performed on 90 breast cancer patients with invasive ductal carcinoma using TRAIL and TRAIL receptor-specific antibodies. Age, menopausal status, tumor size, lymph node status, tumor grade, lymphovascular invasion, perineural invasion, extracapsular tumor extension, presence of an extensive intraductal component, multicentricity, estrogen and progesterone receptor status, and CerbB2 expression levels were analyzed with respect to TRAIL/TRAIL receptor expression patterns. Results: The highest TRAIL receptor expressed in patients with invasive ductal carcinoma was DR4. Although progesterone receptor-positive patients exhibited lower DR5 expression, CerbB2-positive tissues displayed higher levels of both DR5 and TRAIL expressions. Conclusions: DR4 expression positively correlates with the tumor grade in breast cancer patients with invasive ductal carcinoma

  2. Molecular requirements for the combined effects of TRAIL and ionising radiation

    International Nuclear Information System (INIS)

    Marini, Patrizia; Jendrossek, Verena; Durand, Elise; Gruber, Charlotte; Budach, Wilfried; Belka, Claus

    2003-01-01

    Background and purpose: Previously it was shown that combination of death ligand TRAIL and irradiation strongly increases cell kill in several human tumour cell lines. Since Bcl-2 overexpression did not strongly interfere with the efficacy, components of the mitochondrial death pathway are not required for an effective combined treatment. In the present study the minimal molecular prerequisites for the efficacy of a combined treatment were determined. Materials and methods: Apoptosis induction in control, caspase-8 and FADD negative Jurkat cells, BJAB control and FADD-DN cells was analysed by FACS. Activation of caspase-8, -10 and -3 and cleavage of PARP was determined by immunoblotting. TRAIL receptors were activated using recombinant human TRAIL. Surface expression of TRAIL receptors DR4 and DR5 was analysed by FACS. Results: Jurkat T-cells express the agonistic DR5 receptor but not DR4. Presence of FADD was found to be essential for TRAIL induced apoptosis. Caspase-8 negative cells show very low rates of apoptosis after prolonged stimulation with TRAIL. No combined effects of TRAIL with irradiation could be found in FADD-DN over expressing and FADD deficient cells. However, the combination of TRAIL and irradiation clearly lead to a combined effect in caspase-8 negative Jurkat cells, albeit with reduced death rates. In these cells activation of the alternative initiator caspase-10 could be detected after combined treatment. Conclusion: Our data show that a combined therapy with TRAIL and irradiation will only be effective in cells expressing at least one agonistic TRAIL receptor, FADD and caspase-8 or caspase-10

  3. Distribution, abundance and trail characteristics of acorn worms at Australian continental margins

    Science.gov (United States)

    Anderson, T. J.; Przeslawski, R.; Tran, M.

    2011-04-01

    Acorn worms (Enteropneusta), which were previously thought to be a missing link in understanding the evolution of chordates, are an unusual and potentially important component of many deep-sea benthic environments, particularly for nutrient cycling. Very little is known about their distribution, abundance, or behaviour in deep-sea environments around the world, and almost nothing is known about their distribution within Australian waters. In this study, we take advantage of two large-scale deep-sea mapping surveys along the eastern (northern Lord Howe Rise) and western continental margins of Australia to quantify the distribution, abundance and trail-forming behaviour of this highly unusual taxon. This is the first study to quantify the abundance and trail behaviour of acorn worms within Australian waters and provides the first evidence of strong depth-related distributions. Acorn worm densities and trail activity were concentrated between transect-averaged depths of 1600 and 3000 m in both eastern and western continental margins. The shallow limit of their depth distribution was 1600 m. The deeper limit was less well-defined, as individuals were found in small numbers below 3000 down to 4225 m. This distributional pattern may reflect a preference for these depths, possibly due to higher availability of nutrients, rather than a physiological constraint to greater depths. Sediment characteristics alone were poor predictors of acorn worm densities and trail activity. High densities of acorn worms and trails were associated with sandy-mud sediments, but similar sediment characteristics in either shallower or deeper areas did not support similar densities of acorn worms or trails. Trail shapes varied between eastern and western margins, with proportionally more meandering trails recorded in the east, while spiral and meandering trails were both common in the west. Trail shape varied by depth, with spiral-shaped trails dominant in areas of high acorn worm densities

  4. Atmospheric testing of wind turbine trailing edge aerodynamic brakes

    Energy Technology Data Exchange (ETDEWEB)

    Miller, L.S. [Wichita State Univ., KS (United States); Migliore, P.G. [National Renewable Energy Lab., Golden, CO (United States); Quandt, G.A.

    1997-12-31

    An experimental investigation was conducted using an instrumented horizontal-axis wind turbine that incorporated variable span trailing-edge aerodynamic brakes. A primary goal was to directly compare study results with (infinite-span) wind tunnel data and to provide information on how to account for device span effects during turbine design or analysis. Comprehensive measurements were utilized to define effective changes in the aerodynamic coefficients, as a function of angle of attack and control deflection, for three device spans and configurations. Differences in the lift and drag behavior are most pronounced near stall and for device spans of less than 15%. Drag performance is affected only minimally (<70%) for 15% or larger span devices. Interestingly, aerodynamic controls with characteristic vents or openings appear most affected by span reductions and three-dimensional flow.

  5. Experimental and simulated control of lift using trailing edge devices

    Science.gov (United States)

    Cooperman, A.; Blaylock, M.; van Dam, C. P.

    2014-12-01

    Two active aerodynamic load control (AALC) devices coupled with a control algorithm are shown to decrease the change in lift force experienced by an airfoil during a change in freestream velocity. Microtabs are small (1% chord) surfaces deployed perpendicular to an airfoil, while microjets are pneumatic jets with flow perpendicular to the surface of the airfoil near the trailing edge. Both devices are capable of producing a rapid change in an airfoil's lift coefficient. A control algorithm for microtabs has been tested in a wind tunnel using a modified S819 airfoil, and a microjet control algorithm has been simulated for a NACA 0012 airfoil using OVERFLOW. In both cases, the AALC devices have shown the ability to mitigate the changes in lift during a gust.

  6. Experimental and simulated control of lift using trailing edge devices

    International Nuclear Information System (INIS)

    Cooperman, A; Blaylock, M; Van Dam, C P

    2014-01-01

    Two active aerodynamic load control (AALC) devices coupled with a control algorithm are shown to decrease the change in lift force experienced by an airfoil during a change in freestream velocity. Microtabs are small (1% chord) surfaces deployed perpendicular to an airfoil, while microjets are pneumatic jets with flow perpendicular to the surface of the airfoil near the trailing edge. Both devices are capable of producing a rapid change in an airfoil's lift coefficient. A control algorithm for microtabs has been tested in a wind tunnel using a modified S819 airfoil, and a microjet control algorithm has been simulated for a NACA 0012 airfoil using OVERFLOW. In both cases, the AALC devices have shown the ability to mitigate the changes in lift during a gust

  7. Numerical simulation of airfoil trailing edge serration noise

    DEFF Research Database (Denmark)

    Zhu, Wei Jun; Shen, Wen Zhong

    In the present work, numerical simulations are carried out for a low noise airfoil with and without serrated Trailing Edge. The Ffowcs Williams-Hawkings acoustic analogy is implemented into the in-house incompressible flow solver EllipSys3D. The instantaneous hydrodynamic pressure and velocity...... field are obtained using Large Eddy Simulation. To obtain the time history data of sound pressure, the flow quantities are integrated around the airfoil surface through the FW-H approach. The extended length of the serration is about 16.7% of the airfoil chord and the geometric angle of the serration...... is 28 degrees. The chord based Reynolds number is around 1.5x106. Simulations are compared with existing wind tunnel experiments at various angles of attack. Even though the airfoil under investigation is already optimized for low noise emission, numerical simulations and wind tunnel experiments show...

  8. Vindicating capital: heroes and villains in A Lion's Trail

    Directory of Open Access Journals (Sweden)

    Havard Ovesen

    2011-10-01

    Full Text Available http://dx.doi.org/10.5007/2175-8026.2011n61p073 This paper analyses François Verster’s A Lion’s Trail (2002, a documentary about the late musician Solomon Linda andhis hit song, Mbube. Linda died a pauper, despite the fact that his composition became one of the most commerciallysuccessful songs in the history of popular music. Considering the potentially substantial financial benefits due to SolomonLinda’s daughters as heirs to his intellectual property rights, the story of Mbube can easily be read as having a happy, ifsomewhat bittersweet, ending. This ending is remarkably similar to the grand narrative of the new and democraticSouth Africa; in the end, justice was served, although not everybody was around to enjoy it. Such readings, however,obscure certain aspects of the new South African realities. The power structures that enable the continuation of huge socioeconomicdisparities are still in place. We contend that the film’s characertisationof protagonists and antagonists in its narrative as well as the closure that is provided by the actions of Gallo allow viewers to overlook some key problems thatpersist in dominant assumptions about intellectual property, the ill-treatment of countless other black musicians during apartheid, as well as racialised class inequalities that persistnearly two decades after apartheid. The paper will commence with a brief description of Linda’s career in order to set the scene for our analysis of Verster’s documentary. This analysiswill be informed by insights into intellectual property; we will then relate these insights to a discussion of South Africa’sadoption of neo-liberal economic policies. In essence, we argue that, much like the country’s implementation of neoliberalstrategies like Black Economic Empowerment (BEE, the assumptions inherentin A Lion’s Trail about intellectual property vindicate capital and, by implication, the racialised classdivide in post-apartheid South Africa.

  9. Designing trails for subaquatic tourism in Marine Protected Areas

    Directory of Open Access Journals (Sweden)

    Cristina Piñeiro-Corbeira

    2014-05-01

    Full Text Available Although the range of touristic activities that take place in the sea has greatly expanded in recent years, the marine realm continues to be one of the least known to the public. Scuba diving and snorkeling are popular activities in the marine environment. Among its benefits, snorkeling is simple, cheap, and accessible to a wide range of population. In this regard, it has considerable potential as a tool for environmental education as it allows a firsthand observation of the subaquatic seascape as well as a direct interaction with marine wildlife. These attributes, together with its low ecological impact, make snorkeling an activity particularly suitable for marine protected areas. Yet, its implementation in marine protected areas requires new tools for an appropriate use. Here, we show an innovative procedure for assessing the underwater seascape that should help in the designation of touristic subaquatic trails analogous to those commonly used in terrestrial landscapes. We elaborated a system of 18 “Perceptible Seascape Elements”, grouped into 9 Concepts, that leads to a “Potential Observation Index” summarizing the seabed landscape qualities that can be observed while snorkeling. Tests of this approach in a National Park (Parque Nacional Marítimo-Terrestre de las Islas Atlánticas de Galicia led to the design and ranking of 6 underwater trails. On the other hand, we used standardized questionnaires to determine the attributes of park’s visitors, their expectative, their perception of the marine environment, and previous skills in snorkeling. Many visitors were mostly unaware of the qualities of the marine environment of the National Park but we found considerable interest in new alternatives to enjoy the marine environment such as snorkeling. Our procedure and results could help to add snorkeling to the set of environmental education strategies already used in the Park.

  10. The emphysematous lung is abnormally sensitive to TRAIL-mediated apoptosis

    Directory of Open Access Journals (Sweden)

    Milot Julie

    2011-08-01

    Full Text Available Abstract Background Alveolar apoptosis is increased in the emphysematous lung. However, mechanisms involved are not fully understood. Recently, we demonstrated that levels of TRAIL receptor 1 and 2, levels of p53, and Bax/Bcl-xL ratio were elevated in the lung of subjects with emphysema, despite smoking cessation. Thus, we postulate that due to chronic pulmonary oxidative stress, the emphysematous lung would be abnormally sensitive to TRAIL-mediated apoptosis. Methodology A549 cells were exposed to rTRAIL, cigarette smoke extract, and/or H2O2 prior to caspase-3 activity measurement and annexin V staining assessment. In addition, freshly resected lung samples were obtained from non-emphysematous and emphysematous subjects and exposed ex vivo to rTRAIL for up to 18 hours. Lung samples were harvested and levels of active caspase-3 and caspase-8 were measured from tissue lysates. Results Both cigarette smoke extract and H2O2 were able to sensitize A549 cells to TRAIL-mediated apoptosis. Moreover, following exposure to rTRAIL, caspase-3 and -8 were activated in lung explants from emphysematous subjects while being decreased in lung explants from non-emphysematous subjects. Significance of the study Alveolar sensitivity to TRAIL-mediated apoptosis is strongly increased in the emphysematous lung due to the presence of oxidative stress. This might be a new mechanism leading to increased alveolar apoptosis and persistent alveolar destruction following smoking cessation.

  11. Potential prognostic significance of decreased serum levels of TRAIL after acute myocardial infarction.

    Directory of Open Access Journals (Sweden)

    Paola Secchiero

    Full Text Available BACKGROUND: Since soluble TRAIL exhibits anti-inflammatory and anti-atherosclerotic activities both in vitro and in animal models, this study was designed to assess the relationship between the serum levels of TRAIL and clinical outcomes in patients with acute myocardial infarction (AMI. METHODOLOGY/PRINCIPAL FINDINGS: Levels of TRAIL were measured by ELISA in serial serum samples obtained from 60 patients admitted for AMI, both during hospitalization and in a follow-up of 12 months, as well as in 60 healthy control subjects. Serum levels of TRAIL were significantly decreased in patients with AMI at baseline (within 24 hours from admission, compared with healthy controls, and showed a significant inverse correlation with a series of negative prognostic markers, such as CK, CK-MB and BNP. TRAIL serum levels progressively increased at discharge, but normalized only at 6-12 months after AMI. Of note, low TRAIL levels at the patient discharge were associated with increased incidence of cardiac death and heart failure in the 12-month follow-up, even after adjustment for demographic and clinical risk parameters (hazard ratio [HR] of 0.93 [95% CI, 0.89 to 0.97]; p = 0.001. CONCLUSIONS/SIGNIFICANCE: Although the number of patients studied was limited, our findings indicate for the first time that circulating TRAIL might represent an important predictor of cardiovascular events, independent of conventional risk markers.

  12. Cellular characterisation of Candida tropicalis presenting fluconazole-related trailing growth

    Directory of Open Access Journals (Sweden)

    Marcos Dornelas-Ribeiro

    2012-02-01

    Full Text Available We assessed fluconazole susceptibility in 52 Candida tropicalis clinical strains using seven antifungal susceptibility methods, including broth microdilution (BMD [standard M27 A3 (with neutral and acid pH, ATB Fungus 3, Vitek 2 system and flow cytometric analysis] and agar-based methods (disk diffusion and E-test. Trailing growth, detection of cell-associated secreted aspartic proteases (Saps and morphological and ultrastructural traits of these clinical strains were also examined. The ranges of fluconazole 24 h-minimum inhibitory concentration (MIC values were similar among all methods. The essential agreement among the methods used for MIC determinations was excellent and all methods categorised all strains as susceptible, except for one strain that showed a minor error. The presence of the trailing effect was assessed by six methods. Trailing positivity was observed for 86.5-100% of the strains. The exception was the BMD-Ac method where trailing growth was not observed. Morphological and ultrastructural alterations were detected in C. tropicalis trailing cells, including mitochondrial swelling and cell walls with irregular shapes. We tested the production of Saps in 13 C. tropicalis strains expressing trailing growth through flow cytometry. Our results showed that all of the C. tropicalis strains up-regulated surface Sap expression after 24 h or 48 h of exposure to fluconazole, which was not observed in untreated yeast strains. We concluded that C. tropicalis strains expressing trailing growth presented some particular features on both biological and ultrastructural levels.

  13. Spatially characterizing visitor use and its association with informal trails in Yosemite Valley meadows.

    Science.gov (United States)

    Walden-Schreiner, Chelsey; Leung, Yu-Fai

    2013-07-01

    Ecological impacts associated with nature-based recreation and tourism can compromise park and protected area goals if left unrestricted. Protected area agencies are increasingly incorporating indicator-based management frameworks into their management plans to address visitor impacts. Development of indicators requires empirical evaluation of indicator measures and examining their ecological and social relevance. This study addresses the development of the informal trail indicator in Yosemite National Park by spatially characterizing visitor use in open landscapes and integrating use patterns with informal trail condition data to examine their spatial association. Informal trail and visitor use data were collected concurrently during July and August of 2011 in three, high-use meadows of Yosemite Valley. Visitor use was clustered at statistically significant levels in all three study meadows. Spatial data integration found no statistically significant differences between use patterns and trail condition class. However, statistically significant differences were found between the distance visitors were observed from informal trails and visitor activity type with active activities occurring closer to trail corridors. Gender was also found to be significant with male visitors observed further from trail corridors. Results highlight the utility of integrated spatial analysis in supporting indicator-based monitoring and informing management of open landscapes. Additional variables for future analysis and methodological improvements are discussed.

  14. Comparison of trailside degradation across a gradient of trail use in the Sonoran Desert.

    Science.gov (United States)

    Rowe, Helen Ivy; Tluczek, Melanie; Broatch, Jennifer; Gruber, Dan; Jones, Steve; Langenfeld, Debbie; McNamara, Peggy; Weinstein, Leona

    2018-02-01

    As recreational visitation to the Sonoran Desert increases, the concern of scientists, managers and advocates who manage its natural resources deepens. Although many studies have been conducted on trampling of undisturbed vegetation and the effects of trails on adjacent plant and soil communities, little such research has been conducted in the arid southwest. We sampled nine 450-m trail segments with different visitation levels in Scottsdale's McDowell Sonoran Preserve over three years to understand the effects of visitation on soil erosion, trailside soil crusts and plant communities. Soil crust was reduced by 27-34% near medium and high use trails (an estimated peak rate of 13-70 visitors per hour) compared with control plots, but there was less than 1% reduction near low use trails (peak rate of two to four visitors per hour). We did not detect soil erosion in the center 80% of the trampled area of any of the trails. The number of perennial plant species dropped by less than one plant species on average, but perennial plant cover decreased by 7.5% in trailside plots compared with control plots 6 m off-trail. At the current levels of visitation, the primary management focus should be keeping people on the originally constructed trail tread surface to reduce impact to adjacent soil crusts. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. Spatially Characterizing Visitor Use and Its Association with Informal Trails in Yosemite Valley Meadows

    Science.gov (United States)

    Walden-Schreiner, Chelsey; Leung, Yu-Fai

    2013-07-01

    Ecological impacts associated with nature-based recreation and tourism can compromise park and protected area goals if left unrestricted. Protected area agencies are increasingly incorporating indicator-based management frameworks into their management plans to address visitor impacts. Development of indicators requires empirical evaluation of indicator measures and examining their ecological and social relevance. This study addresses the development of the informal trail indicator in Yosemite National Park by spatially characterizing visitor use in open landscapes and integrating use patterns with informal trail condition data to examine their spatial association. Informal trail and visitor use data were collected concurrently during July and August of 2011 in three, high-use meadows of Yosemite Valley. Visitor use was clustered at statistically significant levels in all three study meadows. Spatial data integration found no statistically significant differences between use patterns and trail condition class. However, statistically significant differences were found between the distance visitors were observed from informal trails and visitor activity type with active activities occurring closer to trail corridors. Gender was also found to be significant with male visitors observed further from trail corridors. Results highlight the utility of integrated spatial analysis in supporting indicator-based monitoring and informing management of open landscapes. Additional variables for future analysis and methodological improvements are discussed.

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

    International Nuclear Information System (INIS)

    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

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

    Directory of Open Access Journals (Sweden)

    Heinrich B

    2017-05-01

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

  18. Combination of systemic chemotherapy with local stem cell delivered S-TRAIL in resected brain tumors.

    Science.gov (United States)

    Redjal, Navid; Zhu, Yanni; Shah, Khalid

    2015-01-01

    Despite advances in standard therapies, the survival of glioblastoma multiforme (GBM) patients has not improved. Limitations to successful translation of new therapies include poor delivery of systemic therapies and use of simplified preclinical models which fail to reflect the clinical complexity of GBMs. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis specifically in tumor cells and we have tested its efficacy by on-site delivery via engineered stem cells (SC) in mouse models of GBM that mimic the clinical scenario of tumor aggressiveness and resection. However, about half of tumor lines are resistant to TRAIL and overcoming TRAIL-resistance in GBM by combining therapeutic agents that are currently in clinical trials with SC-TRAIL and understanding the molecular dynamics of these combination therapies are critical to the broad use of TRAIL as a therapeutic agent in clinics. In this study, we screened clinically relevant chemotherapeutic agents for their ability to sensitize resistant GBM cell lines to TRAIL induced apoptosis. We show that low dose cisplatin increases surface receptor expression of death receptor 4/5 post G2 cycle arrest and sensitizes GBM cells to TRAIL induced apoptosis. In vivo, using an intracranial resection model of resistant primary human-derived GBM and real-time optical imaging, we show that a low dose of cisplatin in combination with synthetic extracellular matrix encapsulated SC-TRAIL significantly decreases tumor regrowth and increases survival in mice bearing GBM. This study has the potential to help expedite effective translation of local stem cell-based delivery of TRAIL into the clinical setting to target a broad spectrum of GBMs. © 2014 AlphaMed Press.

  19. Absence of death receptor translocation into lipid rafts in acquired TRAIL-resistant NSCLC cells.

    Science.gov (United States)

    Ouyang, Wen; Yang, Chunxu; Zhang, Simin; Liu, Yu; Yang, Bo; Zhang, Junhong; Zhou, Fuxiang; Zhou, Yunfeng; Xie, Conghua

    2013-02-01

    Resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a major limitation for its clinical use. The mechanisms of TRAIL resistance have been mostly studied in the context of cell lines that are intrinsically resistant to TRAIL. However, little is known about the molecular alterations that contribute to the development of acquired resistance during treatment with TRAIL. In this study, we established H460R, an isogenic cell line with acquired TRAIL resistance, from the TRAIL‑sensitive human lung cancer cell line H460 to investigate the mechanisms of acquired resistance. The acquired TRAIL‑resistant H460R cells remained sensitive to cisplatin. The mRNA and protein expression levels of death receptor 4 (DR4) and death receptor 5 (DR5) were not altered in either of the TRAIL-treated cell lines. Nevertheless, tests in which the DR4 or DR5 gene was overexpressed or silenced suggest that death receptor expression is necessary but not sufficient for TRAIL‑induced apoptosis. Compared with parental TRAIL-sensitive H460 cells, H460R cells showed a decreased TRAIL-induced translocation of DR4/DR5 into lipid rafts. Further studies showed that nystatin partially prevented lipid raft aggregation and DR4 and DR5 clustering and reduced apoptosis in H460 cells again. Analysis of apoptotic molecules showed that more pro-caspase-8, FADD, caspase-3 and Bid, but less cFLIP in H460 cells than in H460R cells. Our findings suggest that the lack of death receptor redistribution negatively impacts DISC assembly in lipid rafts, which at least partially leads to the development of acquired resistance to TRAIL in H460R cells.

  20. Recreational trails as corridors for alien plants in the Rocky Mountains, USA

    Science.gov (United States)

    Wells, Floye H.; Lauenroth, William K.; Bradford, John B.

    2012-01-01

    Alien plant species often use areas of heavy human activity for habitat and dispersal. Roads and utility corridors have been shown to harbor more alien species than the surrounding vegetation and are therefore believed to contribute to alien plant persistence and spread. Recreational trails represent another corridor that could harbor alien species and aid their spread. Effective management of invasive species requires understanding how alien plants are distributed at trailheads and trails and how their dispersal may be influenced by native vegetation. Our overall goal was to investigate the distribution of alien plants at trailheads and trails in the Rocky Mountains of Colorado. At trailheads, we found that although the number of alien species was less than the number of native species, alien plant cover ( x̄=50%) did not differ from native plant cover, and we observed a large number of alien seedlings in the soil seed bank, suggesting that alien plants are a large component of trailhead communities and will continue to be so in the future. Along trails, we found higher alien species richness and cover on trail (as opposed to 4 m from the trail) in 3 out of 4 vegetation types, and we observed higher alien richness and cover in meadows than in other vegetation types. Plant communities at both trailheads and trails, as well as seed banks at trailheads, contain substantial diversity and abundance of alien plants. These results suggest that recreational trails in the Rocky Mountains of Colorado may function as corridors that facilitate the spread of alien species into wildlands. Our results suggest that control of alien plants should begin at trailheads where there are large numbers of aliens and that control efforts on trails should be prioritized by vegetation type.

  1. Aerodynamic behavior of an airfoil with morphing trailing edge for wind turbine applications

    Science.gov (United States)

    Wolff, T.; Ernst, B.; Seume, J. R.

    2014-06-01

    The length of wind turbine rotor blades has been increased during the last decades. Higher stresses arise especially at the blade root because of the longer lever arm. One way to reduce unsteady blade-root stresses caused by turbulence, gusts, or wind shear is to actively control the lift in the blade tip region. One promising method involves airfoils with morphing trailing edges to control the lift and consequently the loads acting on the blade. In the present study, the steady and unsteady behavior of an airfoil with a morphing trailing edge is investigated. Two-dimensional Reynolds-Averaged Navier-Stokes (RANS) simulations are performed for a typical thin wind turbine airfoil with a morphing trailing edge. Steady-state simulations are used to design optimal geometry, size, and deflection angles of the morphing trailing edge. The resulting steady aerodynamic coefficients are then analyzed at different angles of attack in order to determine the effectiveness of the morphing trailing edge. In order to investigate the unsteady aerodynamic behavior of the optimal morphing trailing edge, time- resolved RANS-simulations are performed using a deformable grid. In order to analyze the phase shift between the variable trailing edge deflection and the dynamic lift coefficient, the trailing edge is deflected at four different reduced frequencies for each different angle of attack. As expected, a phase shift between the deflection and the lift occurs. While deflecting the trailing edge at angles of attack near stall, additionally an overshoot above and beyond the steady lift coefficient is observed and evaluated.

  2. Aerodynamic behavior of an airfoil with morphing trailing edge for wind turbine applications

    International Nuclear Information System (INIS)

    Wolff, T; Ernst, B; Seume, J R

    2014-01-01

    The length of wind turbine rotor blades has been increased during the last decades. Higher stresses arise especially at the blade root because of the longer lever arm. One way to reduce unsteady blade-root stresses caused by turbulence, gusts, or wind shear is to actively control the lift in the blade tip region. One promising method involves airfoils with morphing trailing edges to control the lift and consequently the loads acting on the blade. In the present study, the steady and unsteady behavior of an airfoil with a morphing trailing edge is investigated. Two-dimensional Reynolds-Averaged Navier-Stokes (RANS) simulations are performed for a typical thin wind turbine airfoil with a morphing trailing edge. Steady-state simulations are used to design optimal geometry, size, and deflection angles of the morphing trailing edge. The resulting steady aerodynamic coefficients are then analyzed at different angles of attack in order to determine the effectiveness of the morphing trailing edge. In order to investigate the unsteady aerodynamic behavior of the optimal morphing trailing edge, time- resolved RANS-simulations are performed using a deformable grid. In order to analyze the phase shift between the variable trailing edge deflection and the dynamic lift coefficient, the trailing edge is deflected at four different reduced frequencies for each different angle of attack. As expected, a phase shift between the deflection and the lift occurs. While deflecting the trailing edge at angles of attack near stall, additionally an overshoot above and beyond the steady lift coefficient is observed and evaluated

  3. Dust dynamics in off-road vehicle trails: Measurements on 16 arid soil types, Nevada, USA.

    Science.gov (United States)

    Goossens, Dirk; Buck, Brenda

    2009-08-01

    Soil analyses and measurements with the Portable In Situ Wind Erosion Laboratory (PI-SWERL) were conducted on 16 soil types in an area heavily affected by off-road vehicle (ORV) driving. Measurements were performed in ORV trails as well as on undisturbed terrain to investigate how ORV driving affects the vulnerability of a soil to emit PM10 (particlestrail affects those properties of the topsoil that determine its capability to emit PM10. Also, recommendations are given for adequate management of ORV-designed areas. The type of surface (sand, silt, gravel, drainage) is a key factor with respect to dust emission in an ORV trail. Trails in sand, defined in this study as the grain size fraction 63-2000microm, show higher deflation thresholds (the critical wind condition at which wind erosion starts) than the surrounding undisturbed soil. Trails in silt (2-63microm) and in drainages, on the other hand, have lower deflation thresholds than undisturbed soil. The increase in PM10 emission resulting from the creation of a new ORV trail is much higher for surfaces with silt than for surfaces with sand. Also, the creation of a new trail in silt decreases the supply limitation in the top layer: the capacity of the reservoir of emission-available PM10 increases. For sand the situation is reversed: the supply limitation increases, and the capacity of the PM10 reservoir decreases. Finally, ORV trails are characterized by a progressive coarsening of the top layer with time, but the speed of coarsening is much lower in trails in silt than in trails in sand or in drainages. The results of this study suggest that, to minimize emissions of PM10, new ORV fields should preferably be designed on sandy terrain rather than in silt areas or in drainages.

  4. Elastically Deformable Side-Edge Link for Trailing-Edge Flap Aeroacoustic Noise Reduction

    Science.gov (United States)

    Khorrami, Mehdi R. (Inventor); Lockard, David P. (Inventor); Moore, James B. (Inventor); Su, Ji (Inventor); Turner, Travis L. (Inventor); Lin, John C. (Inventor); Taminger, Karen M. (Inventor); Kahng, Seun K. (Inventor); Verden, Scott A. (Inventor)

    2014-01-01

    A system is provided for reducing aeroacoustic noise generated by an aircraft having wings equipped with trailing-edge flaps. The system includes a plurality of elastically deformable structures. Each structure is coupled to and along one of the side edges of one of the trailing-edge flaps, and is coupled to a portion of one of the wings that is adjacent to the one of the side edges. The structures elastically deform when the trailing-edge flaps are deployed away from the wings.

  5. The impacts of trail infrastructure on vegetation and soils: Current literature and future directions.

    Science.gov (United States)

    Ballantyne, Mark; Pickering, Catherine Marina

    2015-12-01

    Reflecting the popularity of nature-based activities such as hiking and mountain biking, there are thousands of kilometres of recreational trails worldwide traversing a range of natural areas. These trails have environmental impacts on soils and vegetation, but where has there been research, what impacts have been found and how were they measured? Using a systematic quantitative literature review methodology, we assessed the impacts of trails on vegetation and soils, highlighting what is known, but also key knowledge gaps. Of the 59 original research papers identified on this topic that have been published in English language peer-reviewed academic journals, most were for research conducted in protected areas (71%), with few from developing countries (17%) or threatened ecosystems (14%). The research is concentrated in a few habitats and biodiversity hotspots, mainly temperate woodland, alpine grassland and Mediterranean habitats, often in the USA (32%) or Australia (20%). Most examined formal trails, with just 15% examining informal trails and 11% assessing both types. Nearly all papers report the results of observational surveys (90%), collecting quantitative data (66%) with 24% using geographic information systems. There was an emphasis on assessing trail impacts at a local scale, either on the trail itself and/or over short gradients away from the trail edge. Many assessed changes in composition and to some degree, structure, of vegetation and soils with the most common impacts documented including reduced vegetation cover, changes in plant species composition, trail widening, soil loss and soil compaction. There were 14 papers assessing how these local impacts can accumulate at the landscape scale. Few papers assessed differences in impacts among trails (7 papers), changes in impacts over time (4), species-specific responses (3) and only one assessed effects on plant community functioning. This review provides evidence that there are key research gaps

  6. Model predictive control of trailing edge flaps on a wind turbine blade

    Energy Technology Data Exchange (ETDEWEB)

    Castaignet, D.B.

    2011-11-15

    Trailing edge flaps on wind turbine blades have been investigated for several years. Aero-servoelastic simulations carried out with different simulation tools, trailing edge flaps configurations and controller designs proved that trailing edge flaps are a suitable solution for reducing some of the wind turbine fatigue and extreme loads. This potential was confirmed with wind tunnel tests made on blade sections with trailing edge flaps and on a scaled two-bladed wind turbine in a wind tunnel. The work presented in this thesis includes a full-scale test run on a Vestas V27 wind turbine equipped with three trailing edge flaps on one blade, located on DTU's Risoe Campus in Roskilde, Denmark. This thesis is divided into three parts: the controller design, results from simulations, and results from the experiments. The trailing edge flaps controller designed for this project is based on a frequency-weighted model predictive control, tuned in order to target only the flapwise blade root loads at the frequencies contributing the most to blade root fatigue damage (the 1P, 2P and 3P frequencies), and to avoid unnecessary wear and tear of the actuators at high frequencies. A disturbance model consisting in periodic disturbances at the rotor speed harmonic frequencies and a quasi-steady input disturbance is aggregated to an analytical model of a spinning blade with trailing edge flaps. Simulations on a multi-megawatt wind turbine show the potential of the trailing edge flaps to reduce the flapwise blade root fatigue loads by 23%, but also the main shaft and the tower fatigue loads by up to 32%. Extreme loads during normal production also benefit from the trailing edge flaps. At last, the same controller was run on the Vestas V27 wind turbine located at the Risoe Campus of the Technical University of Denmark, in Roskilde, Denmark. One blade of the turbine was equipped with three independent trailing edge flaps. In spite of the failure of several sensors and actuators, the

  7. Primary control of a Mach scale swashplateless rotor using brushless DC motor actuated trailing edge flaps

    Science.gov (United States)

    Saxena, Anand

    The focus of this research was to demonstrate a four blade rotor trim in forward flight using integrated trailing edge flaps instead of using a swashplate controls. A compact brushless DC motor was evaluated as an on-blade actuator, with the possibility of achieving large trailing edge flap amplitudes. A control strategy to actuate the trailing edge flap at desired frequency and amplitude was developed and large trailing edge flap amplitudes from the motor (instead of rotational motion) were obtained. Once the actuator was tested on the bench-top, a lightweight mechanism was designed to incorporate the motor in the blade and actuate the trailing edge flaps. A six feet diameter, four bladed composite rotor with motor-flap system integrated into the NACA 0012 airfoil section was fabricated. Systematic testing was carried out for a range of load conditions, first in the vacuum chamber followed by hover tests. Large trailing edge flap deflections were observed during the hover testing, and a peak to peak trailing edge flap amplitude of 18 degree was achieved at 2000 rotor RPM with hover tip Mach number of 0.628. A closed loop controller was designed to demonstrate trailing edge flap mean position and the peak to peak amplitude control. Further, a soft pitch link was designed and fabricated, to replace the stiff pitch link and thereby reduce the torsional stiffness of the blade to 2/rev. This soft pitch link allowed for blade root pitch motion in response to the trailing edge flap inputs. Blade pitch response due to both steady as well as sinusoidal flap deflections were demonstrated. Finally, tests were performed in Glenn L. Martin wind tunnel using a model rotor rig to assess the performance of motor-flap system in forward flight. A swashplateless trim using brushless DC motor actuated trailing edge flaps was achieved for a rotor operating at 1200 RPM and an advance ratio of 0.28. Also, preliminary exploration was carried out to test the scalability of the motor

  8. Silencing the epigenetic silencer KDM4A for TRAIL and DR5 simultaneous induction and antitumor therapy.

    Science.gov (United States)

    Wang, Junjian; Wang, Haibin; Wang, Ling-Yu; Cai, Demin; Duan, Zhijian; Zhang, Yanhong; Chen, Peng; Zou, June X; Xu, Jianzhen; Chen, Xinbin; Kung, Hsing-Jien; Chen, Hong-Wu

    2016-11-01

    Recombinant TRAIL and agonistic antibodies to death receptors (DRs) have been in clinical trial but displayed limited anti-cancer efficacy. Lack of functional DR expression in tumors is a major limiting factor. We report here that chromatin regulator KDM4A/JMJD2A, not KDM4B, has a pivotal role in silencing tumor cell expression of both TRAIL and its receptor DR5. In TRAIL-sensitive and -resistant cancer cells of lung, breast and prostate, KDM4A small-molecule inhibitor compound-4 (C-4) or gene silencing strongly induces TRAIL and DR5 expression, and causes TRAIL-dependent apoptotic cell death. KDM4A inhibition also strongly sensitizes cells to TRAIL. C-4 alone potently inhibits tumor growth with marked induction of TRAIL and DR5 expression in the treated tumors and effectively sensitizes them to the newly developed TRAIL-inducer ONC201. Mechanistically, C-4 does not appear to act through the Akt-ERK-FOXO3a pathway. Instead, it switches histone modifying enzyme complexes at promoters of TRAIL and DR5 transcriptional activator CHOP gene by dissociating KDM4A and nuclear receptor corepressor (NCoR)-HDAC complex and inducing the recruitment of histone acetylase CBP. Thus, our results reveal KDM4A as a key epigenetic silencer of TRAIL and DR5 in tumors and establish inhibitors of KDM4A as a novel strategy for effectively sensitizing tumors to TRAIL pathway-based therapeutics.

  9. Efforts of a Kansas foundation to increase physical activity and improve health by funding community trails, 2012.

    Science.gov (United States)

    Heinrich, Katie M; Lightner, Joseph; Oestman, Katherine B; Hughey, S Morgan; Kaczynski, Andrew T

    2014-11-26

    Trails are associated with increased physical activity; however, little is known about the process of building trails by various types of organizations. From 2005 through 2012 the Sunflower Foundation: Health Care for Kansans (Sunflower) funded multiple organizations to construct 70 trails of varying lengths and surfaces in municipalities, schools, and communities across Kansas. The purpose of this study was to assess the process of developing and implementing community trail projects across Kansas with funding from a public foundation. In 2012, we stratified funded organizations by type and conducted proportional random sampling to select 20 key informants from those organizations to participate in structured telephone interviews. Interviews were recorded and transcribed verbatim. Two researchers coded interview transcripts according to issues identified by participants. Issues associated with trail-building identified as important were collaboration among groups, unexpected construction costs, champions for the project, and level of difficulty of construction. Participants indicated that trails facilitated physical activity. Trails were integrated into communities through events such as walking events and other promotional efforts; these efforts were thought to increase trail use. The perceived outcomes of building the trails included providing the community with a physical activity resource, inspiring the community to start additional trail projects, and increasing the physical activity of local residents. Sunflower's funding was instrumental in developing trail projects to provide new physical activity resources across Kansas. Public health practitioners seeking to increase physical activity should seek funding from foundations that focus on health.

  10. Heat Transfer and Friction Studies in a Tilted and Rib-Roughened Trailing-Edge Cooling Cavity with and without the Trailing-Edge Cooling Holes

    Directory of Open Access Journals (Sweden)

    M. E. Taslim

    2014-01-01

    Full Text Available Local and average heat transfer coefficients and friction factors were measured in a test section simulating the trailing-edge cooling cavity of a turbine airfoil. The test rig with a trapezoidal cross-sectional area was rib-roughened on two opposite sides of the trapezoid (airfoil pressure and suction sides with tapered ribs to conform to the cooling cavity shape and had a 22-degree tilt in the flow direction upstream of the ribs that affected the heat transfer coefficients on the two rib-roughened surfaces. The radial cooling flow traveled from the airfoil root to the tip while exiting through 22 cooling holes along the airfoil trailing-edge. Two rib geometries, with and without the presence of the trailing-edge cooling holes, were examined. The numerical model contained the entire trailing-edge channel, ribs, and trailing-edge cooling holes to simulate exactly the tested geometry. A pressure-correction based, multiblock, multigrid, unstructured/adaptive commercial software was used in this investigation. Realizable k-ε turbulence model in conjunction with enhanced wall treatment approach for the near wall regions was used for turbulence closure. The applied thermal boundary conditions to the CFD models matched the test boundary conditions. Comparisons are made between the experimental and numerical results.

  11. Associations between sociodemographic characteristics and perceptions of the built environment with the frequency, type, and duration of physical activity among trail users.

    Science.gov (United States)

    Maslow, Andréa L; Reed, Julian A; Price, Anna E; Hooker, Steven P

    2012-01-01

    Rail trails are elements of the built environment that support the Task Force on Community Preventive Services' recommendation to create, or enhance access to, places for physical activity (PA). The purpose of this study was to examine the associations between sociodemographic characteristics and perceptions of the built environment with the frequency, type, and duration of PA among users of an urban, paved rail trail segment. Interviewers conducted intercept surveys with 431 rail trail users and analyzed data by using logistic regression to estimate odds ratios between sociodemographic characteristics and perceptions of the built environment on the frequency, type, and duration of PA performed on the trail. Adults who used the trail in the cool months, traveled to the trail by a motorized vehicle, used the trail with others, and had some graduate school education visited the trail less often. Younger adults, men, whites, and those with some graduate school education were more likely to engage in vigorous activities on the trail. Adults who traveled to the trail by a motorized vehicle spent more time engaged in PA on the trail. Our results suggest that the most frequent users of a rail trail for PA are those who use the trail alone and travel to the trail by bicycle or on foot. Trails are an aspect of the built environment that supports active lifestyles, and future studies should evaluate different types of trails among more diverse populations and locations.

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

    Directory of Open Access Journals (Sweden)

    Pittet Anne-Laure

    2006-10-01

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

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

    International Nuclear Information System (INIS)

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

    2012-01-01

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

  14. Curcumin enhances TRAIL-induced apoptosis of breast cancer cells by regulating apoptosis-related proteins

    Czech Academy of Sciences Publication Activity Database

    Park, S.; Cho, D. J.; Anděra, Ladislav; Suh, N.; Kim, I.

    2013-01-01

    Roč. 383, 1-2 (2013), s. 39-48 ISSN 0300-8177 Institutional support: RVO:68378050 Keywords : TRAIL * curcumin * apoptosis * breast cancer Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.388, year: 2013

  15. VisTrails is an open-source scientific workflow and provenance management system

    CSIR Research Space (South Africa)

    Mthombeni, Thabo DM

    2011-12-01

    Full Text Available VisTrails is an open-source scientific workflow and provenance management system that provides support for simulations, data exploration and visualization. Whereas workflows have been traditionally used to automate repetitive tasks, for applications...

  16. Effect of Her-2/neu Signaling on Sensitivity to TRAIL in Prostate Cancer

    National Research Council Canada - National Science Library

    Lee, Yong J

    2005-01-01

    .... In this study, we observed that pretreatment of acetyl salicylic acid (ASA) augmented TRAIL-induced apoptotic death in human prostate adenocarcinoma LNCaP and human colorectal carcinoma CX-1 cells...

  17. Fast Trailed Vorticity Modeling for Wind Turbine Aerodynamics and its Influence on Aeroelastic Stability

    DEFF Research Database (Denmark)

    Pirrung, Georg

    In this work, an aerodynamic model for the use in aeroelastic wind turbine codes is presented. It consists of a simplified lifting line model covering the induction due to the trailed vorticity in the near wake, a 2D shed vorticity model and a far wake model using the well known blade element...... to earlier implementations, the model has been improved in several ways: Among other things, the need for model-specific user input has been removed, the effect of downwind convection of the trailed vorticity is modeled, the near wake induction is iterated to stabilize the computations and the numerical......-of-plane vibrations agrees much better with high fidelity models. Further, the trailed vorticity effects on the aerodynamic work are found to be of the same order of magnitude as the shed vorticity effects. The trailed vorticity effects are, however, mainly important close to the tip in the investigated cases, which...

  18. Trail pheromone of the leaf-cutting ant,Acromyrmex octospinosus (Reich), (Formicidae: Myrmicinae).

    Science.gov (United States)

    Cross, J H; West, J R; Silverstein, R M; Jutsum, A R; Cherrett, J M

    1982-08-01

    The most active component of the trail pheromone of the leafcutting ant,Acromyrmex octospinosus, is methyl 4-methylpyrrole-2-carboxylate (I). Two pyrazine isomers (II) and (III) are present but inactive.

  19. Numerical Investigation of Flow Control Feasibility with a Trailing Edge Flap

    International Nuclear Information System (INIS)

    Zhu, W J; Shen, W Z; Sørensen, J N

    2014-01-01

    This paper concerns a numerical study of employing an adaptive trailing edge flap to control the lift of an airfoil subject to unsteady inflow conditions. The periodically varying inflow is generated by two oscillating airfoils, which are located upstream of the controlled airfoil. To establish the control system, a standard PID controller is implemented in a finite volume based incompressible flow solver. An immersed boundary method is applied to treat the problem of simulating a deformable airfoil trailing edge. The flow field is solved using a 2D Reynolds averaged Navier-Stokes finite volume solver. In order to more accurately simulate wall bounded flows around the immersed boundary, a modified boundary condition is introduced in the k- ω turbulence model. As an example, turbulent flow over a NACA 64418 airfoil with a deformable trailing edge is investigated. Results from numerical simulations are convincing and may give some highlights for practical implementations of trailing edge flap to a wind turbine rotor blade

  20. Fascaplysin sensitizes cells to TRAIL-induced apoptosis through upregulating DR5 expression

    Science.gov (United States)

    Wang, Feng; Chen, Haimin; Yan, Xiaojun; Zheng, Yanling

    2013-05-01

    This study investigated the molecular mechanism of anti-tumor effect of fascaplysin, a nitrogenous red pigment firstly isolated from a marine sponge. Microarray analysis show that the TNF and TNF receptor superfamily in human umbilical vein endothelial cells (HUVEC) and human hepatocarcinoma cells (BEL-7402) were significantly regulated by fascaplysin. Western Blot results reveal that fascaplysin increased the expression of cleaved caspase-9, active caspase-3, and decreased the level of procaspase-8 and Bid. Flow cytometry and cytotoxicity tests indicate that fascaplysin sensitized cells to tumor necrosis-related apoptosisinducing ligand-(TRAIL) induced apoptosis, which was markedly blocked by TRAIL R2/Fc chimera, a dominant negative form of TRAIL receptor DR5. Therefore, our results demonstrate that fascaplysin promotes apoptosis through the activation of TRAIL signaling pathway by upregulating DR5 expression.

  1. Regulation of TRAIL-Mediated Apoptosis in Prostate Cancer by Overexpression in XIAP

    National Research Council Canada - National Science Library

    Bonavida, Benjamin

    2004-01-01

    .... Among the TNF-alpha superfamily, TRAIL has been shown to be selectively cytotoxic to cancer cells and poorly cytotoxic to normal cells and is, therefore, considered as a good candidate for prostate cancer therapy...

  2. Effect of density on traffic and velocity on trunk trails of Formica pratensis.

    Science.gov (United States)

    Hönicke, C; Bliss, P; Moritz, R F A

    2015-04-01

    The allocation of large numbers of workers facilitates the swift intake of locally available resources which is essential for ant colony survival. To organise the traffic between nest and food source, the black-meadow ant Formica pratensis establishes permanent trunk trails, which are maintained by the ants. To unravel the ant organisation and potential traffic rules on these trails, we analysed velocity and lane segregation under various densities by experimentally changing feeding regimes. Even under the highest ant densities achieved, we never observed any traffic jams. On the contrary, velocity increased after supplementary feeding despite an enhanced density. Furthermore, inbound ants returning to the nest had a higher velocity than those leaving the colony. Whilst at low and medium density the ants used the centre of the trail, they used the full width of the trail at high density. Outbound ants also showed some degree of lane segregation which contributes to traffic organisation.

  3. Rats track odour trails accurately using a multi-layered strategy with near-optimal sampling.

    Science.gov (United States)

    Khan, Adil Ghani; Sarangi, Manaswini; Bhalla, Upinder Singh

    2012-02-28

    Tracking odour trails is a crucial behaviour for many animals, often leading to food, mates or away from danger. It is an excellent example of active sampling, where the animal itself controls how to sense the environment. Here we show that rats can track odour trails accurately with near-optimal sampling. We trained rats to follow odour trails drawn on paper spooled through a treadmill. By recording local field potentials (LFPs) from the olfactory bulb, and sniffing rates, we find that sniffing but not LFPs differ between tracking and non-tracking conditions. Rats can track odours within ~1 cm, and this accuracy is degraded when one nostril is closed. Moreover, they show path prediction on encountering a fork, wide 'casting' sweeps on encountering a gap and detection of reappearance of the trail in 1-2 sniffs. We suggest that rats use a multi-layered strategy, and achieve efficient sampling and high accuracy in this complex task.

  4. Recreational trails as a source of negative impacts on the persistence of keystone species and facilitation.

    Science.gov (United States)

    Ballantyne, Mark; Pickering, Catherine Marina

    2015-08-15

    Hiking trails, which are among the most common forms of infrastructure created for nature-based tourism, can alter key ecological processes. Trails can damage plants that facilitate the establishment and growth of other species leading to changes in community and functional composition. This can be a particular concern in harsh alpine ecosystems where plant communities are often dominated by one or two keystone species that provide shelter to a suite of beneficiary species. We analysed how a hiking trail affects interspecific facilitation by a dominant trampling-sensitive nurse shrub in the highest National Park in Australia. First we assessed the effects of the trail on the abundance, size and density of the nurse shrub at different distances from the trail. We then compared species richness and composition between areas in, and out, of the nurse shrub's canopy at different distances from the trail. To better understand why some species may benefit from facilitation and any effects of the trail on the quality of facilitation we compared functional composition between quadrats using community trait weighted means calculated by combining plant composition with species functional traits (canopy height, leaf area, % dry weight of leaves and specific leaf area). The abundance, size and density of nurse shrubs was lower on the trail edges than further away, particularly on the leeward edge, where there was more bare ground and less shrub cover. There were differences in species richness, cover, composition and functional composition in and outside the nurse shrub canopy. The shrubs appeared to facilitate species with more competitive, but less stress tolerant traits (e.g. taller plants with leaves that were larger, had high specific leaf area and low dry matter content). However, despite reductions in nurse shrubs near the trail, where they do exist, they appear to provide the same 'quality' of facilitation as nurse shrubs further away. However, longer-term effects may

  5. Ischemic tolerance modulates TRAIL expression and its receptors and generates a neuroprotected phenotype

    OpenAIRE

    Cantarella, G; Pignataro, G; Di Benedetto, G; Anzilotti, S; Vinciguerra, A; Cuomo, O; Di Renzo, G F; Parenti, C; Annunziato, L; Bernardini, R

    2014-01-01

    TNF-related apoptosis inducing ligand (TRAIL), a member of the TNF superfamily released by microglia, appears to be involved in the induction of apoptosis following focal brain ischemia. Indeed, brain ischemia is associated with progressive enlargement of damaged areas and prominent inflammation. As ischemic preconditioning reduces inflammatory response to brain ischemia and ameliorates brain damage, the purpose of the present study was to evaluate the role of TRAIL and its receptors in strok...

  6. Novel HTS strategy identifies TRAIL-sensitizing compounds acting specifically through the caspase-8 apoptotic axis.

    Directory of Open Access Journals (Sweden)

    Darren Finlay

    Full Text Available Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL is potentially a very important therapeutic as it shows selectivity for inducing apoptosis in cancer cells whilst normal cells are refractory. TRAIL binding to its cognate receptors, Death Receptors-4 and -5, leads to recruitment of caspase-8 and classical activation of downstream effector caspases, leading to apoptosis. As with many drugs however, TRAIL's usefulness is limited by resistance, either innate or acquired. We describe here the development of a novel 384-well high-throughput screening (HTS strategy for identifying potential TRAIL-sensitizing agents that act solely in a caspase-8 dependent manner. By utilizing a TRAIL resistant cell line lacking caspase-8 (NB7 compared to the same cells reconstituted with the wild-type protein, or with a catalytically inactive point mutant of caspase-8, we are able to identify compounds that act specifically through the caspase-8 axis, rather than through general toxicity. In addition, false positive hits can easily be "weeded out" in this assay due to their activity in cells lacking caspase-8-inducible activity. Screening of the library of pharmacologically active compounds (LOPAC was performed as both proof-of-concept and to discover potential unknown TRAIL sensitizers whose mechanism is caspase-8 mediated. We identified known TRAIL sensitizers from the library and identified new compounds that appear to sensitize specifically through caspase-8. In sum, we demonstrate proof-of-concept and discovery of novel compounds with a screening strategy optimized for the detection of caspase-8 pathway-specific TRAIL sensitizers. This screen was performed in the 384-well format, but could easily be further miniaturized, allows easy identification of artifactual false positives, and is highly scalable to accommodate diverse libraries.

  7. Self-guided trails – a route to more responsible tourism?

    OpenAIRE

    MacLeod, Nicola

    2016-01-01

    In recent years, the tourism industry has faced criticism by turning its attention to the development of more responsible tourism. This is a form of tourism that is mindful of the diverse needs of host communities, local business and the visitor. This paper investigates the development of more responsible tourism from the perspective of a popular tourist product – the self-guided trail or route. The trail or route provides a themed and interpreted journey through the urban or rural landscape,...

  8. BAG3 promotes the phenotypic transformation of primary rat vascular smooth muscle cells via TRAIL.

    Science.gov (United States)

    Fu, Yao; Chang, Ye; Chen, Shuang; Li, Yuan; Chen, Yintao; Sun, Guozhe; Yu, Shasha; Ye, Ning; Li, Chao; Sun, Yingxian

    2018-05-01

    Under normal physiological condition, the mature vascular smooth muscle cells (VSMCs) show differentiated phenotype. In response to various environmental stimuluses, VSMCs convert from the differentiated phenotype to dedifferentiated phenotype characterized by the increased ability of proliferation/migration and the reduction of contractile ability. The phenotypic transformation of VSMCs played an important role in atherosclerosis. Both Bcl-2-associated athanogene 3 (BAG3) and tumor necrosis factor-related apopt-osis inducing ligand (TRAIL) involved in apoptosis. The relationship between BAG3 and TRAIL and their effects the proliferation and migration in VSMCs are rarely reported. This study investigated the effects of BAG3 on the phenotypic modulation and the potential underlying mechanisms in primary rat VSMCs. Primary rat VSMCs were extracted and cultured in vitro. Cell proliferation was detected by cell counting, real-time cell analyzer (RTCA) and EdU incorporation. Cell migration was detected by wound healing, Transwell and RTCA. BAG3 and TRAIL were detected using real-time PCR and western blotting and the secreted proteins in the cultured media by dot blot. The expression of BAG3 increased with continued passages in cultured primary VSMCs. BAG3 promoted the proliferation and migration of primary rat VSMC in a time-dependent manner. BAG3 significantly increased the expression of TRAIL while had no effects on its receptors. TRAIL knockdown or blocking by neutralizing antibody inhibited the proliferation of VSMCs induced by BAG3. TRAIL knockdown exerted no obvious influence on the migration of VSMCs. Based on this study, we report for the first time that BAG3 was expressed in cultured primary rat VSMCs and the expression of BAG3 increased with continued passages. Furthermore, BAG3 promoted the proliferation of VSMCs via increasing the expression of TRAIL. In addition, we also demonstrated that BAG3 promoted the migration of VSMCs independent of TRAIL

  9. On the influence of neutral turbulence on ambipolar diffusivities deduced from meteor trail expansion

    Directory of Open Access Journals (Sweden)

    C. M. Hall

    Full Text Available By measuring fading times of radar echoes from underdense meteor trails, it is possible to deduce the ambipolar diffusivities of the ions responsible for these radar echoes. It could be anticipated that these diffusivities increase monotonically with height akin to neutral viscosity. In practice, this is not always the case. Here, we investigate the capability of neutral turbulence to affect the meteor trail diffusion rate.

    Key words. Meteorology and atmospheric dynamics (middle atmosphere dynamics; turbulence

  10. On the influence of neutral turbulence on ambipolar diffusivities deduced from meteor trail expansion

    Directory of Open Access Journals (Sweden)

    C. M. Hall

    2002-11-01

    Full Text Available By measuring fading times of radar echoes from underdense meteor trails, it is possible to deduce the ambipolar diffusivities of the ions responsible for these radar echoes. It could be anticipated that these diffusivities increase monotonically with height akin to neutral viscosity. In practice, this is not always the case. Here, we investigate the capability of neutral turbulence to affect the meteor trail diffusion rate.Key words. Meteorology and atmospheric dynamics (middle atmosphere dynamics; turbulence

  11. Dynamics of foraging trails in the Neotropical termite Velocitermes heteropterus (Isoptera: Termitidae).

    Science.gov (United States)

    Haifig, Ives; Jost, Christian; Fourcassié, Vincent; Zana, Yossi; Costa-Leonardo, Ana Maria

    2015-09-01

    Foraging behavior in termites varies with the feeding habits of each species but often occurs through the formation of well-defined trails that connect the nest to food sources in species that build structured nests. We studied the formation of foraging trails and the change in caste ratio during foraging in the termite Velocitermes heteropterus. This species is widespread in Cerrado vegetation where it builds epigeal nests and forages in open-air at night. Our aim was to understand the processes involved in the formation of foraging trails, from the exploration of new unmarked areas to the recruitment of individuals to food and the stabilization of traffic on the trails, as well as the participation of the different castes during these processes. Foraging trails were videotaped in the laboratory and the videos were then analyzed both manually and automatically to assess the flow of individuals and the caste ratio on the trails as well as to examine the spatial organization of traffic over time. Foraging trails were composed of minor workers, major workers, and soldiers. The flow of individuals on the trails gradually increased from the beginning of the exploration of new areas up to the discovery of the food. The caste ratio remained constant throughout the foraging excursion: major workers, minor workers and soldiers forage in a ratio of 8:1:1, respectively. The speed of individuals was significantly different among castes, with major workers and soldiers being significantly faster than minor workers. Overall, our results show that foraging excursions in V. heteropterus may be divided in three different phases, characterized by individual speeds, differential flows and lane segregation. Copyright © 2015 Elsevier B.V. All rights reserved.

  12. Aerodynamic Characteristics of Airfoils with Blunt Trailing Edge

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    Alejandro Gómez

    2006-11-01

    Full Text Available El siguiente trabajo estudia de manera computacional el comportamiento de las características aerodinámicas de perfiles NACA (National Advisory Committee for Aeronautics, hoy conocido como NASA, con modificaciones en el borde de salida. Las modificaciones consisten en remover secciones del borde de fuga del perfil. La investigación realizada estudia 39 perfiles diferentes de la familia NACA de 4 dígitos, con modelos teóricos sencillos para explicar los fenómenos. Los resultados muestran los cambios en las características de sustentación y arrastre del perfil, y cambios en cuanto a la entrada en pérdida del mismo./ This paper is a computational study of the behaviour of aerodynamic characteristics of NACA (National Advisory Committee for Aeronautics, today known as NASA profiles with tailored trailing edges. 39 different profiles 4-digit NACA family were studied during the research. A computational research was made, using simple theoretical models to explain and to understand the results. The results describe the changes in lift and drag characteristics and changes in stall angle of attack.

  13. Eulerian graph embeddings and trails confined to lattice tubes

    International Nuclear Information System (INIS)

    Soteros, C E

    2006-01-01

    Embeddings of graphs in sublattices of the square and simple cubic lattice known as tubes (or prisms) are considered. For such sublattices, two combinatorial bounds are obtained which each relate the number of embeddings of all closed eulerian graphs with k branch points (vertices of degree greater than two) to the number of self-avoiding polygons. From these bounds it is proved that the entropic critical exponent for the number of embeddings of closed eulerian graphs with k branch points is equal to k, and the entropic critical exponent for the number of closed trails with k branch points is equal to k + 1. One of the required combinatorial bounds is obtained via Madras' 1999 lattice cluster pattern theorem, which yields a bound on the number of ways to convert a self-avoiding polygon into a closed eulerian graph embedding with k branch points. The other combinatorial bound is established by constructing a method for sequentially removing branch points from a closed eulerian graph embedding; this yields a bound on the number of ways to convert a closed eulerian graph embedding into a self-avoiding polygon

  14. Aerodynamic Characteristic of the Active Compliant Trailing Edge Concept

    Science.gov (United States)

    Nie, Rui; Qiu, Jinhao; Ji, Hongli; Li, Dawei

    2016-06-01

    This paper introduces a novel Morphing Wing structure known as the Active Compliant Trailing Edge (ACTE). ACTE structures are designed using the concept of “distributed compliance” and wing skins of ACTE are fabricated from high-strength fiberglass composites laminates. Through the relative sliding between upper and lower wing skins which are connected by a linear guide pairs, the wing is able to achieve a large continuous deformation. In order to present an investigation about aerodynamics and noise characteristics of ACTE, a series of 2D airfoil analyses are established. The aerodynamic characteristics between ACTE and conventional deflection airfoil are analyzed and compared, and the impacts of different ACTE structure design parameters on aerodynamic characteristics are discussed. The airfoils mentioned above include two types (NACA0012 and NACA64A005.92). The computing results demonstrate that: compared with the conventional plane flap airfoil, the morphing wing using ACTE structures has the capability to improve aerodynamic characteristic and flow separation characteristic. In order to study the noise level of ACTE, flow field analysis using LES model is done to provide noise source data, and then the FW-H method is used to get the far field noise levels. The simulation results show that: compared with the conventional flap/aileron airfoil, the ACTE configuration is better to suppress the flow separation and lower the overall sound pressure level.

  15. Trail networks formed by populations of immune cells

    International Nuclear Information System (INIS)

    Yang, Taeseok Daniel; Kwon, Tae Goo; Park, Jin-sung; Lee, Kyoung J

    2014-01-01

    Populations of biological cells that communicate with each other can organize themselves to generate large-scale patterns. Examples can be found in diverse systems, ranging from developing embryos, cardiac tissues, chemotaxing ameba and swirling bacteria. The similarity, often shared by the patterns, suggests the existence of some general governing principle. On the other hand, rich diversity and system-specific properties are exhibited, depending on the type of involved cells and the nature of their interactions. The study on the similarity and the diversity constitutes a rapidly growing field of research. Here, we introduce a new class of self-organized patterns of cell populations that we term as ‘cellular trail networks’. They were observed with populations of rat microglia, the immune cells of the brain and the experimental evidence suggested that haptotaxis is the key element responsible for them. The essential features of the observed patterns are well captured by the mathematical model cells that actively crawl and interact with each other through a decomposing but non-diffusing chemical attractant laid down by the cells. Our finding suggests an unusual mechanism of socially cooperative long-range signaling for the crawling immune cells. (paper)

  16. Public health practitioner incubation plight: following the money trail.

    Science.gov (United States)

    Gordon, L J; McFarlane, D R

    1996-01-01

    Schools of public health have a proud history of educating personnel for leadership roles in the field of practice. Such personnel have played key roles in developing public health. Over the years, however, the missions of the schools of public health have become blurred. To a significant degree, a focus on health care has displaced public health as schools have followed the money trail. Often research takes precedence over teaching, so that, ironically, research findings are not disseminated to those who will practice public health. Educating personnel for practitioner leadership roles in environmental health and protection is inadequate. These and other trends have serious, long-term ramifications for public health practice. This article offers suggestions for improving the situation, including making use of practitioners in schools of public health, encouraging partnerships between practitioners and academics for research and funding support, developing paid student practica, developing a market for MPH graduates, and changing the accreditation requirements of the Council on Education for Public Health.

  17. Management of Vortices Trailing Flapped Wings via Separation Control

    Science.gov (United States)

    Greenblatt, David

    2005-01-01

    A pilot study was conducted on a flapped semi-span model to investigate the concept and viability of near-wake vortex management via separation control. Passive control was achieved by means of a simple fairing and active control was achieved via zero mass-flux blowing slots. Vortex sheet strength, estimated by integrating surface pressure ports, was used to predict vortex characteristics by means of inviscid rollup relations. Furthermore, vortices trailing the flaps were mapped using a seven-hole probe. Separation control was found to have a marked effect on vortex location, strength, tangential velocity, axial velocity and size over a wide range of angles of attack and control conditions. In general, the vortex trends were well predicted by the inviscid rollup relations. Manipulation of the separated flow near the flap edges exerted significant control over both outboard and inboard edge vortices while producing negligible lift excursions. Dynamic separation and attachment control was found to be an effective means for dynamically perturbing the vortex from arbitrarily long wavelengths down to wavelengths less than a typical wingspan. In summary, separation control has the potential for application to time-independent or time-dependent wake alleviation schemes, where the latter can be deployed to minimize adverse effects on ride-quality and dynamic structural loading.

  18. The Trails of Superluminal Jet Components in 3C 111

    Science.gov (United States)

    Kadler, M.; Ros, E.; Perucho, M.; Kovalev, Y. Y.; Homan, D. C.; Agudo, I.; Kellermann, K. I.; Aller, M. F.; Aller, H. D.; Lister, M. L.; hide

    2007-01-01

    The parsec-scale radio jet of the broad-line radio galaxy 3C 111 has been monitored since 1995 as part of the 2cm Survey and MOJAVE monitoring observations conducted with the VLBA. Here, we present results from 18 epochs of VLBA observations of 3C 111 and from 18 years of radio flux density monitoring observations conducted at the University of Michigan. A major radio flux-density outburst of 3C 111 occurred in 1996 and was followed by a particularly bright plasma ejection associated with a superluminal jet component. This major event allows us to study a variety of processes associated with outbursts of radio-loud AGN in much greater detail than possible in other cases: the primary perturbation gives rise to the formation of a forward and a backward-shock, which both evolve in characteristically different ways and allow us to draw conclusions about the workflow of jet-production events; the expansion, acceleration and recollimation of the ejected jet plasma in an environment with steep pressure and density gradients are revealed; trailing components are formed in the wake of the primary perturbation as a result of Kelvin- Helmholtz instabilities from the interaction of the jet with the external medium. The jet-medium interaction is further scrutinized by the linear-polarization signature of jet components traveling along the jet and passing a region of steep pressure/density gradients.

  19. Trails of meaning construction: Symbolic artifacts engage the social brain.

    Science.gov (United States)

    Tylén, Kristian; Philipsen, Johanne Stege; Roepstorff, Andreas; Fusaroli, Riccardo

    2016-07-01

    Symbolic artifacts present a challenge to theories of neurocognitive processing due to their hybrid nature: they are at the same time physical objects and vehicles of intangible social meanings. While their physical properties can be read of their perceptual appearance, the meaning of symbolic artifacts depends on the perceiver's interpretative attitude and embeddedness in cultural practices. In this study, participants built models of LEGO bricks to illustrate their understanding of abstract concepts. They were then scanned with fMRI while presented to photographs of their own and others' models. When participants attended to the meaning of the models in contrast to their bare physical properties, we observed activations in mPFC and TPJ, areas often associated with social cognition, and IFG, possibly related to semantics. When contrasting own and others' models, we also found activations in precuneus, an area associated with autobiographical memory and agency, while looking at one's own collective models yielded interaction effects in rostral ACC, right IFG and left Insula. Interestingly, variability in the insula was predicted by individual differences in participants' feeling of relatedness to their fellow group members during LEGO construction activity. Our findings support a view of symbolic artifacts as neuro-cognitive trails of human social interactions. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Aptamer-miRNA-212 Conjugate Sensitizes NSCLC Cells to TRAIL

    Directory of Open Access Journals (Sweden)

    Margherita Iaboni

    2016-01-01

    Full Text Available TNF-related apoptosis-inducing ligand (TRAIL is a promising antitumor agent for its remarkable ability to selectively induce apoptosis in cancer cells, without affecting the viability of healthy bystander cells. The TRAIL tumor suppressor pathway is deregulated in many human malignancies including lung cancer. In human non-small cell lung cancer (NSCLC cells, sensitization to TRAIL therapy can be restored by increasing the expression levels of the tumor suppressor microRNA-212 (miR-212 leading to inhibition of the anti-apoptotic protein PED/PEA-15 implicated in treatment resistance. In this study, we exploited a previously described RNA aptamer inhibitor of the tyrosine kinase receptor Axl (GL21.T expressed on lung cancer cells, as a means to deliver miR-212 into human NSCLC cells expressing Axl. We demonstrate efficient delivery of miR-212 following conjugation of the miR to GL21.T (GL21.T-miR212 chimera. We show that the chimera downregulates PED and restores TRAIL-mediate cytotoxicity in cancer cells. Importantly, treatment of Axl+ lung cancer cells with the chimera resulted in (i an increase in caspase activation and (ii a reduction of cell viability in combination with TRAIL therapy. In conclusion, we demonstrate that the GL21.T-miR212 chimera can be employed as an adjuvant to TRAIL therapy for the treatment of lung cancer.