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Sample records for tumor trailing strategy

  1. 4D planning over the full course of fractionation: assessment of the benefit of tumor trailing

    International Nuclear Information System (INIS)

    McQuaid, D; Bortfeld, T

    2011-01-01

    Tumor trailing techniques have been proposed as a method of reducing the problem of intrafraction motion in radiotherapy. However the dosimetric assessment of trailing strategies is complicated by the requirement to study dose deposition over a full fraction delivery. Common 4D planning strategies allowing assessment of dosimetric motion effects study a single cycle acquired with 4DCT. In this paper, a methodology to assess dose deposited over an entire treatment course is advanced and used to assess the potential benefit of tumor trailing strategies for lung cancer patients. Two digital phantoms mimicking patient anatomy were each programmed to follow the tumor respiratory trajectory observed from 33 lung cancer patients. The two phantoms were designed to represent the cases of a small (volume = 13.6 cm 3 ) and large (volume = 181.7 cm 3 ) lung lesion. Motion margins required to obtain CTV coverage by 95% of the prescription dose to 90% of the available cases were computed for a standard treatment strategy and a trailing treatment strategy. The trailing strategy facilitated a margin reduction of over 30% relative to the conventional delivery. When the dose was computed across the entire delivery for the 33 cases, the trailing strategy was found to significantly reduce the underdosage to the outlier cases and the reduced trailing margin facilitated a 15% (small lesion) and 4% (large lesion) reduction for the mean lung dose and 7% (small lesion) and 10% (large lesion) for the mean esophagus dose. Finally, for comparison an ideal continuous tracking strategy was assessed and found to further reduce the mean lung and esophagus dose. However, this improvement comes at the price of increased delivery complexity and increased reliance on tumor localization accuracy.

  2. 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...... siRNA on drug sensitization of A549 cells to TRAIL treatment. The results showed that treatment of A549 cells with HSP27 siRNA down-regulated HSP27 expression but did not induce significant apoptosis. However, combination of HSP27 siRNA with TRAIL-induced significant apoptosis in TRAIL-resistant A549...... cells. In addition to inducing caspases activation and apoptosis, combined treatment with HSP27 siRNA and TRAIL also increased JNK and p53 expression and activity. Collectively, these findings provide a conclusion that siRNA targeting of the HSP27 gene specifically down-regulated HSP27 expression in A...

  3. TRAIL-induced programmed necrosis as a novel approach to eliminate tumor cells

    International Nuclear Information System (INIS)

    Voigt, Susann; Kalthoff, Holger; Adam, Dieter; Philipp, Stephan; Davarnia, Parvin; Winoto-Morbach, Supandi; Röder, Christian; Arenz, Christoph; Trauzold, Anna; Kabelitz, Dieter; Schütze, Stefan

    2014-01-01

    The cytokine TRAIL represents one of the most promising candidates for the apoptotic elimination of tumor cells, either alone or in combination therapies. However, its efficacy is often limited by intrinsic or acquired resistance of tumor cells to apoptosis. Programmed necrosis is an alternative, molecularly distinct mode of programmed cell death that is elicited by TRAIL under conditions when the classical apoptosis machinery fails or is actively inhibited. The potential of TRAIL-induced programmed necrosis in tumor therapy is, however, almost completely uncharacterized. We therefore investigated its impact on a panel of tumor cell lines of wide-ranging origin. Cell death/viability was measured by flow cytometry/determination of intracellular ATP levels/crystal violet staining. Cell surface expression of TRAIL receptors was detected by flow cytometry, expression of proteins by Western blot. Ceramide levels were quantified by high-performance thin layer chromatography and densitometric analysis, clonogenic survival of cells was determined by crystal violet staining or by soft agarose cloning. TRAIL-induced programmed necrosis killed eight out of 14 tumor cell lines. Clonogenic survival was reduced in all sensitive and even one resistant cell lines tested. TRAIL synergized with chemotherapeutics in killing tumor cell lines by programmed necrosis, enhancing their effect in eight out of 10 tested tumor cell lines and in 41 out of 80 chemotherapeutic/TRAIL combinations. Susceptibility/resistance of the investigated tumor cell lines to programmed necrosis seems to primarily depend on expression of the pro-necrotic kinase RIPK3 rather than the related kinase RIPK1 or cell surface expression of TRAIL receptors. Furthermore, interference with production of the lipid ceramide protected all tested tumor cell lines. Our study provides evidence that TRAIL-induced programmed necrosis represents a feasible approach for the elimination of tumor cells, and that this treatment may

  4. Inhibition of NF-κB Pathway and Modulation of MAPK Signaling Pathways in Glioblastoma and Implications for Lovastatin and Tumor Necrosis Factor-Related Apoptosis Inducing Ligand (TRAIL Combination Therapy.

    Directory of Open Access Journals (Sweden)

    Pi Chu Liu

    Full Text Available Glioblastoma is a common malignant brain tumor and it is refractory to therapy because it usually contains a mixture of cell types. The tumor necrosis factor-related apoptosis inducing ligand (TRAIL has been shown to induce apoptosis in a range of tumor cell types. Previously, we found that two human glioblastoma cell lines are resistant to TRAIL, while lovastatin sensitizes these glioblastoma cells to TRAIL-induced cell death. In this study, we investigated the mechanisms underlying the TRAIL-induced apoptosis in human glioblastoma cell lines by lovastatin. Furthermore, we have confirmed the anti-tumor effect of combination therapy with lovastatin and TRAIL in the subcutaneous brain tumor model. We showed that lovastatin significantly up-regulated the expression of death receptor 5 (DR5 in glioblastoma cell lines as well as in tumor-bearing mice with peri-tumoral administration of lovastatin. Further study in glioblastoma cell lines suggested that lovastatin treatment could inhibit NF-κB and Erk/MAPK pathways but activates JNK pathway. These results suggest that lovastatin sensitizes TRAIL-induced apoptosis by up-regulation of DR5 level via NF-κB inactivation, but also directly induces apoptosis by dysregulation of MAPK pathway. Our in vivo study showed that local peri-tumoral co-injection of lovastatin and TRAIL substantially reduced tumor growth compared with single injection of lovastatin or TRAIL in subcutaneous nude mice model. This study suggests that combined treatment of lovastatin and TRAIL is a promising therapeutic strategy to TRAIL-resistant glioblastoma.

  5. 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

    .... More effective therapies are urgently needed. One of the most promising therapies in development for ovarian cancer is the use of either the Tumor Necrosis Factor-related Apoptosis Inducing Ligand (TRAIL...

  6. Tumor associated macrophages protect colon cancer cells from TRAIL-induced apoptosis through IL-1beta-dependent stabilization of Snail in tumor cells.

    Directory of Open Access Journals (Sweden)

    Pawan Kaler

    2010-07-01

    Full Text Available We recently reported that colon tumor cells stimulate macrophages to release IL-1beta, which in turn inactivates GSK3beta and enhances Wnt signaling in colon cancer cells, generating a self-amplifying loop that promotes the growth of tumor cells.Here we describe that macrophages protect HCT116 and Hke-3 colon cancer cells from TRAIL-induced apoptosis. Inactivation of IL-1beta by neutralizing IL-1beta antibody, or silencing of IL-1beta in macrophages inhibited their ability to counter TRAIL-induced apoptosis. Accordingly, IL-1beta was sufficient to inhibit TRAIL-induced apoptosis. TRAIL-induced collapse of the mitochondrial membrane potential (Delta psi and activation of caspases were prevented by macrophages or by recombinant IL-1beta. Pharmacological inhibition of IL-1beta release from macrophages by vitamin D(3, a potent chemopreventive agent for colorectal cancer, restored the ability of TRAIL to induce apoptosis of tumor cells cultured with macrophages. Macrophages and IL-1beta failed to inhibit TRAIL-induced apoptosis in HCT116 cells expressing dnIkappaB, dnAKT or dnTCF4, confirming that they oppose TRAIL-induced cell death through induction of Wnt signaling in tumor cells. We showed that macrophages and IL-1beta stabilized Snail in tumor cells in an NF-kappaB/Wnt dependent manner and that Snail deficient tumor cells were not protected from TRAIL-induced apoptosis by macrophages or by IL-1beta, demonstrating a crucial role of Snail in the resistance of tumor cells to TRAIL.We have identified a positive feedback loop between tumor cells and macrophages that propagates the growth and promotes the survival of colon cancer cells: tumor cells stimulate macrophages to secrete IL-1beta, which in turn, promotes Wnt signaling and stabilizes Snail in tumor cells, conferring resistance to TRAIL. Vitamin D(3 halts this amplifying loop by interfering with the release of IL-1beta from macrophages. Accordingly, vitamin D(3 sensitizes tumor cells to TRAIL

  7. Exceptionally Potent Anti-Tumor Bystander Activity of an scFv:sTRAIL Fusion Protein with Specificity for EGP2 Toward Target Antigen-Negative Tumor Cells

    Directory of Open Access Journals (Sweden)

    Edwin Bremer

    2004-09-01

    Full Text Available Previously, we reported on the target cell-restricted fratricide apoptotic activity of scFvC54:sTRAIL, a fusion protein comprising human-soluble tumor necrosis factor-related apoptosis-inducing ligand (TRAIL genetically linked to the antibody fragment scFvC54 specific for the cell surface target antigen EGP2. In the present study, we report that the selective binding of scFvC54:sTRAIL to EGP2-positive target cells conveys an exceptionally potent pro-apoptotic effect toward neighboring tumor cells that are devoid of EGP2 expression (bystander cells. The anti-tumor bystander activity of scFvC54:sTRAIL was detectable at target-tobystander cell ratios as low as 1:100. Treatment in the presence of EGP2-blocking or TRAIL-neutralizing antibody strongly inhibited apoptosis in both target and bystander tumor cells. In the absence of target cells, bystander cell apoptosis induction was abrogated. The bystander apoptosis activity of scFvC54:sTRAIL did not require internalization, enzymatic conversion, diffusion, or communication (gap junctional intracellular communication between target and bystander cells. Furthermore, scFvC54:sTRAIL showed no detectable signs of innocent bystander activity toward freshly isolated blood cells. Further development of this new principle is warranted for approaches where cancer cells can escape from antibody-based therapy due to partial loss of target antigen expression.

  8. Cyclophosphamide chemotherapy sensitizes tumor cells to TRAIL-dependent CD8 T cell-mediated immune attack resulting in suppression of tumor growth.

    Directory of Open Access Journals (Sweden)

    Robbert G van der Most

    Full Text Available BACKGROUND: Anti-cancer chemotherapy can be simultaneously lymphodepleting and immunostimulatory. Pre-clinical models clearly demonstrate that chemotherapy can synergize with immunotherapy, raising the question how the immune system can be mobilized to generate anti-tumor immune responses in the context of chemotherapy. METHODS AND FINDINGS: We used a mouse model of malignant mesothelioma, AB1-HA, to investigate T cell-dependent tumor resolution after chemotherapy. Established AB1-HA tumors were cured by a single dose of cyclophosphamide in a CD8 T cell- and NK cell-dependent manner. This treatment was associated with an IFN-alpha/beta response and a profound negative impact on the anti-tumor and total CD8 T cell responses. Despite this negative effect, CD8 T cells were essential for curative responses. The important effector molecules used by the anti-tumor immune response included IFN-gamma and TRAIL. The importance of TRAIL was supported by experiments in nude mice where the lack of functional T cells could be compensated by agonistic anti-TRAIL-receptor (DR5 antibodies. CONCLUSION: The data support a model in which chemotherapy sensitizes tumor cells for T cell-, and possibly NK cell-, mediated apoptosis. A key role of tumor cell sensitization to immune attack is supported by the role of TRAIL in tumor resolution and explains the paradox of successful CD8 T cell-dependent anti-tumor responses in the absence of CD8 T cell expansion.

  9. Repression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL but not its receptors during oral cancer progression

    Directory of Open Access Journals (Sweden)

    Muller Susan

    2007-06-01

    Full Text Available Abstract Background TRAIL plays an important role in host immunosurveillance against tumor progression, as it induces apoptosis of tumor cells but not normal cells, and thus has great therapeutic potential for cancer treatment. TRAIL binds to two cell-death-inducing (DR4 and DR5 and two decoy (DcR1, and DcR2 receptors. Here, we compare the expression levels of TRAIL and its receptors in normal oral mucosa (NOM, oral premalignancies (OPM, and primary and metastatic oral squamous cell carcinomas (OSCC in order to characterize the changes in their expression patterns during OSCC initiation and progression. Methods DNA microarray, immunoblotting and immunohistochemical analyses were used to examine the expression levels of TRAIL and its receptors in oral epithelial cell lines and in archival tissues of NOM, OPM, primary and metastatic OSCC. Apoptotic rates of tumor cells and tumor-infiltrating lymphocytes (TIL in OSCC specimens were determined by cleaved caspase 3 immunohistochemistry. Results Normal oral epithelia constitutively expressed TRAIL, but expression was progressively lost in OPM and OSCC. Reduction in DcR2 expression levels was noted frequently in OPM and OSCC compared to respective patient-matched uninvolved oral mucosa. OSCC frequently expressed DR4, DR5 and DcR1 but less frequently DcR2. Expression levels of DR4, DR5 and DcR1 receptors were not significantly altered in OPM, primary OSCC and metastatic OSCC compared to patient-matched normal oral mucosa. Expression of proapoptotic TRAIL-receptors DR4 and DR5 in OSCC seemed to depend, at least in part, on whether or not these receptors were expressed in their parental oral epithelia. High DR5 expression in primary OSCC correlated significantly with larger tumor size. There was no significant association between TRAIL-R expression and OSSC histology grade, nodal status or apoptosis rates of tumor cells and TIL. Conclusion Loss of TRAIL expression is an early event during oral

  10. 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...

  11. Receptor-mediated endocytosis is not required for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis.

    Science.gov (United States)

    Kohlhaas, Susan L; Craxton, Andrew; Sun, Xiao-Ming; Pinkoski, Michael J; Cohen, Gerald M

    2007-04-27

    Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is selectively toxic to tumor compared with normal cells. Other members of the TNF family of death ligands (TNF, CD95L) engage their respective receptors (TNF-R1 and CD95), resulting in internalization of receptor and ligand and recruitment of adaptor proteins to the caspase activation platform known as the death-inducing signaling complex (DISC). Recently, TNF-R1 and CD95 have been shown to induce apoptosis with an absolute requirement for internalization of their corresponding receptors in the formation of a DISC. We show that TRAIL and its receptors are rapidly endocytosed in a time- and concentration-dependent manner. Blockade of receptor internalization with hyperosmotic sucrose did not inhibit TRAIL-induced apoptosis but, rather, amplified the apoptotic signaling of TRAIL. Plate-bound and soluble TRAIL induced similar levels of apoptosis. Together these results suggest that neither ligand nor receptor internalization is required for TRAIL-induced apoptosis. Internalization of TRAIL is mediated primarily by clathrin-dependent endocytosis and also by clathrin-independent pathways. Inhibition of clathrin-dependent internalization by overexpression of dominant negative forms of dynamin or AP180 did not inhibit TRAIL-induced apoptosis. Consistent with the finding that neither internalization of TRAIL nor its receptors is required for transmission of its apoptotic signal, recruitment of FADD (Fas-associated death domain) and procaspase-8 to form the TRAIL-associated DISC occurred at 4 degrees C, independent of endocytosis. Our findings demonstrate that TRAIL and TRAIL receptor 1/2, unlike TNF-TNF-R1 or CD95L-CD95, do not require internalization for formation of the DISC, activation of caspase-8, or transmission of an apoptotic signal in BJAB type I cells.

  12. Targeting Death Receptor TRAIL-R2 by Chalcones for TRAIL-Induced Apoptosis in Cancer Cells

    Science.gov (United States)

    Szliszka, Ewelina; Jaworska, Dagmara; Kłósek, Małgorzata; Czuba, Zenon P.; Król, Wojciech

    2012-01-01

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in cancer cells without toxicity to normal cells. TRAIL binds to death receptors, TRAIL-R1 (DR4) and TRAIL-R2 (DR5) expressed on cancer cell surface and activates apoptotic pathways. Endogenous TRAIL plays an important role in immune surveillance and defense against cancer cells. However, as more tumor cells are reported to be resistant to TRAIL mediated death, it is important to search for and develop new strategies to overcome this resistance. Chalcones can sensitize cancer cells to TRAIL-induced apoptosis. We examined the cytotoxic and apoptotic effects of TRAIL in combination with four chalcones: chalcone, isobavachalcone, licochalcone A and xanthohumol on HeLa cancer cells. The cytotoxicity was measured by MTT and LDH assays. The apoptosis was detected using annexin V-FITC staining by flow cytometry and fluorescence microscopy. Death receptor expression was analyzed using flow cytometry. The decreased expression of death receptors in cancer cells may be the cause of TRAIL-resistance. Chalcones enhance TRAIL-induced apoptosis in HeLa cells through increased expression of TRAIL-R2. Our study has indicated that chalcones augment the antitumor activity of TRAIL and confirm their cancer chemopreventive properties. PMID:23203129

  13. Exceptionally potent anti-tumor bystander activity of an scFv : sTRAIL fusion protein with specificity for EGP2 toward target antigen-negative tumor cells

    NARCIS (Netherlands)

    Bremer, E; Samplonius, D; Kroesen, BJ; van Genne, L; de Leij, L; Helfrich, W

    2004-01-01

    Previously, we reported on the target cell-restricted fratricide apoptotic activity of scFvC54:sTRAIL, a fusion protein comprising human-soluble tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) genetically linked to the antibody fragment scFvC54 specific for the cell surface target

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

    Science.gov (United States)

    2011-05-01

    Poor Survival. Cancer Res 67: 3036–3042. 22. Fulda S, Scaffidi C, Pietsch T, Krammer PH, Peter ME, et al. (1998) Activation of the CD95 (APO-1/Fas...in ovarian carcinoma causes resistance to TRAIL-mediated apoptosis and is associated with poor survival. Cancer Res 2007; 67:3036-42. 19. Yu Y ...ovarian cancer in remission. 315 Therapeutic efficacy of folate receptor α blockade with MORAb-003 in ovarian cancer W. A. Spannuth1, Y . G. Lin1, W. M

  15. Construction of pEgr-hTRAIL expression vector induced by irradiaiton and its apoptosis in tumor cells in vitro

    International Nuclear Information System (INIS)

    Piao Chunji; Tian Mei; Yang Wei; Li Xiuyi; Liu Linlin

    2005-01-01

    Objective: To construct the radiation-inducible expression vector pEgr-hTRAIL containing human TNF related apoptosis inducing ligand (hTRAIL) gene and study its expression and function of inducing apoptosis in A549 human lung adenocarcinoma cells. Methods: Expression vector pEgr-hTRAIL was constructed with DNA recombinant technique. pEgr-hTRAIL plasmids were packaged with lipofectin to transfect into A549 cells in vitro. Stably transfected cell line A549-shTRAIL was selected through G418. The expression of hTRAIL gene was detected by RT-PCR. The early stage apoptosis of A549 cells was detected by Annexin-V-FITC apoptosis detecting kit. Results: Expression vector pEgr-hTRAIL was constructed correctly by identification with restriction enzyme digestion. The expression of hTRAIL mRNA in stably transfected cell line A549-shTRAIL was increased significantly. The percentage of apoptotic A549-shTRAIL was increased significantly; it was 1.8 times as much as A549 cells (P<0.05). Conclusion: Expression vector pEgr-hTRAIL is constructed successfully, which can increase the apoptosis of the stably transfected cell line A549-shTRAIL significantly. (authors)

  16. Association of soluble Tumor necrosis factor-Related Apoptosis-Inducing Ligand (TRAIL with central adiposity and low-density lipoprotein cholesterol.

    Directory of Open Access Journals (Sweden)

    Gloria Brombo

    Full Text Available OBJECTIVE: Tumor necrosis factor-Related Apoptosis-Inducing Ligand (TRAIL, in addition to having a prognostic value in patients with cardiovascular disease, seems to interact with adiposity, insulin resistance and other cardiovascular risk factors. However, the results of previous clinical studies, focused on the association of TRAIL with selected metabolic or anthropometric indices were inconclusive. The aim of this study was to further investigate how soluble TRAIL concentrations independently correlate with major cardiovascular risk factors, including lipid, glycemic and anthropometric features. MATERIALS/METHODS: We examined the associations between serum soluble TRAIL concentrations, measured by ELISA, and lipid, glycemic and anthropometric features in 199 subjects recruited at our Metabolic Outpatient Clinic. RESULTS: Soluble TRAIL concentrations had a significant and direct correlation with total cholesterol (p = 0.046, LDL-cholesterol (p = 0.032, triglycerides (p = 0.01, body mass index (p = 0.046, waist circumference (p = 0.008, fat mass (p = 0.056 and insulin (p = 0.046 and an inverse correlation with HDL-cholesterol (p = 0.02. In multivariable regression analyses adjusted for potential confounders (age, gender, C-reactive protein, HDL-cholesterol, triglycerides, waist circumference, and insulin, TRAIL levels continued to have an independent correlation with LDL-cholesterol and waist circumference (r(2 = 0.04. CONCLUSIONS: Serum TRAIL levels were weakly but significantly and independently associated with waist circumference, a marker of visceral adiposity, and with LDL-cholesterol. Further studies are needed to clarify the biological basis of these relationships.

  17. Association of soluble Tumor necrosis factor-Related Apoptosis-Inducing Ligand (TRAIL) with central adiposity and low-density lipoprotein cholesterol.

    Science.gov (United States)

    Brombo, Gloria; Volpato, Stefano; Secchiero, Paola; Passaro, Angelina; Bosi, Cristina; Zuliani, Giovanni; Zauli, Giorgio

    2013-01-01

    Tumor necrosis factor-Related Apoptosis-Inducing Ligand (TRAIL), in addition to having a prognostic value in patients with cardiovascular disease, seems to interact with adiposity, insulin resistance and other cardiovascular risk factors. However, the results of previous clinical studies, focused on the association of TRAIL with selected metabolic or anthropometric indices were inconclusive. The aim of this study was to further investigate how soluble TRAIL concentrations independently correlate with major cardiovascular risk factors, including lipid, glycemic and anthropometric features. We examined the associations between serum soluble TRAIL concentrations, measured by ELISA, and lipid, glycemic and anthropometric features in 199 subjects recruited at our Metabolic Outpatient Clinic. Soluble TRAIL concentrations had a significant and direct correlation with total cholesterol (p = 0.046), LDL-cholesterol (p = 0.032), triglycerides (p = 0.01), body mass index (p = 0.046), waist circumference (p = 0.008), fat mass (p = 0.056) and insulin (p = 0.046) and an inverse correlation with HDL-cholesterol (p = 0.02). In multivariable regression analyses adjusted for potential confounders (age, gender, C-reactive protein, HDL-cholesterol, triglycerides, waist circumference, and insulin), TRAIL levels continued to have an independent correlation with LDL-cholesterol and waist circumference (r(2) = 0.04). Serum TRAIL levels were weakly but significantly and independently associated with waist circumference, a marker of visceral adiposity, and with LDL-cholesterol. Further studies are needed to clarify the biological basis of these relationships.

  18. Regression of prostate tumors after intravenous administration of lactoferrin-bearing polypropylenimine dendriplexes encoding TNF-α, TRAIL, and interleukin-12.

    Science.gov (United States)

    Altwaijry, Najla; Somani, Sukrut; Parkinson, John A; Tate, Rothwelle J; Keating, Patricia; Warzecha, Monika; Mackenzie, Graeme R; Leung, Hing Y; Dufès, Christine

    2018-11-01

    The possibility of using gene therapy for the treatment of prostate cancer is limited by the lack of intravenously administered delivery systems able to safely and selectively deliver therapeutic genes to tumors. Given that lactoferrin (Lf) receptors are overexpressed on prostate cancer cells, we hypothesized that the conjugation of Lf to generation 3-diaminobutyric polypropylenimine dendrimer would improve its transfection and therapeutic efficacy in prostate cancer cells. In this study, we demonstrated that the intravenous administration of Lf-bearing DAB dendriplexes encoding TNFα resulted in the complete suppression of 70% of PC-3 and 50% of DU145 tumors over one month. Treatment with DAB-Lf dendriplex encoding TRAIL led to tumor suppression of 40% of PC-3 tumors and 20% of DU145 tumors. The treatment was well tolerated by the animals. Lf-bearing generation 3-polypropylenimine dendrimer is therefore a highly promising delivery system for non-viral gene therapy of prostate cancer.

  19. BAY61-3606 potentiates the anti-tumor effects of TRAIL against colon cancer through up-regulating DR4 and down-regulating NF-κB.

    Science.gov (United States)

    Du, Jipei; Wang, Yufang; Chen, Degao; Ji, Guangyu; Ma, Qizhao; Liao, Shiping; Zheng, Yanjiang; Zhang, Ji; Hou, Yiping

    2016-12-28

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is well known for its ability to preferentially induce apoptosis in malignant cells without causing damage to most normal cells. However, inherent and acquired resistance of tumor to TRAIL-induced apoptosis limits its therapeutic applicability. Here we show that the orally available tyrosine kinase inhibitor, BAY61-3606, enhances the sensitivity of human colon cancer cells, especially those harboring active mutations in Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) gene, to TRAIL-induced apoptosis in vitro and in vivo. The sensitization was achieved by up-regulating death receptor 4 (DR4) and the tumor suppressor p53. BAY61-3606-induced the up-regulation of DR4 is p53-dependent. Knockout of p53 decreased BAY61-3606-induced DR4 expression and inhibited the effect of BAY61-3606 on TRAIL-induced apoptosis. In addition, BAY61-3606 suppressed activity of NF-κB and regulated its gene products, which might also contribute to TRAIL-induced apoptosis. In conclusion, our results showed that BAY61-3606 sensitizes colon cancer cells to TRAIL-induced apoptosis via up-regulating DR4 expression in p53-dependent manner and inhibiting NF-κB activity, suggesting that the combination of TRAIL and BAY61-3606 may be a promising therapeutic approach in the treatment of colon cancer. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  20. Modulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis by Helicobacter pylori in immune pathogenesis of gastric mucosal damage.

    Science.gov (United States)

    Tsai, Hwei-Fang; Hsu, Ping-Ning

    2017-02-01

    Helicobacter pylori infection is associated with chronic gastritis, peptic ulcer, gastric carcinoma, and gastric mucosa-associated lymphoid tissue lymphomas. Apoptosis induced by microbial infections is implicated in the pathogenesis of H. pylori infection. Enhanced gastric epithelial cell apoptosis during H. pylori infection was suggested to play an important role in the pathogenesis of chronic gastritis and gastric pathology. In addition to directly triggering apoptosis, H. pylori induces sensitivity to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in gastric epithelial cells. Human gastric epithelial cells sensitized to H. pylori confer susceptibility to TRAIL-mediated apoptosis via modulation of death-receptor signaling. The induction of TRAIL sensitivity by H. pylori is dependent upon the activation of caspase-8 and its downstream pathway. H. pylori induces caspase-8 activation via enhanced assembly of the TRAIL death-inducing signaling complex through downregulation of cellular FLICE-inhibitory protein. Moreover, H. pylori infection induces infiltration of T lymphocytes and triggers inflammation to augment apoptosis. In H. pylori infection, significant increases in CCR6 + CD3 + T cell infiltration in the gastric mucosa was observed, and the CCR6 ligand, CCL20 chemokine, was selectively expressed in inflamed gastric tissues. These mechanisms initiate chemokine-mediated T lymphocyte trafficking into inflamed epithelium and induce mucosal injury during Helicobacter infection. This article will review recent findings on the interactions of H. pylori with host-epithelial signaling pathways and events involved in the initiation of gastric pathology, including gastric inflammation and mucosal damage. Copyright © 2016. Published by Elsevier B.V.

  1. T cell avidity and tumor recognition: implications and therapeutic strategies

    Directory of Open Access Journals (Sweden)

    Roszkowski Jeffrey J

    2005-09-01

    Full Text Available Abstract In the last two decades, great advances have been made studying the immune response to human tumors. The identification of protein antigens from cancer cells and better techniques for eliciting antigen specific T cell responses in vitro and in vivo have led to improved understanding of tumor recognition by T cells. Yet, much remains to be learned about the intricate details of T cell – tumor cell interactions. Though the strength of interaction between T cell and target is thought to be a key factor influencing the T cell response, investigations of T cell avidity, T cell receptor (TCR affinity for peptide-MHC complex, and the recognition of peptide on antigen presenting targets or tumor cells reveal complex relationships. Coincident with these investigations, therapeutic strategies have been developed to enhance tumor recognition using antigens with altered peptide structures and T cells modified by the introduction of new antigen binding receptor molecules. The profound effects of these strategies on T cell – tumor interactions and the clinical implications of these effects are of interest to both scientists and clinicians. In recent years, the focus of much of our work has been the avidity and effector characteristics of tumor reactive T cells. Here we review concepts and current results in the field, and the implications of therapeutic strategies using altered antigens and altered effector T cells.

  2. Chloroquine upregulates TRAIL/TRAILR2 expression and potentiates doxorubicin anti-tumor activity in thioacetamide-induced hepatocellular carcinoma model.

    Science.gov (United States)

    Helmy, Sahar A; El-Mesery, Mohamed; El-Karef, Amro; Eissa, Laila A; El Gayar, Amal M

    2018-01-05

    Impaired apoptosis and systemic toxicity of chemotherapeutic drugs make cancer treatment suboptimal. Thus, there is urgency for drug repurposing which facilitates discovery of safe and effective combination therapy. This study aimed to evaluate chloroquine's (CQ) ability to trigger TRAIL/TRAILR2 apoptotic pathway in thioacetamide (TAA)-induced hepatocellular carcinoma (HCC) either alone or in combination with doxorubicin (DOX). Moreover, its ability to attenuate DOX-induced cardiotoxicity was investigated. TAA was injected in male Sprague Dawely rats (200 mg/kg; ip; 2 times/week) for 16 weeks. After the 16th week, rats were further divided into different groups (n = 10) and treated for 7 weeks. CQ group (received CQ 25 mg/kg/day; orally), DOX group (received DOX 1 mg/kg; ip; 2 times/week) and CQ/DOX group. Liver function biomarkers, AFP, hepatic levels of MDA and GSH, serum CK-MB and LDH enzymes activity were measured. Quantitative, Real-Time PCR was used to measure TRAIL, TRAILR2, caspase-8, caspase-9, caspase-3, BCL-2 and TGF-β1 genes expression levels. Necroinflammation and fibrosis were scored by histopathological examination. CQ improved liver functions, reduced AFP level and attenuated HCC progression. CQ induced apoptosis via upregulation of TRAIL/TRAILR2, caspase-8, caspase-3 and caspase-8 genes and downregulation of BCL-2 gene. Moreover, CQ/DOX showed marked decrease in hepatic MDA level, serum CK-MB, LDH enzymes activity, as well as marked increase in hepatic GSH level. In conclusion, this work assess the in vivo efficacy of CQ/DOX combination therapy in this HCC model that not only has enhanced anti-tumor activity but it also protects against DOX-induced cardiotoxicity. Nevertheless, more studies should be performed to illustrate the molecular mechanism of CQ's cardioprotective effect. Copyright © 2017. Published by Elsevier B.V.

  3. Altered control strategy between leading and trailing leg increases knee adduction moment in the elderly while descending stairs.

    Science.gov (United States)

    Karamanidis, Kiros; Arampatzis, Adamantios

    2011-02-24

    The aim of the study was to examine the external knee adduction moments in a group of older and younger adults while descending stairs and thus the possibility of an increased risk of knee osteoarthritis due to altered knee joint loading in the elderly. Twenty-seven older and 16 younger adults descended a purpose-built staircase. A motion capture system and a force plate were used to determine the subjects' 3D kinematics and ground reaction forces (GRF) during locomotion. Calculation of the leg kinematics and kinetics was done by means of a rigid, three-segment, 3D leg model. In the initial portion of the support phase, older adults showed a more medio-posterior GRF vector relative to the ankle joint, leading to lower ankle joint moments (Pelderly (Pcontrol strategy while stepping down is a more medially directed GRF vector increasing the magnitude of external knee adduction moment in the elderly. The observed changes between leading and trailing leg in the elderly may cause a redistribution of the mechanical load at the tibiofemoral joint, affecting the initiation and progression of knee osteoarthritis in the elderly. Copyright © 2010 Elsevier Ltd. All rights reserved.

  4. 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...

  5. NF-κB targeting by way of IKK inhibition sensitizes lung cancer cells to adenovirus delivery of TRAIL

    Directory of Open Access Journals (Sweden)

    Karacay Bahri

    2010-10-01

    Full Text Available Abstract Background Lung cancer causes the highest rate of cancer-related deaths both in men and women. As many current treatment modalities are inadequate in increasing patient survival, new therapeutic strategies are required. TNF-related apoptosis-inducing ligand (TRAIL selectively induces apoptosis in tumor cells but not in normal cells, prompting its current evaluation in a number of clinical trials. The successful therapeutic employment of TRAIL is restricted by the fact that many tumor cells are resistant to TRAIL. The goal of the present study was to test a novel combinatorial gene therapy modality involving adenoviral delivery of TRAIL (Ad5hTRAIL and IKK inhibition (AdIKKβKA to overcome TRAIL resistance in lung cancer cells. Methods Fluorescent microscopy and flow cytometry were used to detect optimum doses of adenovirus vectors to transduce lung cancer cells. Cell viability was assessed via a live/dead cell viability assay. Luciferase assays were employed to monitor cellular NF-κB activity. Apoptosis was confirmed using Annexin V binding. Results Neither Ad5hTRAIL nor AdIKKβKA infection alone induced apoptosis in A549 lung cancer cells, but the combined use of Ad5hTRAIL and AdIKKβKA significantly increased the amount of A549 apoptosis. Luciferase assays demonstrated that both endogenous and TRAIL-induced NF-κB activity was down-regulated by AdIKKβKA expression. Conclusions Combination treatment with Ad5hTRAIL and AdIKKβKA induced significant apoptosis of TRAIL-resistant A549 cells, suggesting that dual gene therapy strategy involving exogenous TRAIL gene expression with concurrent IKK inhibition may be a promising novel gene therapy modality to treat lung cancer.

  6. Modifiers of radiation response in tumor therapy: strategies and expectations

    International Nuclear Information System (INIS)

    Elkind, M.M.

    1982-01-01

    The administration of two (or more) cytotoxic agents to widen the differential between the responses of tumor and normal tissues depends upon the biological properties of the agents in the cells and tissues, their interactive potential, and the strategy employed in their administration. Assuming that one agent is ionizing radiation, and considering response modification in broad terms, the qualitative features of various strategies are developed for physical as well as chemical modifies. The heterogeneity of human tumor cells and the compensatory mechanisms of normal tissues following injury are identified as topical areas requiring sustained research effort. Finally, estimates are developed for the degree of improvement required from a response modifier to effect significant improvements in tumor cure rates

  7. Modifiers of radiation response in tumor therapy: strategies and expectations

    International Nuclear Information System (INIS)

    Elkind, M.M.

    1982-01-01

    The administration of two (or more) cytotoxic agents to widen the differential between the responses of tumor and normal tissues depends upon the biological properties of the agents in the cells and tissues, their interactive potential, and the strategy employed in their administration. Assuming that one agent is ionizing radiation, and considering response modification in broad terms, the qualitative features of various strategies are developed for physical as well as chemical modifiers. The heterogeneity of human tumor cells and the compensatory mechanisms of normal tissues following injury are identified as topical areas requiring sustained research effort. Finally, estimates are developed for the degree of improvement from a response modifier to effect significant improvements in tumor cure rates

  8. Ethanolic Extract of Polish Propolis: Chemical Composition and TRAIL-R2 Death Receptor Targeting Apoptotic Activity against Prostate Cancer Cells

    Directory of Open Access Journals (Sweden)

    Ewelina Szliszka

    2013-01-01

    Full Text Available Propolis possesses chemopreventive properties through direct anticancer and indirect immunomodulatory activities. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL plays a significant role in immunosurveillance and defense against cancer cells. TRAIL triggers apoptosis upon binding to TRAIL-R1 (DR4 and TRAIL-R2 (DR5 death receptors expressed on cancer cell surface. The activation of TRAIL apoptotic signaling is considered an attractive option for cancer prevention. However, as more tumor cells are reported to be resistant to TRAIL-mediated death, it is important to develop new strategies to overcome this resistance. The aim of this study was to investigate the chemical composition and proapoptotic mechanism of ethanolic extract of Polish propolis (EEP-P against cancer cells. The identification and quantification of phenolic compounds in propolis extract were performed using HPLC-DAD and UPLC-Q-TOF-MS methods. TRAIL-resistant LNCaP prostate cancer cells were treated with EEP-P and TRAIL. Cytotoxicity was measured by MTT and LDH assays. Apoptosis was detected using annexin V-FITC staining by flow cytometry and fluorescence microscopy. Death receptors expression was analyzed using flow cytometry. Pinobanksin, chrysin, methoxyflavanone, p-coumaric acid, ferulic acid and caffeic acid were the main phenolics found in EEP-P. Propolis sensitized LNCaP cells through upregulation of TRAIL-R2. These results suggest that EEP-P supports TRAIL-mediated immunochemoprevention in prostate cancer cells.

  9. Ethanolic Extract of Polish Propolis: Chemical Composition and TRAIL-R2 Death Receptor Targeting Apoptotic Activity against Prostate Cancer Cells.

    Science.gov (United States)

    Szliszka, Ewelina; Sokół-Łętowska, Anna; Kucharska, Alicja Z; Jaworska, Dagmara; Czuba, Zenon P; Król, Wojciech

    2013-01-01

    Propolis possesses chemopreventive properties through direct anticancer and indirect immunomodulatory activities. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) plays a significant role in immunosurveillance and defense against cancer cells. TRAIL triggers apoptosis upon binding to TRAIL-R1 (DR4) and TRAIL-R2 (DR5) death receptors expressed on cancer cell surface. The activation of TRAIL apoptotic signaling is considered an attractive option for cancer prevention. However, as more tumor cells are reported to be resistant to TRAIL-mediated death, it is important to develop new strategies to overcome this resistance. The aim of this study was to investigate the chemical composition and proapoptotic mechanism of ethanolic extract of Polish propolis (EEP-P) against cancer cells. The identification and quantification of phenolic compounds in propolis extract were performed using HPLC-DAD and UPLC-Q-TOF-MS methods. TRAIL-resistant LNCaP prostate cancer cells were treated with EEP-P and TRAIL. Cytotoxicity was measured by MTT and LDH assays. Apoptosis was detected using annexin V-FITC staining by flow cytometry and fluorescence microscopy. Death receptors expression was analyzed using flow cytometry. Pinobanksin, chrysin, methoxyflavanone, p-coumaric acid, ferulic acid and caffeic acid were the main phenolics found in EEP-P. Propolis sensitized LNCaP cells through upregulation of TRAIL-R2. These results suggest that EEP-P supports TRAIL-mediated immunochemoprevention in prostate cancer cells.

  10. Epithelial borderline ovarian tumor: Diagnosis and treatment strategy.

    Science.gov (United States)

    Ushijima, Kimio; Kawano, Kouichiro; Tsuda, Naotake; Nishio, Shin; Terada, Atsumu; Kato, Hiroyuki; Tasaki, Kazuto; Matsukuma, Ken

    2015-05-01

    Epithelial borderline ovarian tumors (BOT) are distinctive from benign tumors and carcinoma. They occur in younger women more often than carcinoma, and there is some difficulty making correct diagnosis of BOT. Two subtypes of BOT, serous and mucinous borderline tumor have different characteristics and very different clinical behavior. Serous borderline tumor (SBT) with micropapillary pattern shows more incidence of extra ovarian disease and often coexists with invasive implant. SBT with micropapillary pattern in advanced stage has showed a worse prognosis than typical SBT. Huge mucinous borderline tumors have histologic heterogeneity, and the accuracy of frozen section diagnosis is relatively low. Extensive sampling is required to reach a correct pathological diagnosis. Mucinous adenoma (intestinal type) also runs the risk of recurrence after cystectomy, or intraoperative rupture of cyst. Laparoscopic procedure for BOT has not increased the risk of recurrence. Fertility preserving procedures are generally accepted, except in advanced stage SBT with invasive implants. Only cystectomy shows a significant risk of recurrence. Re-staging surgery and full staging surgery is not necessary for all BOT. We should not attempt to treat them uniformly, by the single diagnosis of "borderline tumor". It depends on histologic type. Close communication with the pathologist is necessary to gain more detail and ask more pathological samples in order to make the optimal treatment strategy for each individual patients.

  11. Snail Trails

    Science.gov (United States)

    Galus, Pamela

    2002-01-01

    The slime trails of snails lead the author's students to a better understanding of science as inquiry and the processes of science. During this five-day activity, students get up close and personal with one of her favorite creatures, the land snail. Students begin by observing the organism and recording their observations. After making initial…

  12. 4D Proton treatment planning strategy for mobile lung tumors

    International Nuclear Information System (INIS)

    Kang Yixiu; Zhang Xiaodong; Chang, Joe Y.; Wang He; Wei Xiong; Liao Zhongxing; Komaki, Ritsuko; Cox, James D.; Balter, Peter A.; Liu, Helen; Zhu, X. Ronald; Mohan, Radhe; Dong Lei

    2007-01-01

    Purpose: To investigate strategies for designing compensator-based 3D proton treatment plans for mobile lung tumors using four-dimensional computed tomography (4DCT) images. Methods and Materials: Four-dimensional CT sets for 10 lung cancer patients were used in this study. The internal gross tumor volume (IGTV) was obtained by combining the tumor volumes at different phases of the respiratory cycle. For each patient, we evaluated four planning strategies based on the following dose calculations: (1) the average (AVE) CT; (2) the free-breathing (FB) CT; (3) the maximum intensity projection (MIP) CT; and (4) the AVE CT in which the CT voxel values inside the IGTV were replaced by a constant density (AVE R IGTV). For each strategy, the resulting cumulative dose distribution in a respiratory cycle was determined using a deformable image registration method. Results: There were dosimetric differences between the apparent dose distribution, calculated on a single CT dataset, and the motion-corrected 4D dose distribution, calculated by combining dose distributions delivered to each phase of the 4DCT. The AVE R IGTV plan using a 1-cm smearing parameter had the best overall target coverage and critical structure sparing. The MIP plan approach resulted in an unnecessarily large treatment volume. The AVE and FB plans using 1-cm smearing did not provide adequate 4D target coverage in all patients. By using a larger smearing value, adequate 4D target coverage could be achieved; however, critical organ doses were increased. Conclusion: The AVE R IGTV approach is an effective strategy for designing proton treatment plans for mobile lung tumors

  13. Synergistic Effect of Subtoxic-dose Cisplatin and TRAIL to Mediate Apoptosis by Down-regulating Decoy Receptor 2 and Up-regulating Caspase-8, Caspase-9 and Bax Expression on NCI-H460 and A549 Cells

    Directory of Open Access Journals (Sweden)

    Xiaoyan Zhang

    2013-05-01

    Full Text Available Objective(s: Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL can selectively induce apoptosis in tumor cells, more than half of tumors including non-small cell lung cancer (NSCLC exhibit TRAIL-resistance. The purpose of this study was to determine whether subtoxic-dose cisplatin and TRAIL could synergistically enhance apoptosis on NSCLC cells and investigate its underlying mechanisms. Materials and Methods:NCI-H460 and A549 cells were treated with TRAIL alone, cisplatin alone or combination treatment in this study. The cytotoxicity was evaluated according to Sulforhodamine B assay, and apoptosis was examined using Hoechst 33342 staining and flow cytometry. The mRNA and protein levels of TRAIL receptors and apoptotic proteins including caspase-8, caspase-9, Bcl-2 and Bax were determined by RT-PCR and Western blotting, respectively. Results:Our results showed that NCI-H460 cells were sensitive to TRAIL, whereas A549 cells were resistant. However, subtoxic-dose cisplatin could enhance the both cells to TRAIL-mediated cell proliferation inhibition and apoptosis. The underlying mechanisms might be associated with the down-regulation of DcR2 and up-regulation of Caspase-8, Caspase-9 and Bax. Conclusion:Subtoxic-dose cisplatin could enhance both TRAIL- sensitive and TRAIL- resistant NSCLC cells to TRAIL-mediated apoptosis. These findings motivated further studies to evaluate such a combinatory therapeutic strategy against NSCLC in the animal models.

  14. HDAC2 attenuates TRAIL-induced apoptosis of pancreatic cancer cells

    Directory of Open Access Journals (Sweden)

    Saur Dieter

    2010-04-01

    Full Text Available Abstract Background Pancreatic ductal adenocarcinoma (PDAC is one of the most malignant tumors with a dismal prognosis and no effective conservative therapeutic strategies. Although it is demonstrated that histone deacetylases (HDACs, especially the class I HDACs HDAC1, 2 and 3 are highly expressed in this disease, little is known about HDAC isoenzyme specific functions. Results Depletion of HDAC2, but not HDAC1, in the pancreatic cancer cell lines MiaPaCa2 and Panc1 resulted in a marked sensitization towards the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL. Correspondingly, the more class I selective HDAC inhibitor (HDACI valproic acid (VPA synergized with TRAIL to induce apoptosis of MiaPaCa2 and Panc1 cells. At the molecular level, an increased expression of the TRAIL receptor 1 (DR5, accelerated processing of caspase 8, pronounced cleavage of the BH3-only protein Bid, and increased effector caspase activation was observed in HDAC2-depleted and TRAIL-treated MiaPaCa2 cells. Conclusions Our data characterize a novel HDAC2 function in PDAC cells and point to a strategy to overcome TRAIL resistance of PDAC cells, a prerequisite to succeed with a TRAIL targeted therapy in clinical settings.

  15. The efficacy of alginate encapsulated CHO-K1 single chain-TRAIL producer cells in the treatment of brain tumors

    NARCIS (Netherlands)

    Kuijlen, JMA; de Haan, BJ; Helfrich, W; de Boer, JF; Samplonius, D; Mooij, JJA; de Vos, P

    Objective: Patients with astrocytic tumors in the central nervous system (CNS) have low survival rates despite surgery and radiotherapy. Innovative therapies and strategies must be developed to prolong survival of these patients. The alginate microencapsulation method, used to continuously release a

  16. 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.

  17. Irradiation enhances the tumor tropism and therapeutic potential of tumor necrosis factor-related apoptosis-inducing ligand-secreting human umbilical cord blood-derived mesenchymal stem cells in glioma therapy.

    Science.gov (United States)

    Kim, Seong Muk; Oh, Ji Hyeon; Park, Soon A; Ryu, Chung Heon; Lim, Jung Yeon; Kim, Dal-Soo; Chang, Jong Wook; Oh, Wonil; Jeun, Sin-Soo

    2010-12-01

    Irradiation is a standard therapy for gliomas and many other cancers. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is one of the most promising candidates for cancer gene therapy. Here, we show that tumor irradiation enhances the tumor tropism of human umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) and the therapeutic effect of TRAIL delivered by UCB-MSCs. The sequential treatment with irradiation followed by TRAIL-secreting UCB-MSCs (MSC-TRAIL) synergistically enhanced apoptosis in either TRAIL-sensitive or TRAIL-resistant glioma cells by upregulating the death receptor 5 and by inducing caspase activation. Migration assays showed greater MSC migration toward irradiated glioma cells and the tumor site in glioma-bearing mice compared with unirradiated tumors. Irradiated glioma cells had increased expression of interleukin-8 (IL-8), which leads to the upregulation of the IL-8 receptor on MSCs. This upregulation, which is involved in the migratory capacity of UCB-MSCs, was confirmed by siRNA inhibition and an antibody-neutralizing assay. In vivo survival experiments in orthotopic xenografted mice showed that MSC-based TRAIL gene delivery to irradiated tumors had greater therapeutic efficacy than a single treatment. These results suggest that clinically relevant tumor irradiation increases the therapeutic efficacy of MSC-TRAIL by increasing tropism of MSCs and TRAIL-induced apoptosis, which may be a more useful strategy for cancer gene therapy.

  18. von Hippel-Lindau disease: surveillance strategy for endolymphatic sac tumors

    DEFF Research Database (Denmark)

    Poulsen, Marie Louise Mølgaard; Gimsing, Steen; Kosteljanetz, Michael

    2011-01-01

    : Up to 16% of patients with the hereditary von Hippel-Lindau disease develop endolymphatic sac tumors of the inner ear. Early diagnosis and treatment of endolymphatic sac tumors can prevent audiovestibular morbidity, but optimal endolymphatic sac tumor surveillance strategy has yet to be determi...... to be determined. We aimed to evaluate endolymphatic sac tumor surveillance to determine the best surveillance strategy.......: Up to 16% of patients with the hereditary von Hippel-Lindau disease develop endolymphatic sac tumors of the inner ear. Early diagnosis and treatment of endolymphatic sac tumors can prevent audiovestibular morbidity, but optimal endolymphatic sac tumor surveillance strategy has yet...

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

    Directory of Open Access Journals (Sweden)

    Aydin Cigdem

    2005-05-01

    Full Text Available Abstract Background 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. Methods 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. Results 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

  20. 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

  1. Clitocine potentiates TRAIL-mediated apoptosis in human colon cancer cells by promoting Mcl-1 degradation.

    Science.gov (United States)

    Sun, Jian-Guo; Ruan, Feng; Zeng, Xue-Li; Xiang, Jun; Li, Xia; Wu, Ping; Fung, Kwok Pui; Liu, Fei-Yan

    2016-10-01

    Among anti-cancer candidate drugs, TRAIL might be the most specific agent against cancer cells due to its low toxicity to normal cells. Unfortunately, cancer cells usually develop drug resistance to TRAIL, which is a major obstacle for its clinical application. One promising strategy is co-administrating with sensitizer to overcome cancer cells resistance to TRAIL. Clitocine, a natural amino nucleoside purified from wild mushroom, is recently demonstrated that can induce apoptosis in multidrug-resistant human cancer cells by targeting Mcl-1. In the present study,we found that pretreatment with clitocine dramatically enhances TRAIL lethality in its resistant human colon cancer cells by inducing apoptosis. More importantly, combination of clitocine and TRAIL also effectively inhibits xenograft growth and induces tumor cells apoptosis in athymic mice. The disruption of the binding between Mcl-1 and Bak as well as mitochondrial translocation of Bax mediated by clitocine are identified as the key underlying mechanisms, which leading to mitochondrial membrane permeabilization. Enforced exogenous Mcl-1 can effectively attenuate clitocine/TRAIL-induced apoptosis by suppressing the activation of intrinsic apoptotic pathway. Furthermore, clitocine regulates Mcl-1 expression at the posttranslational level as no obvious change is observed on mRNA level and proteasome inhibitor MG132 almost blocks the Mcl-1 suppression by clitocine. In fact, more ubiquitinated Mcl-1 was detected under clitocine treatment. Our findings indicate that clitocine is potentially an effective adjuvant agent in TRAIL-based cancer therapy.

  2. Synergistic antitumor effect of AAV-mediated TRAIL expression combined with cisplatin on head and neck squamous cell carcinoma

    International Nuclear Information System (INIS)

    Jiang, Minghong; Liu, Zheng; Xiang, Yang; Ma, Hong; Liu, Shilian; Liu, Yanxin; Zheng, Dexian

    2011-01-01

    Adeno-associated virus-2 (AAV-2)-mediated gene therapy is quite suitable for local or regional application in head and neck cancer squamous cell carcinoma (HNSCC). However, its low transduction efficiency has limited its further development as a therapeutic agent. DNA damaging agents have been shown to enhance AAV-mediated transgene expression. Cisplatin, one of the most effective chemotherapeutic agents, has been recognized to cause cancer cell death by apoptosis with a severe toxicity. This study aims to evaluate the role of cisplatin in AAV-mediated tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression and the effect on HNSCC both in vitro and in vivo. Five human HNSCC cell lines were treated with recombinant soluble TRAIL (rsTRAIL) and infected with AAV/TRAIL to estimate the sensitivity of the cancer cells to TRAIL-induced cytotoxicity. KB cells were infected with AAV/EGFP with or without cisplatin pretreatment to evaluate the effect of cisplatin on AAV-mediated gene expression. TRAIL expression was detected by ELISA and Western blot. Cytotoxicity was measured by MTT assay and Western blot analysis for caspase-3 and -8 activations. Following the in vitro experiments, TRAIL expression and its tumoricidal activity were analyzed in nude mice with subcutaneous xenografts of HNSCC. HNSCC cell lines showed different sensitivities to rsTRAIL, and KB cells possessed both highest transduction efficacy of AAV and sensitivity to TRAIL among five cell lines. Preincubation of KB cells with subtherapeutic dosage of cisplatin significantly augmented AAV-mediated transgene expression in a heparin sulfate proteoglycan (HSPG)-dependent manner. Furthermore, cisplatin enhanced the killing efficacy of AAV/TRAIL by 3-fold on KB cell line. The AAV mediated TRAIL expression was observed in the xenografted tumors and significantly enhanced by cisplatin. AAV/TRAIL suppressed the tumors growth and cisplatin augmented the tumoricidal activity by two-fold. Furthermore

  3. 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...

  4. TRAIL receptor-selective mutants signal to apoptosis via TRAIL-R1 in primary lymphoid malignancies.

    Science.gov (United States)

    MacFarlane, Marion; Kohlhaas, Susan L; Sutcliffe, Michael J; Dyer, Martin J S; Cohen, Gerald M

    2005-12-15

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its agonistic antibodies, which are currently in early clinical trials for treating various malignancies, induce apoptosis through triggering of either TRAIL-R1 or TRAIL-R2. Based on studies using agonistic monoclonal antibodies, we recently proposed that primary chronic lymphocytic leukemic cells seem to signal apoptosis primarily through TRAIL-R1. We have now synthesized mutant forms of TRAIL specific for TRAIL-R1 or TRAIL-R2. The selectivity of these mutants to induce apoptosis in cell lines is due to selective binding to their cognate receptors resulting in apoptosis via formation of a death-inducing signaling complex. Using these mutants, we now unequivocally show that primary cells from patients with chronic lymphocytic leukemia and mantle cell lymphoma signal to apoptosis almost exclusively through TRAIL-R1. Thus, no significant therapeutic benefit can be anticipated from treating such patients with agents currently in clinical trials that signal predominantly through TRAIL-R2, such as HGS-ETR2 or Apo2L/TRAIL. Our study highlights the necessity to determine whether primary cells from a particular tumor signal via TRAIL-R1 or TRAIL-R2. Such information will provide a rational approach to optimize TRAIL therapy.

  5. Where ends the TRAIL in arthritis?

    Directory of Open Access Journals (Sweden)

    Michael Hahne

    2009-10-01

    Full Text Available A hallmark of rheumatoid arthritis (RA is the pseudo-tumoral expansion of fibroblast-like synoviocytes (FLS, as these cells invade and finally destroy the joint structure. RA FLS have been proposed therefore as a therapeutic target. The TNF-related apoptosis-inducing ligand (TRAIL has gained much attention as a possible therapeutic reagent for the treatment of tumors, as TRAIL was described originally to induce apoptosis specifically in cancer cells but not in normal cells. The fact that FLS in RA patients exhibit tumor-like features led to investigations on the effect of TRAIL on ex-vivo RA FLS. In this review we aim to summarize what is presently known on the role of TRAIL in RA.

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

    Science.gov (United States)

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

    2016-05-01

    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.

  7. 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)

  8. The Role of the Tumor Vasculature in the Host Immune Response: Implications for Therapeutic Strategies Targeting the Tumor Microenvironment.

    Science.gov (United States)

    Hendry, Shona A; Farnsworth, Rae H; Solomon, Benjamin; Achen, Marc G; Stacker, Steven A; Fox, Stephen B

    2016-01-01

    Recently developed cancer immunotherapy approaches including immune checkpoint inhibitors and chimeric antigen receptor T cell transfer are showing promising results both in trials and in clinical practice. These approaches reflect increasing recognition of the crucial role of the tumor microenvironment in cancer development and progression. Cancer cells do not act alone, but develop a complex relationship with the environment in which they reside. The host immune response to tumors is critical to the success of immunotherapy; however, the determinants of this response are incompletely understood. The immune cell infiltrate in tumors varies widely in density, composition, and clinical significance. The tumor vasculature is a key component of the microenvironment that can influence tumor behavior and treatment response and can be targeted through the use of antiangiogenic drugs. Blood vascular and lymphatic endothelial cells have important roles in the trafficking of immune cells, controlling the microenvironment, and modulating the immune response. Improving access to the tumor through vascular alteration with antiangiogenic drugs may prove an effective combinatorial strategy with immunotherapy approaches and might be applicable to many tumor types. In this review, we briefly discuss the host's immune response to cancer and the treatment strategies utilizing this response, before focusing on the pathological features of tumor blood and lymphatic vessels and the contribution these might make to tumor immune evasion.

  9. Sulforaphane and TRAIL induce a synergistic elimination of advanced prostate cancer stem-like cells.

    Science.gov (United States)

    Labsch, Sabrina; Liu, Li; Bauer, Nathalie; Zhang, Yiyao; Aleksandrowicz, Ewa; Gladkich, Jury; Schönsiegel, Frank; Herr, Ingrid

    2014-05-01

    Advanced androgen-independent prostate cancer (AIPC) is an aggressive malignancy with a poor prognosis. Apoptosis-resistant cancer stem cells (CSCs) have been identified in AIPC and are not eliminated by current therapeutics. Novel therapeutic options, which are currently being evaluated in patient studies, include TRAIL and the broccoli-derived isothiocyanate sulforaphane. Although neither agent targets normal cells, TRAIL induces apoptosis in most cancer cells, and sulforaphane eliminates CSCs. In this study, the established AIPC cell lines DU145 and PC3, with enriched CSC features, and primary patient-derived prostate CSCs were treated with sulforaphane and recombinant soluble TRAIL. We examined the effects of these drugs on NF-κB activity, self-renewal and differentiation potential, and stem cell signaling via spheroid- and colony-forming assays, FACS and western blot analyses, immunohistochemistry, and an antibody protein array in vitro and after xenotransplantation. We largely found a stronger effect of sulforaphane on CSC properties compared to TRAIL, though the agents acted synergistically when applied in combination. This was associated with the inhibition of TRAIL-induced NF-κB binding; CXCR4, Jagged1, Notch 1, SOX 2, and Nanog expression; ALDH1 activity inhibition; and the elimination of differentiation and self-renewal potential. In vivo, tumor engraftment and tumor growth were strongly inhibited, without the induction of liver necrosis or other obvious side effects. These findings suggest that sulforaphane shifts the balance from TRAIL-induced survival signals to apoptosis and thus explains the observed synergistic effect. A nutritional strategy for high sulforaphane intake may target the cancer-specific activity of TRAIL in CSCs.

  10. TRAIL/bortezomib cotreatment is potentially hepatotoxic but induces cancer-specific apoptosis within a therapeutic window

    NARCIS (Netherlands)

    Koschny, Ronald; Ganten, Tom M.; Sykora, Jaromir; Haas, Tobias L.; Sprick, Martin R.; Kolb, Armin; Stremmel, Wolfgang; Walczak, Henning

    2007-01-01

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) represents a novel promising anticancer biotherapeutic. However, TRAIL-resistant tumor cells require combinatorial regimens to sensitize tumor but not normal cells for TRAIL-induced apoptosis. Here, we investigated the mechanism of the

  11. [DIAGNOSTIC AND TREATMENT STRATEGY IN FOLLICULAR TUMOR OF THYROID GLAND].

    Science.gov (United States)

    Mikhaĭlova, M V; Zubarovskiĭ, I N; Osipenko, S K

    2015-01-01

    The article is based on the treatment results of 44 patients with follicular tunor of thyroid gland. A staged morphological assessment of thyroid nodes was performed for all patients: in case of preoperative fine-needle biopsy, urgent intraoperative study and according to results of final histological research. The urgent histological study of surgical material was conducted for 44 patients with diagnosis "follicular tumor" according to fine-needle biopsy. The data of final histological study were matched with findings of intraoperative research. A micro-follicular adenoma was detected in 22 patients (50%) and 6 (13,6%) patients had this diagnosis combined with autoimmune thyroiditis. The general part of patients didn't changed in final study, but the rate of diagnosis "micro-follicular adenoma against the background of autoimmune thyroiditis" increased. Papillary carcinoma was revealed in 5 (11,4%) patients and follicular cancer had 4 (9,1%) patients detected in intraoperative study and 3 (6,8%) more patients according to data of final research. The histopathologic feature of colloid goiter was observed in 7 (15,9%) cases and a part of such patients reduced to 6,8% during final study. One of the patients (2,3%) had final diagnosis "oncocytoma". In case of thyroid nodules detection the needle biopsy should be carried out regardless to the size of nodule. The authors recommended performing the surgery with the urgent histological study in case of undetermined histological report. The following surgical strategy was specified by the results of the urgent histological report.

  12. New strategies to enhance photodynamic therapy for solid tumors

    NARCIS (Netherlands)

    Broekgaarden, M.

    2016-01-01

    Photodynamic therapy for cancer uses laser light to specifically activate anti-cancer drugs at the tumor site. However, this potentially effective and patient-friendly therapy has seen limited clinical application due to the inability of these drugs to accumulate at the tumor site and the subsequent

  13. TRAIL and microRNAs in the treatment of prostate cancer: therapeutic potential and role of nanotechnology.

    Science.gov (United States)

    Farooqi, Ammad Ahmad; De Rosa, Giuseppe

    2013-10-01

    Disruption of spatiotemporal behavior of intracellular signaling cascades including tumor necrosis factor alpha-related apoptosis-inducing ligand (TRAIL)-mediated signaling in prostate cancer has gained tremendous attention in the past few years. There is an increasing effort in translating the emerging information about TRAIL-mediated signaling obtained through experimental and preclinical data to clinic. Fascinatingly, novel targeting approaches are being developed to enhance the tissue- or subcellular-specific delivery of drugs with considerable focus on prostate cancer. These applications have the potential to revolutionize prostate cancer therapeutic strategies and include the accumulation of drugs in target tissue as well as the selection of internalizing ligands for enhanced receptor-mediated uptake of drugs. In this mini-review, we outline outstanding developments in therapeutic strategies based on the regulation and/or targeting of TRAIL pathway for the treatment of prostate cancer. Moreover, microRNAs (miRNAs), with potential transcriptional and posttranscriptional regulation of gene expression, will be presented for their potential in prostate cancer treatment. Emphasis has been given to the use of delivery approaches, especially based on nanotechnology. Considerably, enhanced information regarding miRNA regulation of TRAIL-mediated signaling in prostate cancer cells may provide potential biomarkers for the characterization of patients as responders and nonresponders of TRAIL-based therapy and could provide rationalized basis for combination therapies with TRAIL death receptor-targeting drugs.

  14. Tumorer

    DEFF Research Database (Denmark)

    Prause, J.U.; Heegaard, S.

    2005-01-01

    oftalmologi, øjenlågstumorer, conjunctivale tumorer, malignt melanom, retinoblastom, orbitale tumorer......oftalmologi, øjenlågstumorer, conjunctivale tumorer, malignt melanom, retinoblastom, orbitale tumorer...

  15. Novel strategies of Raman imaging for brain tumor research.

    Science.gov (United States)

    Anna, Imiela; Bartosz, Polis; Lech, Polis; Halina, Abramczyk

    2017-10-17

    Raman diagnostics and imaging have been shown to be an effective tool for the analysis and discrimination of human brain tumors from normal structures. Raman spectroscopic methods have potential to be applied in clinical practice as they allow for identification of tumor margins during surgery. In this study, we investigate medulloblastoma (grade IV WHO) (n= 5), low-grade astrocytoma (grades I-II WHO) (n =4), ependymoma (n=3) and metastatic brain tumors (n= 1) and the tissue from the negative margins used as normal controls. We compare a high grade medulloblastoma, low grade astrocytoma and non-tumor samples from human central nervous system (CNS) tissue. Based on the properties of the Raman vibrational features and Raman images we provide a real-time feedback method that is label-free to monitor tumor metabolism that reveals reprogramming of biosynthesis of lipids, proteins, DNA and RNA. Our results indicate marked metabolic differences between low and high grade brain tumors. We discuss molecular mechanisms causing these metabolic changes, particularly lipid alterations in malignant medulloblastoma and low grade gliomas that may shed light on the mechanisms driving tumor recurrence thereby revealing new approaches for the treatment of malignant glioma. We have found that the high-grade tumors of central nervous system (medulloblastoma) exhibit enhanced level of β-sheet conformation and down-regulated level of α-helix conformation when comparing against normal tissue. We have found that almost all tumors studied in the paper have increased Raman signals of nucleic acids. This increase can be interpreted as increased DNA/RNA turnover in brain tumors. We have shown that the ratio of Raman intensities I 2930 /I 2845 at 2930 and 2845 cm -1 is a good source of information on the ratio of lipid and protein contents. We have found that the ratio reflects the different lipid and protein contents of cancerous brain tissue compared to the non-tumor tissue. We found that

  16. Kaempferol Sensitizes Human Ovarian Cancer Cells-OVCAR-3 and SKOV-3 to Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL)-Induced Apoptosis via JNK/ERK-CHOP Pathway and Up-Regulation of Death Receptors 4 and 5.

    Science.gov (United States)

    Zhao, Yingmei; Tian, Binqiang; Wang, Yong; Ding, Haiying

    2017-10-26

    BACKGROUND Ovarian cancer is the most common gynecological malignancies in women, with high mortality rates worldwide. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor (TNF) superfamily which preferentially induces apoptosis of cancer cells. However, acquired resistance to TRAIL hampers its therapeutic application. Identification of compounds that sensitize cancer cells to TRAIL is vital in combating resistance to TRAIL. The effect of kaempferol, a flavonoid enhancing TRAIL-induced apoptosis in ovarian cancer cells, was investigated in this study. MATERIAL AND METHODS The cytotoxic effects of TRAIL (25 ng/mL) and kaempferol (20-100 µM) on human ovarian cancer cells OVCAR-3 and SKOV-3 were assessed. Effect of kaempferol on the expression patterns of cell survival proteins (Bcl-xL, Bcl-2, survivin, XIAP, c-FLIP) and apoptotic proteins (caspase-3, caspase-8, caspase-9, Bax) were studied. The influence of kaempferol on expression of DR4 and DR5 death receptors on the cell surface and protein and mRNA levels was also analyzed. Apoptosis following silencing of DR5 and CHOP by small interfering RNA (siRNA), and activation of MAP kinases were analyzed as well. RESULTS Kaempferol enhanced apoptosis and drastically up-regulated DR4, DR5, CHOP, JNK, ERK1/2, p38 and apoptotic protein expression with decline in the expression of anti-apoptotic proteins. Further transfection with siRNA specific to CHOP and DR5 indicated the involvement of CHOP in DR5 up-regulation and also the contribution of DR5 in kaempferol-enhanced TRAIL-induced apoptosis. CONCLUSIONS Kaempferol sensitized ovarian cancer cells to TRAIL-induced apoptosis via up-regulation of DR4 and DR5 through ERK/JNK/CHOP pathways.

  17. 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

  18. Brain tumor radiosurgery. Current status and strategies to enhance the effect of radiosurgery

    Energy Technology Data Exchange (ETDEWEB)

    Niranjan, A.; Lunsford, L.D.; Gobbel, G.T.; Kondziolka, D.; Maitz, A.; Flickinger, J.C. [Univ. of Pittsburgh Medical Center, PA (United States)

    2000-07-01

    First, the current status of brain tumor radiosurgery is reviewed, and radiosurgery for brain tumors, including benign tumors, malignant tumors, primary glial tumors, and metastatic tumors, is described. Rapid developments in neuroimaging, stereotactic techniques, and robotic technology in the last decade have contributed to improved results and wider applications of radiosurgery. Radiosurgery has become the preferred management modality for many intracranial tumors, including schwannomas, meningiomas, and metastatic tumors. Although radiosurgery provides survival benefits in patients with diffuse malignant brain tumors, cure is still not possible. Microscopic tumor infiltration into surrounding normal tissue is the main cause of recurrence. Additional strategies are needed to specifically target tumor cells. Next, strategies to enhance the effect of radiosurgery are reviewed. Whereas the long-term clinical results of radiosurgery have established its role in the treatment of benign tumors, additional strategies are needed to improve cell killing in malignant brain tumors and to protect normal surrounding brain. The first strategy included the use of various agents to protect normal brain while delivering a high dose to the tumor cells, but finding an effective radioprotective agent has been problematic. Pentobarbital and 21-aminosteroid (21-AS) are presented as examples. The second strategy for radiation protection aimed at the repair of radiation-induced damage to the normal brain. The cause of radiation-induced breakdown of normal tissue is unclear. The white matter and the cerebral vasculature appear to be particularly susceptible to radiation. Oligodendrocytes and endothelial cells may be critical targets of radiation. The authors hypothesize that radiation-induced damage to these cell types can be repaired by neural stem cells. They also describe the use of tumor necrosis factor alpha (TNF-alpha) and neural stem cells as a means of enhancing the effect of

  19. Strategies to target drugs to gliomas and CNS metastases of solid tumors

    NARCIS (Netherlands)

    Milojkovic Kerklaan, B.; van Tellingen, O.; Huitema, A. D R; Beijnen, J. H.; Boogerd, W.; Schellens, J. H M; Brandsma, D.

    The treatment for central nervous system metastases of solid tumors and gliomas is limited as the blood–brain barrier (BBB) is an obstacle to systemic therapy. Here, we review the physiochemical properties of the BBB and both current and new drug strategies to penetrate brain tumors. We focus on

  20. Results of novel strategies for treatment of Wilms' tumor

    Directory of Open Access Journals (Sweden)

    Silvio Tucci Jr

    2007-04-01

    Full Text Available OBJECTIVE: To evaluate treatment outcomes in Wilms' tumor (WT. MATERIALS AND METHODS: We studied 53 children with median age of 2 years with WT, stages I-19, II-14, III-12, IV-6 and V-2. Treatment consisted of surgical excision plus adjuvant (40 children or neoadjuvant and adjuvant chemotherapy (unresectable tumor, n = 8, or caval tumor extension, n = 5. Chemotherapy and radiotherapy followed protocols of Brazilian Wilms' Tumor Study Group excepting 16 cases with stage I disease that received a short duration postoperative treatment with vincristine (VCR - 11 doses and dactinomycin (AMD - 4 doses. Relapsed WT was treated with multiagent regimens including cisplatin/carboplatin, cyclophosphamide, ifosfamide and etoposide. One patient with resistant relapsed WT was treated by high-dose conditioning chemotherapy with stem cell rescue. RESULTS: Overall and disease-free survival rates at 5 years were respectively 88.2 ± 5.0% and 76.7 ± 6.6%. Short duration therapy for stage I tumor showed a disease-free survival rate of 100% in a median time of 101 months (range 14 to 248 months. Overall and disease-free survival of 10 patients with recurrent WT at 5 years was 42.8%. The child treated with high-dose chemotherapy plus stem cell transplant is alive without evidence of disease 84 months from relapse. CONCLUSION: The postoperative chemotherapy in stage I disease can be reduced without compromising the cure rate. The treatment of unfavorable stage III and IV disease or relapsed tumor remains a challenge.

  1. Strategies for improving chemotherapeutic delivery to solid tumors mediated by vascular permeability modulation

    Science.gov (United States)

    Roy Chaudhuri, Tista

    An essential mode of distribution of blood-borne chemotherapeutic agents within a solid tumor is via the micro-circulation. Poor tumor perfusion, because of a lack of functional vasculature or a lack of microvessels, as well as low tumor vascular permeability, can prevent adequate deposition of even low molecular-weight agents into the tumor. The modulation of tumor vascular function and density can provides numerous strategies for improving intratumor deposition of chemotherapeutic agents. Here we investigated strategies to improve drug delivery to two tumor types that share in common poor drug delivery, but differ in the underlying cause. First, in an angiogenesis-driven brain tumor model of Glioblastoma, the vascular permeability barrier, along with poorly-functional vasculature, hinders drug delivery. A strategy of nanoparticle-based tumor 'priming' to attack the vascular permeability barrier, employing sterically stabilized liposomal doxorubicin (SSL-DXR), was investigated. Functional and histological evaluation of tumor vasculature revealed that after an initial period of depressed vascular permeability and vascular pruning 3--4 days after SSL-DXR administration, vascular permeability and perfusion were restored and then elevated after 5--7 days. As a result of tumor priming, deposition of subsequently-administered nanoparticles was enhanced, and the efficacy of temozolomide (TMZ), if administered during the window of elevated permeability, was increased. The sequenced regimen resulted in a persistent reduction of the tumor proliferative index and a 40% suppression of tumor volume, compared to animals that received both agents simultaneously. Second, in a hypovascular, pancreatic ductal adenocarcinoma model, disruption of tumor-stromal communication via sonic hedgehog (sHH) signaling pathway inhibition mediated an indirect vascular proliferation and a more than 2-fold increase in intratumor nanoparticle deposition. Enhanced delivery of SSL-DXR in tumors pre

  2. Induction of potent TRAIL-mediated tumoricidal activity by hFLEX/Furin/TRAIL recombinant DNA construct.

    Science.gov (United States)

    Wu, Xiaofeng; Hui, Kam M

    2004-05-01

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to exert selectively cytotoxic activity against many tumor cells but not normal cells. On the other hand, the ligand for the receptor tyrosine kinase Fms-like tyrosine kinase 3 (Flt3L) is a growth factor for hematopoietic progenitors and is a potent stimulating factor for dendritic and NK cells. Previously, we have demonstrated that it is possible to inhibit the outgrowth of primary tumors by the administration of an hFlex (the extracellular domain of the Flt3L) and TRAIL (amino acid residues 95-281) secreted fusion protein. Here, we report that by the insertion of a linker sequence encoding the cleavage site for the Golgi-expressed endoprotease furin between the DNA sequences encoding hFlex and TRAIL, the tumoricidal activity of the cleaved TRAIL protein generated was greatly enhanced in comparison to the hFlex/TRAIL fusion protein. Furthermore, we demonstrate that intratumoral injection of the hFlex/furin/TRAIL DNA, in conjunction with cationic liposomes, significantly suppressed the outgrowth of the human CNE-2 nasopharyngeal tumor xenografts in SCID mice. In situ histological examinations confirmed the expression of TRAIL in the treated tumor nodules and the induction of apoptosis was also evidenced by the presence of numerous pyknotic nuclei.

  3. Adeno-associated virus-mediated doxycycline-regulatable TRAIL expression suppresses growth of human breast carcinoma in nude mice

    Directory of Open Access Journals (Sweden)

    Zheng Liu

    2012-04-01

    Full Text Available Abstract Background Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL functions as a cytokine to selectively kill various cancer cells without toxicity to most normal cells. Numerous studies have demonstrated the potential use of recombinant soluble TRAIL as a cancer therapeutic agent. We have showed previous administration of a recombinant adeno-associated virus (rAAV vector expressing soluble TRAIL results in an efficient suppression of human tumor growth in nude mice. In the present study, we introduced Tet-On gene expression system into the rAAV vector to control the soluble TRAIL expression and evaluate the efficiency of the system in cancer gene therapy. Methods Controllability of the Tet-On system was determined by luciferase activity assay, and Western blotting and enzyme-linked immunoabsorbent assay. Cell viability was determined by MTT assay. The breast cancer xenograft animal model was established and recombinant virus was administrated through tail vein injection to evaluate the tumoricidal activity. Results The expression of soluble TRAIL could be strictly controlled by the Tet-On system in both normal and cancer cells. Transduction of human cancer cell lines with rAAV-TRE-TRAIL&rAAV-Tet-On under the presence of inducer doxycycline resulted in a considerable cell death by apoptosis. Intravenous injection of the recombinant virus efficiently suppressed the growth of human breast carcinoma in nude mice when activated by doxycycline. Conclusion These data suggest that rAAV-mediated soluble TRAIL expression under the control of the Tet-On system is a promising strategy for breast cancer therapy.

  4. 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 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.

  5. Nanovectorized radiotherapy: a new strategy to induce anti-tumor immunity

    International Nuclear Information System (INIS)

    Vanpouille-Box, Claire; Hindré, François

    2012-01-01

    Recent experimental findings show that activation of the host immune system is required for the success of chemo- and radiotherapy. However, clinically apparent tumors have already developed multiple mechanisms to escape anti-tumor immunity. The fact that tumors are able to induce a state of tolerance and immunosuppression is a major obstacle in immunotherapy. Hence, there is an overwhelming need to develop new strategies that overcome this state of immune tolerance and induce an anti-tumor immune response both at primary and metastatic sites. Nanovectorized radiotherapy that combines ionizing radiation and nanodevices, is one strategy that could boost the quality and magnitude of an immune response in a predictable and designable fashion. The potential benefits of this emerging treatment may be based on the unique combination of immunostimulatory properties of nanoparticles with the ability of ionizing radiation to induce immunogenic tumor cell death. In this review, we will discuss available data and propose that the nanovectorized radiotherapy could be a powerful new strategy to induce anti-tumor immunity required for positive patient outcome.

  6. Nanovectorized radiotherapy, a new strategy to induce anti-tumor immunity

    Directory of Open Access Journals (Sweden)

    Claire eVanpouille-Box

    2012-10-01

    Full Text Available Recent experimental findings show that activation of the host immune system is required for the success of chemo- and radio-therapy. However, clinically-apparent tumors have already developed multiple mechanisms to escape anti-tumor immunity. The fact that tumors are able to induce a state of tolerance and immunosuppression is a major obstacle in immunotherapy. Hence, there is an overwhelming need to develop new strategies that overcome this state of immune tolerance and induce an anti-tumor immune response both at primary and metastatic sites. Nanovectorized radiotherapy that combines ionizing radiation and nano-devices, is one strategy that could boost the quality and magnitude of an immune response in a predictable and designable fashion. The potential benefits of this emerging treatment may be based on the unique combination of immuno-stimulatory properties of nanoparticles with the ability of ionizing radiation to induce immunogenic tumor cell death. In this review, we will discuss available data and propose that the nanovectorized radiotherapy could be a powerful new strategy to induce anti-tumor immunity required for positive patient outcome.

  7. In vivo tumor targeting of gold nanoparticles: effect of particle type and dosing strategy

    Directory of Open Access Journals (Sweden)

    Puvanakrishnan P

    2012-03-01

    Full Text Available Priyaveena Puvanakrishnan1, Jaesook Park1, Deyali Chatterjee2, Sunil Krishnan2, James W Tunnell11Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, USA; 2The UT MD Anderson Cancer Center, Houston, TX, USAAbstract: Gold nanoparticles (GNPs have gained significant interest as nanovectors for combined imaging and photothermal therapy of tumors. Delivered systemically, GNPs preferentially accumulate at the tumor site via the enhanced permeability and retention effect, and when irradiated with near infrared light, produce sufficient heat to treat tumor tissue. The efficacy of this process strongly depends on the targeting ability of the GNPs, which is a function of the particle’s geometric properties (eg, size and dosing strategy (eg, number and amount of injections. The purpose of this study was to investigate the effect of GNP type and dosing strategy on in vivo tumor targeting. Specifically, we investigated the in vivo tumor-targeting efficiency of pegylated gold nanoshells (GNSs and gold nanorods (GNRs for single and multiple dosing. We used Swiss nu/nu mice with a subcutaneous tumor xenograft model that received intravenous administration for a single and multiple doses of GNS and GNR. We performed neutron activation analysis to quantify the gold present in the tumor and liver. We performed histology to determine if there was acute toxicity as a result of multiple dosing. Neutron activation analysis results showed that the smaller GNRs accumulated in higher concentrations in the tumor compared to the larger GNSs. We observed a significant increase in GNS and GNR accumulation in the liver for higher doses. However, multiple doses increased targeting efficiency with minimal effect beyond three doses of GNPs. These results suggest a significant effect of particle type and multiple doses on increasing particle accumulation and on tumor targeting ability.Keywords: gold nanorods, gold nanoshells, tumor targeting

  8. 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.

  9. Radiolabeling Strategies for Tumor-Targeting Proteinaceous Drugs

    Directory of Open Access Journals (Sweden)

    Grant Sugiura

    2014-02-01

    Full Text Available Owing to their large size proteinaceous drugs offer higher operative information content compared to the small molecules that correspond to the traditional understanding of druglikeness. As a consequence these drugs allow developing patient-specific therapies that provide the means to go beyond the possibilities of current drug therapy. However, the efficacy of these strategies, in particular “personalized medicine”, depends on precise information about individual target expression rates. Molecular imaging combines non-invasive imaging methods with tools of molecular and cellular biology and thus bridges current knowledge to the clinical use. Moreover, nuclear medicine techniques provide therapeutic applications with tracers that behave like the diagnostic tracer. The advantages of radioiodination, still the most versatile radiolabeling strategy, and other labeled compounds comprising covalently attached radioisotopes are compared to the use of chelator-protein conjugates that are complexed with metallic radioisotopes. With the techniques using radioactive isotopes as a reporting unit or even the therapeutic principle, care has to be taken to avoid cleavage of the radionuclide from the protein it is linked to. The tracers used in molecular imaging require labeling techniques that provide site specific conjugation and metabolic stability. Appropriate choice of the radionuclide allows tailoring the properties of the labeled protein to the application required. Until the event of positron emission tomography the spectrum of nuclides used to visualize cellular and biochemical processes was largely restricted to iodine isotopes and 99m-technetium. Today, several nuclides such as 18-fluorine, 68-gallium and 86-yttrium have fundamentally extended the possibilities of tracer design and in turn caused the need for the development of chemical methods for their conjugation.

  10. Compatibility of Ohio trail users

    Science.gov (United States)

    Roger E. McCay; George H. Moeller

    1976-01-01

    Compatibility indexes show how Ohio trail users feel about meeting each other on the trail. All four of the major types of trail users-hikers, horseback riders, bicycle riders, and motorcycle riders-enjoy meeting their own kind. But they also feel antagonism toward the faster, more mechanized trail users; e.g., everyone likes hikers, but few like motorcycle riders....

  11. 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...

  12. 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...

  13. 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

  14. THE ARC TRAIL

    African Journals Online (AJOL)

    canal to fonn part of Moss. • The trail should be made use of by schools and the public. • The area should be cleared of exotic vegetation. e Indigenous trees should be planted to replace the removed exotic trees. The establishment of the ARC trail in 1985 came about as a direct result of the 1983 team1s rec ommenda ti ons ...

  15. Hierarchical Targeting Strategy for Enhanced Tumor Tissue Accumulation/Retention and Cellular Internalization.

    Science.gov (United States)

    Wang, Sheng; Huang, Peng; Chen, Xiaoyuan

    2016-09-01

    Targeted delivery of therapeutic agents is an important way to improve the therapeutic index and reduce side effects. To design nanoparticles for targeted delivery, both enhanced tumor tissue accumulation/retention and enhanced cellular internalization should be considered simultaneously. So far, there have been very few nanoparticles with immutable structures that can achieve this goal efficiently. Hierarchical targeting, a novel targeting strategy based on stimuli responsiveness, shows good potential to enhance both tumor tissue accumulation/retention and cellular internalization. Here, the recent design and development of hierarchical targeting nanoplatforms, based on changeable particle sizes, switchable surface charges and activatable surface ligands, will be introduced. In general, the targeting moieties in these nanoplatforms are not activated during blood circulation for efficient tumor tissue accumulation, but re-activated by certain internal or external stimuli in the tumor microenvironment for enhanced cellular internalization. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  16. New Strategies for the Treatment of Solid Tumors with CAR-T Cells.

    Science.gov (United States)

    Zhang, Hao; Ye, Zhen-Long; Yuan, Zhen-Gang; Luo, Zheng-Qiang; Jin, Hua-Jun; Qian, Qi-Jun

    2016-01-01

    Recent years, we have witnessed significant progresses in both basic and clinical studies regarding novel therapeutic strategies with genetically engineered T cells. Modification with chimeric antigen receptors (CARs) endows T cells with tumor specific cytotoxicity and thus induce anti-tumor immunity against malignancies. However, targeting solid tumors is more challenging than targeting B-cell malignancies with CAR-T cells because of the histopathological structure features, specific antigens shortage and strong immunosuppressive environment of solid tumors. Meanwhile, the on-target/off-tumor toxicity caused by relative expression of target on normal tissues is another issue that should be reckoned. Optimization of the design of CAR vectors, exploration of new targets, addition of safe switches and combination with other treatments bring new vitality to the CAR-T cell based immunotherapy against solid tumors. In this review, we focus on the major obstacles limiting the application of CAR-T cell therapy toward solid tumors and summarize the measures to refine this new cancer therapeutic modality.

  17. 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.

  18. Combination of arginine deprivation with TRAIL treatment as a targeted-therapy for mesothelioma.

    Science.gov (United States)

    Wangpaichitr, Medhi; Wu, Chunjing; Bigford, Gregory; Theodoropoulos, George; You, Min; Li, Ying Ying; Verona-Santos, Javier; Feun, Lynn G; Nguyen, Dao M; Savaraj, Niramol

    2014-12-01

    In the present study we present data to show that certain tumor cells including malignant pleural mesothelioma (MPM) cells do not express argininosuccinate synthetase (ASS), and thus are unable to synthesize arginine from citrulline. Exposure of these ASS-negative cells to the arginine degrading enzyme, arginine deiminase (ADI-PEG20), for 72 h results in significant increases in cleaved caspase-3. Importantly, this apoptotic signal is further strengthened by the addition of TNF-related apoptosis-inducing ligand (TRAIL). Using flow cytometry, we showed that the combination treatment (ADI-PEG20 at 50 ng/ml and TRAIL at 10 ng/ml) for 24 h resulted in profound cell death with 67% of cells positive for caspase-3 activity, while ADI-PEG20 alone or TRAIL alone resulted in only 10-15% cell death. This positive amplification loop is mediated through the cleavage of proapototic protein "BID". Our work represents a new strategy for treating patients with malignant pleural mesothelioma using targeted molecular therapeutics based on selected tumor markers, thus avoiding the use of potentially cytotoxic chemotherapy. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  19. Chalcones Enhance TRAIL-Induced Apoptosis in Prostate Cancer Cells

    OpenAIRE

    Szliszka, Ewelina; Czuba, Zenon P.; Mazur, Bogdan; Sedek, Lukasz; Paradysz, Andrzej; Krol, Wojciech

    2009-01-01

    Chalcones exhibit chemopreventive and antitumor effects. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a naturally occurring anticancer agent that induces apoptosis in cancer cells and is not toxic to normal cells. We examined the cytotoxic and apoptotic effect of five chalcones in combination with TRAIL on prostate cancer cells. The cytotoxicity was evaluated by the MTT and LDH assays. The apoptosis was determined using flow cytometry with annexin V-FITC. Our study showe...

  20. Precision cancer immunotherapy: optimizing dendritic cell-based strategies to induce tumor antigen-specific T-cell responses against individual patient tumors.

    Science.gov (United States)

    Osada, Takuya; Nagaoka, Koji; Takahara, Masashi; Yang, Xiao Yi; Liu, Cong-Xiao; Guo, Hongtao; Roy Choudhury, Kingshuk; Hobeika, Amy; Hartman, Zachary; Morse, Michael A; Lyerly, H Kim

    2015-05-01

    Most dendritic cell (DC)-based vaccines have loaded the DC with defined antigens, but loading with autologos tumor-derived antigens would generate DCs that activate personalized tumor-specific T-cell responses. We hypothesized that DC matured with an optimized combination of reagents and loaded with tumor-derived antigens using a clinically feasible electroporation strategy would induce potent antitumor immunity. We first studied the effects on DC maturation and antigen presentation of the addition of picibanil (OK432) to a combination of zoledronic acid, tumor necrosis factor-α, and prostaglandin E2. Using DC matured with the optimized combination, we tested 2 clinically feasible sources of autologous antigen for electroloading, total tumor mRNA or total tumor lysate, to determine which stimulated more potent antigen-specific T cells in vitro and activated more potent antitumor immunity in vivo. The combination of tumor necrosis factor-α/prostaglandin E2/zoledronic acid/OK432 generated DC with high expression of maturation markers and antigen-specific T-cell stimulatory function in vitro. Mature DC electroloaded with tumor-derived mRNA [mRNA electroporated dendritic cell (EPDC)] induced greater expansion of antigen-specific T cells in vitro than DC electroloaded with tumor lysate (lysate EPDC). In a therapeutic model of MC38-carcinoembryonic antigen colon cancer-bearing mice, vaccination with mRNA EPDC induced the most efficient anti-carcinoembryonic antigen cellular immune response, which significantly suppressed tumor growth. In conclusion, mature DC electroloaded with tumor-derived mRNA are a potent cancer vaccine, especially useful when specific tumor antigens for vaccination have not been identified, allowing autologous tumor, and if unavailable, allogeneic cell lines to be used as an unbiased source of antigen. Our data support clinical testing of this strategy.

  1. 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.

  2. The confining trailing string

    Energy Technology Data Exchange (ETDEWEB)

    Kiritsis, Elias [APC, Université Paris 7, CNRS/IN2P3, CEA/IRFU, Obs. de Paris, Sorbonne Paris Cité,Bâtiment Condorcet, F-75205, Paris Cedex 13 (UMR du CNRS 7164) (France); Theory Group, Physics Department, CERN,CH-1211, Geneva 23 (Switzerland); Crete Center for Theoretical Physics, Department of Physics, University of Crete,71003 Heraklion (Greece); Mazzanti, Liuba [Institute for Theoretical Physics and Spinoza Institute, Utrecht University,3508 TD Utrecht (Netherlands); Nitti, Francesco [APC, Université Paris 7, CNRS/IN2P3, CEA/IRFU, Obs. de Paris, Sorbonne Paris Cité,Bâtiment Condorcet, F-75205, Paris Cedex 13 (UMR du CNRS 7164) (France)

    2014-02-19

    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.

  3. State-Dependent Impulsive Control Strategies for a Tumor-Immune Model

    Directory of Open Access Journals (Sweden)

    Kwang Su Kim

    2016-01-01

    Full Text Available Controlling the number of tumor cells leads us to expect more efficient strategies for treatment of tumor. Towards this goal, a tumor-immune model with state-dependent impulsive treatments is established. This model may give an efficient treatment schedule to control tumor’s abnormal growth. By using the Poincaré map and analogue of Poincaré criterion, some conditions for the existence and stability of a positive order-1 periodic solution of this model are obtained. Moreover, we carry out numerical simulations to illustrate the feasibility of our main results and compare fixed-time impulsive treatment effects with state-dependent impulsive treatment effects. The results of our simulations say that, in determining optimal treatment timing, the model with state-dependent impulsive control is more efficient than that with fixed-time impulsive control.

  4. Delivery of viral vectors to tumor cells: extracellular transport, systemic distribution, and strategies for improvement.

    Science.gov (United States)

    Wang, Yong; Yuan, Fan

    2006-01-01

    It is a challenge to deliver therapeutic genes to tumor cells using viral vectors because (i) the size of these vectors are close to or larger than the space between fibers in extracellular matrix and (ii) viral proteins are potentially toxic in normal tissues. In general, gene delivery is hindered by various physiological barriers to virus transport from the site of injection to the nucleus of tumor cells and is limited by normal tissue tolerance of toxicity determined by local concentrations of transgene products and viral proteins. To illustrate the obstacles encountered in the delivery and yet limit the scope of discussion, this review focuses only on extracellular transport in solid tumors and distribution of viral vectors in normal organs after they are injected intravenously or intratumorally. This review also discusses current strategies for improving intratumoral transport and specificity of viral vectors.

  5. Selective killing of tumors deficient in methylthioadenosine phosphorylase: a novel strategy.

    Directory of Open Access Journals (Sweden)

    Martin Lubin

    2009-05-01

    Full Text Available The gene for methylthioadenosine phosphorylase (MTAP lies on 9p21, close to the gene CDKN2A that encodes the tumor suppressor proteins p16 and p14ARF. MTAP and CDKN2A are homozygously co-deleted, with a frequency of 35 to 70%, in lung and pancreatic cancer, glioblastoma, osteosarcoma, soft-tissue sarcoma, mesothelioma, and T-cell acute lymphoblastic leukemia. In normal cells, but not in tumor cells lacking MTAP, MTAP cleaves the natural substrate, 5'-deoxy-5'-methylthioadenosine (MTA, to adenine and 5-methylthioribose-1-phosphate (MTR-1-P, which are then converted to adenine nucleotides and methionine. This distinct difference between normal MTAP-positive cells and tumor MTAP-negative cells led to several proposals for therapy. We offer a novel strategy in which both MTA and a toxic adenine analog, such as 2,6-diaminopurine (DAP, 6-methylpurine (MeP, or 2-fluoroadenine (F-Ade, are administered. In MTAP-positive cells, abundant adenine, generated from supplied MTA, competitively blocks the conversion of an analog, by adenine phosphoribosyltransferase (APRT, to its active nucleotide form. In MTAP-negative tumor cells, the supplied MTA cannot generate adenine; hence conversion of the analog is not blocked.We show that this combination treatment--adenine analog plus MTA--kills MTAP-negative A549 lung tumor cells, while MTAP-positive human fibroblasts (HF are protected. In co-cultures of the breast tumor cell line, MCF-7, and HF cells, MCF-7 is inhibited or killed, while HF cells proliferate robustly. 5-Fluorouracil (5-FU and 6-thioguanine (6-TG may also be used with our strategy. Though neither analog is activated by APRT, in MTAP-positive cells, adenine produced from supplied MTA blocks conversion of 5-FU and 6-TG to their toxic nucleotide forms by competing for 5-phosphoribosyl-1-pyrophosphate (PRPP. The combination of MTA with 5-FU or 6-TG, in the treatment of MTAP-negative tumors, may produce a significantly improved therapeutic index

  6. 9th TRAIL Congress 2006, TRAIL in MOTION

    OpenAIRE

    TRAIL RESEARCH SCHOOL

    2006-01-01

    TRAIL is a Research School on Transport, Infrastructure and Logistics. TRAIL trains Ph.D. candidates and performs scientific and applied scientific research in the fields of mobility, transport, logistics, traffic, infrastructure and transport systems. TRAIL is a collaborative initiative of five Dutch universities, and is accredited as research school since 1997

  7. A Trail of Roses

    DEFF Research Database (Denmark)

    Ørum, Tania

    2015-01-01

    and reality as as well as about what is endlessly the same and endlessly different. And thus the text is seen to voice an entire ontology which, in its utter simplicity, exemplifies the poetical power and philosophical depth of Gertrude Stein’s writing. From this point Gertrude Stein’s influence is visible...... as a trail of roses through Danish 1960s art. The trail leads from Nielsen’s reading of Stein’s rose to the Danish composer Henning Christiansen, who put the sentence to music in his orchestral work A Rose for Miss Stein (1965). The chain of roses was continued by the painter and performance artist John...

  8. 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...

  9. Nanomedicine targeting the tumor microenvironment: Therapeutic strategies to inhibit angiogenesis, remodel matrix, and modulate immune responses

    Directory of Open Access Journals (Sweden)

    Elizabeth L. Siegler

    2016-11-01

    Full Text Available Increasing attention has been given to the tumor microenvironment (TME, which includes cellular and structural components such as fibroblasts, immune cells, vasculature, and extracellular matrix (ECM that surround tumor sites. These components contribute to tumor growth and metastasis and are one reason why traditional chemotherapy often is insufficient to eradicate the tumor completely. Newer treatments that target aspects of the TME, such as antiangiogenic and immunostimulatory therapies, have seen limited clinical success despite promising preclinical results. This can be attributed to a number of reasons, including a lack of drug penetration deeper into the necrotic tumor core, nonspecific delivery, rapid clearance from serum, or toxic side effects at high doses. Nanoparticles offer a potential solution to all of these obstacles, and many recent studies have shown encouraging results using nanomedicine to target TME vasculature, ECM, and immune response. While few of these platforms have made it to clinical trials to date, these strategies are relatively new and may offer a way to improve the effects of anticancer therapies.

  10. Nanotechnology-Based Strategies for Early Cancer Diagnosis Using Circulating Tumor Cells as a Liquid Biopsy.

    Science.gov (United States)

    Huang, Qinqin; Wang, Yin; Chen, Xingxiang; Wang, Yimeng; Li, Zhiqiang; Du, Shiming; Wang, Lianrong; Chen, Shi

    2018-01-01

    Circulating tumor cells (CTCs) are cancer cells that shed from a primary tumor and circulate in the bloodstream. As a form of "tumor liquid biopsy", CTCs provide important information for the mechanistic investigation of cancer metastasis and the measurement of tumor genotype evolution during treatment and disease progression. However, the extremely low abundance of CTCs in the peripheral blood and the heterogeneity of CTCs make their isolation and characterization major technological challenges. Recently, nanotechnologies have been developed for sensitive CTC detection; such technologies will enable better cell and molecular characterization and open up a wide range of clinical applications, including early disease detection and evaluation of treatment response and disease progression. In this review, we summarize the nanotechnology-based strategies for CTC isolation, including representative nanomaterials (such as magnetic nanoparticles, gold nanoparticles, silicon nanopillars, nanowires, nanopillars, carbon nanotubes, dendrimers, quantum dots, and graphene oxide) and microfluidic chip technologies that incorporate nanoroughened surfaces and discuss their key challenges and perspectives in CTC downstream analyses, such as protein expression and genetic mutations that may reflect tumor aggressiveness and patient outcome.

  11. TRAIL receptor–mediated JNK activation and Bim phosphorylation critically regulate Fas-mediated liver damage and lethality

    Science.gov (United States)

    Corazza, Nadia; Jakob, Sabine; Schaer, Corinne; Frese, Steffen; Keogh, Adrian; Stroka, Deborah; Kassahn, Daniela; Torgler, Ralph; Mueller, Christoph; Schneider, Pascal; Brunner, Thomas

    2006-01-01

    TNF-related apoptosis–inducing ligand (TRAIL) is a member of the TNF family with potent apoptosis-inducing properties in tumor cells. In particular, TRAIL strongly synergizes with conventional chemotherapeutic drugs to induce tumor cell death. Thus, TRAIL has been proposed as a promising future cancer therapy. Little, however, is known regarding what the role of TRAIL is in normal untransformed cells and whether therapeutic administration of TRAIL, alone or in combination with other apoptotic triggers, may cause tissue damage. In this study, we investigated the role of TRAIL in Fas-induced (CD95/Apo-1–induced) hepatocyte apoptosis and liver damage. While TRAIL alone failed to induce apoptosis in isolated murine hepatocytes, it strongly amplified Fas-induced cell death. Importantly, endogenous TRAIL was found to critically regulate anti-Fas antibody–induced hepatocyte apoptosis, liver damage, and associated lethality in vivo. TRAIL enhanced anti-Fas–induced hepatocyte apoptosis through the activation of JNK and its downstream substrate, the proapoptotic Bcl-2 homolog Bim. Consistently, TRAIL- and Bim-deficient mice and wild-type mice treated with a JNK inhibitor were protected against anti-Fas–induced liver damage. We conclude that TRAIL and Bim are important response modifiers of hepatocyte apoptosis and identify liver damage and lethality as a possible risk of TRAIL-based tumor therapy. PMID:16955144

  12. Cooperative TRAIL production mediates IFNα/Smac mimetic-induced cell death in TNFα-resistant solid cancer cells.

    Science.gov (United States)

    Roesler, Stefanie; Eckhardt, Ines; Wolf, Sebastian; Fulda, Simone

    2016-01-26

    Smac mimetics antagonize IAP proteins, which are highly expressed in several cancers. Recent reports indicate that Smac mimetics trigger a broad cytokine response and synergize with immune modulators to induce cell death. Here, we identify a differential requirement of TRAIL or TNFα as mediators of IFNα/Smac mimetic-induced cell death depending on the cellular context. Subtoxic concentrations of Smac mimetics cooperate with IFNα to induce cell death in various solid tumor cell lines in a highly synergistic manner as determined by combination index. Mechanistic studies show that IFNα/BV6 cotreatment promotes the formation of a caspase-8-activating complex together with the adaptor protein FADD and RIP1. Assembly of this RIP1/FADD/caspase-8 complex represents a critical event, since RIP1 silencing inhibits IFNα/BV6-induced cell death. Strikingly, pharmacological inhibition of paracrine/autocrine TNFα signaling by the TNFα scavenger Enbrel rescues HT-29 colon carcinoma cells, but not A172 glioblastoma cells from IFNα/BV6-induced cell death. By comparison, A172 cells are significantly protected against IFNα/BV6 treatment by blockage of TRAIL signaling through genetic silencing of TRAIL or its cognate receptor TRAIL receptor 2 (DR5). Despite this differential requirement of TNFα and TRAIL signaling, mRNA and protein expression is increased by IFNα/BV6 cotreatment in both cell lines. Interestingly, A172 cells turn out to be resistant to exogenously added recombinant TNFα even in the presence of BV6, whereas they display a high sensitivity towards TRAIL/BV6. In contrast, BV6 efficiently sensitizes HT-29 cells to TNFα while TRAIL only had limited efficacy. This demonstrates that a differential sensitivity towards TRAIL or TNFα determines the dependency on either death receptor ligand for IFNα/Smac mimetic-induced cell death. Thus, by concomitant stimulation of both death receptor systems IFNα/Smac mimetic combination treatment is an effective strategy to

  13. 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.

  14. Resilience and Coping Strategies Influencing the Quality of Life in Patients With Brain Tumor.

    Science.gov (United States)

    Pan, Chiu-Ju; Liu, Hui-Chun; Liang, Shu-Yuan; Liu, Chieh-Yu; Wu, Wei-Wen; Cheng, Su-Fen

    2017-06-01

    The study purpose was to evaluate how much of the variance in quality of life (QOL) among Taiwanese patients with brain tumor could be accounted for by resilience and coping strategy. This cross-sectional study included 95 patients who had undergone a treatment of operations or chemotherapy or radiotherapy relevant to brain tumor after at least 1 month and completed the European Organization for Research and Treatment of Cancer QOL Questionnaire-Brain Cancer Module (EORTC QLQ-BN20), Resilience Scale (RS), and Ways of Coping Checklist-Revised (WCC-R). There was a significant negative correlation between resilience and future uncertainty QOL and motor dysfunction QOL. In addition, there was a significant positive correlation between the emotion-focused coping and future uncertainty QOL, as well as a significant negative correlation between problem-focused coping and motor dysfunction QOL. Resilience accounted for 4.8% and the emotion-focused coping accounted for 10.20% of the variance in separately predicting the future uncertainty QOL. This study highlights the potential importance of resilience and coping strategies in patients' QOL, which is relevant to brain tumor treatment.

  15. Prognostic significance of TRAIL death receptors in Middle Eastern colorectal carcinomas and their correlation to oncogenic KRAS alterations

    Directory of Open Access Journals (Sweden)

    Hussain Azhar R

    2010-07-01

    Full Text Available Abstract Background Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL is a member of the tumour necrosis factor cytokine family that induces apoptosis upon binding to its death domain containing receptors, TRAIL receptor 1 (DR4 and TRAIL receptor 2 (DR5. Expression of TRAIL receptors is higher in colorectal carcinoma (CRC as compared to normal colorectal mucosa and targeted therapy with TRAIL leads to preferential killing of tumor cells sparing normal cells. Methods We investigated the expression of TRAIL and its receptors in a tissue microarray cohort of 448 Middle Eastern CRC. We also studied the correlation between TRAIL receptors and various clinico-pathological features including key molecular alterations and overall survival. Results CRC subset with TRAIL-R1 expression was associated with a less aggressive phenotype characterized by early stage (p = 0.0251 and a histology subtype of adenocarcinomas (p = 0.0355. Similarly CRC subset with TRAIL-R2 expression was associated with a well-differentiated tumors (p KIP1 and KRAS4A isoforms was significantly higher in CRC subset with TRAIL-R1 and TRAIL-R2 expression; TRAIL-R1 expression was also associated with cleaved caspase-3(p = 0.0011. Interestingly, TRAIL-R2 expression was associated with a microsatellite stable (MS--S/L phenotype (p = 0.0003 and with absence of KRAS mutations (p = 0.0481. Conclusion TRAIL-R1 expression was an independent prognostic marker for better survival in all CRC samples and even in the CRC group that received adjuvant therapy. The biological effects of TRAIL in CRC models, its enhancement of chemosensitivity towards standard chemotherapeutic agents and the effect of endogenous TRAIL receptor levels on survival make TRAIL an extremely attractive therapeutic target.

  16. The policy trail methodology

    DEFF Research Database (Denmark)

    Holford, John; Larson, Anne; Melo, Susana

    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....../national/regional/local), but also by a diversification of types of actor (public/private; for-profit/not-for-profit). Multi-level governance has been particularly marked – and has taken specific forms – in the European context, but it is by no means limited to the EU. The policy trail method aims to capture the increased influence...... of transnational organisations and public-private networks in policymaking. The concept of policy trails sought to theorise how this widened policy space – including new and variously-sited actors – is negotiated and how power is distributed across sites (Holford & McKenzie, 2013). Cort (2014) developed the notion...

  17. 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

  18. The TRAIL to Viral Pathogenesis: The Good, the Bad and the Ugly

    Science.gov (United States)

    Cummins, Nathan; Badley, Andrew

    2011-01-01

    Since the discovery of Tumor Necrosis Factor-Related Apoptosis Inducing Ligand (TRAIL) in 1995, much has been learned about the protein, its receptors and signaling cascade to induce apoptosis and the regulation of its expression. However, the physiologic role or roles that TRAIL may play in vivo are still being explored. The expression of TRAIL on effector T cells and the ability of TRAIL to induce apoptosis in virally infected cells provided early clues that TRAIL may play an active role in the immune defense against viral infections. However, increasing evidence is emerging that TRAIL may have a dual function in the immune system, both as a means to kill virally infected cells and in the regulation of cytokine production. TRAIL has been implicated in the immune response to viral infections (good), and in the pathogenesis of multiple viral infections (bad). Furthermore, several viruses have evolved mechanisms to manipulate TRAIL signaling to increase viral replication (ugly). It is likely that whether TRAIL ultimately has a proviral or antiviral effect will be dependent on the specific virus and the overall cytokine milieu of the host. Knowledge of the factors that determine whether TRAIL is proviral or antiviral is important because the TRAIL system may become a target for development of novel antiviral therapies. PMID:19519406

  19. Small molecule XIAP inhibitors cooperate with TRAIL to induce apoptosis in childhood acute leukemia cells and overcome Bcl-2-mediated resistance.

    Science.gov (United States)

    Fakler, Melanie; Loeder, Sandra; Vogler, Meike; Schneider, Katja; Jeremias, Irmela; Debatin, Klaus-Michael; Fulda, Simone

    2009-02-19

    Defects in apoptosis contribute to poor outcome in pediatric acute lymphoblastic leukemia (ALL), calling for novel strategies that counter apoptosis resistance. Here, we demonstrate for the first time that small molecule inhibitors of the antiapoptotic protein XIAP cooperate with TRAIL to induce apoptosis in childhood acute leukemia cells. XIAP inhibitors at subtoxic concentrations, but not a structurally related control compound, synergize with TRAIL to trigger apoptosis and to inhibit clonogenic survival of acute leukemia cells, whereas they do not affect viability of normal peripheral blood lymphocytes, suggesting some tumor selectivity. Analysis of signaling pathways reveals that XIAP inhibitors enhance TRAIL-induced activation of caspases, loss of mitochondrial membrane potential, and cytochrome c release in a caspase-dependent manner, indicating that they promote a caspase-dependent feedback mitochondrial amplification loop. Of note, XIAP inhibitors even overcome Bcl-2-mediated resistance to TRAIL by enhancing Bcl-2 cleavage and Bak conformational change. Importantly, XIAP inhibitors kill leukemic blasts from children with ALL ex vivo and cooperate with TRAIL to induce apoptosis. In vivo, they significantly reduce leukemic burden in a mouse model of pediatric ALL engrafted in non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice. Thus, XIAP inhibitors present a promising novel approach for apoptosis-based therapy of childhood ALL.

  20. MADD knock-down enhances doxorubicin and TRAIL induced apoptosis in breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Andrea Turner

    Full Text Available The Map kinase Activating Death Domain containing protein (MADD isoform of the IG20 gene is over-expressed in different types of cancer tissues and cell lines and it functions as a negative regulator of apoptosis. Therefore, we speculated that MADD might be over-expressed in human breast cancer tissues and that MADD knock-down might synergize with chemotherapeutic or TRAIL-induced apoptosis of breast cancer cells. Analyses of breast tissue microarrays revealed over-expression of MADD in ductal and invasive carcinomas relative to benign tissues. MADD knockdown resulted in enhanced spontaneous apoptosis in human breast cancer cell lines. Moreover, MADD knockdown followed by treatment with TRAIL or doxorubicin resulted in increased cell death compared to either treatment alone. Enhanced cell death was found to be secondary to increased caspase-8 activation. These data indicate that strategies to decrease MADD expression or function in breast cancer may be utilized to increase tumor cell sensitivity to TRAIL and doxorubicin induced apoptosis.

  1. Tumor initiating cells and chemoresistance: which is the best strategy to target colon cancer stem cells?

    Science.gov (United States)

    Paldino, Emanuela; Tesori, Valentina; Casalbore, Patrizia; Gasbarrini, Antonio; Puglisi, Maria Ausiliatrice

    2014-01-01

    There is an emerging body of evidence that chemoresistance and minimal residual disease result from selective resistance of a cell subpopulation from the original tumor that is molecularly and phenotypically distinct. These cells are called "cancer stem cells" (CSCs). In this review, we analyze the potential targeting strategies for eradicating CSCs specifically in order to develop more effective therapeutic strategies for metastatic colon cancer. These include induction of terminal epithelial differentiation of CSCs or targeting some genes expressed only in CSCs and involved in self-renewal and chemoresistance. Ideal targets could be cell regulators that simultaneously control the stemness and the resistance of CSCs. Another important aspect of cancer biology, which can also be harnessed to create novel broad-spectrum anticancer agents, is the Warburg effect, also known as aerobic glycolysis. Actually, little is yet known with regard to the metabolism of CSCs population, leaving an exciting unstudied avenue in the dawn of the emerging field of metabolomics.

  2. 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...

  3. BCDC Bay Trail Alignment 2009

    Data.gov (United States)

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

  4. Apigenin promotes TRAIL-mediated apoptosis regardless of ROS generation.

    Science.gov (United States)

    Kang, Chang-Hee; Molagoda, Ilandarage Menu Neelaka; Choi, Yung Hyun; Park, Cheol; Moon, Dong-Oh; Kim, Gi-Young

    2018-01-01

    Apigenin is a bioactive flavone in several herbs including parsley, thyme, and peppermint. Apigenin possesses anti-cancer and anti-inflammatory properties; however, whether apigenin enhances TRAIL-mediated apoptosis in cancer cells is unknown. In the current study, we found that apigenin enhanced TRAIL-induced apoptosis by promoting caspase activation and death receptor 5 (DR5) expression and a chimeric antibody against DR5 completely blocked the apoptosis. Apigenin also upregulated reactive oxygen species (ROS) generation; however, intriguingly, ROS inhibitors, glutathione (GSH) or N-acetyl-l-cysteine (NAC), moderately increased apigenin/TRAIL-induced apoptosis. Additional results showed that an autophagy inducer, rapamycin, enhanced apigenin/TRAIL-mediated apoptosis by a slight increase of ROS generation. Accordingly, NAC and GSH rather decreased apigenin-induced autophagy formation, suggesting that apigenin-induced ROS generation increased autophagy formation. However, autophagy inhibitors, bafilomycin (BAF) and 3-methyladenine (3-MA), showed different result in apigenin/TRAIL-mediated apoptosis without ROS generation. 3-MA upregulated the apoptosis but remained ROS levels; however, no changes on apoptosis and ROS generation were observed by BAF treatment. Taken together, these findings reveal that apigenin enhances TRAIL-induced apoptosis by activating apoptotic caspases by upregulating DR5 expression regardless of ROS generation, which may be a promising strategy for an adjuvant of TRAIL. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. Meteor trail spectra

    International Nuclear Information System (INIS)

    Ovezgeldyev, O.G.; Mukhamednazarov, S.; Shafiev, R.I.; Maltsev, N.V.

    1987-01-01

    Meteor radiation appears as a result of collisions between meteoroid atoms and air molecules. Depending on duration, this radiation is usually divided into the following types: radiation of the meteor head; radiation of a coma surrounding or immediately following the meteor head; radiation of a trail formed as a result of fragments lagging behind or by the afterglow; and radiation of a meteor train forming from a tail as a result of various chemical and dynamical processes. To investigate physical processes caused by each of the above types, it is necessary to obtain the corresponding experimental data. The physical processes of the radiation and the measurement of the experimental data is discussed

  6. 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

  7. On Entropy Trail

    Science.gov (United States)

    Farokhi, Saeed; Taghavi, Ray; Keshmiri, Shawn

    2015-11-01

    Stealth technology is developed for military aircraft to minimize their signatures. The primary attention was focused on radar signature, followed by the thermal and noise signatures of the vehicle. For radar evasion, advanced configuration designs, extensive use of carbon composites and radar-absorbing material, are developed. On thermal signature, mainly in the infra-red (IR) bandwidth, the solution was found in blended rectangular nozzles of high aspect ratio that are shielded from ground detectors. For noise, quiet and calm jets are integrated into vehicles with low-turbulence configuration design. However, these technologies are totally incapable of detecting new generation of revolutionary aircraft. These shall use all electric, distributed, propulsion system that are thermally transparent. In addition, composite skin and non-emitting sensors onboard the aircraft will lead to low signature. However, based on the second-law of thermodynamics, there is no air vehicle that can escape from leaving an entropy trail. Entropy is thus the only inevitable signature of any system, that once measured, can detect the source. By characterizing the entropy field based on its statistical properties, the source may be recognized, akin to face recognition technology. Direct measurement of entropy is cumbersome, however as a derived property, it can be easily measured. The measurement accuracy depends on the probe design and the sensors onboard. One novel air data sensor suite is introduced with promising potential to capture the entropy trail.

  8. ROS-activated anticancer prodrugs: a new strategy for tumor-specific damage

    Science.gov (United States)

    Peng, Xiaohua; Gandhi, Varsha

    2013-01-01

    Targeting tumor cells is an important strategy to improve the selectivity of cancer therapies. With the advanced studies in cancer biology, we know that cancer cells are usually under increased oxidative stress. The high level of reactive oxygen species in cancer cells has been exploited for developing novel therapeutic strategies to preferentially kill cancer cells. Our group, amongst others, have used boronic acids/esters as triggers for developing ROS-activated anticancer prodrugs that target cancer cells. The selectivity was achieved by combining a specific reaction between boronates and H2O2 with the efficient masking of drug toxicity in the prodrug via boronates. Prodrugs activated via ferrocene-mediated oxidation have also been developed to improve the selectivity of anticancer drugs. We describe how the strategies of ROS-activation can be used for further development of new ROS-targeting prodrugs, eventually leading to novel approaches and/or combined technology for more efficient and selective treatment of cancers. PMID:22900465

  9. Combination of Id2 Knockdown Whole Tumor Cells and Checkpoint Blockade: A Potent Vaccine Strategy in a Mouse Neuroblastoma Model.

    Directory of Open Access Journals (Sweden)

    Lina Chakrabarti

    Full Text Available Tumor vaccines have held much promise, but to date have demonstrated little clinical success. This lack of success is conceivably due to poor tumor antigen presentation combined with immuno-suppressive mechanisms exploited by the tumor itself. Knock down of Inhibitor of differentiation protein 2 (Id2-kd in mouse neuroblastoma whole tumor cells rendered these cells immunogenic. Id2-kd neuroblastoma (Neuro2a cells (Id2-kd N2a failed to grow in most immune competent mice and these mice subsequently developed immunity against further wild-type Neuro2a tumor cell challenge. Id2-kd N2a cells grew aggressively in immune-compromised hosts, thereby establishing the immunogenicity of these cells. Therapeutic vaccination with Id2-kd N2a cells alone suppressed tumor growth even in established neuroblastoma tumors and when used in combination with immune checkpoint blockade eradicated large established tumors. Mechanistically, immune cell depletion studies demonstrated that while CD8+ T cells are critical for antitumor immunity, CD4+ T cells are also required to induce a sustained long-lasting helper effect. An increase in number of CD8+ T-cells and enhanced production of interferon gamma (IFNγ was observed in tumor antigen stimulated splenocytes of vaccinated mice. More importantly, a massive influx of cytotoxic CD8+ T-cells infiltrated the shrinking tumor following combined immunotherapy. These findings show that down regulation of Id2 induced tumor cell immunity and in combination with checkpoint blockade produced a novel, potent, T-cell mediated tumor vaccine strategy.

  10. Adaptive radiotherapy strategies for pelvic tumors - a systematic review of clinical implementations

    DEFF Research Database (Denmark)

    Thörnqvist, Sara; Hysing, Liv B; Tuomikoski, Laura

    2016-01-01

    Med. For each tumor site, the identified papers were screened independently by two researches for selection of studies describing all processes of an ART workflow: treatment monitoring and evaluation, decision and execution of adaptations. Both brachytherapy and external beam studies were eligible for review......, but increases workload and thereby challenges clinical implementation. This paper reviews strategies and workflows for clinical and in silico implemented ART for prostate, bladder, gynecological (gyne) and ano-rectal cancers. MATERIAL AND METHODS: Initial identification of papers was based on searches in Pub....... RESULTS: The review consisted of 43 clinical studies and 51 in silico studies. For prostate, 1219 patients were treated with offline re-planning, mainly to adapt prostate motion relative to bony anatomy. For gyne 1155 patients were treated with online brachytherapy re-planning while 25 ano-rectal cancer...

  11. Gamma knife surgery for pineal region tumors: an alternative strategy for negative pathology

    Directory of Open Access Journals (Sweden)

    Peng Wang

    2014-02-01

    Full Text Available Objective : Pineal region tumors (PRTs are uncommon, and treatments vary among neoplasm types. The authors report their experience with gamma knife surgery (GKS as an initial treatment in a series of PRT patients with unclear pathological diagnoses. Method : Seventeen PRT patients with negative pathology who underwent GKS were retrospectively studied. Nine patients had further whole-brain and spinal cord radiotherapy and chemotherapy 6–9 months after GKS. Results : Sixteen of 17 cases were followed up over a mean of 33.3 months. The total response rate was 75%, and the control rate was 81.3%. No obvious neurological deficits or complications were attributable to GKS. Conclusion : The findings indicate that GKS may be an alternative strategy in selected PRT patients who have negative pathological diagnoses, and that good outcomes and quality of life can be obtained with few complications.

  12. Gamma knife surgery for pineal region tumors: an alternative strategy for negative pathology

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Peng [Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu (China); Department of Neurosurgery, The Fifth People' s Hospital of Chengdu, Chengdu (China); Mao, Qing; Wang, Wei; Zhou, Liang-Xue; Liu, Yan-Hui, E-mail: liuyanhui9@gmail.com [Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu (China)

    2014-03-01

    Objective: pineal region tumors (PRTs) are uncommon, and treatments vary among neoplasm types. The authors report their experience with gamma knife surgery (GKS) as an initial treatment in a series of PRT patients with unclear pathological diagnoses. Method: seventeen PRT patients with negative pathology who underwent GKS were retrospectively studied. Nine patients had further whole-brain and spinal cord radiotherapy and chemotherapy 6-9 months after GKS. Results: Sixteen of 17 cases were followed up over a mean of 33.3 months. The total response rate was 75%, and the control rate was 81.3%. No obvious neurological deficits or complications were attributable to GKS. Conclusion: the findings indicate that GKS may be an alternative strategy in selected PRT patients who have negative pathological diagnoses, and that good outcomes and quality of life can be obtained with few complications. (author)

  13. Increasing productivity trailed scraper

    Directory of Open Access Journals (Sweden)

    Nilov V.A.

    2016-12-01

    Full Text Available Considered the issue of improving the operational characteristics of trailing scraper through the use of a combined knife system, which combines in one machine the widespread speed stab system and shovels cutting on. Requirements are formulated to knife scraper systems and the new combined knife system. It allows you to develop soil in terms of minimum energy and the free cutting of the soil. The practical possibility of obtaining a smooth face, more intense filling of the bucket, rational distribution of soil in the bucket in conditions of free cutting and filling of the bucket when the increased cutting depth of soil, without additional machines. The obtained data on the value of the coefficient of the specific resistance to cutting when the width of the free cut in the range of 1.0 to 2.2 m. The recommendations for a rational distribution of the soil in the bucket during the free cutting.

  14. Mathematical modeling of tumor-induced immunosuppression by myeloid-derived suppressor cells: Implications for therapeutic targeting strategies.

    Science.gov (United States)

    Shariatpanahi, Seyed Peyman; Shariatpanahi, Seyed Pooya; Madjidzadeh, Keivan; Hassan, Moustapha; Abedi-Valugerdi, Manuchehr

    2018-04-07

    Myeloid-derived suppressor cells (MDSCs) belong to immature myeloid cells that are generated and accumulated during the tumor development. MDSCs strongly suppress the anti-tumor immunity and provide conditions for tumor progression and metastasis. In this study, we present a mathematical model based on ordinary differential equations (ODE) to describe tumor-induced immunosuppression caused by MDSCs. The model consists of four equations and incorporates tumor cells, cytotoxic T cells (CTLs), natural killer (NK) cells and MDSCs. We also provide simulation models that evaluate or predict the effects of anti-MDSC drugs (e.g., l-arginine and 5-Fluorouracil (5-FU)) on the tumor growth and the restoration of anti-tumor immunity. The simulated results obtained using our model were in good agreement with the corresponding experimental findings on the expansion of splenic MDSCs, immunosuppressive effects of these cells at the tumor site and effectiveness of l-arginine and 5-FU on the re-establishment of antitumor immunity. Regarding this latter issue, our predictive simulation results demonstrated that intermittent therapy with low-dose 5-FU alone could eradicate the tumors irrespective of their origins and types. Furthermore, at the time of tumor eradication, the number of CTLs prevailed over that of cancer cells and the number of splenic MDSCs returned to the normal levels. Finally, our predictive simulation results also showed that the addition of l-arginine supplementation to the intermittent 5-FU therapy reduced the time of the tumor eradication and the number of iterations for 5-FU treatment. Thus, the present mathematical model provides important implications for designing new therapeutic strategies that aim to restore antitumor immunity by targeting MDSCs. Copyright © 2018 Elsevier Ltd. All rights reserved.

  15. Smac mimetics in combination with TRAIL selectively target cancer stem cells in nasopharyngeal carcinoma.

    Science.gov (United States)

    Wu, Man-Si; Wang, Guang-Feng; Zhao, Zhi-Qiang; Liang, Yi; Wang, Heng-Bang; Wu, Miao-Yi; Min, Ping; Chen, Li-zhen; Feng, Qi-Sheng; Bei, Jin-Xin; Zeng, Yi-Xin; Yang, Dajun

    2013-09-01

    Nasopharyngeal carcinoma is a common malignancy in Southern China. After radiotherapy and chemotherapy, a considerable proportion of patients with nasopharyngeal carcinoma suffered tumor relapse and metastasis. Cancer stem cells (CSC) have been shown with resistance against therapies and thus considered as the initiator of recurrence and metastasis in tumors, where the antiapoptotic property of CSCs play an important role. Smac/DIABLO is an inverse regulator for the inhibitors of apoptosis protein family (IAP), which have been involved in apoptosis. Here, the effects of Smac mimetics on the CSCs of nasopharyngeal carcinoma were studied both in vitro and in vivo, using two clones of nasopharyngeal carcinoma cell line CNE2 as models. We found that one of the clones, S18, had CSC-like properties and IAPs were overexpressed. The combination of Smac mimetics and TNF-related apoptosis-inducing ligand (TRAIL) can reduce the percentage of SP cells and inhibit the colony- and sphere-forming abilities of S18 cells, indicating their ability to attenuate the CSCs. Moreover, in a nasopharyngeal carcinoma xenograft model, the administration of Smac mimetics in combination with TRAIL also led to the elimination of nasopharyngeal carcinoma stem cells. Furthermore, the Smac mimetics in combination with TRAIL induced the degradation of cIAP1 and XIAP and thus induced apoptosis in vitro and in vivo. Taken together, our data show that Smac mimetics exerted an antitumor effect on nasopharyngeal carcinoma cancer stem cells, and this combination treatment should be considered as a promising strategy for the treatment of nasopharyngeal carcinoma.

  16. Tumor Initiating Cells and Chemoresistance: Which Is the Best Strategy to Target Colon Cancer Stem Cells?

    Directory of Open Access Journals (Sweden)

    Emanuela Paldino

    2014-01-01

    Full Text Available There is an emerging body of evidence that chemoresistance and minimal residual disease result from selective resistance of a cell subpopulation from the original tumor that is molecularly and phenotypically distinct. These cells are called “cancer stem cells” (CSCs. In this review, we analyze the potential targeting strategies for eradicating CSCs specifically in order to develop more effective therapeutic strategies for metastatic colon cancer. These include induction of terminal epithelial differentiation of CSCs or targeting some genes expressed only in CSCs and involved in self-renewal and chemoresistance. Ideal targets could be cell regulators that simultaneously control the stemness and the resistance of CSCs. Another important aspect of cancer biology, which can also be harnessed to create novel broad-spectrum anticancer agents, is the Warburg effect, also known as aerobic glycolysis. Actually, little is yet known with regard to the metabolism of CSCs population, leaving an exciting unstudied avenue in the dawn of the emerging field of metabolomics.

  17. 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...

  18. Chalcones Enhance TRAIL-Induced Apoptosis in Prostate Cancer Cells

    Directory of Open Access Journals (Sweden)

    Ewelina Szliszka

    2009-12-01

    Full Text Available Chalcones exhibit chemopreventive and antitumor effects. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL is a naturally occurring anticancer agent that induces apoptosis in cancer cells and is not toxic to normal cells. We examined the cytotoxic and apoptotic effect of five chalcones in combination with TRAIL on prostate cancer cells. The cytotoxicity was evaluated by the MTT and LDH assays. The apoptosis was determined using flow cytometry with annexin V-FITC. Our study showed that all five tested chalcones: chalcone, licochalcone-A, isobavachalcone, xanthohumol, butein markedly augmented TRAIL-mediated apoptosis and cytotoxicity in prostate cancer cells and confirmed the significant role of chalcones in chemoprevention of prostate cancer.

  19. Chalcones Enhance TRAIL-Induced Apoptosis in Prostate Cancer Cells

    Science.gov (United States)

    Szliszka, Ewelina; Czuba, Zenon P; Mazur, Bogdan; Sedek, Lukasz; Paradysz, Andrzej; Krol, Wojciech

    2009-01-01

    Chalcones exhibit chemopreventive and antitumor effects. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a naturally occurring anticancer agent that induces apoptosis in cancer cells and is not toxic to normal cells. We examined the cytotoxic and apoptotic effect of five chalcones in combination with TRAIL on prostate cancer cells. The cytotoxicity was evaluated by the MTT and LDH assays. The apoptosis was determined using flow cytometry with annexin V-FITC. Our study showed that all five tested chalcones: chalcone, licochalcone-A, isobavachalcone, xanthohumol, butein markedly augmented TRAIL-mediated apoptosis and cytotoxicity in prostate cancer cells and confirmed the significant role of chalcones in chemoprevention of prostate cancer. PMID:20161998

  20. 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.

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

    Science.gov (United States)

    Wei, Ruo-Jing; Zhang, Xin-Shi; He, Da-Lin

    2018-01-01

    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.

  2. Chimeric antigen receptor T cell (CAR-T) immunotherapy for solid tumors: lessons learned and strategies for moving forward.

    Science.gov (United States)

    Li, Jian; Li, Wenwen; Huang, Kejia; Zhang, Yang; Kupfer, Gary; Zhao, Qi

    2018-02-13

    Recently, the US Food and Drug Administration (FDA) approved the first chimeric antigen receptor T cell (CAR-T) therapy for the treatment CD19-positive B cell acute lymphoblastic leukemia. While CAR-T has achieved remarkable success in the treatment of hematopoietic malignancies, whether it can benefit solid tumor patients to the same extent is still uncertain. Even though hundreds of clinical trials are undergoing exploring a variety of tumor-associated antigens (TAA), no such antigen with comparable properties like CD19 has yet been identified regarding solid tumors CAR-T immunotherapy. Inefficient T cell trafficking, immunosuppressive tumor microenvironment, suboptimal antigen recognition specificity, and lack of safety control are currently considered as the main obstacles in solid tumor CAR-T therapy. Here, we reviewed the solid tumor CAR-T clinical trials, emphasizing the studies with published results. We further discussed the challenges that CAR-T is facing for solid tumor treatment and proposed potential strategies to improve the efficacy of CAR-T as promising immunotherapy.

  3. Anti-angiogenic therapy in pediatric brain tumors : An effective strategy?

    NARCIS (Netherlands)

    Sie, Mariska; den Dunnen, Wilfred F. A.; Hoving, Eelco W.; de Bont, Eveline S. J. M.

    Brain tumors are still the leading cause of cancer morbidity and mortality among children, despite different therapeutic options including neurosurgery, chemotherapy and radiation. As angiogenesis is highly crucial in brain tumor growth and progression, numerous clinical trials evaluating diverse

  4. Paving TRAIL's Path with Ubiquitin.

    Science.gov (United States)

    Lafont, Elodie; Hartwig, Torsten; Walczak, Henning

    2018-01-01

    Despite its name, signalling induced by the tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is versatile. Besides eliciting cell death by both apoptosis and necroptosis, TRAIL can also induce migration, proliferation, and cytokine production in cancerous and non-cancerous cells. Unravelling the mechanisms regulating the intricate balance between these different outputs could therefore facilitate our understanding of the role of TRAIL in tissue homeostasis, immunity, and cancer. Ubiquitination and its reversal, deubiquitination, are crucial modulators of immune receptor signalling. This review discusses recent progress on the orchestration of TRAIL signalling outcomes by ubiquitination of various components of the signalling complexes, our understanding of the molecular switches that decide between cell death and gene activation, and what remains to be discovered. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. Targeting pro-apoptotic trail receptors sensitizes HeLa cervical cancer cells to irradiation-induced apoptosis

    NARCIS (Netherlands)

    Maduro, John H.; de Vries, Elisabeth G. E.; Meersma, Gert-Jan; Hougardy, Brigitte M. T.; van der Zee, Ate G. J.; De Jong, Steven

    2008-01-01

    Purpose: To investigate the potential of irradiation in combination with drugs targeting the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor (DR)4 and DR5 and their mechanism of action in a cervical cancer cell line. Methods and Materials: Recombinant human TRAIL

  6. Glioblastoma angiogenesis: VEGF resistance solutions and new strategies based on molecular mechanisms of tumor vessel formation.

    Science.gov (United States)

    Takano, Shingo

    2012-04-01

    Glioblastomas are highly vascular tumors. Recent preclinical and clinical investigations have revealed that agents targeting angiogenesis may have efficacy against this type of tumor. Antibodies to vascular endothelial growth factor are being studied in this patient population. Unfortunately, treatment inevitably fails. This review provides an update on recent research on the mechanisms by which tumor cells acquire resistance, and discusses recent preclinical and experimental development of novel new-generation anti-angiogenic agents that overcome this problem, especially those based on the molecular mechanisms of tumor vessel formation. The tumor vasculature not only nourishes glioblastomas, but also provides a specialized microenvironment for tumor stem-like cells and for the brain tumor. The factors, pathways, and interactions described in this review provide information about the cell biology of glioblastomas which may ultimately result in new modes of treatment.

  7. 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.

  8. Tumor-targeted inhibition by a novel strategy - mimoretrovirus expressing siRNA targeting the Pokemon gene.

    Science.gov (United States)

    Tian, Zhiqiang; Wang, Huaizhi; Jia, Zhengcai; Shi, Jinglei; Tang, Jun; Mao, Liwei; Liu, Hongli; Deng, Yijing; He, Yangdong; Ruan, Zhihua; Li, Jintao; Wu, Yuzhang; Ni, Bing

    2010-12-01

    Pokemon gene has crucial but versatile functions in cell differentiation, proliferation and tumorigenesis. It is a master regulator of the ARF-HDM2-p53 and Rb-E2F pathways. The facts that the expression of Pokemon is essential for tumor formation and many kinds of tumors over-express the Pokemon gene make it an attractive target for therapeutic intervention for cancer treatment. In this study, we used an RNAi strategy to silence the Pokemon gene in a cervical cancer model. To address the issues involving tumor specific delivery and durable expression of siRNA, we applied the Arg-Gly-Asp (RGD) peptide ligand and polylysine (K(18)) fusion peptide to encapsulate a recombinant retrovirus plasmid expressing a siRNA targeting the Pokemon gene and produced the 'mimoretrovirus'. At charge ratio 2.0 of fusion peptide/plasmid, the mimoretrovirus formed stable and homogenous nanoparticles, and provided complete DNase I protection and complete gel retardation. This nanoparticle inhibited SiHa cell proliferation and invasion, while it promoted SiHa cell apoptosis. The binding of the nanoparticle to SiHa cells was mediated via the RGD-integrin α(v)β(3) interaction, as evidenced by the finding that unconjugated RGD peptide inhibited this binding significantly. This tumor-targeting mimoretrovirus exhibited excellent anti-tumor capacity in vivo in a nude mouse model. Moreover, the mimoretrovirus inhibited tumor growth with a much higher efficiency than recombinant retrovirus expressing siRNA or the K(18)/P4 nanoparticle lacking the RGD peptide. Results suggest that the RNAi/RGD-based mimoretrovirus developed in this study represents a novel anti-tumor strategy that may be applicable to most research involving cancer therapy and, thus, has promising potential as a cervical cancer treatment.

  9. 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.

  10. Cyproterone acetate enhances TRAIL-induced androgen-independent prostate cancer cell apoptosis via up-regulation of death receptor 5.

    Science.gov (United States)

    Chen, Linjie; Wolff, Dennis W; Xie, Yan; Lin, Ming-Fong; Tu, Yaping

    2017-03-07

    Virtually all prostate cancer deaths occur due to obtaining the castration-resistant phenotype after prostate cancer cells escaped from apoptosis and/or growth suppression initially induced by androgen receptor blockade. TNF-related apoptosis-inducing ligand (TRAIL) was an attractive cancer therapeutic agent due to its minimal toxicity to normal cells and remarkable apoptotic activity in tumor cells. However, most localized cancers including prostate cancer are resistant to TRAIL-induced apoptosis, thereby creating a therapeutic challenge of inducing TRAIL sensitivity in cancer cells. Herein the effects of cyproterone acetate, an antiandrogen steroid, on the TRAIL-induced apoptosis of androgen receptor-negative prostate cancer cells are reported. Cell apoptosis was assessed by both annexin V/propidium iodide labeling and poly (ADP-ribose) polymerase cleavage assays. Gene and protein expression changes were determined by quantitative real-time PCR and western blot assays. The effect of cyproterone acetate on gene promoter activity was determined by luciferase reporter assay. Cyproterone acetate but not AR antagonist bicalutamide dramatically increased the susceptibility of androgen receptor-negative human prostate cancer PC-3 and DU145 cells to TRAIL-induced apoptosis but no effects on immortalized human prostate stromal PS30 cells and human embryonic kidney HEK293 cells. Further investigation of the TRAIL-induced apoptosis pathway revealed that cyproterone acetate exerted its effect by selectively increasing death receptor 5 (DR5) mRNA and protein expression. Cyproterone acetate treatment also increased DR5 gene promoter activity, which could be abolished by mutation of a consensus binding domain of transcription factor CCAAT-enhancer-binding protein homologous protein (CHOP) in the DR5 gene promoter. Cyproterone acetate increases CHOP expression in a concentration and time-dependent manner and endoplasmic reticulum stress reducer 4-phenylbutyrate could block

  11. TRAIL/DR5 signaling promotes macrophage foam cell formation by modulating scavenger receptor expression.

    Directory of Open Access Journals (Sweden)

    Fang Fang Liu

    Full Text Available Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L has been shown to have protective effects against atherosclerosis. However, whether TRAIL has any effects on expression of macrophage scavenger receptors and lipid uptake has not yet been studied. Macrophage lines RAW264.7 and THP-1, and mouse primary peritoneal macrophages, were cultured in vitro and treated with recombinant human TRAIL. Real-time PCR and western blot were performed to measure mRNA and protein expressions. Foam cell formation was assessed by internalization of acetylated and oxidized low-density lipoproteins (LDL. Apoptosis was measured by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling. We found that TRAIL treatment increased expression of scavenger receptor (SR-AI and SR-BI in a time- and dose-dependent manner, and this effect was accompanied by increased foam cell formation. These effects of TRAIL were abolished by a TRAIL neutralizing antibody or in DR5 receptor-deficient macrophages. The increased LDL uptake by TRAIL was blocked by SR-AI gene silencing or the SR-AI inhibitor poly(I:C, while SR-BI blockade with BLT-1 had no effect. TRAIL-induced SR-AI expression was blocked by the inhibitor of p38 mitogen-activated protein kinase, but not by inhibitors of ERK1/2 or JNK. TRAIL also induced apoptosis in macrophages. In contrast to macrophages, TRAIL showed little effects on SR expression or apoptosis in vascular smooth muscle cells. In conclusion, our results demonstrate that TRAIL promotes macrophage lipid uptake via SR-AI upregulation through activation of the p38 pathway.

  12. Drug discovery strategies in the field of tumor energy metabolism: Limitations by metabolic flexibility and metabolic resistance to chemotherapy.

    Science.gov (United States)

    Amoedo, N D; Obre, E; Rossignol, R

    2017-08-01

    The search for new drugs capable of blocking the metabolic vulnerabilities of human tumors has now entered the clinical evaluation stage, but several projects already failed in phase I or phase II. In particular, very promising in vitro studies could not be translated in vivo at preclinical stage and beyond. This was the case for most glycolysis inhibitors that demonstrated systemic toxicity. A more recent example is the inhibition of glutamine catabolism in lung adenocarcinoma that failed in vivo despite a strong addiction of several cancer cell lines to glutamine in vitro. Such contradictory findings raised several questions concerning the optimization of drug discovery strategies in the field of cancer metabolism. For instance, the cell culture models in 2D or 3D might already show strong limitations to mimic the tumor micro- and macro-environment. The microenvironment of tumors is composed of cancer cells of variegated metabolic profiles, supporting local metabolic exchanges and symbiosis, but also of immune cells and stroma that further interact with and reshape cancer cell metabolism. The macroenvironment includes the different tissues of the organism, capable of exchanging signals and fueling the tumor 'a distance'. Moreover, most metabolic targets were identified from their increased expression in tumor transcriptomic studies, or from targeted analyses looking at the metabolic impact of particular oncogenes or tumor suppressors on selected metabolic pathways. Still, very few targets were identified from in vivo analyses of tumor metabolism in patients because such studies are difficult and adequate imaging methods are only currently being developed for that purpose. For instance, perfusion of patients with [ 13 C]-glucose allows deciphering the metabolomics of tumors and opens a new area in the search for effective targets. Metabolic imaging with positron emission tomography and other techniques that do not involve [ 13 C] can also be used to evaluate tumor

  13. The Murine Natural Cytotoxic Receptor NKp46/NCR1 Controls TRAIL Protein Expression in NK Cells and ILC1s

    Directory of Open Access Journals (Sweden)

    Sam Sheppard

    2018-03-01

    Full Text Available Summary: TRAIL is an apoptosis-inducing ligand constitutively expressed on liver-resident type 1 innate lymphoid cells (ILC1s and a subset of natural killer (NK cells, where it contributes to NK cell anti-tumor, anti-viral, and immunoregulatory functions. However, the intrinsic pathways involved in TRAIL expression in ILCs remain unclear. Here, we demonstrate that the murine natural cytotoxic receptor mNKp46/NCR1, expressed on ILC1s and NK cells, controls TRAIL protein expression. Using NKp46-deficient mice, we show that ILC1s lack constitutive expression of TRAIL protein and that NK cells activated in vitro and in vivo fail to upregulate cell surface TRAIL in the absence of NKp46. We show that NKp46 regulates TRAIL expression in a dose-dependent manner and that the reintroduction of NKp46 in mature NK cells deficient for NKp46 is sufficient to restore TRAIL surface expression. These studies uncover a link between NKp46 and TRAIL expression in ILCs with potential implications in pathologies involving NKp46-expressing cells. : Sheppard et al. find that mice deficient in the activating receptor NCR1/NKp46 (Ncr1−/− fail to express the apoptosis-inducing ligand TRAIL at the surface of group 1 innate lymphoid cells (ILC1s. Keywords: NK cell, natural killer cell, NKp46, ILC1, TRAIL, IL-15, IL-2

  14. Impact of the scintigraphy of somatostatin receptors upon the therapeutic strategy in patients bearing digestive endocrine tumors

    International Nuclear Information System (INIS)

    Lebtahi, R.; Cadiot, G.; Genin, R.; Delahaye, N.; Faraggi, M.; Daou, D.; Peker, C.; Migon, M.; Le Guludec, D.

    1997-01-01

    The scintigraphy of somatostatin receptors (SSR) is a sensible method for detecting the gastroenteric-pancreatic endocrine tumors and their metastases. The aim of this study is to evaluate the clinical impact of the results of SSR in taking patients in therapeutic charge. A hundred and sixty patients bearing biologically and/or histologically proved digestive endocrine tumors were prospectively studied. The patients were classified in 3 groups: group I - 90 patients with no known metastases; group II - 59 patients with liver metastases and group III - 11 patients with known extra-hepatic metastases. The results of the scintigraphy were compared with those of conventional imaging. The following results were obtained: in group 1 (90 patients) the conventional imaging has allowed detecting 53 primitive tumors in 44 patients. The SSR visualized 68% of these sites and has detected 26 supplementary primitive sites in 20 patients and 29 metastatic sites in 25 patients. In group II the scintigraphy has detected 95% of hepatic metastases and revealed 23 new metastasis sites and 18/59 patients. In group III the scintigraphy has detected 11 new sites in 7 patients. The results of scintigraphy modified the patient's classification in 38 cases (24%). The therapeutic strategy was modified for 40 patients (25%). In conclusion, the scintigraphy of somatostatin receptors is able to detect a significant number of digestive endocrine tumors what has important implications for therapeutical planning of the treatment of patients. It must be carried out during pre-therapeutic extension examination of these tumors

  15. Complete Eradication of Xenograft Hepatoma by Oncolytic Adenovirus ZD55 Harboring TRAIL-IETD-Smac Gene with Broad Antitumor Effect

    Science.gov (United States)

    Wang, Shi-bing; Tan, Yuan; Lei, Wen; Wang, Yi-gang; Zhou, Xiu-mei; Jia, Xiao-yuan; Zhang, Kang-jian; Chu, Liang

    2012-01-01

    Abstract Cancer-targeting dual-gene virotherapy (CTGVT-DG) is an important modification of CTGVT, in which two suitable genes are used to obtain an excellent antitumor effect. A key problem is to join the two genes to form one fused gene, and then to clone it into the oncolytic viral vector so that only one investigational new drug application, instead of two, is required for clinical use. Many linkers (e.g., internal ribosome entry site) are used to join two genes together, but they are not all equally efficacious. Here, we describe finding the best linker, that is, sequence encoding the four amino acids IETD, to join the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene and the second mitochondria-derived activator of caspase (Smac) gene to form TRAIL-IETD-Smac and inserting it into oncolytic viral vector ZD55 to construct ZD55-TRAIL-IETD-Smac, which matched ZD55-TRAIL plus ZD55-Smac in completely eliminating xenograft hepatoma. ZD55-TRAIL-IETD-Smac works by quantitative cleavage at IETD↓by inducing caspase-8; activation or inhibition of caspase-8 could up- or downregulate cleavage, respectively. The cleaved product, TRAIL-IETD, does not affect the function of TRAIL. Numerous experiments have shown that the combined use of ZD55-TRAIL plus ZD55-X could completely eradicate many xenograft tumors, and therefore the IETD is potentially a useful linker to construct many antitumor drugs, for example, ZD55-TRAIL-IETD-X, where X has a compensative or synergetic effect on TRAIL. We found that the antitumor effect of ZD55-IL-24-IETD-TRAIL also has an equivalent antitumor effect compared with the combined use of ZD55-IL-24 plus ZD55-TRAIL, because ZD55-IL-24 could also induce caspase-8. This means that IETD, as a two-gene linker, may have broad use. PMID:22530834

  16. 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...

  17. A comparison of prostate tumor targeting strategies using magnetic resonance imaging-targeted, transrectal ultrasound-guided fusion biopsy.

    Science.gov (United States)

    Martin, Peter R; Cool, Derek W; Fenster, Aaron; Ward, Aaron D

    2018-03-01

    Magnetic resonance imaging (MRI)-targeted, three-dimensional (3D) transrectal ultrasound (TRUS)-guided prostate biopsy aims to reduce the 21-47% false-negative rate of clinical two-dimensional (2D) TRUS-guided systematic biopsy, but continues to yield false-negative results. This may be improved via needle target optimization, accounting for guidance system errors and image registration errors. As an initial step toward the goal of optimized prostate biopsy targeting, we investigated how needle delivery error impacts tumor sampling probability for two targeting strategies. We obtained MRI and 3D TRUS images from 49 patients. A radiologist and radiology resident assessed these MR images and contoured 81 suspicious regions, yielding tumor surfaces that were registered to 3D TRUS. The biopsy system's root-mean-squared needle delivery error (RMSE) and systematic error were modeled using an isotropic 3D Gaussian distribution. We investigated two different prostate tumor-targeting strategies using (a) the tumor's centroid and (b) a ring in the lateral-elevational plane. For each simulation, targets were spaced at equal arc lengths on a ring with radius equal to the systematic error magnitude. A total of 1000 biopsy simulations were conducted for each tumor, with RMSE and systematic error magnitudes ranging from 1 to 6 mm. The difference in median tumor sampling probability and probability of obtaining a 50% core involvement was determined for ring vs centroid targeting. Our simulation results indicate that ring targeting outperformed centroid targeting in situations where systematic error exceeds RMSE. In these instances, we observed statistically significant differences showing 1-32% improvement in sampling probability due to ring targeting. Likewise, we observed statistically significant differences showing 1-39% improvement in 50% core involvement probability due to ring targeting. Our results suggest that the optimal targeting scheme for prostate biopsy depends on

  18. MicroRNA-138 enhances TRAIL-induced apoptosis through interferon-stimulated gene 15 downregulation in hepatocellular carcinoma cells.

    Science.gov (United States)

    Zuo, Chaohui; Sheng, Xinyi; Liu, Zhuo; Ma, Min; Xiong, Shuhan; Deng, Hongyu; Li, Sha; Yang, Darong; Wang, Xiaohong; Xiao, Hua; Quan, Hu; Xia, Man

    2017-06-01

    Hepatocellular carcinoma is a leading cause of cancer-related mortality worldwide. TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) is a potential target for cancer therapy. However, many cancer cells are resistant to TRAIL-induced apoptosis and its mechanism is not well understood. In this study, to identify potential therapeutic targets for TRAIL-resistant cancer cells, we compared the expression levels of interferon-stimulated gene 15 in TRAIL-sensitive and TRAIL-resistant hepatocellular carcinoma cell lines. Western blot analysis showed that interferon-stimulated gene 15 expression levels were significantly higher in resistant HLCZ01and Huh7 cells than in sensitive LH86 and SMMC-7721 cells. Interferon-stimulated gene 15 knockdown in resistance cells led to TRAIL sensitivity. Conversely, interferon-stimulated gene 15 overexpression in sensitive cells resulted in TRAIL resistance. Our bioinformatics search detected a putative target sequence for microRNA miR-138 in the 3' untranslated region of the interferon-stimulated gene 15. Real-time quantitative polymerase chain reaction analysis demonstrated that miR-138 was significantly downregulated in TRAIL-resistant cells compared to TRAIL-sensitive cells. Forced expression of miR-138 in resistant cells decreased both messenger RNA and protein levels of interferon-stimulated gene 15, and when exposed to TRAIL, activated poly(adenosine diphosphate-ribose) polymerase, indicating sensitization to TRAIL. The results suggested that miR-138 regulates the interferon-stimulated gene 15 expression by directly targeting the 3' untranslated region of interferon-stimulated gene 15 and modulates the sensitivity to TRAIL-induced apoptosis. MiR-138 may be a target for therapeutic intervention in TRAIL-based drug treatments of resistant hepatocellular carcinoma or could be a biomarker to select patients who may benefit from the treatment.

  19. Vatuximab(Trademark): Optimizing Therapeutic Strategies for Prostate Cancer Based on Dynamic MR Tumor Oximetry

    Science.gov (United States)

    2010-01-01

    therapeutic efficacy in experimental diabetic retinopathy . Invest Ophthalmol Vis Sci, 42, 2964-9 (2001) 141. Berkowitz, B. A., C. McDonald, Y. Ito, P...tumors measured over a period of 11 weeks of thrice weekly treatment with bavituximab (2.5 mg/kg IP). A predicted mean growth rate for untreated... predicted control tumor in Figure 18. However, R1L1 and R0L0 both show growth rates considerably slower than control and greatly increased DCE

  20. 77 FR 45721 - Consolidated Audit Trail

    Science.gov (United States)

    2012-08-01

    ... 242 Consolidated Audit Trail; Final Rule #0;#0;Federal Register / Vol. 77, No. 148 / Wednesday, August... 242 [Release No. 34-67457; File No. S7-11-10] RIN 3235-AK51 Consolidated Audit Trail AGENCY... maintain a consolidated order tracking system, or consolidated audit trail, with respect to the trading of...

  1. 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...

  2. 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.

  3. Activation of Wnt/β-catenin signaling increases apoptosis in melanoma cells treated with trail.

    Directory of Open Access Journals (Sweden)

    Zachary F Zimmerman

    Full Text Available While the TRAIL pathway represents a promising therapeutic target in melanoma, resistance to TRAIL-mediated apoptosis remains a barrier to its successful adoption. Since the Wnt/β-catenin pathway has been implicated in facilitating melanoma cell apoptosis, we investigated the effect of Wnt/β-catenin signaling on regulating the responses of melanoma cells to TRAIL. Co-treatment of melanoma cell lines with WNT3A-conditioned media and recombinant TRAIL significantly enhanced apoptosis compared to treatment with TRAIL alone. This apoptosis correlates with increased abundance of the pro-apoptotic proteins BCL2L11 and BBC3, and with decreased abundance of the anti-apoptotic regulator Mcl1. We then confirmed the involvement of the Wnt/β-catenin signaling pathway by demonstrating that siRNA-mediated knockdown of an intracellular β-catenin antagonist, AXIN1, or treating cells with an inhibitor of GSK-3 also enhanced melanoma cell sensitivity to TRAIL. These studies describe a novel regulation of TRAIL sensitivity in melanoma by Wnt/β-catenin signaling, and suggest that strategies to enhance Wnt/β-catenin signaling in combination with TRAIL agonists warrant further investigation.

  4. EGFR-targeted TRAIL and a Smac mimetic synergize to overcome apoptosis resistance in KRAS mutant colorectal cancer cells.

    Directory of Open Access Journals (Sweden)

    Yvonne Möller

    Full Text Available TRAIL is a death receptor ligand that induces cell death preferentially in tumor cells. Recombinant soluble TRAIL, however, performs poorly as an anti-cancer therapeutic because oligomerization is required for potent biological activity. We previously generated a diabody format of tumor-targeted TRAIL termed Db(αEGFR-scTRAIL, comprising single-stranded TRAIL molecules (scTRAIL and the variable domains of a humanized variant of the EGFR blocking antibody Cetuximab. Here we define the bioactivity of Db(αEGFR-scTRAIL with regard to both EGFR inhibition and TRAIL receptor activation in 3D cultures of Caco-2 colorectal cancer cells, which express wild-type K-Ras. Compared with conventional 2D cultures, Caco-2 cells displayed strongly enhanced sensitivity toward Db(αEGFR-scTRAIL in these 3D cultures. We show that the antibody moiety of Db(αEGFR-scTRAIL not only efficiently competed with ligand-induced EGFR function, but also determined the apoptotic response by specifically directing Db(αEGFR-scTRAIL to EGFR-positive cells. To address how aberrantly activated K-Ras, which leads to Cetuximab resistance, affects Db(αEGFR-scTRAIL sensitivity, we generated stable Caco-2tet cells inducibly expressing oncogenic K-Ras(G12V. In the presence of doxycycline, these cells showed increased resistance to Db(αEGFR-scTRAIL, associated with the elevated expression of the anti-apoptotic proteins cIAP2, Bcl-xL and FlipS. Co-treatment of cells with the Smac mimetic SM83 restored the Db(αEGFR-scTRAIL-induced apoptotic response. Importantly, this synergy between Db(αEGFR-scTRAIL and SM83 also translated to 3D cultures of oncogenic K-Ras expressing HCT-116 and LoVo colorectal cancer cells. Our findings thus support the notion that Db(αEGFR-scTRAIL therapy in combination with apoptosis-sensitizing agents may be promising for the treatment of EGFR-positive colorectal cancers, independently of their KRAS status.

  5. A "Trojan horse" strategy to reverse drug-resistance in brain tumors

    OpenAIRE

    Pinzon-Daza, Martha L.

    2014-01-01

    Los gliomas malignos representan una de las formas más agresivas de los tumores del sistema nervioso central (SNC). De acuerdo con la clasificación de los tumores cerebrales de la Organización Mundial de la Salud (OMS), los astrocitomas han sido categorizados en cuatro grados, determinados por la patología subyacente. Es así como los gliomas malignos (o de alto grado) incluyen el glioma anaplásico (grado III) así como el glioblastoma multiforme (GBM, grado IV),estos últimos los más agresiv...

  6. 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.

  7. Aptamer-miRNA-212 Conjugate Sensitizes NSCLC Cells to TRAIL.

    Science.gov (United States)

    Iaboni, Margherita; Russo, Valentina; Fontanella, Raffaela; Roscigno, Giuseppina; Fiore, Danilo; Donnarumma, Elvira; Esposito, Carla Lucia; Quintavalle, Cristina; Giangrande, Paloma H; de Franciscis, Vittorio; Condorelli, Gerolama

    2016-03-08

    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.

  8. The Roles of ROS and Caspases in TRAIL-Induced Apoptosis and Necroptosis in Human Pancreatic Cancer Cells.

    Directory of Open Access Journals (Sweden)

    Min Zhang

    Full Text Available Death signaling provided by tumor necrosis factor (TNF-related apoptosis-inducing ligand (TRAIL can induce death in cancer cells with little cytotoxicity to normal cells; this cell death has been thought to involve caspase-dependent apoptosis. Reactive oxygen species (ROS are also mediators that induce cell death, but their roles in TRAIL-induced apoptosis have not been elucidated fully. In the current study, we investigated ROS and caspases in human pancreatic cancer cells undergoing two different types of TRAIL-induced cell death, apoptosis and necroptosis. TRAIL treatment increased ROS in two TRAIL-sensitive pancreatic cancer cell lines, MiaPaCa-2 and BxPC-3, but ROS were involved in TRAIL-induced apoptosis only in MiaPaCa-2 cells. Unexpectedly, inhibition of ROS by either N-acetyl-L-cysteine (NAC, a peroxide inhibitor, or Tempol, a superoxide inhibitor, increased the annexin V-/propidium iodide (PI+ early necrotic population in TRAIL-treated cells. Additionally, both necrostatin-1, an inhibitor of receptor-interacting protein kinase 1 (RIP1, and siRNA-mediated knockdown of RIP3 decreased the annexin V-/PI+ early necrotic population after TRAIL treatment. Furthermore, an increase in early apoptosis was induced in TRAIL-treated cancer cells under inhibition of either caspase-2 or -9. Caspase-2 worked upstream of caspase-9, and no crosstalk was observed between ROS and caspase-2/-9 in TRAIL-treated cells. Together, these results indicate that ROS contribute to TRAIL-induced apoptosis in MiaPaCa-2 cells, and that ROS play an inhibitory role in TRAIL-induced necroptosis of MiaPaCa-2 and BxPC-3 cells, with caspase-2 and -9 playing regulatory roles in this process.

  9. Human agonistic TRAIL receptor antibodies Mapatumumab and Lexatumumab induce apoptosis in malignant mesothelioma and act synergistically with cisplatin

    Directory of Open Access Journals (Sweden)

    Felley-Bosco Emanuela

    2007-10-01

    Full Text Available Abstract Background The incidence of malignant pleural mesothelioma (MPM is associated with exposure to asbestos, and projections suggest that the yearly number of deaths in Western Europe due to MPM will increase until 2020. Despite progress in chemo- and in multimodality therapy, MPM remains a disease with a poor prognosis. Inducing apoptosis by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL or agonistic monoclonal antibodies which target TRAIL-receptor 1 (TRAIL-R1 or TRAIL-R2 has been thought to be a promising cancer therapy. Results We have compared the sensitivity of 13 MPM cell lines or primary cultures to TRAIL and two fully human agonistic monoclonal antibodies directed to TRAIL-R1 (Mapatumumab and TRAIL-R2 (Lexatumumab and examined sensitization of the MPM cell lines to cisplatin-induced by the TRAIL-receptor antibodies. We found that sensitivity of MPM cells to TRAIL, Mapatumumab and Lexatumumab varies largely and is independent of TRAIL-receptor expression. TRAIL-R2 contributes more than TRAIL-R1 to death-receptor mediated apoptosis in MPM cells that express both receptors. The combination of cisplatin with Mapatumumab or Lexatumumab synergistically inhibited the cell growth and enhanced apoptotic death. Furthermore, pre-treatment with cisplatin followed by Mapatumumab or Lexatumumab resulted in significant higher cytotoxic effects as compared to the reverse sequence. Combination-induced cell growth inhibition was significantly abrogated by pre-treatment of the cells with the antioxidant N-acetylcysteine. Conclusion Our results suggest that the sequential administration of cisplatin followed by Mapatumumab or Lexatumumab deserves investigation in the treatment of patients with MPM.

  10. Tumor vaccines

    International Nuclear Information System (INIS)

    Frank, M.; Ihan, A.

    2006-01-01

    Tumor vaccines have several potential advantages over standard anticancer regiments. They represent highly specific anticancer therapy. Inducing tumor-specific memory T-lymphocytes, they have potential for long-lived antitumor effects. However, clinical trials, in which cancer patients were vaccinated with tumor vaccines, have been so far mainly disappointing. There are many reasons for the inefficiency of tumor vaccines. Most cancer antigens are normal self-molecules to which immune tolerance exists. That is why the population of tumor-specific lymphocytes is represented by a small number of low-affinity T-lymphocytes that induce weak antitumor immune response. Simultaneously, tumors evolve many mechanisms to actively evade immune system, what makes them poorly immunogenic or even tolerogenic. Novel immunotherapeutic strategies are directed toward breaking immune tolerance to tumor antigens, enhancing immunogenicity of tumor vaccines and overcoming mechanisms of tumor escape. There are several approaches, unfortunately, all of them still far away from an ideal tumor vaccine that would reject a tumor. Difficulties in the activation of antitumor immune response by tumor vaccines have led to the development of alternative immunotherapeutic strategies that directly focus on effector mechanisms of immune system (adoptive tumor- specific T-lymphocyte transfer and tumor specific monoclonal antibodies). (author)

  11. The Offshore Bucket Trail Installation

    DEFF Research Database (Denmark)

    Nielsen, Søren Andreas; Ibsen, Lars Bo

    The Bucket Trail Installation project has gathered a substantial amount of date in a unique soil database which enable update of the used standards for penetration prediction. This update will lead to less conservative design of bucket foundations and is vital for the aim of cost reduction...... in the offshore wind business. Furthermore is serial offshore operation with the bucket concept was demonstrated with achieving full installation depth and inclination within given tolerance....

  12. A list of and some comments about the trail pheromones of ants.

    Science.gov (United States)

    Cerdá, Xim; van Oudenhove, Louise; Bernstein, Carlos; Boulay, Raphaël R

    2014-08-01

    Ants use many different chemical compounds to communicate with their nestmates. Foraging success depends on how efficiently ants communicate the presence of food and thus recruit workers to exploit the food resource. Trail pheromones, produced by different exocrine glands, are a key part of ant foraging strategies. By combing through the literature, we compiled a list of the identity and glandular origin of the chemical compounds found in the trail pheromones of 75 different ant species. Of the 168 compounds identified, more than 40% are amines. In the subfamily Myrmicinae, trail pheromones are mostly produced in the venom gland, while in the subfamily Formicinae, they come from the rectal gland.

  13. Alternating current electrical stimulation enhanced chemotherapy: a novel strategy to bypass multidrug resistance in tumor cells

    International Nuclear Information System (INIS)

    Janigro, Damir; Perju, Catalin; Fazio, Vincent; Hallene, Kerri; Dini, Gabriele; Agarwal, Mukesh K; Cucullo, Luca

    2006-01-01

    Tumor burden can be pharmacologically controlled by inhibiting cell division and by direct, specific toxicity to the cancerous tissue. Unfortunately, tumors often develop intrinsic pharmacoresistance mediated by specialized drug extrusion mechanisms such as P-glycoprotein. As a consequence, malignant cells may become insensitive to various anti-cancer drugs. Recent studies have shown that low intensity very low frequency electrical stimulation by alternating current (AC) reduces the proliferation of different tumor cell lines by a mechanism affecting potassium channels while at intermediate frequencies interfere with cytoskeletal mechanisms of cell division. The aim of the present study is to test the hypothesis that permeability of several MDR1 over-expressing tumor cell lines to the chemotherapic agent doxorubicin is enhanced by low frequency, low intensity AC stimulation. We grew human and rodent cells (C6, HT-1080, H-1299, SKOV-3 and PC-3) which over-expressed MDR1 in 24-well Petri dishes equipped with an array of stainless steel electrodes connected to a computer via a programmable I/O board. We used a dedicated program to generate and monitor the electrical stimulation protocol. Parallel cultures were exposed for 3 hours to increasing concentrations (1, 2, 4, and 8 μM) of doxorubicin following stimulation to 50 Hz AC (7.5 μA) or MDR1 inhibitor XR9576. Cell viability was assessed by determination of adenylate kinase (AK) release. The relationship between MDR1 expression and the intracellular accumulation of doxorubicin as well as the cellular distribution of MDR1 was investigated by computerized image analysis immunohistochemistry and Western blot techniques. By the use of a variety of tumor cell lines, we show that low frequency, low intensity AC stimulation enhances chemotherapeutic efficacy. This effect was due to an altered expression of intrinsic cellular drug resistance mechanisms. Immunohistochemical, Western blot and fluorescence analysis revealed

  14. A New Player in the Development of TRAIL Based Therapies for Hepatocarcinoma Treatment: ATM Kinase

    Energy Technology Data Exchange (ETDEWEB)

    Stagni, Venturina; Santini, Simonetta; Barilà, Daniela, E-mail: daniela.barila@uniroma2.it [Department of Biology, University of Tor Vergata, Rome 00133 (Italy); Laboratory of Cell Signaling, Santa Lucia Foundation-IRCCS, Rome 00179 (Italy)

    2012-04-05

    Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. HCCs are genetically and phenotypically heterogeneous tumors characterized by very poor prognosis, mainly due to the lack, at present, of effective therapeutic options, as these tumors are rarely suitable for radiotherapy and often resistant to chemotherapy protocols. In the last years, agonists targeting the Tumor Necrosis Factor Related Apoptosis Inducing Ligand (TRAIL) death receptor, has been investigated as a valuable promise for cancer therapy, based on their selectivity for malignant cells and low toxicity for healthy cells. However, many cancer models display resistance to death receptor induced apoptosis, pointing to the requirement for the development of combined therapeutic approaches aimed to selectively sensitize cancer cells to TRAIL. Recently, we identified ATM kinase as a novel modulator of the ability of chemotherapeutic agents to enhance TRAIL sensitivity. Here, we review the biological determinants of HCC responsiveness to TRAIL and provide an exhaustive and updated analysis of the molecular mechanisms exploited for combined therapy in this context. The role of ATM kinase as potential novel predictive biomarker for combined therapeutic approaches based on TRAIL and chemotherapeutic drugs will be closely discussed.

  15. Quantitative antibody-free LC-MS/MS analysis of sTRAIL in sputum and saliva at the sub-ng/mL level

    NARCIS (Netherlands)

    Wilffert, Daniel; Donzelli, Riccardo; Asselman, Angela; Hermans, Jos; Govorukhina, Natalia; ten Hacken, Nick H. T.; Quax, Wim J.; Merbel, van de Nico; Bischoff, Rainer

    2016-01-01

    Soluble tumor necrosis factor-related apoptosis-inducing ligand (sTRAIL) induces apoptosis via the extrinsic death receptor pathway and maybe a biomarker in the pathogenesis of a broad range of diseases. To investigate the role of sTRAIL in asthma, we developed a quantitative LC-MS/MS method with a

  16. Biological characteristics and treatment outcomes of metastatic or recurrent neuroendocrine tumors: tumor grade and metastatic site are important for treatment strategy

    Directory of Open Access Journals (Sweden)

    Kim Su-Jung

    2010-08-01

    Full Text Available Abstract Background Studies about the biology, treatment pattern, and treatment outcome of metastatic/recurrent neuroendocrine tumor (NET have been few. Methods We enrolled patients with metastatic/recurrent NET diagnosed between January 1996 and July 2007 and retrospectively analyzed. Results A total of 103 patients were evaluated. Twenty-six patients (25.2% had pancreatic NET, 27 (26.2% had gastrointestinal NET, 2 (1.9% had lung NET, 28 (27.2% had NET from other sites, and 20 (19.4% had NET from unknown origin. The liver was the most common metastatic site (68.9%. Thirty-four patients had grade 1 disease, 1 (1.0% had grade 2 disease, 15 (14.6% had grade 3 disease, 9 (8.7% had large cell disease, and 7 (6.8% had small cell disease. Sixty-six patients received systemic treatment (interferon, somatostatin analogues or chemotherapy, 64 patients received local treatment (TACE, radiofrequency ablation, metastasectomy, etc.. Thirty-six patients received both systemic and local treatments. Median overall survival (OS was 29.0 months (95% confidence interval, 25.0-33.0 in the103 patients. OS was significantly influenced by grade (p = .001. OS was 43.0, 23.0, and 29.0 months in patients who received local treatment only, systemic treatment only, and both treatments, respectively (p = .245. The median time-to-progression (TTP was 6.0 months. Overall response rate was 34.0% and disease-control rate was 64.2%. TTP was influenced by the presence of liver metastasis (p = .011. Conclusions OS of metastatic/recurrent NET was different according to tumor grade. TTP was different according to metastasis site. Therefore, development of optimal treatment strategy based on the characteristics of NET is warranted.

  17. An unusual presentation of a malignant jejunal tumor and a different management strategy

    Directory of Open Access Journals (Sweden)

    Parida Dillip K

    2005-01-01

    Full Text Available Abstract Background Malignant small bowel tumors are very rare and leiomyosarcoma accounts for less than 15% of the cases. Management of these tumors is challenging in view of nonspecific symptoms, unusual presentation and high incidence of metastasis. In this case report, an unusual presentation of jejunal sarcoma and management of liver metastasis with radiofrequency ablation (RFA is discussed. Case presentation A 45-year-old male presented with anemia and features of small bowel obstruction. Operative findings revealed a mass lesion in jejunum with intussusception of proximal loop. Resection of bowel mass was performed. Histopathological findings were suggestive of leiomyosarcoma. After 3-years of follow-up, the patient developed recurrence in infracolic omentum and a liver metastasis. The omental mass was resected and liver lesion was managed with radiofrequency ablation. Conclusion Jejunal leiomyosarcoma is a rare variety of malignant small bowel tumor and a clinical presentation with intussusception is unusual. We suggest that an aggressive management approach using a combination of surgery and a newer technique like RFA can be attempted in patients with limited metastatic spread to liver to prolong the long-term survival in a subset of patients.

  18. The effect of a trail use intervention on urban trail use in Southern Nevada.

    Science.gov (United States)

    Clark, Sheila; Bungum, Tim; Shan, Guogen; Meacham, Mindy; Coker, Lisa

    2014-10-01

    Communities are building or improving trail networks for biking and walking to encourage physical activity, but the relationship between trail environments and physical activity is not well understood. We examined the effect of a trail use intervention in Southern Nevada. We monitored the usage of urban trails (n=10) in Southern Nevada before, during, and after an intervention which included a marketing campaign promoting trail use and the addition of way-finding and incremental distance signage to selected trails (October 2011-October 2012). Data were collected with infrared monitors placed on the trails for three periods of 7days. We compared pre-, mid-, and post-intervention usage rates on the 6 trails where signage was added to usage rates on the 4 control trails. The groups of trails experienced different patterns of increases and decreases over the 1-year study period. Mean users per hour increased 31% for the study trails and 35% for the control trails (p<0.001), but the total increase did not vary between the groups. Trail use increased about 33% during the 1-year study period for the intervention. Adding wayfinding and incremental distance signage appeared to support the increase in usage which followed the marketing campaign. Copyright © 2014 Elsevier Inc. All rights reserved.

  19. Induction of tumor stem cell differentiation--novel strategy to overcome therapy resistance in gastric cancer.

    Science.gov (United States)

    Zieker, Derek; Bühler, Sarah; Ustündag, Zeynep; Königsrainer, Ingmar; Manncke, Sebastian; Bajaeifer, Khaled; Vollmer, Jörg; Fend, Falko; Northoff, Hinnak; Königsrainer, Alfred; Glatzle, Jörg

    2013-04-01

    Metastases are a frequent finding in gastric cancer and are associated with poor prognosis. A recently discovered link between metabolic changes, differentiation, and therapy resistance due to tumor stem cells could depict a novel approach in cancer research and therapy. Phosphoglycerate kinase 1 (PGK1) is a metabolic enzyme and is known to be involved in enabling gastric cancer cells to be invasive and to disseminate. In this study, we investigated if PGK1 is a promising candidate in inducing stem cell differentiation in gastric cancer. MKN45 gastric cancer cells were used due to their known cancer stem cell population, which is defined by the surface marker CD44. MKN45 cells were separated between CD44+ and CD44- cells and, in equal parts, incubated with shRNA anti-PGK1 using fluorescence-activated cell sorting (FACS) analysis; they were then injected into nude mice to evaluate their tumor growth behavior in vivo. Further, the invasive potential of gastric cancer cells was evaluated in vitro using the xCelligence analyzing system. CD44+ gastric cancer cells treated with and without shRNA anti-PGK1 were capable to cause tumor growth in vivo, whereas tumor growth in CD44+ cells treated with shRNA anti-PGK1 was considerably smaller in comparison with that in CD44+ cells without treatment. CD44- cells did not show any noticeable tumor growth in vivo. By targeting PGK1, the invasive potential of gastric cancer cells was impressively reduced in vitro. In all our cells, which were targeted with shRNA anti-PGK1, we did not find any change that is in accordance with the phenotype of the cells using FACS analysis. Our findings suggest that targeting the key metabolic enzyme PGK1 in gastric cancer cells may open a new chapter in cancer treatment, which is well worth for further exploration in combination with recent chemotherapy, and might be a promising possibility to overcome therapy resistance in gastric cancer.

  20. TNFα cooperates with IFN-γ to repress Bcl-xL expression to sensitize metastatic colon carcinoma cells to TRAIL-mediated apoptosis.

    Directory of Open Access Journals (Sweden)

    Feiyan Liu

    Full Text Available BACKGROUND: TNF-related apoptosis-inducing ligand (TRAIL is an immune effector molecule that functions as a selective anti-tumor agent. However, tumor cells, especially metastatic tumor cells often exhibit a TRAIL-resistant phenotype, which is currently a major impediment in TRAIL therapy. The aim of this study is to investigate the synergistic effect of TNFα and IFN-γ in sensitizing metastatic colon carcinoma cells to TRAIL-mediated apoptosis. METHODOLOGY/PRINCIPAL FINDINGS: The efficacy and underlying molecular mechanism of cooperation between TNFα and IFN-γ in sensitizing metastatic colon carcinoma cells to TRAIL-mediated apoptosis were examined. The functional significance of TNFα- and IFN-γ-producing T lymphocyte immunotherapy in combination with TRAIL therapy in suppression of colon carcinoma metastasis was determined in an experimental metastasis mouse model. We observed that TNFα or IFN-γ alone exhibits minimal sensitization effects, but effectively sensitized metastatic colon carcinoma cells to TRAIL-induced apoptosis when used in combination. TNFα and IFN-γ cooperate to repress Bcl-xL expression, whereas TNFα represses Survivin expression in the metastatic colon carcinoma cells. Silencing Bcl-xL expression significantly increased the metastatic colon carcinoma cell sensitivity to TRAIL-induced apoptosis. Conversely, overexpression of Bcl-xL significantly decreased the tumor cell sensitivity to TRAIL-induced apoptosis. Furthermore, TNFα and IFN-γ also synergistically enhanced TRAIL-induced caspase-8 activation. TNFα and IFN-γ was up-regulated in activated primary and tumor-specific T cells. TRAIL was expressed in tumor-infiltrating immune cells in vivo, and in tumor-specific cytotoxic T lymphocytes (CTL ex vivo. Consequently, TRAIL therapy in combination with TNFα/IFN-γ-producing CTL adoptive transfer immunotherapy effectively suppressed colon carcinoma metastasis in vivo. CONCLUSIONS/SIGNIFICANCE: TNFα and IFN

  1. Ag-HPBs by a coating-etching strategy and their derived injectable implants for enhanced tumor photothermal treatment.

    Science.gov (United States)

    Su, Yun Yan; Yao, Hui; Zhao, Shuang; Tian, Wei; Liu, Wen Fei; Wang, Shou Ju; Liu, Ying; Tian, Ying; Zhang, Xiao Dong; Teng, Zhao Gang; Lu, Guang Ming; Zhang, Long Jiang

    2018-02-15

    Herein, we demonstrate a coating-etching strategy to directly synthesize hollow Prussian blue (PB) nanocubes with well-dispersed Ag nanoparticles (denoted as Ag-HPB). The method is accomplished by introduction of PB precursors, K 3 Fe(CN) 6 and Fe 3+ into a reaction system containing AgNO 3 and ascorbic acid, in which a series reactions contain formation of Ag nanoparticles, coating of PB on the nanoparticles, and diffusion of Ag into the PB frameworks occur. The strategy for preparation of the hollow structured Ag-HPB is intrinsically simple and does not require pre-preparation of any sacrificial templates or toxic etching agents. The obtained Ag-HPB nanocubes possess uniform size (69 nm), well-defined hollow structure, strong near-infrared photothermal conversion capacity, and excellent photoacoustic and magnetic resonance imaging abilities. Furthermore, an injectable photothermal implants are prepared for the first time by mixing the Ag-HPB nanocubes with clinically used biological glue, which significantly enhance photothermal anti-tumor efficacy, showing great potential for clinical tumor treatment. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. A new anti-tumor strategy based on in vivo tumstatin overexpression after plasmid electrotransfer in muscle

    International Nuclear Information System (INIS)

    Thevenard, Jessica; Ramont, Laurent; Mir, Lluis M.; Dupont-Deshorgue, Aurélie; Maquart, François-Xavier; Monboisse, Jean-Claude; Brassart-Pasco, Sylvie

    2013-01-01

    Highlights: ► A new therapeutic strategy based on tumstatin in vivo overexpression is proposed. ► pVAX1©–tumstatin electrotransfer in muscle mediates protein expression in muscle. ► A substantial expression of tumstatin is detected in the serum of electrotransfected mice. ► Tumstatin overexpression decreases tumor growth and increases mouse survival. -- Abstract: The NC1 domains from the different α(IV) collagen chains were found to exert anti-tumorigenic and/or anti-angiogenic activities. A limitation to the therapeutic use of these matrikines is the large amount of purified recombinant proteins, in the milligram range in mice that should be administered daily throughout the experimental procedures. In the current study, we developed a new therapeutic approach based on tumstatin (NC1α3(IV)) overexpression in vivo in a mouse melanoma model. Gene electrotransfer of naked plasmid DNA (pDNA) is particularly attractive because of its simplicity, its lack of immune responsiveness and its safety. The pDNA electrotransfer in muscle mediates a substantial gene expression that lasts several months. A pVAX1© vector containing the tumstatin cDNA was injected into the legs of C57BL/6 mice and submitted to electrotranfer. Sera were collected at different times and tumstatin was quantified by ELISA. Tumstatin secretion reached a plateau at day 21 with an expression level of 12 μg/mL. For testing the effects of tumstatin expression on tumor growth in vivo, B16F1 melanoma cells were subcutaneously injected in mice 7 days after empty pVAX1© (Mock) or pVAX1©–tumstatin electrotransfer. Tumstatin expression triggered a large decrease in tumor growth and an increase in mouse survival. This new therapeutic approach seems promising to inhibit tumor progression in vivo

  3. A modular labeling strategy for in vivo PET and near-infrared fluorescence imaging of nanoparticle tumor targeting.

    Science.gov (United States)

    Pérez-Medina, Carlos; Abdel-Atti, Dalya; Zhang, Yachao; Longo, Valerie A; Irwin, Chrisopher P; Binderup, Tina; Ruiz-Cabello, Jesús; Fayad, Zahi A; Lewis, Jason S; Mulder, Willem J M; Reiner, Thomas

    2014-10-01

    Advances in preclinical molecular imaging have generated new opportunities to noninvasively visualize the biodistribution and tumor targeting of nanoparticle therapeutics. Capitalizing on recent achievements in this area, we sought to develop an (89)Zr-based labeling strategy for liposomal nanoparticles that accumulate in tumors via passive targeting mechanisms. (89)Zr-labeled liposomes were prepared using 2 different approaches: click labeling and surface chelation. Pharmacokinetic and biodistribution studies, as well as PET/CT imaging of the radiolabeled nanoparticles, were performed on a mouse model of breast cancer. In addition, a dual PET/optical probe was prepared by incorporation of a near-infrared fluorophore and tested in vivo by PET and near-infrared fluorescence imaging. The surface chelation approach proved to be superior in terms of radiochemical yield and stability, as well as in vivo performance. Accumulation of these liposomes in tumor peaked at 24 h after injection and was measured to be 13.7 ± 1.8 percentage injected dose per gram. The in vivo performance of this probe was not essentially perturbed by the incorporation of a near-infrared fluorophore. We have developed a highly modular and efficient strategy for the labeling of liposomal nanoparticles with (89)Zr. In xenograft and orthotopic mouse models of breast cancer, we demonstrated that the biodistribution of these nanoparticles can be visualized by PET imaging. In combination with a near-infrared dye, these liposomal nanoparticles can serve as bimodal PET/optical imaging agents. The liposomes target malignant growth, and their bimodal features may be useful for simultaneous PET and intraoperative imaging. © 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

  4. 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 < .001) from 3.91 to 5.95 users per hour (52.17%) after the promotional campaign. We observed significant increases at 7 individual 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.

  5. Downregulation of DcR3 sensitizes hepatocellular carcinoma cells to TRAIL-induced apoptosis

    Directory of Open Access Journals (Sweden)

    Liang CJ

    2017-01-01

    Full Text Available Chaojie Liang,* Yingchen Xu,* Guangming Li, Tuanjie Zhao, Feng Xia, Guanqun Li, Dongxin Zhang, Jixiang Wu Department of General Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, People’s Republic of China *These authors contributed equally to this work Abstract: Decoy receptor 3 (DcR3 has been recently described as an antiapoptosis and prometastasis factor since it can competitively bind to FasL, TL1A, and LIGHT, and it is highly expressed in many malignant tumors. Downregulation of DcR3 can promote tumor cell apoptosis and inhibit metastasis. A previous study demonstrated that reduction of DcR3 could induce tumor necrosis factor-related apoptosis-inducing ligand (TRAIL-mediated apoptosis in pancreatic cancer cells. However, whether such an effect is seen in hepatocellular carcinoma (HCC remains to be explored. This study was designed to investigate the sensitivity of HCC cells to TRAIL after silencing DcR3, and this was done by evaluating the expression of DcR3 in HCC cells and the effect on TRAIL-mediated apoptosis after downregulation of DcR3. Our data showed that DcR3 was highly expressed in HepG2, BEL-7402, Hep3B, Huh-7, MHCC97H, and SMCC7721 cell lines compared with normal liver cell line LO-2. Both HepG2 and BEL-7402 were tolerant to TRAIL-mediated apoptosis, and the tolerance was negatively correlated to the expression of DcR3. Silencing of DcR3 with shRNA and treatment with TRAIL induced obvious apoptosis in HepG2 and BEL-7402, with more cancer cells found in the G1 phase. SiDcR3 combined with TRAIL could induce activation of caspases-3, -8, and -9, raise the expression of the apoptotic protein Bax, and reduce the expression of antiapoptotic proteins (Bcl-2, Mcl-1, Bcl-XL, IAP-2, and survivin. Caspase-8 inhibitor Ac-IETD-CHO significantly decreased the activation of caspase cascade, indicating that the extrinsic pathway may have a vital role in the apoptotic events induced by SiDcR3/TRAIL. Furthermore, our

  6. Trails at LANL - Public Meeting and Forum - July 26, 2016

    Energy Technology Data Exchange (ETDEWEB)

    Pava, Daniel Seth [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2016-07-26

    These are the slides of a meeting about trails at Los Alamos National Laboratory. The meeting goals are the folllowing: to inform and educate citizens about LANL trails management issues that include resource protection, safety, security and trails etiquette; to explain how and why LANL trails can be closed and reopened; and to understand your concerns and ideas about LANL trails use.

  7. Trails research: where do we go from here?

    Science.gov (United States)

    Michael A. Schuett; Patricia Seiser

    2002-01-01

    This paper describes a recent study focusing on trails research needs. This study was supported by American Trails. Using a Delphi technique, 86 trails experts representing a variety of federal, state and local agencies, nonprofits, and trail uses were queried by email on trails research needs. A Delphi technique is a prognostic tool for dealing with complex problems...

  8. Parallel screening of FDA-approved antineoplastic drugs for identifying sensitizers of TRAIL-induced apoptosis in cancer cells

    International Nuclear Information System (INIS)

    Taylor, David J; Parsons, Christine E; Han, Haiyong; Jayaraman, Arul; Rege, Kaushal

    2011-01-01

    Tumor Necrosis Factor-α Related Apoptosis Inducing Ligand (TRAIL) and agonistic antibodies to death receptor 4 and 5 are promising candidates for cancer therapy due to their ability to induce apoptosis selectively in a variety of human cancer cells, while demonstrating little cytotoxicity in normal cells. Although TRAIL and agonistic antibodies to DR4 and DR5 are considered safe and promising candidates in cancer therapy, many malignant cells are resistant to DR-mediated, TRAIL-induced apoptosis. In the current work, we screened a small library of fifty-five FDA and foreign-approved anti-neoplastic drugs in order to identify candidates that sensitized resistant prostate and pancreatic cancer cells to TRAIL-induced apoptosis. FDA-approved drugs were screened for their ability to sensitize TRAIL resistant prostate cancer cells to TRAIL using an MTT assay for cell viability. Analysis of variance was used to identify drugs that exhibited synergy with TRAIL. Drugs demonstrating the highest synergy were selected as leads and tested in different prostate and pancreatic cancer cell lines, and one immortalized human pancreatic epithelial cell line. Sequential and simultaneous dosing modalities were investigated and the annexin V/propidium iodide assay, in concert with fluorescence microscopy, was employed to visualize cells undergoing apoptosis. Fourteen drugs were identified as having synergy with TRAIL, including those whose TRAIL sensitization activities were previously unknown in either prostate or pancreatic cancer cells or both. Five leads were tested in additional cancer cell lines of which, doxorubicin, mitoxantrone, and mithramycin demonstrated synergy in all lines. In particular, mitoxantrone and mithramycin demonstrated significant synergy with TRAIL and led to reduction of cancer cell viability at concentrations lower than 1 μM. At these low concentrations, mitoxantrone demonstrated selectivity toward malignant cells over normal pancreatic epithelial cells

  9. Parallel screening of FDA-approved antineoplastic drugs for identifying sensitizers of TRAIL-induced apoptosis in cancer cells

    Directory of Open Access Journals (Sweden)

    Taylor David J

    2011-11-01

    Full Text Available Abstract Background Tumor Necrosis Factor-α Related Apoptosis Inducing Ligand (TRAIL and agonistic antibodies to death receptor 4 and 5 are promising candidates for cancer therapy due to their ability to induce apoptosis selectively in a variety of human cancer cells, while demonstrating little cytotoxicity in normal cells. Although TRAIL and agonistic antibodies to DR4 and DR5 are considered safe and promising candidates in cancer therapy, many malignant cells are resistant to DR-mediated, TRAIL-induced apoptosis. In the current work, we screened a small library of fifty-five FDA and foreign-approved anti-neoplastic drugs in order to identify candidates that sensitized resistant prostate and pancreatic cancer cells to TRAIL-induced apoptosis. Methods FDA-approved drugs were screened for their ability to sensitize TRAIL resistant prostate cancer cells to TRAIL using an MTT assay for cell viability. Analysis of variance was used to identify drugs that exhibited synergy with TRAIL. Drugs demonstrating the highest synergy were selected as leads and tested in different prostate and pancreatic cancer cell lines, and one immortalized human pancreatic epithelial cell line. Sequential and simultaneous dosing modalities were investigated and the annexin V/propidium iodide assay, in concert with fluorescence microscopy, was employed to visualize cells undergoing apoptosis. Results Fourteen drugs were identified as having synergy with TRAIL, including those whose TRAIL sensitization activities were previously unknown in either prostate or pancreatic cancer cells or both. Five leads were tested in additional cancer cell lines of which, doxorubicin, mitoxantrone, and mithramycin demonstrated synergy in all lines. In particular, mitoxantrone and mithramycin demonstrated significant synergy with TRAIL and led to reduction of cancer cell viability at concentrations lower than 1 μM. At these low concentrations, mitoxantrone demonstrated selectivity toward

  10. The Murine Natural Cytotoxic Receptor NKp46/NCR1 Controls TRAIL Protein Expression in NK Cells and ILC1s.

    Science.gov (United States)

    Sheppard, Sam; Schuster, Iona S; Andoniou, Christopher E; Cocita, Clement; Adejumo, Thomas; Kung, Sam K P; Sun, Joseph C; Degli-Esposti, Mariapia A; Guerra, Nadia

    2018-03-27

    TRAIL is an apoptosis-inducing ligand constitutively expressed on liver-resident type 1 innate lymphoid cells (ILC1s) and a subset of natural killer (NK) cells, where it contributes to NK cell anti-tumor, anti-viral, and immunoregulatory functions. However, the intrinsic pathways involved in TRAIL expression in ILCs remain unclear. Here, we demonstrate that the murine natural cytotoxic receptor mNKp46/NCR1, expressed on ILC1s and NK cells, controls TRAIL protein expression. Using NKp46-deficient mice, we show that ILC1s lack constitutive expression of TRAIL protein and that NK cells activated in vitro and in vivo fail to upregulate cell surface TRAIL in the absence of NKp46. We show that NKp46 regulates TRAIL expression in a dose-dependent manner and that the reintroduction of NKp46 in mature NK cells deficient for NKp46 is sufficient to restore TRAIL surface expression. These studies uncover a link between NKp46 and TRAIL expression in ILCs with potential implications in pathologies involving NKp46-expressing cells. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

  11. Multifunctionalized polyethyleneimine-based nanocarriers for gene and chemotherapeutic drug combination therapy through one-step assembly strategy

    Directory of Open Access Journals (Sweden)

    Jiang D

    2017-12-01

    Full Text Available Dandan Jiang,1,* Mingfang Wang,1,* Tianqi Wang,1 Bo Zhang,1 Chunxi Liu,2 Na Zhang1 1Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Jinan, China; 2Pharmaceutical Department, Qilu Hospital of Shandong University, Jinan, China *These authors contributed equally to this work Abstract: Gene therapy combined with chemotherapy to achieve synergistic therapeutic effects has been a hot topic in recent years. In this project, the human tumor necrosis factor-related apoptosis-inducing ligand-encoding plasmid gene (TRAIL and doxorubicin (Dox-coloaded multifunctional nanocarrier was constructed based on the theory of circulation, accumulation, internalization, and release. Briefly, polyethyleneimine (PEI was selected as skeleton material to synthesize PEI–polyethylene glycol (PEG–TAT (PPT. Dox was conjugated to PEI using C6-succinimidyl 6-hydrazinonicotinate acetone hydrazone (C6-SANH, and a pH-sensitive Dox-PEI (DP conjugate was obtained. Then, intracellular cationic pH-sensitive cellular assistant PPT and DP were mixed to condense TRAIL, and TRAIL–Dox coloaded PPT/DP/TRAIL (PDT nanocarriers were obtained by one-step assembly. TRAIL was completely condensed by DP or PPT when mass ratios (DP/PPT to TRAIL were up to 100:64, which indicated that DP and PPT could be mixed at any ratio for TRAIL condensation. The intracellular uptake rate of PDT was enhanced (P<0.05 when the contents of PPT in PPT+DP increased from 0 to 30%. Free Dox and TRAIL-loaded nanocarriers (PPT/C6-SANH-PEI/TRAIL [PCT] were selected as controls to verify the synergistic antitumor effects of PDT. Compared with free TRAIL, TRAIL-protein expression was upregulated by PDT and PCT on Western blotting assays. The in vitro cytotoxicity of PDT was significantly enhanced compared to free Dox and PCT (P<0.01. Furthermore, murine PDT nanocarriers showed higher in vivo antitumor ability than both the

  12. Novel Prognostic Groups in Thymic Epithelial Tumors: Assessment of Risk and Therapeutic Strategy Selection

    International Nuclear Information System (INIS)

    D'Angelillo, Rolando M.; Trodella, Lucio; Ramella, Sara; Cellini, Numa; Balducci, Mario; Mantini, Giovanna; Cellini, Francesco; Ciresa, Marzia; Fiore, Michele; Evoli, Amelia; Sterzi, Silvia; Russo, Patrizia; Grozio, Alessia; Cesario, Alfredo; Granone, Pierluigi

    2008-01-01

    Purpose: To assess the role of multimodality treatment on patients with thymic epithelial tumors (TETs) (i.e., thymomas and thymic squamous cell carcinoma) and to define the prognostic classes according to the Masaoka and World Health Organization histologic classification systems. Methods and Materials: Primary surgery was the mainstay of therapy. Extended thymectomy was performed in all cases. The cases were primarily staged according to the Masaoka system. Adjuvant radiotherapy was given to patients diagnosed with Masaoka Stage II, III, and IVA TET. Adjuvant chemotherapy was administered in selected cases. Results: We reviewed the records of 120 patients with TETs, with a mean follow-up of 13.8 years. Of the 120 patients, 98 (81.6%) received adjuvant radiotherapy. Of these 98 patients, Grade 1-2 pulmonary or esophageal toxicity was acute in 12 (12.2%) and late in 8 (8.2%). The median overall survival was 21.6 years. Of the 120 patients, 106 were rediagnosed and reclassified according to the World Health Organization system, and the survival rate was correlated with it. Three different prognostic classes were defined: favorable, Masaoka Stage I and histologic grade A, AB, B1, B2 or Masaoka Stage II and histologic grade A, AB, B1; unfavorable, Stage IV disease or histologic grade C or Stage III and histologic grade B3; intermediate, all other combinations. The 10- and 20-year survival rate was 95% and 81% for the favorable group, 90% and 65% for the intermediate group, and 50% and 0% for the unfavorable group, respectively. Local recurrence, distant recurrence, and tumor-related deaths were also evaluated. Conclusion: The analysis of our experience singled out three novel prognostic classes and the assessment of risk identified treatment selection criteria

  13. 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...

  14. TRAIL-Based High Throughput Screening Reveals a Link between TRAIL-Mediated Apoptosis and Glutathione Reductase, a Key Component of Oxidative Stress Response.

    Directory of Open Access Journals (Sweden)

    Dmitri Rozanov

    Full Text Available A high throughput screen for compounds that induce TRAIL-mediated apoptosis identified ML100 as an active chemical probe, which potentiated TRAIL activity in prostate carcinoma PPC-1 and melanoma MDA-MB-435 cells. Follow-up in silico modeling and profiling in cell-based assays allowed us to identify NSC130362, pharmacophore analog of ML100 that induced 65-95% cytotoxicity in cancer cells and did not affect the viability of human primary hepatocytes. In agreement with the activation of the apoptotic pathway, both ML100 and NSC130362 synergistically with TRAIL induced caspase-3/7 activity in MDA-MB-435 cells. Subsequent affinity chromatography and inhibition studies convincingly demonstrated that glutathione reductase (GSR, a key component of the oxidative stress response, is a target of NSC130362. In accordance with the role of GSR in the TRAIL pathway, GSR gene silencing potentiated TRAIL activity in MDA-MB-435 cells but not in human hepatocytes. Inhibition of GSR activity resulted in the induction of oxidative stress, as was evidenced by an increase in intracellular reactive oxygen species (ROS and peroxidation of mitochondrial membrane after NSC130362 treatment in MDA-MB-435 cells but not in human hepatocytes. The antioxidant reduced glutathione (GSH fully protected MDA-MB-435 cells from cell lysis induced by NSC130362 and TRAIL, thereby further confirming the interplay between GSR and TRAIL. As a consequence of activation of oxidative stress, combined treatment of different oxidative stress inducers and NSC130362 promoted cell death in a variety of cancer cells but not in hepatocytes in cell-based assays and in in vivo, in a mouse tumor xenograft model.

  15. Andrographolide sensitizes cancer cells to TRAIL-induced apoptosis via p53-mediated death receptor 4 up-regulation.

    Science.gov (United States)

    Zhou, Jing; Lu, Guo-Dong; Ong, Chye-Sun; Ong, Choon-Nam; Shen, Han-Ming

    2008-07-01

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an important member of the tumor necrosis factor subfamily with great potential in cancer therapy. Andrographolide (Andro), a diterpenoid lactone isolated from a traditional herbal medicine Andrographis paniculata, is known to possess potent anti-inflammatory and anticancer activities. Here, we showed that pretreatment with Andro significantly enhances TRAIL-induced apoptosis in various human cancer cell lines, including those TRAIL-resistant cells. Such sensitization is achieved through transcriptional up-regulation of death receptor 4 (DR4), a death receptor of TRAIL. In search of the molecular mechanisms responsible for DR4 up-regulation, we found that the tumor suppressor p53 plays an essential role in DR4 transcriptional activation. Andro is capable of activating p53 via increased p53 phosphorylation and protein stabilization, a process mediated by enhanced reactive oxygen species production and subsequent c-Jun NH(2)-terminal kinase activation. Pretreatment with an antioxidant (N-acetylcysteine) or a c-Jun NH(2)-terminal kinase inhibitor (SP600125) effectively prevented Andro-induced p53 activation and DR4 up-regulation and eventually blocked the Andro-induced sensitization on TRAIL-induced apoptosis. Taken together, these results present a novel anticancer effect of Andro and support its potential application in cancer therapy to overcome TRAIL resistance.

  16. Energy saving through trail following in a marine snail

    OpenAIRE

    Davies, Mark S; Blackwell, Janine

    2007-01-01

    Most snails and slugs locomote over a layer of mucus and although the resultant mucus trail is expensive to produce, we show that this expense can be reduced by trail following. When tracking over fresh conspecific trails, the marine intertidal snail Littorina littorea (L.) produced only approximately 27% of the mucus laid by marker snails. When tracking over weathered trails, snails adjusted their mucus production to recreate a convex trail profile of similar shape and thickness to the trail...

  17. On coagulation process in meteor trails

    International Nuclear Information System (INIS)

    Bergkhanov, M.

    1988-01-01

    Structure of the meteors processes of collisions of paricles formd after interaction of meteoric matter with the Earth atmosphere are shortly described. Equation describing coagulation in meteor trails is obtained. Primary and secondary particles of meteor nature, representing the source of polydisperse aerosol, exist in meteor zone. Coagulation in meteor trails can be referred to Brownian one

  18. Neutrophils with protumor potential could efficiently suppress tumor growth after cytokine priming and in presence of normal NK cells.

    Science.gov (United States)

    Sun, Rui; Luo, Jing; Li, Dong; Shu, Yu; Luo, Chao; Wang, Shan-Shan; Qin, Jian; Zhang, Gui-Mei; Feng, Zuo-Hua

    2014-12-30

    In tumor-bearing state, the function of neutrophils is converted from tumor-suppressing to tumor-promoting. Here we report that priming with IFN-γ and TNF-α could convert the potential of neutrophils from tumor-promoting to tumor-suppressing. The neutrophils with protumor potential have not lost their responsiveness to IFN-γ and TNF-α. After priming with IFN-γ and TNF-α, the potential of the neutrophils to express Bv8 and Mmp9 genes was reduced. Conversely, the tumor-promotional neutrophils recovered the expression of Rab27a and Trail, resumed the activation levels of PI3K and p38 MAPK pathways in response to stimuli, and expressed higher levels of IL-18 and NK-activating ligands such as RAE-1, MULT-1, and H60. Therefore, the anti-tumor function of the neutrophils was augmented, including the cytotoxicity to tumor cells, the capability of degranulation, and the capacity to activate NK cells. Since the function of NK cells is impaired in tumor-bearing state, the administration of normal NK cells could significantly augment the efficiency of tumor therapy based on neutrophil priming. These findings highlight the reversibility of neutrophil function in tumor-bearing state, and suggest that neutrophil priming by IFN-γ/TNF-α might be a potential approach to eliminate residual tumor cells in comprehensive strategy for tumor therapy.

  19. The Role of mTOR in Neuroendocrine Tumors: Future Cornerstone of a Winning Strategy?

    Directory of Open Access Journals (Sweden)

    Giuseppe Lamberti

    2018-03-01

    Full Text Available The mechanistic target of rapamycin (mTOR is part of the phosphoinositide-3-kinase (PI3K/protein kinase B (AkT/mTOR pathway and owes its name to the inhibitory effect of rapamycin. The mTOR has a central converging role for many cell functions, serving as a sensor for extracellular signals from energy status and nutrients availability, growth factors, oxygen and stress. Thus, it also modulates switch to anabolic processes (protein and lipid synthesis and autophagy, in order to regulate cell growth and proliferation. Given its functions in the cell, its deregulation is implicated in many human diseases, including cancer. Its predominant role in tumorigenesis and progression of neuroendocrine tumors (NETs, in particular, has been demonstrated in preclinical studies and late clinical trials. mTOR inhibition by everolimus is an established therapeutic target in NETs, but there are no identified predictive or prognostic factors. This review is focused on the role of mTOR and everolimus in NETs, from preclinical studies to major clinical trials, and future perspectives involving mTOR in the treatment of NETs.

  20. Thermal and mechanical high-intensity focused ultrasound: perspectives on tumor ablation, immune effects and combination strategies

    NARCIS (Netherlands)

    Bijgaart, R.J.E. van den; Eikelenboom, D.C.; Hoogenboom, M.; Futterer, J.J.; Brok, M.H.M.G.M. den; Adema, G.J.

    2017-01-01

    Tumor ablation technologies, such as radiofrequency-, cryo- or high-intensity focused ultrasound (HIFU) ablation will destroy tumor tissue in a minimally invasive manner. Ablation generates large volumes of tumor debris in situ, releasing multiple bio-molecules like tumor antigens and

  1. 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

  2. Strategy to find molecular signatures in a small series of rare cancers: validation for radiation-induced breast and thyroid tumors.

    Directory of Open Access Journals (Sweden)

    Nicolas Ugolin

    Full Text Available Methods of classification using transcriptome analysis for case-by-case tumor diagnosis could be limited by tumor heterogeneity and masked information in the gene expression profiles, especially as the number of tumors is small. We propose a new strategy, EMts_2PCA, based on: 1 The identification of a gene expression signature with a great potential for discriminating subgroups of tumors (EMts stage, which includes: a a learning step, based on an expectation-maximization (EM algorithm, to select sets of candidate genes whose expressions discriminate two subgroups, b a training step to select from the sets of candidate genes those with the highest potential to classify training tumors, c the compilation of genes selected during the training step, and standardization of their levels of expression to finalize the signature. 2 The predictive classification of independent prospective tumors, according to the two subgroups of interest, by the definition of a validation space based on a two-step principal component analysis (2PCA. The present method was evaluated by classifying three series of tumors and its robustness, in terms of tumor clustering and prediction, was further compared with that of three classification methods (Gene expression bar code, Top-scoring pair(s and a PCA-based method. Results showed that EMts_2PCA was very efficient in tumor classification and prediction, with scores always better that those obtained by the most common methods of tumor clustering. Specifically, EMts_2PCA permitted identification of highly discriminating molecular signatures to differentiate post-Chernobyl thyroid or post-radiotherapy breast tumors from their sporadic counterparts that were previously unsuccessfully classified or classified with errors.

  3. Integration of chemotherapy into current treatment strategies for brain metastases from solid tumors

    International Nuclear Information System (INIS)

    Nieder, Carsten; Grosu, Anca L; Astner, Sabrina; Thamm, Reinhard; Molls, Michael

    2006-01-01

    Patients with brain metastases represent a heterogeneous group where selection of the most appropriate treatment depends on many patient- and disease-related factors. Eventually, a considerable proportion of patients are treated with palliative approaches such as whole-brain radiotherapy. Whole-brain radiotherapy in combination with chemotherapy has recently gained increasing attention and is hoped to augment the palliative effect of whole-brain radiotherapy alone and to extend survival in certain subsets of patients with controlled extracranial disease and good performance status. The randomized trials of whole-brain radiotherapy vs. whole-brain radiotherapy plus chemotherapy suggest that this concept deserves further study, although they failed to improve survival. However, survival might not be the most relevant endpoint in a condition, where most patients die from extracranial progression. Sometimes, the question arises whether patients with newly detected brain metastases and the indication for systemic treatment of extracranial disease can undergo standard systemic chemotherapy with the option of deferred rather than immediate radiotherapy to the brain. The literature contains numerous small reports on this issue, mainly in malignant melanoma, breast cancer, lung cancer and ovarian cancer, but very few sufficiently powered randomized trials. With chemotherapy alone, response rates were mostly in the order of 20–40%. The choice of chemotherapy regimen is often complicated by previous systemic treatment and takes into account the activity of the drugs in extracranial metastatic disease. Because the blood-brain barrier is partially disrupted in most macroscopic metastases, systemically administered agents can gain access to such tumor sites. Our systematic literature review suggests that both chemotherapy and radiochemotherapy for newly diagnosed brain metastases need further critical evaluation before standard clinical implementation. A potential chemotherapy

  4. 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.

  5. 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

  6. 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.

  7. Short-hairpin RNA-induced suppression of adenine nucleotide translocase-2 in breast cancer cells restores their susceptibility to TRAIL-induced apoptosis by activating JNK and modulating TRAIL receptor expression

    Directory of Open Access Journals (Sweden)

    Kim Chul-Woo

    2010-09-01

    Full Text Available Abstract Background Tumor necrosis factor (TNF-related apoptosis-inducing ligand (TRAIL; apo2 ligand induces apoptosis in cancer cells but has little effect on normal cells. However, many cancer cell types are resistant to TRAIL-induced apoptosis, limiting the clinical utility of TRAIL as an anti-cancer agent. We previously reported that the suppression of adenine nucleotide translocase-2 (ANT2 by short-hairpin RNA (shRNA induces apoptosis of breast cancer cells, which frequently express high levels of ANT2. In the present study, we examined the effect of RNA shRNA-induced suppression of ANT2 on the resistance of breast cancer cells to TRAIL-induced apoptosis in vitro and in vivo. Results ANT2 shRNA treatment sensitized MCF7, T47 D, and BT474 cells to TRAIL-induced apoptosis by up-regulating the expression of TRAIL death receptors 4 and 5 (DR4 and DR5 and down-regulating the TRAIL decoy receptor 2 (DcR2. In MCF7 cells, ANT2 knockdown activated the stress kinase c-Jun N-terminal kinase (JNK, subsequently stabilizing and increasing the transcriptional activity of p53 by phosphorylating it at Thr81; it also enhanced the expression and activity of DNA methyltransferase 1 (DNMT1. ANT2 shRNA-induced overexpression of DR4/DR5 and TRAIL sensitization were blocked by a p53 inhibitor, suggesting that p53 activation plays an important role in the transcriptional up-regulation of DR4/DR5. However, ANT2 knockdown also up-regulated DR4/DR5 in the p53-mutant cell lines BT474 and T47 D. In MCF7 cells, ANT2 shRNA treatment led to DcR2 promoter methylation and concomitant down-regulation of DcR2 expression, consistent with the observed activation of DNMT1. Treatment of the cells with a demethylating agent or JNK inhibitor prevented the ANT2 shRNA-induced down-regulation of DcR2 and activation of both p53 and DNMT1. In in vivo experiments using nude mice, ANT2 shRNA caused TRAIL-resistant MCF7 xenografts to undergo TRAIL-induced cell death, up-regulated DR4/DR5

  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 trails on the Rocky Flats SAN system

  9. Low Circulating TRAIL Levels Are Associated with Increase of Resistin and Lipocalin-2/ngal Adipokines in Postmenopausal Women

    Directory of Open Access Journals (Sweden)

    Veronica Tisato

    2017-01-01

    Full Text Available Objective. Tumor necrosis factor- (TNF- related apoptosis-inducing ligand (TRAIL is attracting attention for its role in the physiopathology of metabolic disease/diabetes. Evidence suggests that it might protect against metabolic abnormalities driven by obesity-induced dysregulated secretion of adipokines, but this role of TRAIL has not yet been fully established. On this basis, we aimed to investigate the potential association between TRAIL and adipokine levels in a cohort of subjects in which age/gender/hormonal interferences were excluded. Methods. Serum levels of TRAIL and a panel of adipokines were measured in postmenopausal women (n=147 stratified according to waist circumference measures as normal, overweight, or obese. The panel of adipokines included interleukin- (IL- 6, IL-8, IL-1β, adipsin, lipocalin-2/neutrophil gelatinase-associated lipocalin (ngal, TNF-alpha, monocyte chemoattractant protein-1, plasminogen activator inhibitor-1, hepatocyte growth factor, resistin, leptin, adiponectin, and nerve growth factor. Results. Low serum TRAIL concentration (deciles I–IV was significantly and inversely correlated with resistin and lipocalin 2/ngal levels (r=−0.502 and p<0.001 and r=−0.360 and p<0.01, resp.. Both associations retained their statistical significance after adjustment for confounding factors, such as waist circumference and age. Conclusions. Our data indicate a link between low circulating levels of TRAIL and markers of obesity-induced diseases (resistin and lipocalin-2/ngal, highlighting a new potential axis of TRAIL functions.

  10. Formation of the IGF1R/CAV1/SRC tri-complex antagonizes TRAIL-induced apoptosis in gastric cancer cells.

    Science.gov (United States)

    Guo, Tianshu; Xu, Ling; Che, Xiaofang; Zhang, Simeng; Li, Ce; Wang, Jin; Gong, Jing; Ma, Rui; Fan, Yibo; Hou, Kezuo; Zhou, Huiming; Hu, Xuejun; Liu, Yunpeng; Qu, Xiujuan

    2017-07-01

    Lipid rafts provide a biological platform for apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). We previously reported that insulin-like growth factor 1 receptor (IGF1R) translocation into lipid rafts helped to explain TRAIL resistance. However, it was not clear whether TRAIL resistance was caused by the interaction of IGF1R with caveolin-1 (CAV1) and the non-receptor tyrosine kinase SRC in lipid rafts of gastric cancer cells. Here, we observed high IGF1R expression in TRAIL-resistant gastric cancer cells, and showed that IGF1R combined with both CAV1 and SRC in a native complex. TRAIL was shown to promote the formation of the IGF1R/CAV1/SRC tri-complex and the activation of these three molecules. Knockdown of IGF1R or CAV1 or inhibition of SRC activity reduced the formation of this tri-complex and enhanced TRAIL-induced apoptosis. Furthermore, the overexpression of microRNA-194 reversed TRAIL resistance by reducing IGF1R expression. In summary, TRAIL increased formation of the IGF1R/CAV1/SRC tri-complex and the activation of downstream survival pathways, leading to TRAIL resistance in gastric cancer cells. © 2017 International Federation for Cell Biology.

  11. Strategies to reduce the systematic error due to tumor and rectum motion in radiotherapy of prostate cancer

    International Nuclear Information System (INIS)

    Hoogeman, Mischa S.; Herk, Marcel van; Bois, Josien de; Lebesque, Joos V.

    2005-01-01

    carried out later in the treatment (based on the data of more scans) the overall reduction was less. For the rectum, the first strategy performed best at the upper anterior side, where a reduction of the anterior-posterior displacement of 30% could be achieved. The systematic error could be reduced by 43% for the whole rectum by using the data of 4 repeat CT scans and the planning CT scan. Conclusions: Both the pre-treatment as well as the adaptive correction strategy reduced the systematic error in the prostate position and rectum position and shape. A smaller systematic error makes it possible to safely reduce the margin around the clinical tumor volume, so that normal tissues can be spared or the prescription dose can be escalated

  12. 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...

  13. Classification of mountain bike trails using vehicle-pavement ...

    African Journals Online (AJOL)

    Various mountain bike trails exist in South Africa, but their difficulty ratings are generally unknown. By classifying the trails, risk of injury and uncertainty can be limited as information are provided on the difficulty of the trail. In creating a Trail Classification System (TCS) the principles of Vehicle-Pavement Interaction (V-PI) can ...

  14. Interferon-α and cyclooxygenase-2 inhibitor cooperatively mediates TRAIL-induced apoptosis in hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Zuo, Chaohui, E-mail: zuochaohui@vip.sina.com [Department of Gastroduodenal and Pancreatic Surgery, Translation Medicine Research Center of Liver Cancer, Hunan Province Tumor Hospital & Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, Hunan Province (China); Department of Pathology, Immunology and Laboratory Medicine and Shands Cancer Center, University of Florida, Gainesville, FL (United States); Qiu, Xiaoxin [Department of Gastroduodenal and Pancreatic Surgery, Translation Medicine Research Center of Liver Cancer, Hunan Province Tumor Hospital & Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, Hunan Province (China); Cancer Research Institute, University of South China, Hengyang, Hunan Province (China); Liu, Nianli; Yang, Darong [Cancer Research Institute, University of South China, Hengyang, Hunan Province (China); Xia, Man [Department of Gastroduodenal and Pancreatic Surgery, Translation Medicine Research Center of Liver Cancer, Hunan Province Tumor Hospital & Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, Hunan Province (China); Department of Pathology, Immunology and Laboratory Medicine and Shands Cancer Center, University of Florida, Gainesville, FL (United States); Liu, Jingshi [Department of Gastroduodenal and Pancreatic Surgery, Translation Medicine Research Center of Liver Cancer, Hunan Province Tumor Hospital & Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, Hunan Province (China); Wang, Xiaohong [Cancer Research Institute, University of South China, Hengyang, Hunan Province (China); and others

    2015-05-01

    Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. Interferon-alpha (IFN-α) has recently been recognized to harbor therapeutic potential in the prevention and treatment of HCC, but it remains controversial as to whether IFN-α exerts direct cytotoxicity against HCC. Cyclooxygenase-2 (COX-2) is overexpressed in HCC and is considered to play a role in hepatocarcinogenesis. Therefore, we aimed to elucidate the combined effect of a COX-2 inhibitor, celecoxib, and IFN-α on in vitro growth suppression of HCC using the hepatoma cell line HLCZ01 and the in vivo nude mouse xenotransplantation model using HLCZ01 cells. Treatment with celecoxib and IFN-α synergistically inhibited cell proliferation in a dose- and time-dependent manner. Apoptosis was identified by 4',6-diamidino-2-phenylindole dihydrochloride and fluorescent staining. IFN-α upregulated the expression of TRAIL, while celecoxib increased the expression of TRAIL receptors. The combined regimen with celecoxib and IFN-α reduced the growth of xenotransplanted HCCs in nude mice. The regulation of IFN-α- and COX-2 inhibitor-induced cell death is impaired in a subset of TRAIL-resistant cells. The molecular mechanisms of HCC cells resistant to TRAIL-induced apoptosis were explored using molecular biological and immunological methods. Interferon-α and the COX-2 inhibitor celecoxib synergistically increased TRAIL-induced apoptosis in hepatocellular carcinoma. These data suggest that IFN-α and celecoxib may offer a novel role with important implications in designing new therapeutics for TRAIL-resistant tumors. - Highlights: ●The cytotoxic effect of TRAIL on a developed HCC HLCZ01 cells infected with HBV. ●IFN-α and celecoxib induced apoptosis in HLCZ01 cells infected with HBV. ●The combined regime reduced the growth of xenotransplanted HCCs in nude mice model.

  15. Epigenetic silencing of apoptosis-inducing gene expression can be efficiently overcome by combined SAHA and TRAIL treatment in uterine sarcoma cells.

    Directory of Open Access Journals (Sweden)

    Leopold F Fröhlich

    Full Text Available The lack of knowledge about molecular pathology of uterine sarcomas with a representation of 3-7% of all malignant uterine tumors prevents the establishment of effective therapy protocols. Here, we explored advanced therapeutic options to the previously discovered antitumorigenic effects of the histone deacetylase (HDAC inhibitor suberoylanilide hydroxamic acid (SAHA by combined treatment with the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo-2L. In addition, we investigated the uterine sarcoma cell lines, MES-SA and ESS-1, regarding the underlying molecular mechanisms of SAHA and TRAIL-induced apoptosis and their resistance towards TRAIL. Compared to single SAHA or TRAIL treatment, the combination of SAHA with TRAIL led to complete cell death of both tumor cell lines after 24 to 48 hours. In contrast to single SAHA treatment, apoptosis occured faster and was more pronounced in ESS-1 cells than in MES-SA cells. Induction of SAHA- and TRAIL-induced apoptosis was accompanied by upregulation of the intrinsic apoptotic pathway via reduction of mitochondrial membrane potential, caspase-3, -6, and -7 activation, and PARP cleavage, but was also found to be partially caspase-independent. Apoptosis resistance was caused by reduced expression of caspase-8 and DR 4/TRAIL-R1 in ESS-1 and MES-SA cells, respectively, due to epigenetic silencing by DNA hypermethylation of gene promoter sequences. Treatment with the demethylating agent 5-Aza-2'-deoxycytidine or gene transfer therefore restored gene expression and increased the sensitivity of both cell lines against TRAIL-induced apoptosis. Our data provide evidence that deregulation of epigenetic silencing by histone acetylation and DNA hypermethylation might play a fundamental role in the origin of uterine sarcomas. Therefore, tumor growth might be efficiently overcome by a cytotoxic combinatorial treatment of HDAC inhibitors with TRAIL.

  16. Miniature Trailing Edge Effector for Aerodynamic Control

    Science.gov (United States)

    Lee, Hak-Tae (Inventor); Bieniawski, Stefan R. (Inventor); Kroo, Ilan M. (Inventor)

    2008-01-01

    Improved miniature trailing edge effectors for aerodynamic control are provided. Three types of devices having aerodynamic housings integrated to the trailing edge of an aerodynamic shape are presented, which vary in details of how the control surface can move. A bucket type device has a control surface which is the back part of a C-shaped member having two arms connected by the back section. The C-shaped section is attached to a housing at the ends of the arms, and is rotatable about an axis parallel to the wing trailing edge to provide up, down and neutral states. A flip-up type device has a control surface which rotates about an axis parallel to the wing trailing edge to provide up, down, neutral and brake states. A rotating type device has a control surface which rotates about an axis parallel to the chord line to provide up, down and neutral states.

  17. 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...

  18. 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...

  19. 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...

  20. Ischemic tolerance modulates TRAIL expression and its receptors and generates a neuroprotected phenotype.

    Science.gov (United States)

    Cantarella, G; Pignataro, G; Di Benedetto, G; Anzilotti, S; Vinciguerra, A; Cuomo, O; Di Renzo, G F; Parenti, C; Annunziato, L; Bernardini, R

    2014-07-17

    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 stroke and ischemic preconditioning and to propose, by modulating TRAIL pathway, a new therapeutic strategy in stroke. In order to achieve this aim a rat model of harmful focal ischemia, obtained by subjecting animals to 100 min of transient occlusion of middle cerebral artery followed by 24 h of reperfusion and a rat model of ischemic preconditioning in which the harmful ischemia was preceded by 30 mins of tMCAO, which represents the preconditioning protective stimulus, were used. Results show that the neuroprotection elicited by ischemic preconditioning occurs through both upregulation of TRAIL decoy receptors and downregulation of TRAIL itself and of its death receptors. As a counterproof, immunoneutralization of TRAIL in tMCAO animals resulted in significant restraint of tissue damage and in a marked functional recovery. Our data shed new light on the mechanisms that propagate ongoing neuronal damage after ischemia in the adult mammalian brain and provide new molecular targets for therapeutic intervention. Strategies aimed to repress the death-inducing ligands TRAIL, to antagonize the death receptors, or to activate the decoy receptors open new perspectives for the treatment of stroke.

  1. Activation of the Tumor Suppressor PP2A Emerges as a Potential Therapeutic Strategy for Treating Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Ion Cristóbal

    2015-05-01

    Full Text Available Protein phosphatase 2A (PP2A is a tumor suppressor complex that has recently been reported as a novel and highly relevant molecular target in prostate cancer (PCa. However, its potential therapeutic value remains to be fully clarified. We treated PC-3 and LNCaP cell lines with the PP2A activators forskolin and FTY720 alone or combined with the PP2A inhibitor okadaic acid. We examined PP2A activity, cell growth, prostasphere formation, levels of PP2A phosphorylation, CIP2A and SET expression, and AKT and ERK activation. Interestingly, both forskolin and FTY720 dephosphorylated and activated PP2A, impairing proliferation and prostasphere formation and inducing changes in AKT and ERK phosphorylation. Moreover, FTY720 led to reduced CIP2A levels. Treatment with okadaic acid impaired PP2A activation thus demonstrating the antitumoral PP2A-dependent mechanism of action of both forskolin and FTY720. Levels of PP2A phosphorylation together with SET and CIP2A protein expression were studied in 24 PCa patients and both were associated with high Gleason scores and presence of metastatic disease. Altogether, our results suggest that PP2A inhibition could be involved in PCa progression, and the use of PP2A-activating drugs might represent a novel alternative therapeutic strategy for treating PCa patients.

  2. Smac peptide potentiates TRAIL- or paclitaxel-mediated ovarian cancer cell death in vitro and in vivo.

    Science.gov (United States)

    Mao, Hong Luan; Pang, Yingxin; Zhang, Xiaolei; Yang, Fang; Zheng, Jingfang; Wang, Yu; Liu, Peishu

    2013-02-01

    Second mitochondria-derived activator of caspases (Smac) is a recently identified protein that is released from mitochondria in response to apoptotic stimuli and promotes apoptosis by antagonizing the inhibitor of apoptosis proteins (IAPs). Our previous study showed that ectopic overexpression of Smac sensitizes drug-resistant tumor cells to TRAIL- or paclitaxel-induced apoptosis in vitro. The present study was designed to explore the effect of the synthesized Smac N7 peptide in a human ovarian cancer cell line and xenograft model. The results showed that the single-agent Smac N7 had a non-cytotoxic effect, but it effectively enhanced TRAIL- or paclitaxel-induced inhibition of cell proliferation in a dose-dependent manner, even in TRAIL-resistant A2780 cells. When Smac N7 was combined with TRAIL or paclitaxel in treating A2780 cell tumor xenografts, synergistic anticancer effects were achieved. Furthermore, the combination therapy caused less damage in normal tissues and more apoptosis in tumor xenografts compared with TRAIL or paclitaxel alone. Increased apoptosis was associated with the downregulation of XIAP, survivin and the increased activity of caspase-3, along with an increased amount of cleaved PARP. In conclusion, this Smac N7 peptide is a promising candidate for ovarian cancer combination therapy, and Smac may be the target for the development of a novel class of anticancer drugs.

  3. Comparison of IGRT Registration Strategies for Optimal Coverage of Primary Lung Tumors and Involved Nodes Based on Multiple Four-Dimensional CT Scans Obtained Throughout the Radiotherapy Course

    Energy Technology Data Exchange (ETDEWEB)

    Mohammed, Nasiruddin; Kestin, Larry; Grills, Inga; Shah, Chirag; Glide-Hurst, Carri; Yan, Di [Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, MI (United States); Ionascu, Dan, E-mail: Dan.ionascu@beaumont.edu [Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, MI (United States)

    2012-03-15

    Purpose: To investigate the impact of primary tumor and involved lymph node (LN) geometry (centroid, shape, volume) on internal target volume (ITV) throughout treatment for locally advanced non-small cell lung cancer using weekly four-dimensional computed tomography (4DCT). Methods and Materials: Eleven patients with advanced non-small cell lung cancer were treated using image-guided radiotherapy with acquisition of weekly 10-Phase 4DCTs (n = 51). Initial ITV was based on planning 4DCT. Master-ITV incorporated target geometry across the entire treatment (all 4DCTs). Geographic miss was defined as the % Master-ITV positioned outside of the initial planning ITV after registration is complete. Registration strategies considered were bony (B), primary tumor soft tissue alone (T), and registration based on primary tumor and involved LNs (T{sub L}N). Results: The % geographic miss for the primary tumor, mediastinal, and hilar lymph nodes based on each registration strategy were (1) B: 30%, 30%, 30%; (2) T: 21%, 40%, 36%; and (3) T{sub L}N: 26%, 26%, 27%. Mean geographic expansions to encompass 100% of the primary tumor and involved LNs were 1.2 {+-} 0.7 cm and 0.8 {+-} 0.3 cm, respectively, for B and T{sub L}N. Primary and involved LN expansions were 0.7 {+-} 0.5 cm and 1.1 {+-} 0.5 cm for T. Conclusion: T is best for solitary targets. When treatments include primary tumor and LNs, B and T{sub L}N provide more comprehensive geographic coverage. We have identified high % geographic miss when considering multiple registration strategies. The dosimetric implications are the subject of future study.

  4. Comparison of IGRT Registration Strategies for Optimal Coverage of Primary Lung Tumors and Involved Nodes Based on Multiple Four-Dimensional CT Scans Obtained Throughout the Radiotherapy Course

    International Nuclear Information System (INIS)

    Mohammed, Nasiruddin; Kestin, Larry; Grills, Inga; Shah, Chirag; Glide-Hurst, Carri; Yan, Di; Ionascu, Dan

    2012-01-01

    Purpose: To investigate the impact of primary tumor and involved lymph node (LN) geometry (centroid, shape, volume) on internal target volume (ITV) throughout treatment for locally advanced non–small cell lung cancer using weekly four-dimensional computed tomography (4DCT). Methods and Materials: Eleven patients with advanced non–small cell lung cancer were treated using image-guided radiotherapy with acquisition of weekly 10-Phase 4DCTs (n = 51). Initial ITV was based on planning 4DCT. Master-ITV incorporated target geometry across the entire treatment (all 4DCTs). Geographic miss was defined as the % Master-ITV positioned outside of the initial planning ITV after registration is complete. Registration strategies considered were bony (B), primary tumor soft tissue alone (T), and registration based on primary tumor and involved LNs (T L N). Results: The % geographic miss for the primary tumor, mediastinal, and hilar lymph nodes based on each registration strategy were (1) B: 30%, 30%, 30%; (2) T: 21%, 40%, 36%; and (3) T L N: 26%, 26%, 27%. Mean geographic expansions to encompass 100% of the primary tumor and involved LNs were 1.2 ± 0.7 cm and 0.8 ± 0.3 cm, respectively, for B and T L N. Primary and involved LN expansions were 0.7 ± 0.5 cm and 1.1 ± 0.5 cm for T. Conclusion: T is best for solitary targets. When treatments include primary tumor and LNs, B and T L N provide more comprehensive geographic coverage. We have identified high % geographic miss when considering multiple registration strategies. The dosimetric implications are the subject of future study.

  5. A Novel Strategy for Inducing the Antitumor Effects of Triterpenoid Compounds: Blocking the Protumoral Functions of Tumor-Associated Macrophages via STAT3 Inhibition

    Directory of Open Access Journals (Sweden)

    Yukio Fujiwara

    2014-01-01

    Full Text Available There are many types of nontumor cells, including leukocytes, fibroblasts, and endothelial cells, in the tumor microenvironment. Among these cells, infiltrating macrophages have recently received attention as novel target cells due to their protumoral functions. Infiltrating macrophages are called tumor-associated macrophages (TAMs. TAMs polarized to the M2 phenotype are involved in tumor development and are associated with a poor clinical prognosis. Therefore, the regulation of TAM activation or M2 polarization is a new strategy for antitumor therapy. We screened natural compounds possessing an inhibitory effect on the M2 polarization of human macrophages. Among 200 purified natural compounds examined, corosolic acid (CA and oleanolic acid (OA, both are categorized in triterpenoid compounds, inhibited macrophage polarization to M2 phenotype by suppressing STAT3 activation. CA and OA also directly inhibited tumor cell proliferation and sensitized tumor cells to anticancer drugs, such as adriamycin and cisplatin. The in vivo experiments showed that CA significantly suppressed subcutaneous tumor development and lung metastasis in a murine sarcoma model. The application of triterpenoid compounds, such as CA and OA, is a potential new anticancer therapy targeting macrophage activation, with synergistic effects with anticancer agents.

  6. Multi-omics enrichment analysis using the GeneTrail2 web service.

    Science.gov (United States)

    Stöckel, Daniel; Kehl, Tim; Trampert, Patrick; Schneider, Lara; Backes, Christina; Ludwig, Nicole; Gerasch, Andreas; Kaufmann, Michael; Gessler, Manfred; Graf, Norbert; Meese, Eckart; Keller, Andreas; Lenhof, Hans-Peter

    2016-05-15

    Gene set analysis has revolutionized the interpretation of high-throughput transcriptomic data. Nowadays, with comprehensive studies that measure multiple -omics from the same sample, powerful tools for the integrative analysis of multi-omics datasets are required. Here, we present GeneTrail2, a web service allowing the integrated analysis of transcriptomic, miRNomic, genomic and proteomic datasets. It offers multiple statistical tests, a large number of predefined reference sets, as well as a comprehensive collection of biological categories and enables direct comparisons between the computed results. We used GeneTrail2 to explore pathogenic mechanisms of Wilms tumors. We not only succeeded in revealing signaling cascades that may contribute to the malignancy of blastemal subtype tumors but also identified potential biomarkers for nephroblastoma with adverse prognosis. The presented use-case demonstrates that GeneTrail2 is well equipped for the integrative analysis of comprehensive -omics data and may help to shed light on complex pathogenic mechanisms in cancer and other diseases. GeneTrail2 can be freely accessed under https://genetrail2.bioinf.uni-sb.de : dstoeckel@bioinf.uni-sb.de Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  7. PTEN and TRAIL genes loaded zein nanoparticles as potential therapy for hepatocellular carcinoma.

    Science.gov (United States)

    El Sharkawi, Fathia Zaki; Ewais, Shaimaa Mohammed; Fahmy, Rania Hassan; Rashed, Laila Ahmed

    2017-07-01

    Gene therapy is one of the recent approaches in treatment of hepatocellular carcinoma (HCC). Development of a vector or vehicle that can selectively and efficiently deliver the gene to target cells with minimal toxicity is an urgent demand. In the present study, phosphatase and tensin homolog (PTEN) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) genes were loaded to zein nanoparticles (ZNPs). The formulated PTEN and TRAIL-loaded ZNPs were tested for their in vitro and in vivo potential antitumor efficacy using liver tumor cells (HepG2) and HCC-induced rats as animal model. Also, mRNA expression of p53, VGEF and MMP-2 were carried out as markers of apoptosis, angiogenesis and metastasis in animal liver tissues. The results of the study showed that both PTEN and TRAIL-loaded ZNPs proved anti-proliferative activity against HepG2 cell lines with IC 50 values of 0.09, 0.25 µg/ml, respectively. In vivo assay confirmed decrease in mRNA expression of both VEGF and MMP-2 with increased in P53 expression level in liver tissues of the treated animals. Therefore, authors introduced new integration between gene therapy and nanotechnology in the form of PTEN and TRAIL-loaded ZNPs that proved potential to be used in gene therapy for the treatment of HCC.

  8. Variants of Osteoprotegerin Lacking TRAIL Binding for Therapeutic Bone Remodeling in Osteolytic Malignancies

    Science.gov (United States)

    Higgs, Jerome T.; Jarboe, John S.; Lee, Joo Hyoung; Chanda, Diptiman; Lee, Carnellia M.; Deivanayagam, Champion; Ponnazhagan, Selvarangan

    2015-01-01

    Osteolytic bone damage is a major cause of morbidity in several metastatic pathologies. Current therapies using bisphosphonates provide modest improvement, but cytotoxic side effects still occur prompting the need to develop more effective therapies to target aggressive osteoclastogenesis. Increased levels of Receptor Activator of Nuclear Factor Kappa B Ligand (TNFSF11/RANKL), leading to RANKL-RANK signaling, remains the key axis for osteoclast activation and bone resorption. Osteoprotegerin (TNFRSF11B/OPG), a decoy receptor for RANKL is significantly decreased in patients who present with bone lesions. Despite its potential in inhibiting osteoclast activation, OPG also binds to tumor necrosis factor related apoptosis-inducing ligand (TNFSF10/TRAIL), making tumor cells resistant to apoptosis. Towards uncoupling the events of TRAIL binding of OPG and to improve its utility for bone remodeling without inducing tumor resistance to apoptosis, OPG mutants were developed by structural homology modeling based on interactive domain identification and by superimposing models of OPG, TRAIL and its receptor DR5 (TNFRSF10B) to identify regions of OPG for rational design. The OPG mutants were purified and extensively characterized for their ability to decrease osteoclast damage without affecting tumor apoptosis pathway both in vitro and in vivo, confirming their potential in bone remodeling following cancer-induced osteolytic damage. PMID:25636966

  9. 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

  10. 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…

  11. DR4 specific TRAIL variants are more efficacious than wild-type TRAIL in pancreatic cancer

    NARCIS (Netherlands)

    Yu, Rui; Albarenque, Stella Maris; Cool, Robbert H.; Quax, Wim J.; Mohr, Andrea; Zwacka, Ralf M.

    2014-01-01

    Current treatment modalities for pancreatic carcinoma afford only modest survival benefits. TRAIL, as a potent and specific inducer of apoptosis in cancer cells, would be a promising new treatment option. However, since not all pancreatic cancer cells respond to TRAIL, further improvements and

  12. Energy saving through trail following in a marine snail.

    Science.gov (United States)

    Davies, Mark S; Blackwell, Janine

    2007-05-07

    Most snails and slugs locomote over a layer of mucus and although the resultant mucus trail is expensive to produce, we show that this expense can be reduced by trail following. When tracking over fresh conspecific trails, the marine intertidal snail Littorina littorea (L.) produced only approximately 27% of the mucus laid by marker snails. When tracking over weathered trails, snails adjusted their mucus production to recreate a convex trail profile of similar shape and thickness to the trail as originally laid. Maximum energy saving occurs when following recently laid trails which are little weathered. Many and diverse ecological roles for trail following have been proposed. Energy saving is the only role that applies across the Gastropoda and so may help to explain why trail following is such a well-established behaviour.

  13. 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.

  14. Synergistic antitumor effects of CDK inhibitor SNS-032 and an oncolytic adenovirus co-expressing TRAIL and Smac in pancreatic cancer

    Science.gov (United States)

    Ge, Yun; Lei, Wen; Ma, Yingyu; Wang, Yigang; Wei, Buyun; Chen, Xiaoyi; Ru, Guoqing; He, Xianglei; Mou, Xiaozhou; Wang, Shibing

    2017-01-01

    Gene therapy using oncolytic adenoviruses is a novel approach for human cancer therapeutics. The current study aimed to investigate whether the combined use of an adenovirus expressing tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and second mitochondria-derived activator of caspase (Smac) upon caspase activation (ZD55-TRAIL-IETD-Smac) and cyclin-dependent kinase (CDK) inhibitor SNS-032 will synergistically reinforce their anti-pancreatic cancer activities. The experiments in vitro demonstrated that SNS-032 enhances ZD55-TRAIL-IETD-Smac-induced apoptosis and causes marked pancreatic cancer cell death. Western blot assays suggested that the SNS-032 intensified ZD55-TRAIL-IETD-Smac-induced apoptosis of pancreatic cancer cells by affecting anti-apoptotic signaling elements, including CDK-2, CDK-9, Mcl-1 and XIAP. Additionally, animal experiments further confirmed that the combination of SNS-032 and ZD55-TRAIL-IETD-Smac significantly inhibited the growth of BxPC-3 pancreatic tumor xenografts. In conclusion, the present study demonstrated that SNS-032 sensitizes human pancreatic cancer cells to ZD55-TRAIL-IETD-Smac-induced cell death in vitro and in vivo. These findings indicate that combined treatment with SNS-032 and ZD55-TRAIL-IETD-Smac could represent a rational approach for anti-pancreatic cancer therapy. PMID:28440486

  15. Effect of miR-21 and miR-30b/c on TRAIL-induced apoptosis in glioma cells.

    Science.gov (United States)

    Quintavalle, C; Donnarumma, E; Iaboni, M; Roscigno, G; Garofalo, M; Romano, G; Fiore, D; De Marinis, P; Croce, C M; Condorelli, G

    2013-08-22

    Glioblastoma is the most frequent brain tumor in adults and is the most lethal form of human cancer. Despite the improvements in treatments, survival of patients remains poor. To define novel pathways that regulate susceptibility to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in glioma, we have performed genome-wide expression profiling of microRNAs (miRs). We show that in TRAIL-resistant glioma cells, levels of different miRs are increased, and in particular, miR-30b/c and -21. We demonstrate that these miRs impair TRAIL-dependent apoptosis by inhibiting the expression of key functional proteins. T98G-sensitive cells treated with miR-21 or -30b/c become resistant to TRAIL. Furthermore, we demonstrate that miR-30b/c and miR-21 target respectively the 3' untranslated region of caspase-3 and TAp63 mRNAs, and that those proteins mediate some of the effects of miR-30 and -21 on TRAIL resistance, even in human glioblastoma primary cells and in lung cancer cells. In conclusion, we show that high expression levels of miR-21 and -30b/c are needed to maintain the TRAIL-resistant phenotype, thus making these miRs as promising therapeutic targets for TRAIL resistance in glioma.

  16. Comparison of Two Output-Coding Strategies for Multi-Class Tumor Classification Using Gene Expression Data and Latent Variable Model as Binary Classifier

    Directory of Open Access Journals (Sweden)

    Sandeep J. Joseph

    2010-03-01

    Full Text Available Multi-class cancer classification based on microarray data is described. A generalized output-coding scheme based on One Versus One (OVO combined with Latent Variable Model (LVM is used. Results from the proposed One Versus One (OVO output- coding strategy is compared with the results obtained from the generalized One Versus All (OVA method and their efficiencies of using them for multi-class tumor classification have been studied. This comparative study was done using two microarray gene expression data: Global Cancer Map (GCM dataset and brain cancer (BC dataset. Primary feature selection was based on fold change and penalized t-statistics. Evaluation was conducted with varying feature numbers. The OVO coding strategy worked quite well with the BC data, while both OVO and OVA results seemed to be similar for the GCM data. The selection of output coding methods for combining binary classifiers for multi-class tumor classification depends on the number of tumor types considered, the discrepancies between the tumor samples used for training as well as the heterogeneity of expression within the cancer subtypes used as training data.

  17. Comparison of two output-coding strategies for multi-class tumor classification using gene expression data and Latent Variable Model as binary classifier.

    Science.gov (United States)

    Joseph, Sandeep J; Robbins, Kelly R; Zhang, Wensheng; Rekaya, Romdhane

    2010-03-10

    Multi-class cancer classification based on microarray data is described. A generalized output-coding scheme based on One Versus One (OVO) combined with Latent Variable Model (LVM) is used. Results from the proposed One Versus One (OVO) outputcoding strategy is compared with the results obtained from the generalized One Versus All (OVA) method and their efficiencies of using them for multi-class tumor classification have been studied. This comparative study was done using two microarray gene expression data: Global Cancer Map (GCM) dataset and brain cancer (BC) dataset. Primary feature selection was based on fold change and penalized t-statistics. Evaluation was conducted with varying feature numbers. The OVO coding strategy worked quite well with the BC data, while both OVO and OVA results seemed to be similar for the GCM data. The selection of output coding methods for combining binary classifiers for multi-class tumor classification depends on the number of tumor types considered, the discrepancies between the tumor samples used for training as well as the heterogeneity of expression within the cancer subtypes used as training data.

  18. Trailing edge modifications for flatback airfoils.

    Energy Technology Data Exchange (ETDEWEB)

    Kahn, Daniel L. (University of California, Davis, CA); van Dam, C.P. (University of California, Davis, CA); Berg, Dale E.

    2008-03-01

    The adoption of blunt trailing edge airfoils (also called flatback airfoils) for the inboard region of large wind turbine blades has been proposed. Blunt trailing edge airfoils would not only provide a number of structural benefits, such as increased structural volume and ease of fabrication and handling, but they have also been found to improve the lift characteristics of thick airfoils. Therefore, the incorporation of blunt trailing edge airfoils would allow blade designers to more freely address the structural demands without having to sacrifice aerodynamic performance. These airfoils do have the disadvantage of generating high levels of drag as a result of the low-pressure steady or periodic flow in the near-wake of the blunt trailing edge. Although for rotors, the drag penalty appears secondary to the lift enhancement produced by the blunt trailing edge, high drag levels are of concern in terms of the negative effect on the torque and power generated by the rotor. Hence, devices are sought that mitigate the drag of these airfoils. This report summarizes the literature on bluff body vortex shedding and bluff body drag reduction devices and proposes four devices for further study in the wind tunnel.

  19. The role of TRAIL in fatigue induced by repeated stress from radiotherapy.

    Science.gov (United States)

    Feng, Li Rebekah; Suy, Simeng; Collins, Sean P; Saligan, Leorey N

    2017-08-01

    Fatigue is one of the most common and debilitating side effects of cancer and cancer treatment, and yet its etiology remains elusive. The goal of this study is to understand the role of chronic inflammation in fatigue following repeated stress from radiotherapy. Fatigue and non-fatigue categories were assessed using ≥ 3-point change in Functional Assessment of Cancer Therapy-Fatigue questionnaire (FACT-F) administered to participants at baseline/before radiotherapy and one year post-radiotherapy. Whole genome microarray and cytokine multiplex panel were used to examine fatigue-related transcriptome and serum cytokine changes, respectively. The study included 86 subjects (discovery phase n = 40, validation phase n = 46). The sample in the discovery phase included men with prostate cancer scheduled to receive external-beam radiotherapy. A panel of 48 cytokines were measured and the significantly changed cytokine found in the discovery phase was validated using sera from a separate cohort of men two years after completing radiotherapy for prostate cancer at a different institution. Effects of the significantly changed cytokine on cell viability was quantified using the MTT assay. During the discovery phase, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and TRAIL decoy receptor, TNFRSF10C (TRAIL-R3), were significantly upregulated in fatigued (≥3-point decrease from baseline to 1yr-post radiotherapy) subjects (n = 15). In the validation phase, TRAIL correlated with fatigue scores 2yrs post-radiotherapy. TRAIL caused selective cytotoxicity in neuronal cells, but not in microglial and muscle cells, in vitro. Late-onset inflammation directed by TRAIL may play a role in fatigue pathogenesis post-repeated stress from irradiation. Published by Elsevier Ltd.

  20. Pathway-based association analyses identified TRAIL pathway for osteoporotic fractures.

    Directory of Open Access Journals (Sweden)

    Yin-Ping Zhang

    Full Text Available Hip OF carries the highest morbidity and mortality. Previous studies revealed that individual genes/loci in the Tumor Necrosis Factor (TNF-Related Apoptosis-Inducing Ligand (TRAIL pathway were associated with bone metabolism. This study aims to verify the potential association between hip OF and TRAIL pathway.Using genome-wide genotype data from Affymetrix 500 K SNP arrays, we performed novel pathway-based association analyses for hip OF in 700 elderly Chinese Han subjects (350 with hip OF and 350 healthy matched controls.The TRAIL pathway achieved a significant p value (p = 0.01 for association with hip OF. Among the 38 genes in the TRAIL pathway, seven genes achieved nominally significant association with hip OF (p<0.05; the TNFSF10 (TRAIL gene obtained the most significant p value (p = 1.70×10(-4. SNPs (rs719126, rs6533015, rs9594738, rs1805034, rs11160706 from five genes (CFLAR, NFKB1, TNFSF11, TNFRSF11A, TRAF3 of the pathway had minor alleles that appear to be protective to hip OF. SNPs (rs6445063 and rs4259415 from two genes (TNFSF10 and TNFRSF10B of the pathway had minor alleles (A that are associated with an increased risk of hip OF, with the ORs (odds ratios of 16.51 (95%CI:3.83-71.24 and 1.37 (95%CI:1.08-1.74, respectively.Our study supports the potential role of the TRAIL pathway in the pathogenesis of hip OF in Chinese Han population. Further functional study of this pathway will be pursued to determine the mechanism by which it confers risk to hip OF.

  1. X irradiation combined with TNF alpha-related apoptosis-inducing ligand (TRAIL) reduces hypoxic regions of human gastric adenocarcinoma xenografts in SCID mice

    International Nuclear Information System (INIS)

    Takahashi, Momoko; Yasui, Hironobu; Ogura, Aki; Asanuma, Taketoshi; Inanami, Osamu; Kubota, Nobuo; Tsujitani, Michihiko; Kuwabara, Mikinori

    2008-01-01

    Our previous study showed that X irradiation induced the expression of death receptor DR5 on the cell surface in tumor cell lines under not only normoxia but also hypoxia. X irradiation combined with TNF α-related apoptosis-inducing ligand (TRAIL), which is the ligand of DR5, induced apoptosis in vitro (Takahashi et al., (2007) Journal of Radiation Research, 48: 461-468). In this report, we examined the in vivo antitumor efficacy of X irradiation combined with TRAIL treatment in tumor xenograft models derived from human gastric adenocarcinoma MKN45 and MKN28 cells in severe combined immunodeficiency (SCID) mice. X irradiation combined with TRAIL synergistically suppressed the tumor growth rates in the xenograft models derived from MKN45 and MKN28 cells, which have wild type Tp53 and mutated Tp53, respectively, indicating that the antitumor effects occurred in a Tp53-independent manner. Histological analysis showed that the combination of X irradiation and TRAIL induced caspase-3-dependent apoptotic cell death. Moreover, the immunohistochemical detection of hypoxic regions using the hypoxic marker pimonidazole revealed that caspase-3-dependent apoptosis occurred in the hypoxic regions in the tumors. These results indicated that X irradiation combined with TRAIL may be a useful treatment to reduce tumor growth in not only normoxic but also hypoxic regions. (author)

  2. Actual and future strategies in interdisciplinary treatment of medulloblastomas, supratentorial PNET and intracranial germ cell tumors in childhood

    International Nuclear Information System (INIS)

    Kortmann, R.D.; Timmermann, B.; Bamberg, M.; Kuehl, J.; Calaminus, G.; Goebel, U.; Dieckmann, K.; Wurm, R.; Soerensen, N.; Urban, C.

    2001-01-01

    Methods: Systemic irradiation of neuroaxis is an essential part in the management of medulloblastoma, stPNET and intracranial germ cell tumors. The introduction of quality assurance programs in radiooncology assures a precise radiotherapy of target volumes and is a prerequisite to improve survival. Results: Hyperfractionated radiotherapy has the potential of increasing dose to tumor more safely without increasing the risk for late adverse effects. Pilot studies revealed excellent tumor control in medulloblastoma with acceptable acute toxicity and a long-term survival of up to 96%. In medulloblastoma stereotactic radiation techniques reveal an acceptable toxicity and promising results in tumor control in recurrent disease or as primary treatment. They are now part of future treatment protocols in case of persisting residual tumor. Radiotherapy alone in pure germinoma is continuously yielding high cure rates. In secreting germ cell tumors cisplatin containing chemotherapies in conjunction with radiotherapy achieve a long-term survival rate of 80% today. Especially in high risk medulloblastoma and secreting germ cell tumors chemotherapies are playing an increasingly important role in the interdisciplinary management. It can be expected that future developments of chemotherapeutic protocols and the introduction of new cytostatic substances will further improve the therapeutic outcome. (orig.) [de

  3. Synergistic effects of rmhTRAIL and 17-AAG on the proliferation and apoptosis of multiple myeloma cells.

    Science.gov (United States)

    Wang, Jing; Li, Yun; Sun, Wei; Liu, Jing; Chen, Wenming

    2018-03-22

    This study aimed to investigate synergistic effects of recombinant mutant human tumor necrosis factor-related apoptosis-inducing ligand (rmhTRAIL) and heat-shock protein 90 (HSP90) inhibitor (geldanamycin derivative 17 -allylamino- 17-demethoxy -geldanamycin, 17-AAG) on the proliferation and apoptosis of multiple myeloma (MM) cells. MTT assays evaluated inhibitory effects of rmhTRAIL and 17-AAG in different concentrations and treatment durations on the proliferation of RPMI8226 and U266 cells. The half maximal inhibitory concentration was calculated using OriginPro7.5. Synergistic effects of rmhTRAIL and 17-AAG on apoptosis of MM cells were detected using flow cytometry at 24 and 48 h post-treatment. To evaluate synergistic effects of rmhTRAIL and 17-AAG, the Q-value was calculated using King's formula. rmhTRAIL exhibited significant inhibitory effects on the proliferation of RPMI8226 cells in a dose- and time-dependent manner (>50%), whereas U266 cells were not sensitive to rmhTRAIL (AAG inhibited the proliferation of RPMI8226 and U266 cells in a dose-dependent manner (>80%). Significant synergistic effects of rmhTRAIL and 17-AAG on the proliferation of RPMI8226 cells were revealed (Q-value > 1.15), whereas synergistic effects were not evident on the proliferation of U266 cells (Q-value AAG exhibited significant synergistic effects on apoptosis of RPMI8226 and U266 cells (Q-value > 1.15). The combined application of rmhTRAIL and 17-AAG revealed favorable synergistic effects in the treatment of MM.

  4. The sesquiterpene lactone eupatolide sensitizes breast cancer cells to TRAIL through down-regulation of c-FLIP expression.

    Science.gov (United States)

    Lee, Jongkyu; Hwangbo, Cheol; Lee, Jung Joon; Seo, Juhee; Lee, Jeong-Hyung

    2010-01-01

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising candidate for cancer therapeutics due to its ability to induce apoptosis selectively in cancer cells. However, sensitivity of cancer cells for induction of apoptosis by TRAIL varies considerably. Therefore, it is important to develop agents that overcome this resistance. We show, for the first time, that eupatolide, the sesquiterpene lactone isolated from the medicinal plant Inula britannica, sensitizes human breast cancer cells to TRAIL-induced apoptosis. Treatment with TRAIL in combination with subtoxic concentrations of eupatolide enhanced the TRAIL-induced cytotoxicity in MCF-7, MDA-MB-231 and MDA-MB-453 breast cancer cells, whereas each reagent alone slightly induced cell death. The combination induced sub-G1 phase DNA content and annexin V-staining in MCF-7 cells, which are major features of apoptosis. Apoptotic characteristics induced by the combined treatment were significantly inhibited by a pan-caspase inhibitor. The sensitization to TRAIL-induced apoptosis was accompanied by the activation of caspase-8 and was concomitant with Bid and poly(ADP-ribose) polymerase (PARP) cleavage. Treatment of eupatolide alone significantly down-regulated the expression of cellular FLICE inhibitory protein (c-FLIP) in MCF-7 cells. Furthermore, enforced expression of c-FLIP significantly attenuated the apoptosis induced by this combination in MCF-7 cells, suggesting a key role for c-FLIP down-regulation in these events. We also observed that euaptolide inhibited AKT phosphorylation in a dose- and time-dependent manner. Moreover, inhibition of Akt by LY294002, a specific PI3K inhibitor, down-regulated c-FLIP expression in MCF-7 cells. Taken together, these results indicate that eupatolide could augment TRAIL-induced apoptosis in human breast cancer cells by down-regulating c-FLIP expression through the inhibition of AKT phosphorylation and be a valuable compound to overcome TRAIL resistance in

  5. 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...

  6. 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...

  7. 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...

  8. Pathology-oriented treatment strategy of malignant ovarian tumor in pregnant women: analysis of 41 cases in Japan.

    Science.gov (United States)

    Morikawa, Asuka; Ueda, Kazu; Takahashi, Kazuaki; Fukunaga, Masaharu; Iwashita, Mitsutoshi; Kobayashi, Yoichi; Takechi, Kimihiro; Umezawa, Satoshi; Terauchi, Fumitoshi; Kiguchi, Kazushige; Aoki, Daisuke; Nomura, Hiroyuki; Yoshikawa, Hiroyuki; Satoh, Toyomi; Jobo, Toshiko; Fujiwara, Hiroyuki; Takei, Yuji; Kamoi, Seiryu; Terao, Yasuhisa; Isonishi, Seiji

    2014-12-01

    The aim of this study was to investigate the impact of the histological findings on the treatment of malignant ovarian tumors in pregnant women. This is a retrospective study of 41 patients diagnosed and treated for ovarian malignancy during pregnancy between 1985 and 2010. The median age of the study group was 30 years old, ranging from 20 to 41. Thirty-eight (92 %) patients were diagnosed with stage I, and one (2 %) with each of stages II, III, and IV. Twenty-five (61 %) patients had borderline malignancy, 8 (20 %) were diagnosed with epithelial ovarian cancer, 7 (17 %) with germ cell tumor, and one with sex cord stromal tumor. All patients received primary surgery; 7 (17 %) patients had cystectomy, 32 (78 %) had unilateral salpingo-oophorectomy, and 3 (7 %) underwent hysterectomy with bilateral salpingo-oophorectomy. Thirty-one (76 %) patients delivered live newborns; 21 had borderline tumor (84 %), 2 had ovarian cancers (25 %), and 8 had non-epithelial tumor (100 %). Six cases were terminated in order to perform the standard treatment for ovarian malignancy and 2 cases aborted spontaneously. In pregnant women, ovarian cancer is exceptionally less frequent compared with non-pregnant women, i.e. age-matched, statistically-corrected controls based on the Japanese annual report [8/33 (24 %) vs. control (60 %); ovarian cancer/(ovarian cancer + borderline tumor), P = 0.001]. The pregnant women with ovarian cancer chose to prioritize treatment of ovarian cancer at the sacrifice of their babies while those with borderline tumor or non-epithelial tumor were able to successfully deliver live newborns.

  9. 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...

  10. The trail guide system as a backcountry management tool

    Science.gov (United States)

    Herbert E. Echelberger; Raymond E. Leonard; Marysewall Lindsey Hamblin

    1978-01-01

    A trail guide booklet containing a map, directional and distance data, and information about the natural and human history and management problems of a backcountry hiking trail was keyed to small, numbered, wooden markers along the trail. This system was evaluated on an 8-mile loop in the White Mountain National Forest in New Hampshire. The system may be useful for...

  11. 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 ...

  12. Optimized horse trail design for Illinois soil

    Science.gov (United States)

    C.J. Jones; Logan O. Park

    2014-01-01

    One of the fastest growing forms of outdoor recreation is equestrian trail riding. In a study examining long-term trends of use on Forest Service lands, equestrian-based recreation was identified as one of the top five activities experiencing growth. As the numbers of horse riders rise, the economic impact of equestrian recreation can be expected to increase across the...

  13. A cellular automata model for ant trails

    Indian Academy of Sciences (India)

    It is easy to comprehend the population biology of social insect colonies [11] using the basic principles which affect the formation of the ant trails. ..... [19] M G Deborah, Ant encounters interaction networks and colony behavior (Princeton Univer- sity Press, Princeton, New Jersey, 2010). [20] K Nishinari, D Chowdhury and A ...

  14. On the Trail of George Peabody.

    Science.gov (United States)

    Parker, Franklin

    1994-01-01

    One in a collection of articles on George Peabody describes the author's experiences writing and publishing a doctoral dissertation on Peabody's educational philanthropy. The paper lists the sources to which the research trail led and gives an overview of Peabody's importance as a merchant turned international banker and educational…

  15. 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...

  16. 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.

  17. System for accurate ranging of meteor trails

    International Nuclear Information System (INIS)

    Tshebotaryov, R.P.; Sidorin, V.N.

    1970-01-01

    The necessity of precise ranging of meteor trails is emphasised possible methods are considered. A scheme with a non ius circular trace and intensity indication giving an unique for meteor radar accuracy ± 50 m is described in detail. Results are given of experimental and practical work of the system

  18. A cellular automata model for ant trails

    Indian Academy of Sciences (India)

    Abstract. In this study, the unidirectional ant traffic flow with U-turn in an ant trail was inves- tigated 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 ...

  19. Unique resistance of breast carcinoma cell line T47D to TRAIL but not anti-Fas is linked to p43cFLIP(L).

    Science.gov (United States)

    Guseva, Natalya V; Rokhlin, Oskar W; Taghiyev, Agshin F; Cohen, Michael B

    2008-02-01

    The majority of breast cancer cell lines are resistant to tumor necrosis factor -related apoptosis inducing ligand (TRAIL) induced apoptosis. TRAIL and Fas receptor death-inducing signaling complex (DISCs) formation are similar and involve ligand-dependent recruitment of FADD and caspase-8. We have found that the breast carcinoma cell line T47D is an unusual example of selective sensitivity to anti-Fas mAb treatment but resistant to TRAIL. Therefore, a detailed comparison of these two signaling pathways in one cell line should provide insight into the mechanism of TRAIL resistance. We observed that only anti-Fas mAb induces caspase activation and cell death in T47D. Further, FADD and caspase-8 interact with both TRAIL-R1 and TRAIL-R2, and that the amount of caspase-8 recruited by Fas-, TRAIL-R1 and TRAIL-R2 are the same. cFLIP(S) and cFLIP(R )isoforms block death receptor-induced apoptosis by inhibiting caspase-8 activation at the DISC; the role of cFLIP(L )at the DISC is still controversial. It has been suggested that the presence of the cleaved form of FLIP(L)-p43 at the DISC prevents caspase-8 cleavage. We found that both TRAIL and anti-Fas mAb-induced DISCs contain the cleaved form of p43 cFLIP(L) and its amount at the Fas DISC was higher compared to the TRAIL DISC. We also found that inhibition of cFLIP(L) expression in T47D cells decreased Fas-mediated caspase-8 activation and activation of effector caspases. We propose that in T47D p43 cFLIP(L) in the Fas-DISC may promote caspase-8 activation. The mechanism by which different amounts of p43cFLIP(L) regulates caspase-8 activation remains to be investigated.

  20. Pharmacological activation of tumor suppressor, wild-type p53 as a promising strategy to fight cancer

    Directory of Open Access Journals (Sweden)

    Alicja Sznarkowska

    2010-08-01

    Full Text Available A powerful tumor suppressor – p53 protein is a transcription factor which plays a critical role in eliciting cellular responses to a variety of stress signals, including DNA damage, hypoxia and aberrant proliferative signals, such as oncogene activation. Since its discovery thirty one years ago, p53 has been connected to tumorigenesis as it accumulates in the transformed tumor cells. Cellular stress induces stabilization of p53 and promotes, depending on the stress level, cell cycle arrest or apoptosis in the irreversibly damaged cells. The p53 protein is found inactive in more than 50�0of human tumors either by enhanced proteasomal degradation or due to the inactivating point mutations in its gene. Numerous data indicate that low molecular weight compounds, identified by molecular modeling or in the functional, cell-based assays, efficiently activate non-mutated p53 in cancer cells which in consequence leads to their elimination due to p53-dependent apoptosis. In this work we describe the structure and cellular function of p53 as well as the latest discoveries on the compounds with high anti-tumor activities aiming at reactivation of the tumor suppressor function of p53.

  1. Tumor-specific expression of shVEGF and suicide gene as a novel strategy for esophageal cancer therapy.

    Science.gov (United States)

    Liu, Ting; Wu, Hai-Jun; Liang, Yu; Liang, Xu-Jun; Huang, Hui-Chao; Zhao, Yan-Zhong; Liao, Qing-Chuan; Chen, Ya-Qi; Leng, Ai-Min; Yuan, Wei-Jian; Zhang, Gui-Ying; Peng, Jie; Chen, Yong-Heng

    2016-06-21

    To develop a potent and safe gene therapy for esophageal cancer. An expression vector carrying fusion suicide gene (yCDglyTK) and shRNA against vascular endothelial growth factor (VEGF) was constructed and delivered into EC9706 esophageal cancer cells by calcium phosphate nanoparticles (CPNP). To achieve tumor selectivity, expression of the fusion suicide gene was driven by a tumor-specific human telomerase reverse transcriptase (hTERT) promoter. The biologic properties and therapeutic efficiency of the vector, in the presence of prodrug 5-fluorocytosine (5-FC), were evaluated in vitro and in vivo. Both in vitro and in vivo testing showed that the expression vector was efficiently introduced by CPNP into tumor cells, leading to cellular expression of yCDglyTK and decreased VEGF level. With exposure to 5-FC, it exhibited strong anti-tumor effects against esophageal cancer. Combination of VEGF shRNA with the fusion suicide gene demonstrated strong anti-tumor activity. The shVEGF-hTERT-yCDglyTK/5-FC system provided a novel approach for esophageal cancer-targeted gene therapy.

  2. SAHM:VisTrails (Software for Assisted Habitat Modeling for VisTrails): training course

    Science.gov (United States)

    Holcombe, Tracy

    2014-01-01

    VisTrails is an open-source management and scientific workflow system designed to integrate the best of both scientific workflow and scientific visualization systems. Developers can extend the functionality of the VisTrails system by creating custom modules for bundled VisTrails packages. The Invasive Species Science Branch of the U.S. Geological Survey (USGS) Fort Collins Science Center (FORT) and the U.S. Department of the Interior’s North Central Climate Science Center have teamed up to develop and implement such a module—the Software for Assisted Habitat Modeling (SAHM). SAHM expedites habitat modeling and helps maintain a record of the various input data, the steps before and after processing, and the modeling options incorporated in the construction of an ecological response model. There are four main advantages to using the SAHM:VisTrails combined package for species distribution modeling: (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; and (4) extensibility to incorporate future and additional modeling routines and tools. In order to meet increased interest in the SAHM:VisTrails package, the FORT offers a training course twice a year. The course includes a combination of lecture, hands-on work, and discussion. Please join us and other ecological modelers to learn the capabilities of the SAHM:VisTrails package.

  3. Recreation trails in Maine and New Hampshire: A comparison of notorized, non-motorized, and non-mechanized trails

    Science.gov (United States)

    Ethel Wilkerson; Andrew. Whitman

    2010-01-01

    We sampled 112 trail segments in Maine and New Hampshire to assess the impact of motorized and non-motorized recreation on trail conditions and stream sedimentation. On each segment, we assessed physical trail conditions (width, cross-sectional area, occurrence of excessively muddy and rutted/eroded sections), presence of trash, and sedimentation at stream crossings....

  4. 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.

  5. Hiking shared-use single-track trails: a look at hikers and hunters along the Falls Lake Trail

    Science.gov (United States)

    Christopher M. Snow; Roger L. Moore

    2007-01-01

    The Falls Lake Trail, a 26.8-mile, single-track pedestrian trail located near the Research Triangle Region of North Carolina, traverses lands managed by the United States Army Corps of Engineers; North Carolina Division of Parks and Recreation; North Carolina Division of Wildlife Resources; and Wake County Parks, Recreation and Open Space. The non-profit trail advocacy...

  6. Identification of new tumor associated antigens and their usage for new therapeutic strategies based on the combination of chemotherapy and immunotherapy for colorectal cancer patients

    International Nuclear Information System (INIS)

    Proietti, E.; Maccalli, C.; Rosenberg, S.A.; Robbins, P.F.

    2009-01-01

    The main general objective of this project was to characterize a new colorectal carcinoma (CRC) tumor-associated antigen (TAA) and validate a new therapeutic strategy combining chemotherapy and tumor vaccination for the treatment of cancer patients. To this purpose a strategic interaction between Drs. Proietti/Maccali at the ISS and the group of Drs. Rosenberg/Robbins at the NIH was established. A stage of Dr. Maccalli at the NIH allowed to carry out the first steps for the identification and the initial characterization of the CRC TAA named COA-1. A laboratory meeting with Dr. Robbins has been planned on May 24-25 2006 at the ISS, during the International Meeting on Immunotherapy of Cancer: Challenges and Needs, for discussing results and perspectives of this research project

  7. The tourism carrying capacity of underwater trails in Isabel Island National Park, Mexico.

    Science.gov (United States)

    Ríos-Jara, Eduardo; Galván-Villa, Cristian Moisés; Rodríguez-Zaragoza, Fabián Alejandro; López-Uriarte, Ernesto; Muñoz-Fernández, Vicente Teófilo

    2013-08-01

    The popularity of ecotourism in the marine protected areas of Mexico has increased over the last 10 years; in particular there is a large development of a SCUBA diving industry in the Mexican Pacific including Isabel Island. Given the risks associated with human activity in the marine environments around this island, we propose two ecotourism management strategies: (1) the creation and use of underwater trails, and (2) the estimation of the specific tourism carrying capacity (TCC) for each trail. Six underwater trails were selected in sites that presented elements of biological, geological, and scenic interest, using information obtained during field observations. The methodology used to estimate the TCC was based upon the physical and biological conditions of each site, the infrastructure and equipment available, and the characteristics of the service providers and the administrators of the park. Correction factors of the TCC included elements of the quality of the visit and the threat and vulnerability of the marine environment of each trail (e.g., divers' expertise, size and distance between groups of divers, accessibility, wind, coral coverage). The TCC values ranged between 1,252 and 1,642 dives/year/trail, with a total of 8,597 dives/year for all six trails. Although these numbers are higher than the actual number of recreational visitors to the island (~1,000 dives per year), there is a need for adequate preventive management if the diving sites are to maintain their esthetic appeal and biological characteristics. Such management might be initially directed toward using only the sites and the TCC proposed here.

  8. The Tourism Carrying Capacity of Underwater Trails in Isabel Island National Park, Mexico

    Science.gov (United States)

    Ríos-Jara, Eduardo; Galván-Villa, Cristian Moisés; Rodríguez-Zaragoza, Fabián Alejandro; López-Uriarte, Ernesto; Muñoz-Fernández, Vicente Teófilo

    2013-08-01

    The popularity of ecotourism in the marine protected areas of Mexico has increased over the last 10 years; in particular there is a large development of a SCUBA diving industry in the Mexican Pacific including Isabel Island. Given the risks associated with human activity in the marine environments around this island, we propose two ecotourism management strategies: (1) the creation and use of underwater trails, and (2) the estimation of the specific tourism carrying capacity (TCC) for each trail. Six underwater trails were selected in sites that presented elements of biological, geological, and scenic interest, using information obtained during field observations. The methodology used to estimate the TCC was based upon the physical and biological conditions of each site, the infrastructure and equipment available, and the characteristics of the service providers and the administrators of the park. Correction factors of the TCC included elements of the quality of the visit and the threat and vulnerability of the marine environment of each trail (e.g., divers' expertise, size and distance between groups of divers, accessibility, wind, coral coverage). The TCC values ranged between 1,252 and 1,642 dives/year/trail, with a total of 8,597 dives/year for all six trails. Although these numbers are higher than the actual number of recreational visitors to the island (~1,000 dives per year), there is a need for adequate preventive management if the diving sites are to maintain their esthetic appeal and biological characteristics. Such management might be initially directed toward using only the sites and the TCC proposed here.

  9. 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.

  10. Novel Water-Borne Polyurethane Nanomicelles for Cancer Chemotherapy: Higher Efficiency of Folate Receptors Than TRAIL Receptors in a Cancerous Balb/C Mouse Model.

    Science.gov (United States)

    Ajorlou, Elham; Khosroushahi, Ahmad Yari; Yeganeh, Hamid

    2016-06-01

    Since the introduction of nanocarriers, the delivery of chemotherapeutic agents for treatment of patients with cancer has been possible with better effectiveness. The latest findings are also support that further enhancement in therapeutic effectiveness of these nanocarriers can be attained, if surface decoration with proper targeting agents is considered. This study aimed at treating a variety of 4T1 murine breast cancer cell line, mainly demonstrating high folate and TRAIL receptor expression of cancerous cells. The therapeutic efficacy of paclitaxel loaded Cremophore EL (Taxol®), paclitaxel loaded waterborne polyurethane nanomicelles (PTX-PU) and paclitaxel loaded waterborne polyurethane nanomicelles conjugated with folate (PTX-PU-FA) and TRAIL (PTX-PU-TRAIL) on treating 4T1 cell was also compared. The findings that worth noting are: PTX-PU outperformed Taxol® in a Balb/C mouse model, furthermore, tumor growth was adequately curbed by folate and TRAIL-decorated nanomicelles rather than the unconjugated formulation. Tumors of mice treated with PTX-PU-FA and PTX-PU-TRAIL shrank substantially compared to those treated with Taxol®, PTX-PU and PTX-PU-TRAIL (average 573 mm(3) versus 2640, 846, 717 mm(3) respectively), 45 days subsequent to tumor inoculation. The microscopic study of hematoxylin-eosin stained tumors tissue and apoptotic cell fraction substantiated that the most successful therapeutic effects have been observed for the mice treated with PTX-PU-FA (about 90% in PTX-PU-FA versus 75%, 60%, 15% in PTX-PU-TRAIL, PTX-PU, and Taxol® group respectively). Using folate-targeted nanocarriers to treat cancers characterized by a high level of folate ligand expression is well substantiated by the findings of this study.

  11. Systemically administered AAV9-sTRAIL combats invasive glioblastoma in a patient-derived orthotopic xenograft model

    Directory of Open Access Journals (Sweden)

    Matheus HW Crommentuijn

    2016-01-01

    Full Text Available Adeno-associated virus (AAV vectors expressing tumoricidal genes injected directly into brain tumors have shown some promise, however, invasive tumor cells are relatively unaffected. Systemic injection of AAV9 vectors provides widespread delivery to the brain and potentially the tumor/microenvironment. Here we assessed AAV9 for potential glioblastoma therapy using two different promoters driving the expression of the secreted anti-cancer agent sTRAIL as a transgene model; the ubiquitously active chicken β-actin (CBA promoter and the neuron-specific enolase (NSE promoter to restrict expression in brain. Intravenous injection of AAV9 vectors encoding a bioluminescent reporter showed similar distribution patterns, although the NSE promoter yielded 100-fold lower expression in the abdomen (liver, with the brain-to-liver expression ratio remaining the same. The main cell types targeted by the CBA promoter were astrocytes, neurons and endothelial cells, while expression by NSE promoter mostly occurred in neurons. Intravenous administration of either AAV9-CBA-sTRAIL or AAV9-NSE-sTRAIL vectors to mice bearing intracranial patient-derived glioblastoma xenografts led to a slower tumor growth and significantly increased survival, with the CBA promoter having higher efficacy. To our knowledge, this is the first report showing the potential of systemic injection of AAV9 vector encoding a therapeutic gene for the treatment of brain tumors.

  12. TNF-related apoptosis-inducing ligand (TRAIL) for bone sarcoma treatment: Pre-clinical and clinical data.

    Science.gov (United States)

    Gamie, Zakareya; Kapriniotis, Konstantinos; Papanikolaou, Dimitra; Haagensen, Emma; Da Conceicao Ribeiro, Ricardo; Dalgarno, Kenneth; Krippner-Heidenreich, Anja; Gerrand, Craig; Tsiridis, Eleftherios; Rankin, Kenneth Samora

    2017-11-28

    Bone sarcomas are rare, highly malignant mesenchymal tumours that affect teenagers and young adults, as well as older patients. Despite intensive, multimodal therapy, patients with bone sarcomas have poor 5-year survival, close to 50%, with lack of improvement over recent decades. TNF-related apoptosis-inducing ligand (TRAIL), a member of the tumour necrosis factor (TNF) ligand superfamily (TNFLSF), has been found to induce apoptosis in cancer cells while sparing nontransformed cells, and may therefore offer a promising new approach to treatment. We cover the existing preclinical and clinical evidence about the use of TRAIL and other death receptor agonists in bone sarcoma treatment. In vitro studies indicate that TRAIL and other death receptor agonists are generally potent against bone sarcoma cell lines. Ewing's sarcoma cell lines present the highest sensitivity, whereas osteosarcoma and chondrosarcoma cell lines are considered less sensitive. In vivo studies also demonstrate satisfactory results, especially in Ewing's sarcoma xenograft models. However, the few clinical trials in the literature show only low or moderate efficacy of TRAIL in treating bone sarcoma. Potential strategies to overcome the in vivo resistance reported include co-administration with other drugs and the potential to deliver TRAIL on the surface of primed mesenchymal or immune cells and the use of targeted single chain antibodies such as scFv-scTRAIL. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Novel anti-cancer strategy in bone tumors by targeting molecular and cellular modulators of bone resorption.

    Science.gov (United States)

    Brounais, Bénédicte; Ruiz, Carmen; Rousseau, Julie; Lamoureux, François; Blanchard, Frédéric; Heymann, Dominique; Redini, Françoise

    2008-11-01

    Tumor cells alter the balanced process of bone formation and bone resorption mediated respectively by osteoblasts and osteoclasts, leading to the disruption of the normal equilibrium and resulting in a spectrum of osteolytic to osteoblastic lesions. This review will summarize research on molecules that play direct and essential roles in the differentiation and activity of osteoclasts, and the role of these molecules in bone destruction caused by cancer. Results from experimental models suggest that the Receptor Activator of NF-kB Ligand (RANKL), a member of the TNF superfamily is a common effector of bony lesions in osteolysis caused by primary and secondary bone tumors. Therefore, osteoclast represents an attractive target across a broad range of tumors that develop in bone. Elucidation of the mechanisms of RANKL interactions with its activator (RANK) and decoy (osteoprotegerin: OPG) receptors has enable the development of pharmacological inhibitors of RANKL (and of its signalling pathway) which have been recently patented, with potential for the treatment of cancer-induced bone disease. Blocking bone resorption by specific other drugs such as bisphosphonates, inhibitors of cathepsin K (the main enzyme involved in bone resorption mechanisms) or signalling pathways regulating osteoclast differentiation and activation is also a promising target for the treatment of osteolysis associated to bone tumors.

  14. Sensitization of glioblastoma tumor micro-environment to chemo- and immunotherapy by Galectin-1 intranasal knock-down strategy.

    Science.gov (United States)

    Van Woensel, Matthias; Mathivet, Thomas; Wauthoz, Nathalie; Rosière, Rémi; Garg, Abhishek D; Agostinis, Patrizia; Mathieu, Véronique; Kiss, Robert; Lefranc, Florence; Boon, Louis; Belmans, Jochen; Van Gool, Stefaan W; Gerhardt, Holger; Amighi, Karim; De Vleeschouwer, Steven

    2017-04-27

    In this study, we evaluated the consequences of reducing Galectin-1 (Gal-1) in the tumor micro-environment (TME) of glioblastoma multiforme (GBM), via nose-to-brain transport. Gal-1 is overexpressed in GBM and drives chemo- and immunotherapy resistance. To promote nose-to-brain transport, we designed siRNA targeting Gal-1 (siGal-1) loaded chitosan nanoparticles that silence Gal-1 in the TME. Intranasal siGal-1 delivery induces a remarkable switch in the TME composition, with reduced myeloid suppressor cells and regulatory T cells, and increased CD4+ and CD8+ T cells. Gal-1 knock-down reduces macrophages' polarization switch from M1 (pro-inflammatory) to M2 (anti-inflammatory) during GBM progression. These changes are accompanied by normalization of the tumor vasculature and increased survival for tumor bearing mice. The combination of siGal-1 treatment with temozolomide or immunotherapy (dendritic cell vaccination and PD-1 blocking) displays synergistic effects, increasing the survival of tumor bearing mice. Moreover, we could confirm the role of Gal-1 on lymphocytes in GBM patients by matching the Gal-1 expression and their T cell signatures. These findings indicate that intranasal siGal-1 nanoparticle delivery could be a valuable adjuvant treatment to increase the efficiency of immune-checkpoint blockade and chemotherapy.

  15. 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...

  16. Plasma-stimulated medium kills TRAIL-resistant human malignant cells by promoting caspase-independent cell death via membrane potential and calcium dynamics modulation.

    Science.gov (United States)

    Tokunaga, Tomohiko; Ando, Takashi; Suzuki-Karasaki, Miki; Ito, Tomohisa; Onoe-Takahashi, Asuka; Ochiai, Toyoko; Soma, Masayoshi; Suzuki-Karasaki, Yoshihiro

    2018-03-01

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and cold plasma-stimulated medium (PSM) have been shown to exhibit tumor-selective cytotoxicity and have emerged as promising new tools for cancer treatment. However, to date, at least to the best of our knowledge, no data are available as to which substance is more potent in killing cancer cells. Thus, in this study, we systematically compared their abilities to kill human malignant cells from different origins. We found that PSM dose-dependently killed TRAIL-resistant melanoma, osteosarcoma and neuroblastoma cells. Moreover, PSM had little cytotoxicity toward osteoblasts. PSM was more potent than TRAIL in inducing caspase-3/7 activation, mitochondrial network aberration and caspase-independent cell death. We also found that PSM was more potent in inducing plasma membrane depolarization (PMD) and disrupting endoplasmic-mitochondrial Ca2+ homeostasis. Moreover, persistent PMD was caused by different membrane-depolarizing agents; the use of the anti-type II diabetes drug, glibenclamide, alone caused mitochondrial fragmentation and enhanced TRAIL-induced Ca2+ modulation, mitochondrial network abnormalities and caspase-independent cell killing. These results demonstrate that PSM has a therapeutic advantage over TRAIL owing to its greater capacity to evoke caspase-independent cell death via mitochondrial network aberration by disrupting membrane potential and Ca2+ homeostasis. These findings may provide a strong rationale for developing PSM as a novel approach for the treatment of TRAIL-resistant malignant cells.

  17. Feasibility of an Adaptive Strategy in Preoperative Radiochemotherapy for Rectal Cancer With Image-Guided Tomotherapy: Boosting the Dose to the Shrinking Tumor

    International Nuclear Information System (INIS)

    Passoni, Paolo; Fiorino, Claudio; Slim, Najla; Ronzoni, Monica; Ricci, Vincenzo; Di Palo, Saverio; De Nardi, Paola; Orsenigo, Elena; Tamburini, Andrea; De Cobelli, Francesco; Losio, Claudio; Iacovelli, Nicola A.; Broggi, Sara; Staudacher, Carlo; Calandrino, Riccardo; Di Muzio, Nadia

    2013-01-01

    Purpose: To investigate the feasibility of preoperative adaptive radiochemotherapy by delivering a concomitant boost to the residual tumor during the last 6 fractions of treatment. Methods and Materials: Twenty-five patients with T3/T4N0 or N+ rectal cancer were enrolled. Concomitant chemotherapy consisted of oxaliplatin 100 mg/m 2 on days −14, 0, and +14, and 5-fluorouracil 200 mg/m 2 /d from day −14 to the end of radiation therapy (day 0 is the start of radiation therapy). Radiation therapy consisted of 41.4 Gy in 18 fractions (2.3 Gy per fraction) with Tomotherapy to the tumor and regional lymph nodes (planning target volume, PTV) defined on simulation CT and MRI. After 9 fractions simulation CT and MRI were repeated for the planning of the adaptive phase: PTV adapt was generated by adding a 5-mm margin to the residual tumor. In the last 6 fractions a boost of 3.0 Gy per fraction (in total 45.6 Gy in 18 fractions) was delivered to PTV adapt while concomitantly delivering 2.3 Gy per fraction to PTV outside PTV adapt . Results: Three patients experienced grade 3 gastrointestinal toxicity; 2 of 3 showed toxicity before the adaptive phase. Full dose of radiation therapy, oxaliplatin, and 5-fluorouracil was delivered in 96%, 96%, and 88% of patients, respectively. Two patients with clinical complete response (cCR) refused surgery and were still cCR at 17 and 29 months. For the remaining 23 resected patients, 15 of 23 (65%) showed tumor regression grade 3 response, and 7 of 23 (30%) had pathologic complete response; 8 (35%) and 12 (52%) tumor regression grade 3 patients had ≤5% and 10% residual viable cells, respectively. Conclusions: An adaptive boost strategy is feasible, with an acceptable grade 3 gastrointestinal toxicity rate and a very encouraging tumor response rate. The results suggest that there should still be room for further dose escalation of the residual tumor with the aim of increasing pathologic complete response and/or cCR rates

  18. Osteoprotegerin and osteoprotegerin/TRAIL ratio are associated with cardiovascular dysfunction and mortality among patients with renal failure.

    Science.gov (United States)

    Kuźniewski, Marek; Fedak, Danuta; Dumnicka, Paulina; Stępień, Ewa; Kuśnierz-Cabala, Beata; Cwynar, Marcin; Sułowicz, Władysław

    2016-09-01

    The high prevalence of cardiovascular morbidity and mortality among patients with chronic kidney disease (CKD) is observed especially in those undergoing dialysis. Osteoprotegerin (OPG) and its ligands, receptor activator of nuclear factor kappa-B ligand (RANKL) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) have been associated with cardiovascular complications. Our aim was to study their role as cardiovascular risk factors in stage 5 CKD patients. OPG, RANKL and TRAIL concentrations were measured in 69 hemodialyzed CKD patients and 35 healthy volunteers. In CKD patients, cardiovascular dysfunction was assessed with aortic pulse wave velocity (AoPWV), carotid artery intima-media thickness (CCA-IMT), coronary artery calcium score (CACS) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) serum concentrations. Cardiovascular and overall mortality data were collected during a 7-years follow-up. OPG plasma concentrations were higher in CKD patients comparing to controls. Total soluble RANKL was lower and OPG/RANKL ratio higher in patients. Soluble TRAIL concentrations did not differ between the groups and OPG/TRAIL ratio was higher in CKD patients. OPG and OPG/TRAIL positively predicted long-term mortality (all-cause and cardiovascular) in CKD patients. OPG positively correlated with AoPWV, CCA-IMT and NT-proBNP whereas OPG/TRAIL with AoPWV and NT-proBNP. Described relationships were independent of classical and non-classical cardiovascular risk factors, with exception of age. Our study confirmed the role of OPG as a biomarker of cardiovascular dysfunction and a predictor of mortality in stage 5 CKD. OPG/TRAIL ratio can be proposed as a predictor of cardiovascular dysfunction and mortality. Copyright © 2016 Medical University of Bialystok. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  19. General Sensitization of melanoma cells for TRAIL-induced apoptosis by the potassium channel inhibitor TRAM-34 depends on release of SMAC.

    Directory of Open Access Journals (Sweden)

    Sandra-Annika Quast

    Full Text Available The death ligand TRAIL represents a promising therapeutic strategy for metastatic melanoma, however prevalent and inducible resistance limit its applicability. A new approach is presented here for sensitization to TRAIL. It is based on inhibition of the membrane potassium channel KCa3.1 (IK1, which serves fundamental cellular functions related to membrane potential. The selective inhibitor TRAM-34 did not induce apoptosis by itself but synergistically enhanced TRAIL sensitivity and overrode TRAIL resistance in a large panel of melanoma cell lines. Expression of IK1 was also found in mitochondria, and its inhibition resulted in mitochondrial membrane hyperpolarization and an early activation of Bax. The combination of TRAM-34 and TRAIL resulted in massive release of mitochondrial factors, cytochrome c, AIF and SMAC/DIABLO. Bax knockdown and Bcl-2 overexpression abolished apoptosis. Overexpression of XIAP diminished apoptosis by two-fold, and SMAC knockdown almost completely abolished apoptosis. These data uncover the existence of a rheostat in melanoma cells, consisting of inhibitor of apoptosis proteins and SMAC, which regulates TRAIL sensitivity. Thus, a new strategy is described based on mitochondrial membrane channels, which correspond to Bax activation. As both TRAIL and IK1 inhibitors had shown only minor side effects in clinical trials, a clinical application of this combination is conceivable.

  20. Radiation- and Photo-induced Activation of 5-Fluorouracil Prodrugs as a Strategy for the Selective Treatment of Solid Tumors

    Directory of Open Access Journals (Sweden)

    Sei-ichi Nishimoto

    2008-10-01

    Full Text Available 5-Fluorouracil (5-FU is used widely as an anticancer drug to treat solid cancers, such as colon, breast, rectal, and pancreatic cancers, although its clinical application is limited because 5-FU has gastrointestinal and hematological toxicity. Many groups are searching for prodrugs with functions that are tumor selective in their delivery and can be activated to improve the clinical utility of 5-FU as an important cancer chemotherapeutic agent. UV and ionizing radiation can cause chemical reactions in a localized area of the body, and these have been applied in the development of site-specific drug activation and sensitization. In this review, we describe recent progress in the development of novel 5-FU prodrugs that are activated site specifically by UV light and ionizing radiation in the tumor microenvironment. We also discuss the chemical mechanisms underlying this activation.

  1. A Smac-mimetic sensitizes prostate cancer cells to TRAIL-induced apoptosis via modulating both IAPs and NF-kappaB

    International Nuclear Information System (INIS)

    Dai, Yao; Liu, Meilan; Tang, Wenhua; Li, Yongming; Lian, Jiqin; Lawrence, Theodore S; Xu, Liang

    2009-01-01

    Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising agent for human cancer therapy, prostate cancer still remains resistant to TRAIL. Both X-linked inhibitor of apoptosis (XIAP) and nuclear factor-kappaB function as key negative regulators of TRAIL signaling. In this study, we evaluated the effect of SH122, a small molecule mimetic of the second mitochondria-derived activator of caspases (Smac), on TRAIL-induced apoptosis in prostate cancer cells. The potential of Smac-mimetics to bind XIAP or cIAP-1 was examined by pull-down assay. Cytotoxicity of TRAIL and/or Smac-mimetics was determined by a standard cell growth assay. Silencing of XIAP or cIAP-1 was achieved by transient transfection of short hairpin RNA. Apoptosis was detected by Annexin V-PI staining followed by flow cytometry and by Western Blot analysis of caspases, PARP and Bid. NF-kappaB activation was determined by subcellular fractionation, real time RT-PCR and reporter assay. SH122, but not its inactive analog, binds to XIAP and cIAP-1. SH122 significantly sensitized prostate cancer cells to TRAIL-mediated cell death. Moreover, SH122 enhanced TRAIL-induced apoptosis via both the death receptor and the mitochondrial pathway. Knockdown of both XIAP and cIAP-1 sensitized cellular response to TRAIL. XIAP-knockdown attenuated sensitivity of SH122 to TRAIL-induced cytotoxicity, confirming that XIAP is an important target for IAP-inhibitor-mediated TRAIL sensitization. SH122 also suppressed TRAIL-induced NF-kappaB activation by preventing cytosolic IkappaB-alpha degradation and RelA nuclear translocation, as well as by suppressing NF-kappaB target gene expression. These results demonstrate that SH122 sensitizes human prostate cancer cells to TRAIL-induced apoptosis by mimicking Smac and blocking both IAPs and NF-kappaB. Modulating IAPs may represent a promising approach to overcoming TRAIL-resistance in human prostate cancer with constitutively active NF-kappaB signaling

  2. Plasmid pORF-hTRAIL targeting to glioma using transferrin-modified polyamidoamine dendrimer

    Directory of Open Access Journals (Sweden)

    Gao S

    2015-12-01

    Full Text Available Song Gao,1,* Jianfeng Li,2 Chen Jiang,2 Bo Hong,3 Bing Hao4,* 1Department of Clinical Laboratory, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 2Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai, 3Department of Pathology, The Second Affiliated Hospital, 4Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China *These authors contributed equally to this work Abstract: A gene drug delivery system for glioma therapy based on transferrin (Tf-modified polyamidoamine dendrimer (PAMAM was prepared. Gene drug, tumor necrosis factor-related apoptosis-inducing ligand (hTRAIL-encoding plasmid open reading frame (pORF-hTRAIL, Trail, was condensed by Tf-modified PAMAM to form nanoparticles (NPs. PAMAM-PEG-Tf/DNA NPs showed higher cellular uptake, in vitro gene expression, and cytotoxicity than PAMAM-PEG/DNA NPs in C6 cells. The in vivo targeting efficacy of NPs was visualized by ex vivo fluorescence imaging. Tf-modified NPs showed obvious glioma-targeting trend. Plasmid encoding green fluorescence protein (GFP was also condensed by modified or unmodified PAMAM to evaluate the in vivo gene expression level. The PAMAM-PEG-Tf/plasmid encoding enhanced green fluorescence protein (pEGFP NPs exhibited higher GFP expression level than PAMAM-PEG/pEGFP NPs. TUNEL assay revealed that Tf-modified NPs could induce much more tumor apoptosis. The median survival time of PAMAM-PEG-Tf/Trail-treated rats (28.5 days was longer than that of rats treated with PAMAM-PEG/Trail (25.5 days, temozolomide (24.5 days, PAMAM-PEG-Tf/pEGFP (19 days, or saline (17 days. The therapeutic effect was further confirmed by magnetic resonance imaging. This study demonstrated that targeting gene delivery system had potential application for the

  3. TRAIL-Based Anticancer Drug Development

    Science.gov (United States)

    2002-07-01

    145- 8. Sarr MG, Carpenter HA, Prabhakar LP, Orchard TF, Hughes SJ, van Heerden JA, DiMagno EP Clinical and pathologic correlation of 84 mucinous...several clonal cell lines that express different amount of XIAP. These cell lines will be exposed to TRAIL recombinant protein and analyzed for...hypoxia and gene expression-implications for malignant progression and therapy. Acta Oncol, 37: 561-51 A, 1998. 66. Semenza, G. L. Hypoxia, clonal

  4. 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)

  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. Lipopolysaccharide-induced expression of TRAIL promotes dendritic cell differentiation.

    Science.gov (United States)

    Cho, Young S; Challa, Sreerupa; Clancy, Lauren; Chan, Francis K-M

    2010-08-01

    Tumour necrosis factor-related apoptosis inducing ligand (TRAIL) is a death-inducing cytokine whose physiological function is not well understood. Here, we show that TRAIL has a role in programming human dendritic cell (DC) differentiation. TRAIL expression was strongly induced in DCs upon stimulation with lipopolysaccharide (LPS) or Polyinosine-polycytidylic acid (poly(I:C)) stimulation. Blockade of TRAIL with neutralizing antibody partially inhibited LPS-induced up-regulation of co-stimulatory molecules and the expression of inflammatory cytokines including interleukin-12 (IL-12) p70. In addition, neutralization of TRAIL in LPS-treated DCs inhibited the DC-driven differentiation of T cells into interferon-gamma (IFN-gamma) -producing effectors. The effects of TRAIL neutralization in poly(I:C)-treated DCs were similar, except that IL-12 production and the differentiation of effector T cells into IFN-gamma producers were not inhibited. Strikingly, TRAIL stimulation alone was sufficient to induce morphological changes resembling DC maturation, up-regulation of co-stimulatory molecules, and enhancement of DC-driven allogeneic T-cell proliferation. However, TRAIL alone did not induce inflammatory cytokine production. We further show that the effects of TRAIL on DC maturation were not the result of the induction of apoptosis, but may involve p38 activation. Hence, our data demonstrate that TRAIL co-operates with other cytokines to facilitate DC functional maturation in response to Toll-like receptor activation.

  7. The Effect of Nozzle Trailing Edge Thickness on Jet Noise

    Science.gov (United States)

    Henderson, Brenda; Kinzie, Kevin; Haskin, Henry

    2004-01-01

    The effect of nozzle trailing edge thickness on broadband acoustic radiation and the production of tones is investigated for coannular nozzles. Experiments were performed for a core nozzle trailing edge thickness between 0.38 mm and 3.17 mm. The on-set of discrete tones was found to be predominantly affected by the velocity ratio, the ratio of the fan velocity to the core velocity, although some dependency on trailing edge thickness was also noted. For a core nozzle trailing edge thickness greater than or equal to 0.89 mm, tones were produced for velocity ratios between 0.91 and 1.61. For a constant nozzle trailing edge thickness, the frequency varied almost linearly with the core velocity. The Strouhal number based on the core velocity changed with nozzle trailing edge thickness and varied between 0.16 and 0.2 for the core nozzles used in the experiments. Increases in broadband noise with increasing trailing edge thickness were observed for tone producing and non-tone producing conditions. A variable thickness trailing edge (crenellated) nozzle resulted in no tonal production and a reduction of the broadband trailing edge noise relative to that of the corresponding constant thickness trailing edge.

  8. Trail-Based Search for Efficient Event Report to Mobile Actors in Wireless Sensor and Actor Networks.

    Science.gov (United States)

    Xu, Zhezhuang; Liu, Guanglun; Yan, Haotian; Cheng, Bin; Lin, Feilong

    2017-10-27

    In wireless sensor and actor networks, when an event is detected, the sensor node needs to transmit an event report to inform the actor. Since the actor moves in the network to execute missions, its location is always unavailable to the sensor nodes. A popular solution is the search strategy that can forward the data to a node without its location information. However, most existing works have not considered the mobility of the node, and thus generate significant energy consumption or transmission delay. In this paper, we propose the trail-based search (TS) strategy that takes advantage of actor's mobility to improve the search efficiency. The main idea of TS is that, when the actor moves in the network, it can leave its trail composed of continuous footprints. The search packet with the event report is transmitted in the network to search the actor or its footprints. Once an effective footprint is discovered, the packet will be forwarded along the trail until it is received by the actor. Moreover, we derive the condition to guarantee the trail connectivity, and propose the redundancy reduction scheme based on TS (TS-R) to reduce nontrivial transmission redundancy that is generated by the trail. The theoretical and numerical analysis is provided to prove the efficiency of TS. Compared with the well-known expanding ring search (ERS), TS significantly reduces the energy consumption and search delay.

  9. Peran Layanan Jasa Search Engine Optimization untuk Meningkatkan Daya Saing pada Bisnis Startup (Studi pada Kaldera Trail and Jeep Adventure Malang)

    OpenAIRE

    Wira Bharata

    2016-01-01

    This study aimed to investigate the role of SEO as a strategic competitive advantage. This study uses a qualitative approach with case studies are used as a research design. Researchers in the interviews to the owner Caldera Trail & Jeep Adventure. The results of this study indicate that the role of SEO to optimize the website proved successful in the company’s competitive advantage strategy Caldera Trail & Jeep Adventure. The results showed online marketing is done through Facebook, ...

  10. 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....

  11. Mountain bike trail compaction relation to selected physical parameters

    Science.gov (United States)

    Jeff Hale; Rodney R. Zwick

    2002-01-01

    The purpose of this research is to explore the rates of compaction and their relation to trail contextual aspects of: soil type, slope and crown cover on a newly established mountain bike trail in the northern reach of Vermont. A random sample of 52 sites was selected for monitoring on the 1.09-mile trail. Three penetrometer readings were taken at each of the sample...

  12. Left Lobe Mobilization Strategy of Right-Sided Major Hepatectomy for Treatment of a Tumor Causing Severe Inferior Vena Cava Compression: A Novel Strategy Using the Modified Liver-Hanging Maneuver.

    Science.gov (United States)

    Araki, Kenichiro; Kubo, Norio; Ishii, Norihiro; Tsukagoshi, Mariko; Igarashi, Takamichi; Watanabe, Akira; Kuwano, Hiroyuki; Shirabe, Ken

    2018-02-14

    Massive bleeding during major hepatectomy is associated with greater mortality and morbidity.1 Our previous study shows that inferior vena cava (IVC) compression by tumor and an anterior approach without the liver-hanging maneuver (LHM) are risk factors for massive bleeding.2 The LHM is useful for controlling bleeding in deeper parenchymal transection planes.3 However, severe compression of the IVC by tumor makes it difficult to insert a hanging tape.4 The study shows a novel modified LHM strategy for severe IVC compression to minimize intraoperative bleeding. The procedure was disassembled into six steps: (1) the glissonian bifurcation is encircled using an extrahepatic approach (2) the hepatic ligaments are dissected, and the root of each hepatic vein trunk is exposed (3) the left lobe is fully mobilized, and the short hepatic veins are carefully dissected with a systematic procedure established from hemi-left lobe procurement in living donor liver transplantation5 (4) the tape is inserted from the space between the right and middle hepatic vein trunks into the glissonian bifurcation along the anterior surface of the IVC (5) liver parenchymal transection is performed with upward pulling of the tape (6) the right hepatic vein is dissected, and the right lobe is dissected from the diaphragm and the right hepatic ligaments. Right hepatectomy with this procedure was performed for two patients with IVC compressed by hepatocellular carcinoma. The operative times were respectively 483 and 396 min. The respective estimated blood losses were 1195 and 485 ml, without transfusion. Both patients had acceptable outcomes without complications. The novel modified LHM strategy ensured minimal bleeding in the resection of a huge liver tumor causing severe IVC compression.

  13. Bone tumor

    Science.gov (United States)

    Tumor - bone; Bone cancer; Primary bone tumor; Secondary bone tumor; Bone tumor - benign ... The cause of bone tumors is unknown. They often occur in areas of the bone that grow rapidly. Possible causes include: Genetic defects ...

  14. 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.

  15. Sustainable Trail Management in Costa Rica National Parks: The use of photography for trail surfacing decisions under tropical rainforest conditions

    Directory of Open Access Journals (Sweden)

    Aguirre G., Juan A.

    2009-01-01

    Full Text Available Volcan Poas National Park (VPNP is Costa Rica’s most visited park. Its facilities, accessibility, and proximity to the major cities of the country make VPNP a preferred destination for local and foreigner visitors. Aside from its active volcanic cone, the park trails are a major asset. The extremely wet conditions prevailing throughout the year and heavy visitation made it essential to determine visitor’s trail surface preferences to guarantee park trail sustainability. The purpose of this study was to explore the feasibility of using photos in combination with a regular survey to identify the socio-demographic characteristics and other trail related variables that affect trail surface selection to guide management decisions and resource allocation related to trail design, construction, and maintenance. The study was conducted during May, June and July of 2005.

  16. α-Hispanolol sensitizes hepatocellular carcinoma cells to TRAIL-induced apoptosis via death receptor up-regulation

    International Nuclear Information System (INIS)

    Mota, Alba; Jiménez-Garcia, Lidia; Herránz, Sandra; Heras, Beatriz de las; Hortelano, Sonsoles

    2015-01-01

    Hispanolone derivatives have been previously described as anti-inflammatory and antitumoral agents. However, their effects on overcoming Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance remain to be elucidated. In this study, we analyzed the cytotoxic effects of the synthetic hispanolone derivative α-hispanolol (α-H) in several tumor cell lines, and we evaluated the induction of apoptosis, as well as the TRAIL-sensitizing potential of α-H in the hepatocellular carcinoma cell line HepG2. Our data show that α-H decreased cell viability in a dose-dependent manner in HeLa, MDA-MB231, U87 and HepG2 cell lines, with a more prominent effect in HepG2 cells. Interestingly, α-H had no effect on non-tumoral cells. α-H induced activation of caspase-8 and caspase-9 and also increased levels of the proapoptotic protein Bax, decreasing antiapoptotic proteins (Bcl-2, X-IAP and IAP-1) in HepG2 cells. Specific inhibition of caspase-8 abrogated the cascade of caspase activation, suggesting that the extrinsic pathway has a critical role in the apoptotic events induced by α-H. Furthermore, combined treatment of α-H with TRAIL enhanced apoptosis in HepG2 cells, activating caspase-8 and caspase-9. This correlated with up-regulation of both the TRAIL death receptor DR4 and DR5. DR4 or DR5 neutralizing antibodies abolished the effect of α-H on TRAIL-induced apoptosis, suggesting that sensitization was mediated through the death receptor pathway. Our results demonstrate that α-H induced apoptosis in the human hepatocellular carcinoma cell line HepG2 through activation of caspases and induction of the death receptor pathway. In addition, we describe a novel function of α-H as a sensitizer on TRAIL-induced apoptotic cell death in HepG2 cells. - Highlights: • α-Hispanolol induced apoptosis in the human hepatocellular carcinoma cell line HepG2. • α-Hispanolol induced activation of caspases and the death receptor pathway. • α-Hispanolol enhanced

  17. α-Hispanolol sensitizes hepatocellular carcinoma cells to TRAIL-induced apoptosis via death receptor up-regulation

    Energy Technology Data Exchange (ETDEWEB)

    Mota, Alba, E-mail: amota@iib.uam.es [Unidad de Terapias Farmacológicas, Área de Genética Humana, Instituto de Investigación de Enfermedades Raras (IIER), Instituto de Salud Carlos III, Madrid (Spain); Jiménez-Garcia, Lidia, E-mail: ljimenez@isciii.es [Unidad de Terapias Farmacológicas, Área de Genética Humana, Instituto de Investigación de Enfermedades Raras (IIER), Instituto de Salud Carlos III, Madrid (Spain); Herránz, Sandra, E-mail: sherranz@isciii.es [Unidad de Terapias Farmacológicas, Área de Genética Humana, Instituto de Investigación de Enfermedades Raras (IIER), Instituto de Salud Carlos III, Madrid (Spain); Heras, Beatriz de las, E-mail: lasheras@ucm.es [Departamento de Farmacología, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), Madrid (Spain); Hortelano, Sonsoles, E-mail: shortelano@isciii.es [Unidad de Terapias Farmacológicas, Área de Genética Humana, Instituto de Investigación de Enfermedades Raras (IIER), Instituto de Salud Carlos III, Madrid (Spain)

    2015-08-01

    Hispanolone derivatives have been previously described as anti-inflammatory and antitumoral agents. However, their effects on overcoming Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance remain to be elucidated. In this study, we analyzed the cytotoxic effects of the synthetic hispanolone derivative α-hispanolol (α-H) in several tumor cell lines, and we evaluated the induction of apoptosis, as well as the TRAIL-sensitizing potential of α-H in the hepatocellular carcinoma cell line HepG2. Our data show that α-H decreased cell viability in a dose-dependent manner in HeLa, MDA-MB231, U87 and HepG2 cell lines, with a more prominent effect in HepG2 cells. Interestingly, α-H had no effect on non-tumoral cells. α-H induced activation of caspase-8 and caspase-9 and also increased levels of the proapoptotic protein Bax, decreasing antiapoptotic proteins (Bcl-2, X-IAP and IAP-1) in HepG2 cells. Specific inhibition of caspase-8 abrogated the cascade of caspase activation, suggesting that the extrinsic pathway has a critical role in the apoptotic events induced by α-H. Furthermore, combined treatment of α-H with TRAIL enhanced apoptosis in HepG2 cells, activating caspase-8 and caspase-9. This correlated with up-regulation of both the TRAIL death receptor DR4 and DR5. DR4 or DR5 neutralizing antibodies abolished the effect of α-H on TRAIL-induced apoptosis, suggesting that sensitization was mediated through the death receptor pathway. Our results demonstrate that α-H induced apoptosis in the human hepatocellular carcinoma cell line HepG2 through activation of caspases and induction of the death receptor pathway. In addition, we describe a novel function of α-H as a sensitizer on TRAIL-induced apoptotic cell death in HepG2 cells. - Highlights: • α-Hispanolol induced apoptosis in the human hepatocellular carcinoma cell line HepG2. • α-Hispanolol induced activation of caspases and the death receptor pathway. • α-Hispanolol enhanced

  18. 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

  19. 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.

  20. Tumor necrosis factor related apoptosis inducing ligand triggers apoptosis in dividing but not in differentiating human epidermal keratinocytes

    NARCIS (Netherlands)

    Jansen, Bastiaan J. H.; van Ruissen, Fred; Cerneus, Stefanie; Cloin, Wendy; Bergers, Mieke; van Erp, Piet E. J.; Schalkwijk, Joost

    2003-01-01

    Using serial analysis of gene expression we have previously identified the expression of several pro-apoptotic and anti-apoptotic genes in cultured human primary epidermal keratinocytes, including tumor necrosis factor related apoptosis inducing ligand (TRAIL). TRAIL is a potent inducer of apoptosis

  1. Potential of epigenetic therapies in the management of solid tumors

    Directory of Open Access Journals (Sweden)

    Valdespino V

    2015-07-01

    Full Text Available Victor Valdespino,1 Patricia M Valdespino2 1Health Attention Department, Universidad Autónoma Metropolitana, Mexico; 2Bacterial Ecology and Epigenetics Laboratory, Universidad Nacional Autónoma de México, Mexico Abstract: Cancer is a complex disease with both genetic and epigenetic origins. The growing field of epigenetics has contributed to our understanding of oncogenesis and tumor progression, and has allowed the development of novel therapeutic drugs. First-generation epigenetic inhibitor drugs have obtained modest clinical results in two types of hematological malignancy. Second-generation epigenetic inhibitors are in development, and have intrinsically greater selectivity for their molecular targets. Solid tumors are more genetic and epigenetically complex than hematological malignancies, but the transcriptome and epigenome biomarkers have been identified for many of these malignancies. This solid tumor molecular aberration profile may be modified using specific or quasi-specific epidrugs together with conventional and innovative anticancer treatments. In this critical review, we briefly analyze the strategies to select the targeted epigenetic changes, enumerate the second-generation epigenetic inhibitors, and describe the main signs indicating the potential of epigenetic therapies in the management of solid tumors. We also highlight the work of consortia or academic organizations that support the undertaking of human epigenetic therapeutic projects as well as some examples of transcriptome/epigenome profile determination in clinical assessment of cancer patients treated with epidrugs. There is a good chance that epigenetic therapies will be able to be used in patients with solid tumors in the future. This may happen soon through collaboration of diverse scientific groups, making the selection of targeted epigenetic aberration(s more rapid, the design and probe of drug candidates, accelerating in vitro and in vivo assays, and

  2. A robust ex vivo model for evaluation of induction of apoptosis by rhTRAIL in combination with proteasome inhibitor MG132 in human premalignant cervical explants

    NARCIS (Netherlands)

    Hougardy, Brigitte M. T.; Reesink-Peters, Nathalie; van den Heuvel, Fiona A. J.; ten Hoor, Klaske A.; Hollema, Harry; de Vries, Elisabeth G. E.; de Jong, Steven; van der Zee, Ate G. J.

    2008-01-01

    Development of medical therapies for high-grade cervical intraepithelial neoplasia (CIN II/III) is hampered by the lack of CIN II/III cell lines. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis upon binding to its receptors DR4 or DR5. Proteasome inhibition by MG132

  3. The Proteasome Inhibitor Bortezomib Sensitizes AML with Myelomonocytic Differentiation to TRAIL Mediated Apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Dijk, Marianne van; Murphy, Eoin [Apoptosis Research Center, National University of Ireland, University Road, Galway (Ireland); School of Natural Sciences, National University of Ireland, University Road, Galway (Ireland); Morrell, Ruth [Apoptosis Research Center, National University of Ireland, University Road, Galway (Ireland); School of Natural Sciences, National University of Ireland, University Road, Galway (Ireland); School of Medicine, National University of Ireland, University Road, Galway (Ireland); Knapper, Steven [Department of Haematology, School of Medicine, Cardiff University, Heath Park, CF14 4XN Cardiff (United Kingdom); O' Dwyer, Michael [Apoptosis Research Center, National University of Ireland, University Road, Galway (Ireland); School of Medicine, National University of Ireland, University Road, Galway (Ireland); Samali, Afshin; Szegezdi, Eva, E-mail: eva.szegezdi@nuigalway.ie [Apoptosis Research Center, National University of Ireland, University Road, Galway (Ireland); School of Natural Sciences, National University of Ireland, University Road, Galway (Ireland)

    2011-03-15

    Acute myeloid leukemia (AML) is an aggressive stem cell malignancy that is difficult to treat. There are limitations to the current treatment regimes especially after disease relapse, and therefore new therapeutic agents are urgently required which can overcome drug resistance whilst avoiding unnecessary toxicity. Among newer targeted agents, both tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and proteasome inhibitors show particular promise. In this report we show that a combination of the proteasome inhibitor bortezomib and TRAIL is effective against AML cell lines, in particular, AML cell lines displaying myelomonocytic/monocytic phenotype (M4/M5 AML based on FAB classification), which account for 20-30% of AML cases. We show that the underlying mechanism of sensitization is at least in part due to bortezomib mediated downregulation of c-FLIP and XIAP, which is likely to be regulated by NF-κB. Blockage of NF-κB activation with BMS-345541 equally sensitized myelomonocytic AML cell lines and primary AML blasts to TRAIL.

  4. RegulatorTrail: a web service for the identification of key transcriptional regulators.

    Science.gov (United States)

    Kehl, Tim; Schneider, Lara; Schmidt, Florian; Stöckel, Daniel; Gerstner, Nico; Backes, Christina; Meese, Eckart; Keller, Andreas; Schulz, Marcel H; Lenhof, Hans-Peter

    2017-07-03

    Transcriptional regulators such as transcription factors and chromatin modifiers play a central role in most biological processes. Alterations in their activities have been observed in many diseases, e.g. cancer. Hence, it is of utmost importance to evaluate and assess the effects of transcriptional regulators on natural and pathogenic processes. Here, we present RegulatorTrail, a web service that provides rich functionality for the identification and prioritization of key transcriptional regulators that have a strong impact on, e.g. pathological processes. RegulatorTrail offers eight methods that use regulator binding information in combination with transcriptomic or epigenomic data to infer the most influential regulators. Our web service not only provides an intuitive web interface, but also a well-documented RESTful API that allows for a straightforward integration into third-party workflows. The presented case studies highlight the capabilities of our web service and demonstrate its potential for the identification of influential regulators: we successfully identified regulators that might explain the increased malignancy in metastatic melanoma compared to primary tumors, as well as important regulators in macrophages. RegulatorTrail is freely accessible at: https://regulatortrail.bioinf.uni-sb.de/. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

  5. Chalcones and Dihydrochalcones Augment TRAIL-Mediated Apoptosis in Prostate Cancer Cells

    Directory of Open Access Journals (Sweden)

    Wojciech Krol

    2010-08-01

    Full Text Available Chalcones and dihydrochalcones exhibit chemopreventive and antitumor activity. TRAIL (tumor necrosis factor-related apoptosis-inducing ligand is a natural endogenous anticancer agent. We examined the cytotoxic and apoptotic effect of chalcones and dihydrochalcones on TRAIL-mediated apoptosis in LNCaP prostate cancer cells. The cytotoxicity was evaluated by the MTT and LDH assays. The apoptosis was detected using annexin V-FITC by flow cytometry and fluorescence microscopy. The ΔΨm was evaluated using DePsipher staining by fluorescence microscopy. Our study showed that two tested chalcones (chalcone and 2’,6’dihydroxy-4’-methoxychalcone and three dihydrochalcones (2’,6’-dihydroxy-4’4-dimethoxydihydrochalcone, 2’,6’-dihydroxy-4’-methoxydihydro- chalcone,  and 2’,4’,6’-trihydroxydihydrochalcone, called phloretin markedly augmented TRAIL-induced apoptosis and cytotoxicity in LNCaP cells and confirmed the significant role of chalcones in chemoprevention of prostate cancer.

  6. The Proteasome Inhibitor Bortezomib Sensitizes AML with Myelomonocytic Differentiation to TRAIL Mediated Apoptosis

    Directory of Open Access Journals (Sweden)

    Eva Szegezdi

    2011-03-01

    Full Text Available Acute myeloid leukemia (AML is an aggressive stem cell malignancy that is difficult to treat. There are limitations to the current treatment regimes especially after disease relapse, and therefore new therapeutic agents are urgently required which can overcome drug resistance whilst avoiding unnecessary toxicity. Among newer targeted agents, both tumor necrosis factor (TNF-related apoptosis-inducing ligand (TRAIL and proteasome inhibitors show particular promise. In this report we show that a combination of the proteasome inhibitor bortezomib and TRAIL is effective against AML cell lines, in particular, AML cell lines displaying myelomonocytic/monocytic phenotype (M4/M5 AML based on FAB classification, which account for 20-30% of AML cases. We show that the underlying mechanism of sensitization is at least in part due to bortezomib mediated downregulation of c-FLIP and XIAP, which is likely to be regulated by NF-κB. Blockage of NF-κB activation with BMS-345541 equally sensitized myelomonocytic AML cell lines and primary AML blasts to TRAIL.

  7. Targeting the cell cycle and the PI3K pathway: a possible universal strategy to reactivate innate tumor suppressor programmes in cancer cells.

    Science.gov (United States)

    David-Pfeuty, Thérèse; Legraverend, Michel; Ludwig, Odile; Grierson, David S

    2010-04-01

    Corruption of the Rb and p53 pathways occurs in virtually all human cancers. This could be because it lends oncogene-bearing cells a surfeit of Cdk activity and growth, enabling them to elaborate strategies to evade tumor-suppressive mechanisms and divide inappropriately. Targeting both Cdk activities and the PI3K pathway might be therefore a potentially universal means to palliate their deficiency in cancer cells. We showed that the killing efficacy of roscovitine and 16 other purines and potentiation of roscovitine-induced apoptosis by the PI3K inhibitor, LY294002, decreased with increasing corruption of the Rb and p53 pathways. Further, we showed that purines differing by a single substitution, which exerted little lethal effect on distant cell types in rich medium, could display widely-differing cytotoxicity profiles toward the same cell types in poor medium. Thus, closely-related compounds targeting similar Cdks may interact with different targets that could compete for their interaction with therapeutically-relevant Cdk targets. In the perspective of clinical development in association with the PI3K pathway inhibitors, it might thus be advisable to select tumor cell type-specific Cdk inhibitors on the basis of their toxicity in cell-culture-based assays performed at a limiting serum concentration sufficient to suppress their interaction with undesirable crossreacting targets whose range and concentration would depend on the cell genotype.

  8. Insulin/insulin like growth factors in cancer: new roles for the aryl hydrocarbon receptor, tumor resistance mechanisms and new blocking strategies

    Directory of Open Access Journals (Sweden)

    Travis B Salisbury

    2015-02-01

    Full Text Available The insulin-like growth factor 1 receptor (IGF1R and the insulin receptor (IR are receptor tyrosine kinases (RTKs that are expressed in cancer cells. The results of different studies indicate that tumor proliferation and survival is dependent on the IGF1R and IR, and that their inhibition leads to reductions in proliferation and increases in cell death. Molecular targeting therapies that have been used in solid tumors include: anti-IGF1R antibodies, anti-IGF1/IGF2 antibodies and small molecule inhibitors that suppress IGF1R and IR kinase activity. New advances in the molecular basis of anti-IGF1R blocking antibodies reveal they are biased agonists and promote the binding of IGF1 to integrin β3 receptors in some cancer cells. Our recent reports indicate that pharmacological aryl hydrocarbon receptor (AHR ligands inhibit breast cancer cell responses to IGFs, suggesting that targeting AHR may have benefit in cancers whose proliferation and survival are dependent on insulin/IGF signaling. Novel aspects of IGF1R/IR in cancer, such as biased agonism, integrin β3 signaling, AHR and new therapeutic targeting strategies will be discussed.

  9. Therapeutic strategy for hepatocellular carcinoma with tumor thrombi in the major portal branches by using 3 dimensional-conformal radiation therapies

    International Nuclear Information System (INIS)

    Yamada, Terumasa; Sasaki, Yo; Nishiyama, Kinji; Eguchi, Hidetoshi; Ohigashi, Hiroaki; Ishikawa, Osamu; Kasugai, Hiroshi; Inoue, Atsuo; Imaoka, Shingi

    2004-01-01

    The prognosis of hepatocellular carcinoma with tumor thrombus in the major portal branches (Vp-HCC) is extremely poor. Twenty-six inoperable patients and 5 operable patients with Vp-HCC were treated with 3-dimensional conformal radiation therapy (3D-CRT). All patients except for one could receive full-dose 3D-CRT without severe side effects. Six of 21 inoperable patients could receive additional treatments and showed better prognosis than the other patients. Five patients who had received curative hepatectomy after 3D-CRT, showed better prognosis than the patients with Vp-HCC who received hepatectomies without 3D-CRT. These results indicated the usefulness of 3D-CRT as a new therapeutic strategy for Vp-HCCs. (author)

  10. Analysis of pairwise correlations in multi-parametric PET/MR data for biological tumor characterization and treatment individualization strategies

    Energy Technology Data Exchange (ETDEWEB)

    Leibfarth, Sara; Moennich, David; Thorwarth, Daniela [University Hospital Tuebingen, Section for Biomedical Physics, Department of Radiation Oncology, Tuebingen (Germany); Simoncic, Urban [University Hospital Tuebingen, Section for Biomedical Physics, Department of Radiation Oncology, Tuebingen (Germany); University of Ljubljana, Faculty of Mathematics and Physics, Ljubljana (Slovenia); Jozef Stefan Institute, Ljubljana (Slovenia); Welz, Stefan; Zips, Daniel [University Hospital Tuebingen, Department of Radiation Oncology, Tuebingen (Germany); Schmidt, Holger; Schwenzer, Nina [University Hospital Tuebingen, Department of Diagnostic and Interventional Radiology, Tuebingen (Germany)

    2016-07-15

    The aim of this pilot study was to explore simultaneous functional PET/MR for biological characterization of tumors and potential future treatment adaptations. To investigate the extent of complementarity between different PET/MR-based functional datasets, a pairwise correlation analysis was performed. Functional datasets of N=15 head and neck (HN) cancer patients were evaluated. For patients of group A (N=7), combined PET/MR datasets including FDG-PET and ADC maps were available. Patients of group B (N=8) had FMISO-PET, DCE-MRI and ADC maps from combined PET/MRI, an additional dynamic FMISO-PET/CT acquired directly after FMISO tracer injection as well as an FDG-PET/CT acquired a few days earlier. From DCE-MR, parameter maps K{sup trans}, v{sub e} and v{sub p} were obtained with the extended Tofts model. Moreover, parameter maps of mean DCE enhancement, ΔS{sub DCE}, and mean FMISO signal 0-4 min p.i., anti A{sub FMISO}, were derived. Pairwise correlations were quantified using the Spearman correlation coefficient (r) on both a voxel and a regional level within the gross tumor volume. Between some pairs of functional imaging modalities moderate correlations were observed with respect to the median over all patient datasets, whereas distinct correlations were only present on an individual basis. Highest inter-modality median correlations on the voxel level were obtained for FDG/FMISO (r = 0.56), FDG/ anti A{sub FMISO} (r = 0.55), anti A{sub FMISO}/ΔS{sub DCE} (r = 0.46), and FDG/ADC (r = -0.39). Correlations on the regional level showed comparable results. The results of this study suggest that the examined functional datasets provide complementary information. However, only pairwise correlations were examined, and correlations could still exist between combinations of three or more datasets. These results might contribute to the future design of individually adapted treatment approaches based on multiparametric functional imaging.

  11. A trail pheromone component of the ant Mayriella overbecki Viehmeyer (Formicidae: Myrmicinae)

    Science.gov (United States)

    Kohl, E.; Hölldobler, B.; Bestmann, H.-J.

    The myrmicine ant Mayriella overbecki lays recruitment trails during foraging and nest emigrations. The trail pheromone originates from the poison gland. From ten identified components of the poison gland secretions only methyl 6-methylsalicylate 1 elicited trail following behavior.

  12. TRAIL death receptor 4 signaling via lysosome fusion and membrane raft clustering in coronary arterial endothelial cells: evidence from ASM knockout mice.

    Science.gov (United States)

    Li, Xiang; Han, Wei-Qing; Boini, Krishna M; Xia, Min; Zhang, Yang; Li, Pin-Lan

    2013-01-01

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptor, death receptor 4 (DR4), have been implicated in the development of endothelial dysfunction and atherosclerosis. However, the signaling mechanism mediating DR4 activation leading to endothelial injury remains unclear. We recently demonstrated that ceramide production via hydrolysis of membrane sphingomyelin by acid sphingomyelinase (ASM) results in membrane raft (MR) clustering and the formation of important redox signaling platforms, which play a crucial role in amplifying redox signaling in endothelial cells leading to endothelial dysfunction. The present study aims to investigate whether TRAIL triggers MR clustering via lysosome fusion and ASM activation, thereby conducting transmembrane redox signaling and changing endothelial function. Using confocal microscopy, we found that TRAIL induced MR clustering and co-localized with DR4 in coronary arterial endothelial cells (CAECs) isolated from wild-type (Smpd1 (+/+)) mice. Furthermore, TRAIL triggered ASM translocation, ceramide production, and NADPH oxidase aggregation in MR clusters in Smpd1 ( +/+ ) CAECs, whereas these observations were not found in Smpd1 (-/-) CAECs. Moreover, ASM deficiency reduced TRAIL-induced O(2) (-[Symbol: see text]) production in CAECs and abolished TRAIL-induced impairment on endothelium-dependent vasodilation in small resistance arteries. By measuring fluorescence resonance energy transfer, we found that Lamp-1 (lysosome membrane marker protein) and ganglioside G(M1) (MR marker) were trafficking together in Smpd1 (+/+) CAECs, which was absent in Smpd1 (-/-) CAECs. Consistently, fluorescence imaging of living cells with specific lysosome probes demonstrated that TRAIL-induced lysosome fusion with membrane was also absent in Smpd1 (-/-) CAECs. Taken together, these results suggest that ASM is essential for TRAIL-induced lysosomal trafficking, membrane fusion and formation of MR redox signaling platforms

  13. 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...

  14. Tangeretin sensitises human lung cancer cells to TRAIL- induced ...

    African Journals Online (AJOL)

    expression of death receptor 5 and CEBP homologous protein (CHOP) mRNA. The cytotoxic effects of ... mediated TRAIL sensitisation. Conclusions: Tangeretin induces death receptors and enhances TRAIL-induced apoptosis through up- .... cold whole-cell lysate buffer (5 M NaCl, 10 %. Nonidet P-40, 0.2 M sodium ...

  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. 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…

  17. 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…

  18. Mediastinal tumor

    Science.gov (United States)

    Thymoma - mediastinal; Lymphoma - mediastinal ... mediastinal tumors in adults occur in the anterior mediastinum. They are usually cancerous (malignant) lymphomas, germ cell tumors, or thymomas. These tumors are ...

  19. 77 FR 37438 - Draft Trail Management Plan and Environmental Impact Statement for Cuyahoga Valley National Park...

    Science.gov (United States)

    2012-06-21

    ... visitation and programs, some park trails requiring increased operational investment due to their location and use patterns, expansion of regional trail networks, and change in outdoor recreation trends...

  20. 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.

  1. Health Impact Assessment, Physical Activity and Federal Lands Trail Policy.

    Science.gov (United States)

    Davis, Sally M; Cruz, Theresa H; Kozoll, Richard L

    2014-01-01

    The objectives of this paper are to describe the application of Health Impact Assessment (HIA) to inform trail decisions affecting a rural, under-resourced community and propose the routine integration of HIAs to enhance NEPA environmental assessments and environmental impact statements for trail decisions on federal lands. Screening, scoping, assessment, recommendations, reporting, monitoring and evaluation are being used to examine the health impact of trail location and design. HIA recommendations are being integrated into the public lands National Environmental Protection Act process for planning access to a new segment of the Continental Divide National Scenic Trail. Potential users from a nearby rural New Mexico community and a region of almost one million may benefit from this HIA-informed planning. HIA can be integrated into the policy and decision-making process for trails on public lands.

  2. The role and strategy of IMRT in radiotherapy of pelvic tumors: Dose escalation and critical organ sparing in prostate cancer

    International Nuclear Information System (INIS)

    Liu, Y.-M.; Shiau, C.-Y.; Lee, M.-L.; Huang, P.-I.; Hsieh, C.-M.; Chen, P.-H.; Lin, Y.-H.; Wang, L.-W.; Yen, S.-H.

    2007-01-01

    Purpose: To investigate the intensity-modulated radiotherapy (IMRT) strategy in dose escalation of prostate and pelvic lymph nodes. Methods and Materials: Plan dosimetric data of 10 prostate cancer patients were compared with two-dimensional (2D) or IMRT techniques for pelvis (two-dimensional whole pelvic radiation therapy [2D-WPRT] or IM-WPRT) to receive 50 Gy or 54 Gy and additional prostate boost by three-dimensional conformal radiation therapy or IMRT (3D-PBRT or IM-PBRT) techniques up to 72 Gy or 78 Gy. Dose-volume histograms (DVHs), normal tissue complication probabilities (NTCP) of critical organ, and conformity of target volume in various combinations were calculated. Results: In DVH analysis, the plans with IM-WPRT (54 Gy) and additional boost up to 78 Gy had lower rectal and bladder volume percentage at 50 Gy and 60 Gy, compared with those with 2D-WPRT (50 Gy) and additional boost up to 72 Gy or 78 Gy. Those with IM-WPRT (54 Gy) also had better small bowel sparing at 30 Gy and 50 Gy, compared with those with 2D-WPRT (50 Gy). In NTCP, those with IM-WPRT and total dose of 78 Gy achieved lower complication rates in rectum and small bowel, compared with those of 2D-WPRT with total dose of 72 Gy. In conformity, those with IM-WPRT had better conformity compared with those with 2D-WPRT with significance (p < 0.005). No significant difference in DVHs, NTCP, or conformity was found between IM-PBRT and 3D-PBRT after IM-WPRT. Conclusions: Initial pelvic IMRT is the most important strategy in dose escalation and critical organ sparing. IM-WPRT is recommended for patients requiring WPRT. There is not much benefit for critical organ sparing by IMRT after 2D-WPRT

  3. Mcl-1 and YY1 inhibition and induction of DR5 by the BH3-mimetic Obatoclax (GX15-070) contribute in the sensitization of B-NHL cells to TRAIL apoptosis

    Science.gov (United States)

    Martínez-Paniagua, Melisa A; Baritaki, Stavroula; Huerta-Yepez, Sara; Ortiz-Navarrete, Vianney F; González-Bonilla, Cesar

    2011-01-01

    The pan Bcl-2 family antagonist Obatoclax (GX15-070), currently in clinical trials, was shown to sensitize TRAIL-resistant tumors to TRAIL-mediated apoptosis via the release of Bak and Bim from Mcl-1 or Bcl-2/Bcl-XL complexes or by the activation of Bax, though other mechanisms were not examined. Herein, we hypothesize that Obatoclax-mediated sensitization to TRAIL apoptosis may also result from alterations of the apoptotic pathways. The TRAIL-resistant B-cell line Ramos was used as a model for investigation. Treatment of Ramos cells with obatoclax significantly inhibited the expression of several members of the Bcl-2 family, dissociated Bak from Mcl-1 and inhibited the NFκB activity. Cells treated with Mcl-1 siRNA were sensitized to TRAIL apoptosis. We examined whether the sensitization of Ramos to TRAIL by Obatoclax resulted from signaling of the DR4 and/or DR5. Transfection with DR5 siRNA, but not with DR4 siRNA, sensitized the cells to apoptosis following treatment with Obatoclax and TRAIL. The signaling via DR5 correlated with Obatoclax-induced inhibition of the DR5 repressor Yin Yang 1 (YY1). Transfection with YY1 siRNA sensitized the cells to TRAIL apoptosis following treatment with Obatoclax and TRAIL. Overall, the present findings reveal a new mechanism of Obatoclax-induced sensitization to TRAIL apoptosis and the involvement of the inhibition of NFκB activity and downstream Mcl-1 and YY1 expressions and activities. PMID:21822052

  4. The pyrrolo-1,5-benzoxazepine, PBOX-15, enhances TRAIL-induced apoptosis by upregulation of DR5 and downregulation of core cell survival proteins in acute lymphoblastic leukaemia cells

    Science.gov (United States)

    NATHWANI, SEEMA-MARIA; GREENE, LISA M.; BUTINI, STEFANIA; CAMPIANI, GIUSEPPE; WILLIAMS, D. CLIVE; SAMALI, AFSHIN; SZEGEZDI, EVA; ZISTERER, DANIELA M.

    2016-01-01

    Apoptotic defects are frequently associated with poor outcome in pediatric acute lymphoblastic leukaemia (ALL) hence there is an ongoing demand for novel strategies that counteract apoptotic resistance. The death ligand TRAIL (tumour necrosis factor-related apoptosis-inducing ligand) and its selective tumour receptor system has attracted exceptional clinical interest. However, many malignancies including ALL are resistant to TRAIL monotherapy. Tumour resistance can be overcome by drug combination therapy. TRAIL and its agonist antibodies are currently undergoing phase II clinical trials with established chemotherapeutics. Herein, we present promising therapeutic benefits in combining TRAIL with the selective anti-leukaemic agents, the pyrrolo-1,5-benzoxazepines (PBOXs) for the treatment of ALL. PBOX-15 synergistically enhanced apoptosis induced by TRAIL and a DR5-selective TRAIL variant in ALL-derived cells. PBOX-15 enhanced TRAIL-induced apoptosis by dual activation of extrinsic and intrinsic apoptotic pathways. The specific caspase-8 inhibitor, Z-IETD-FMK, identified the extrinsic pathway as the principal mode of apoptosis. We demonstrate that PBOX-15 can enhance TRAIL-induced apoptosis by upregulation of DR5, reduction of cellular mitochondrial potential, activation of the caspase cascade and downregulation of PI3K/Akt, c-FLIP, Mcl-1 and IAP survival pathways. Of note, the PI3K pathway inhibitor LY-294002 significantly enhanced the apoptotic potential of TRAIL and PBOX-15 validating the importance of Akt downregulation in the TRAIL/PBOX-15 synergistic combination. Considering the lack of cytotoxicity to normal cells and ability to downregulate several survival pathways, PBOX-15 may represent an effective agent for use in combination with TRAIL for the treatment of ALL. PMID:27176505

  5. 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.

  6. 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.

  7. Potential of epigenetic therapies in the management of solid tumors

    International Nuclear Information System (INIS)

    Valdespino, Victor; Valdespino, Patricia M

    2015-01-01

    Cancer is a complex disease with both genetic and epigenetic origins. The growing field of epigenetics has contributed to our understanding of oncogenesis and tumor progression, and has allowed the development of novel therapeutic drugs. First-generation epigenetic inhibitor drugs have obtained modest clinical results in two types of hematological malignancy. Second-generation epigenetic inhibitors are in development, and have intrinsically greater selectivity for their molecular targets. Solid tumors are more genetic and epigenetically complex than hematological malignancies, but the transcriptome and epigenome biomarkers have been identified for many of these malignancies. This solid tumor molecular aberration profile may be modified using specific or quasi-specific epidrugs together with conventional and innovative anticancer treatments. In this critical review, we briefly analyze the strategies to select the targeted epigenetic changes, enumerate the second-generation epigenetic inhibitors, and describe the main signs indicating the potential of epigenetic therapies in the management of solid tumors. We also highlight the work of consortia or academic organizations that support the undertaking of human epigenetic therapeutic projects as well as some examples of transcriptome/epigenome profile determination in clinical assessment of cancer patients treated with epidrugs. There is a good chance that epigenetic therapies will be able to be used in patients with solid tumors in the future. This may happen soon through collaboration of diverse scientific groups, making the selection of targeted epigenetic aberration(s) more rapid, the design and probe of drug candidates, accelerating in vitro and in vivo assays, and undertaking new cancer epigenetic-therapy clinical trails

  8. Effect of Trailing Edge Flow Injection on Fan Noise and Aerodynamic Performance

    Science.gov (United States)

    Fite, E. Brian; Woodward, Richard P.; Podboy, Gary G.

    2006-01-01

    implementation of injecting flow at/near the trailing edge as a wake filling strategy. However, data do support the notion that noise reductions can be realized not only for tones but perhaps more importantly, also for broadband. Furthermore, the technique can be implemented without adversely effecting overall fan aerodynamic performance.

  9. Photometry of 1998/1999 Persistent Trails from Leonid Meteors

    Science.gov (United States)

    Milster, S. P.; Grime, B.; Drummond, J.; Fugate, R.; Kane, T. J.; Liu, A.; Papen, C. S.; Kelly, M. C.; Kruschwitz, C.

    2000-05-01

    Surface brightness and line emission rates are derived for two persistent trails from the 1998 and 1999 Leonid meteor showers. The trails are optically thin, and in places appear as cylinders with a very dark center. This center is roughly as wide as the bright emission walls, but is as dark as the sky background. This situation is not in agreement with the simple hollow-cylinder model of shell burning. The data was acquired at the Starfire Optical Range on Kirtland AFB. The instruments were guided by a human observer onto the lingering trails of the meteors. A 5 degree wide Xybion camera, attached to the headring of the telescope, recorded the scene. The University of Illinois' sodium lidar determined the distance to the persistent trails. A 200-W copper vapor laser (CVL) was also used in an attempt to measure back-scatter from particulates in the contrails of the Leonids. Almost all of the meteors that produced lingering trails greatly enhanced the naturally occurring sodium layer at 100 km. The lingering trails generally appeared as evanescent smoke rings that evolved rather quickly, with the path of the meteor marked by a double walled, optically thin tube. A 15-minute highlight video will be presented showing the evolution of the lingering trails as well as the lidar and the CVL probing them.

  10. Xerox trails: a new web-based publishing technology

    Science.gov (United States)

    Rao, Venkatesh G.; Vandervort, David; Silverstein, Jesse

    2010-02-01

    Xerox Trails is a new digital publishing model developed at the Xerox Research Center, Webster. The primary purpose of the technology is to allow Web users and publishers to collect, organize and present information in the form of a useful annotated narrative (possibly non-sequential) with editorial content and metadata, that can be consumed both online and offline. The core concept is a trail: a digital object that improves online content production, consumption and navigation user experiences. When appropriate, trails can also be easily sequenced and transformed into printable documents, thereby bridging the gap between online and offline content experiences. The model is partly inspired by Vannevar Bush's influential idea of the "Memex" [1] which has inspired several generations of Web technology [2]. Xerox Trails is a realization of selected elements from the idea of the Memex, along with several original design ideas. It is based on a primitive data construct, the trail. In Xerox Trails, the idea of a trail is used to support the architecture of a Web 2.0 product suite called Trailmeme, that includes a destination Web site, plugins for major content management systems, and a browser toolbar.

  11. A divide-and-conquer strategy in tumor sampling enhances detection of intratumor heterogeneity in routine pathology: A modeling approach in clear cell renal cell carcinoma [version 2; referees: 4 approved

    Directory of Open Access Journals (Sweden)

    José I. Lopez

    2016-04-01

    Full Text Available Intratumor heterogeneity (ITH is an inherent process in cancer development which follows for most of the cases a branched pattern of evolution, with different cell clones evolving independently in space and time across different areas of the same tumor. The determination of ITH (in both spatial and temporal domains is nowadays critical to enhance patient treatment and prognosis. Clear cell renal cell carcinoma (CCRCC provides a good example of ITH. Sometimes the tumor is too big to be totally analyzed for ITH detection and pathologists decide which parts must be sampled for the analysis. For such a purpose, pathologists follow internationally accepted protocols. In light of the latest findings, however, current sampling protocols seem to be insufficient for detecting ITH with significant reliability. The arrival of new targeted therapies, some of them providing promising alternatives to improve patient survival, pushes the pathologist to obtain a truly representative sampling of tumor diversity in routine practice. How large this sampling must be and how this must be performed are unanswered questions so far.  Here we present a very simple method for tumor sampling that enhances ITH detection without increasing costs. This method follows a divide-and-conquer (DAC strategy, that is, rather than sampling a small number of large-size tumor-pieces as the routine protocol (RP advises, we suggest sampling many small-size pieces along the tumor. We performed a computational modeling approach to show that the usefulness of the DAC strategy is twofold: first, we show that DAC outperforms RP with similar laboratory costs, and second, DAC is capable of performing similar to total tumor sampling (TTS but, very remarkably, at a much lower cost. We thus provide new light to push forward a shift in the paradigm about how pathologists should sample tumors for achieving efficient ITH detection.

  12. 5'/ 3' imbalance strategy to detect ALK fusion genes in circulating tumor RNA from patients with non-small cell lung cancer.

    Science.gov (United States)

    Tong, Yongqing; Zhao, Zhijun; Liu, Bei; Bao, Anyu; Zheng, Hongyun; Gu, Jian; McGrath, Mary; Xia, Ying; Tan, Bihua; Song, Chunhua; Li, Yan

    2018-03-27

    Detecting an ALK fusion gene in patients with non-small cell lung cancer (NSCLC) could provide evidence to guide individualized therapy. The 5'/3' imbalance strategy for quantitative reverse transcription-PCR (RT-qPCR) was developed to detect ALK fusion genes in circulating tumor RNA (ctRNA) of NSCLC patients. This method was validated in patients with the ALK fusion gene confirmed by next generation sequencing (NGS). The amount of the ALK fusion gene detected by the new method ranged from 33.2 to 987.4, (mean 315.2), in the patients confirmed to have the ALK fusion gene (+). This is much higher than the amount of fusion gene detected in the patients who are negative for the ALK fusion gene (-). The amount detected in the ALK fusion gene (-) samples ranged from 0.36 to 13.04, (mean 4.58). In 188 NSCLC patients, the specificity and sensitivity of the method was compared to that of the FISH method. About 10.64% of the patients showed higher ALK fusion gene expression, and were classified as ALK fusion gene (+). This is identical to the percentage of patients detected by the FISH method to be ALK fusion gene (+). The cutoff value for diagnosis of ALK fusion (+) is 32.9 as determined by this method. A new RT-PCR method using a 5'/3' imbalance strategy was developed, with high specificity and sensitivity, for detection of the ALK fusion gene in ctRNA of NSCLC patients. This method can rapidly detect ALK fusion genes in patients, which will be helpful for guiding targeted therapy, particularly the individualized usage of TKIs in these patients.

  13. 77 FR 1723 - Notice of Availability, Potomac Heritage National Scenic Trail

    Science.gov (United States)

    2012-01-11

    ...; volunteers; and other Trail stakeholders, the Trail network today includes over 830 miles of existing and planned Trail segments for non-motorized travel. Communities have invested in the Trail concept for a... transportation, education and/or heritage tourism. The Foundation assembles in one document decisions and...

  14. 76 FR 71601 - Record of Decision, Long Walk National Historic Trail Feasibility Study/Abbreviated Final...

    Science.gov (United States)

    2011-11-18

    ... National Park Service Record of Decision, Long Walk National Historic Trail Feasibility Study/Abbreviated... Environmental Impact Statement for the Long Walk National Historic Trail Feasibility Study. SUMMARY: Pursuant to... Statement for the Long Walk National Historic Trail Feasibility Study, prepared by National Trails...

  15. Development of TRAIL Resistance by Radiation-Induced Hypermethylation of DR4 CpG Island in Recurrent Laryngeal Squamous Cell Carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Jong Cheol [Department of Otorhinolaryngology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan (Korea, Republic of); Department of Biomedical Research Center, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan (Korea, Republic of); Lee, Won Hyeok [Department of Biomedical Research Center, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan (Korea, Republic of); Min, Young Joo [Department of Biomedical Research Center, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan (Korea, Republic of); Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan (Korea, Republic of); Cha, Hee Jeong [Department of Pathology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan (Korea, Republic of); Han, Myung Woul [Department of Otorhinolaryngology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan (Korea, Republic of); Chang, Hyo Won [Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Kim, Sun-A [Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Choi, Seung-Ho [Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Kim, Seong Who, E-mail: swhokim@gmail.com [Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Kim, Sang Yoon, E-mail: sykim3715@gmail.com [Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Biomedical Research Institute, Korea Institute of Science and Technology, Seoul (Korea, Republic of)

    2014-04-01

    Purpose: There are limited therapeutic options for patients with recurrent head and neck cancer after radiation therapy failure. To assess the use of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) as a salvage chemotherapeutic agent for recurrent cancer after radiation failure, we investigated the effect of clinically relevant cumulative irradiation on TRAIL-induced apoptosis. Methods and Materials: Using a previously established HN3 cell line from a laryngeal carcinoma patient, we generated a chronically irradiated HN3R isogenic cell line. Viability and apoptosis in HN3 and HN3R cells treated with TRAIL were analyzed with MTS and PI/annexin V-FITC assays. Western blotting and flow cytometry were used to determine the underlying mechanism of TRAIL resistance. DR4 expression was semiquantitatively scored in a tissue microarray with 107 laryngeal cancer specimens. Methylation-specific polymerase chain reaction and bisulfite sequencing for DR4 were performed for genomic DNA isolated from each cell line. Results: HN3R cells were more resistant than HN3 cells to TRAIL-induced apoptosis because of significantly reduced levels of the DR4 receptor. The DR4 staining score in 37 salvage surgical specimens after radiation failure was lower in 70 surgical specimens without radiation treatment (3.03 ± 2.75 vs 5.46 ± 3.30, respectively; P<.001). HN3R cells had a methylated DR4 CpG island that was partially demethylated by the DNA demethylating agent 5-aza-2′-deoxycytidine. Conclusion: Epigenetic silencing of the TRAIL receptor by hypermethylation of a DR4 CpG island might be an underlying mechanism for TRAIL resistance in recurrent laryngeal carcinoma treated with radiation.

  16. 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.

  17. 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 ...

  18. 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...

  19. A Computational Modeling Mystery Involving Airfoil Trailing Edge Treatments

    Science.gov (United States)

    Choo, Yeunun; Epps, Brenden

    2015-11-01

    In a curious result, Fairman (2002) observed that steady RANS calculations predicted larger lift than the experimentally-measured data for six different airfoils with non-traditional trailing edge treatments, whereas the time average of unsteady RANS calculations matched the experiments almost exactly. Are these results reproducible? If so, is the difference between steady and unsteady RANS calculations a numerical artifact, or is there a physical explanation? The goals of this project are to solve this thirteen year old mystery and further to model viscous/load coupling for airfoils with non-traditional trailing edges. These include cupped, beveled, and blunt trailing edges, which are common anti-singing treatments for marine propeller sections. In this talk, we present steady and unsteady RANS calculations (ANSYS Fluent) with careful attention paid to the possible effects of asymmetric unsteady vortex shedding and the modeling of turbulence anisotropy. The effects of non-traditional trailing edge treatments are visualized and explained.

  20. Using external data sources to improve audit trail analysis.

    OpenAIRE

    Herting, R. L.; Asaro, P. V.; Roth, A. C.; Barnes, M. R.

    1999-01-01

    Audit trail analysis is the primary means of detection of inappropriate use of the medical record. While audit logs contain large amounts of information, the information required to determine useful user-patient relationships is often not present. Adequate information isn't present because most audit trail analysis systems rely on the limited information available within the medical record system. We report a feature of the STAR (System for Text Archive and Retrieval) audit analysis system wh...

  1. Forced Diffusion of Trailing Vorticity from a Hovering Rotor

    Science.gov (United States)

    McAlister, Kenneth W.; Tung, Chee; Heineck, James T.; Aiken, Edwin W. (Technical Monitor)

    2001-01-01

    A small turbulence generating device was Attached near the tip of a hovering rotor blade In order to alter the structure of the trailing vortex. Stereo particle image velocimetry (PIV) images were used to quantify the wake behind the rotor blade during the first revolution. An analysis of the 3D-velocity field includes a method for accounting for vortex wander. The results show that a major change in the size and intensity of the trailing vortex can be achieved.

  2. 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)

  3. Induction of proapoptotic antibodies to triple-negative breast cancer by vaccination with TRAIL death receptor DR5 DNA.

    Science.gov (United States)

    Piechocki, Marie P; Wu, Gen Sheng; Jones, Richard F; Jacob, Jennifer B; Gibson, Heather; Ethier, Stephen P; Abrams, Judith; Yagita, Hideo; Venuprasad, K; Wei, Wei-Zen

    2012-12-01

    TNF-related apoptosis-inducing ligand receptor 2 [TRAIL-R2 or death receptor 5 (DR5)] is expressed at elevated levels in a broad range of solid tumors to mediate apoptotic signals from TRAIL or agonist antibodies. We tested the hypothesis that DR5 DNA vaccination will induce proapoptotic antibody to trigger apoptosis of tumor cells. BALB/c mice were electrovaccinated with DNA-encoding wild-type human DR5 (phDR5) or its derivatives. Resulting immune serum or purified immune IgG induced apoptosis in triple-negative breast cancer (TNBC) cells, which were also TRAIL sensitive. The proapoptotic activity of immune serum at dilutions of 0.5-2% was comparable to that of 1-2 μg/ml of TRAIL. Apoptotic activity of immune serum was enhanced by antibody crosslinking. Apoptotic cell death induced by anti-DR5 antibody was shown by the cleavage of PARP and caspase-3. In contrast, immune serum had no effect on the proliferation of activated human T cells, which expressed low levels of DR5. In vivo, hDR5 reactive immune serum prevented growth of SUM159 TNBC cells in severe combined immune-deficient mice. DR5-specific IFN-γ-secreting T cells were also induced by DNA vaccination. Furthermore, the feasibility to overcome immune tolerance to self DR5 was shown by the induction of mouse DR5-binding antibody after electrovaccination of BALB/c mice with pmDR5ectm-Td1 encoding a fusion protein of mouse DR5 and an immunogenic fragment of tetanus toxin. These findings support DR5 as a promising vaccine target for controlling TNBC and other DR5-positive cancers. Copyright © 2012 UICC.

  4. Osteoprotegerin and TRAIL in Acute Onset of Atrial Fibrillation

    Directory of Open Access Journals (Sweden)

    Krzysztof Rewiuk

    2015-01-01

    Full Text Available Background. There is a growing amount of evidence that inflammatory processes are involved in the development of atrial fibrillation (AF and its complications. We decided to investigate the behavior of osteoprotegerin (OPG and TNF-related apoptosis inducing ligand (TRAIL in terms of acute onset of AF. Methods and Results. We included 60 patients with acute onset of AF, candidates for pharmacological cardioversion. The presence of cardiovascular comorbidities was connected with higher concentration of OPG and lower level of TRAIL right from the first hours of AF paroxysm. The initial TRAIL level correlated also positively with left ventricle ejection fraction and negatively with left atrium diameter. We found subsequent increase of OPG in subgroups selected on the basis of CHA2DS2-VASc scoring. Although basal concentrations of studied markers did not allow prediction of the restoration of sinus rhythm, we observed important increase of TRAIL concentration in subgroup with sinus rhythm maintenance (94.11 ± 29.46 versus 111.39 ± 30.23 pg/mL; p=0.002. Conclusions. OPG and TRAIL are associated with the underlying cardiovascular damage in AF, but their balance is modulated by the fact of sinus rhythm restoration. Determining the suitability of OPG and TRAIL as predictive markers in AF requires further prospective studies.

  5. Osteoprotegerin and TRAIL in Acute Onset of Atrial Fibrillation.

    Science.gov (United States)

    Rewiuk, Krzysztof; Grodzicki, Tomasz

    2015-01-01

    There is a growing amount of evidence that inflammatory processes are involved in the development of atrial fibrillation (AF) and its complications. We decided to investigate the behavior of osteoprotegerin (OPG) and TNF-related apoptosis inducing ligand (TRAIL) in terms of acute onset of AF. We included 60 patients with acute onset of AF, candidates for pharmacological cardioversion. The presence of cardiovascular comorbidities was connected with higher concentration of OPG and lower level of TRAIL right from the first hours of AF paroxysm. The initial TRAIL level correlated also positively with left ventricle ejection fraction and negatively with left atrium diameter. We found subsequent increase of OPG in subgroups selected on the basis of CHA2DS2-VASc scoring. Although basal concentrations of studied markers did not allow prediction of the restoration of sinus rhythm, we observed important increase of TRAIL concentration in subgroup with sinus rhythm maintenance (94.11 ± 29.46 versus 111.39 ± 30.23 pg/mL; p = 0.002). OPG and TRAIL are associated with the underlying cardiovascular damage in AF, but their balance is modulated by the fact of sinus rhythm restoration. Determining the suitability of OPG and TRAIL as predictive markers in AF requires further prospective studies.

  6. Computational investigation of miniature trailing edge effectors

    Science.gov (United States)

    Lee, Hak-Tae

    Miniature trailing edge effectors (MiTEs) are small flaps (typically 1% to 5% chord) actuated with deflection angles of up to 90 degrees. The small size, combined with little required power and good control authority, enables the device to be used for high bandwidth control as well as conventional attitude control. However, some of the aerodynamic characteristics of these devices are complex and poorly understood. This research investigated the aerodynamics of MiTEs using incompressible Navier-Stokes flow solvers, INS2D and INS3D. To understand the flow structure and establish a parametric database, two dimensional steady-state computations were performed for MiTEs with various geometries and flow conditions. Time accurate computations were used to resolve the unsteady characteristics including transient response and vortex shedding phenomena. The frequency response was studied to fully identify the dynamics of MiTEs. Three dimensional computations show the change in control effectiveness with respect to the spanwise length of MiTEs as well as the spanwise lift distribution induced by these devices. Based on the CFD results, an approximate vortex panel model was developed for design purposes that reproduces the key characteristics of MiTEs. Two application areas for MiTEs were explored. Flutter suppression was demonstrated by combining a finite element structural model with the vortex panel model. The application of MiTEs to augment maximum lift and improve the post stall behavior of an airfoil was also investigated.

  7. Multicellular Self-Organization of P. aeruginosa due to Interactions with Secreted Trails

    Science.gov (United States)

    Gelimson, Anatolij; Zhao, Kun; Lee, Calvin K.; Kranz, W. Till; Wong, Gerard C. L.; Golestanian, Ramin

    2016-10-01

    Guided movement in response to slowly diffusing polymeric trails provides a unique mechanism for self-organization of some microorganisms. To elucidate how this signaling route leads to microcolony formation, we experimentally probe the trajectory and orientation of Pseudomonas aeruginosa that propel themselves on a surface using type IV pili motility appendages, which preferentially attach to deposited exopolysaccharides. We construct a stochastic model by analyzing single-bacterium trajectories and show that the resulting theoretical prediction for the many-body behavior of the bacteria is in quantitative agreement with our experimental characterization of how cells explore the surface via a power-law strategy.

  8. [Immune system and tumors].

    Science.gov (United States)

    Terme, Magali; Tanchot, Corinne

    2017-02-01

    Despite having been much debated, it is now well established that the immune system plays an essential role in the fight against cancer. In this article, we will highlight the implication of the immune system in the control of tumor growth and describe the major components of the immune system involved in the antitumoral immune response. The immune system, while exerting pressure on tumor cells, also will play a pro-tumoral role by sculpting the immunogenicity of tumors cells as they develop. Finally, we will illustrate the numerous mechanisms of immune suppression that take place within the tumoral microenvironment which allow tumor cells to escape control from the immune system. The increasingly precise knowledge of the brakes to an effective antitumor immune response allows the development of immunotherapy strategies more and more innovating and promising of hope. Copyright © 2016. Published by Elsevier Masson SAS.

  9. Therapeutic advantage of combining calcium channel blockers and TRAIL in prostate cancer.

    Science.gov (United States)

    Kaddour-Djebbar, Ismail; Lakshmikanthan, Vijayabaskar; Shirley, Robert B; Ma, Yulin; Lewis, Ronald W; Kumar, M Vijay

    2006-08-01

    Disruption of intracellular calcium initiates multiple cell-damaging processes, such as apoptosis. In normal cells, the levels of Ca(2+) are low in the mitochondria, whereas in apoptotic cells, Ca(2+) increases. Mitochondria uptake Ca(2+) via an inner membrane channel called the uniporter and extrude it into the cytoplasm through a Na(+)/Ca(2+) exchanger. Overload of Ca(2+) in the mitochondria in CGP-treated cells leads to its damage, thus affecting cellular function and survival. The goal of these experiments was to determine the importance of mitochondrial calcium ([Ca(2+)](m)) in apoptosis of prostate cancer cells. Furthermore, we have examined the advantages of increasing the [Ca(2+)](m) and treating the cells with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a potent apoptotic agent. Our results show that, under these treatment conditions, inhibiting the Na(+)/Ca(2+) exchanger using benzothiazepin CGP-37157 (CGP) did not induce apoptosis. However, combination of CGP and TRAIL increased the apoptotic response approximately 25-fold compared with control. Increase in apoptosis followed enhanced levels of [Ca(2+)](m) and was accompanied by pronounced mitochondrial changes characteristic of mitochondria-mediated apoptosis. Experiments with calcium ionophores showed that mere increase in cytosolic and/or mitochondrial Ca(2+) was not sufficient to induce apoptosis. These results have therapeutic implications as inhibitors of Na(+)/Ca(2+) exchanger are being used for treating some neurologic and cardiologic ailments, and TRAIL induces apoptosis preferentially in cancer cells. Furthermore, this system provides an excellent model to investigate the role of [Ca(2+)](m) in apoptosis.

  10. GTL001 and bivalent CyaA-based therapeutic vaccine strategies against human papillomavirus and other tumor-associated antigens induce effector and memory T-cell responses that inhibit tumor growth.

    Science.gov (United States)

    Esquerré, Michaël; Momot, Marie; Goubier, Anne; Gonindard, Christophe; Leung-Theung-Long, Stéphane; Misseri, Yolande; Bissery, Marie-Christine

    2017-03-13

    GTL001 is a bivalent therapeutic vaccine containing human papillomavirus (HPV) 16 and HPV18 E7 proteins inserted in the Bordetella pertussis adenylate cyclase (CyaA) vector intended to prevent cervical cancer in HPV-infected women with normal cervical cytology or mild abnormalities. To be effective, therapeutic cervical cancer vaccines should induce both a T cell-mediated effector response against HPV-infected cells and a robust CD8 + T-cell memory response to prevent potential later infection. We examined the ability of GTL001 and related bivalent CyaA-based vaccines to induce, in parallel, effector and memory CD8 + T-cell responses to both vaccine antigens. Intradermal vaccination of C57BL/6 mice with GTL001 adjuvanted with a TLR3 agonist (polyinosinic-polycytidylic acid) or a TLR7 agonist (topical 5% imiquimod cream) induced strong HPV16 E7-specific T-cell responses capable of eradicating HPV16 E7-expressing tumors. Tumor-free mice also had antigen-specific memory T-cell responses that protected them against a subsequent challenge with HPV18 E7-expressing tumor cells. In addition, vaccination with bivalent vaccines containing CyaA-HPV16 E7 and CyaA fused to a tumor-associated antigen (melanoma-specific antigen A3, MAGEA3) or to a non-viral, non-tumor antigen (ovalbumin) eradicated HPV16 E7-expressing tumors and protected against a later challenge with MAGEA3- and ovalbumin-expressing tumor cells, respectively. These results show that CyaA-based bivalent vaccines such as GTL001 can induce both therapeutic and prophylactic anti-tumor T-cell responses. The CyaA platform can be adapted to different antigens and adjuvants, and therefore may be useful for developing other therapeutic vaccines. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  11. Helicobacter pylori enhances tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in human gastric epithelial cells

    Science.gov (United States)

    Wu, Yi-Ying; Tsai, Hwei-Fang; Lin, We-Cheng; Chou, Ai-Hsiang; Chen, Hui-Ting; Yang, Jyh-Chin; Hsu, Ping-I; Hsu, Ping-Ning

    2004-01-01

    AIM: To investigate the relations between tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and Helicobacter pylori (H pylori) infection in apoptosis of gastric epithelial cells and to assess the expression of TRAIL on the surface of infiltrating T-cells in H pylori-infected gastric mucosa. METHODS: Human gastric epithelial cell lines and primary gastric epithelial cells were co-cultured with H pylori in vitro, then recombinant TRAIL proteins were added to the culture. Apoptosis of gastric epithelial cells was determined by a specific ELISA for cell death. Infiltrating lymphocytes were isolated from H pylori-infected gastric mucosa, and expression of TRAIL in T cells was analyzed by flow cytometry. RESULTS: The apoptosis of gastric epithelial cell lines and primary human gastric epithelial cells was mildly increased by interaction with either TRAIL or H pylori alone. Interestingly, the apoptotic indices were markedly elevated when gastric epithelial cells were incubated with both TRAIL and H pylori (Control vs TRAIL and H pylori: 0.51 ± 0.06 vs 2.29 ± 0.27, P = 0.018). A soluble TRAIL receptor (DR4-Fc) could specifically block the TRAIL-mediated apoptosis. Further studies demonstrated that infiltrating T-cells in gastric mucosa expressed TRAIL on their surfaces, and the induction of TRAIL sensitivity by H pylori was dependent upon direct cell contact of viable bacteria, but not CagA and VacA of H pylori. CONCLUSION: H pylori can sensitize human gastric epithelial cells and enhance susceptibility to TRAIL-mediated apoptosis. Modulation of host cell sensitivity to apoptosis by bacterial interaction adds a new dimension to the immunopathogenesis of H pylori infection. PMID:15285015

  12. [Immunological mechanisms of graft versus tumor effect].

    Science.gov (United States)

    Ine, Shoji; Yamada, Minami; Miyamura, Koichi; Sasaki, Takeshi

    2003-09-01

    Lesson from hematopoietic stem cell transplantation demonstrated that donor immuno-surveillance system can eradicate tumor cells. This is so-call graft versus tumor(GVT) effect. Antigen presenting cells show peptide from minor antigen rather leukemic specific antigen in the context of major histocompatibility complex. The effector cells composed of CD8 T lymphocyte, CD4 T lymphocyte, natural killer cell and natural killer T cell. Death signal was transmitted from effector cells via granzyme/perforin system and FasL/Fas system, and recently TRAIL system seems most important for GVT effect.

  13. Influence of soluble or matrix-bound isoforms of vascular endothelial growth factor-A on tumor response to vascular-targeted strategies.

    Science.gov (United States)

    Akerman, Simon; Fisher, Matthew; Daniel, Rachel A; Lefley, Diane; Reyes-Aldasoro, Constantino C; Lunt, Sarah Jane; Harris, Sheila; Bjorndahl, Meit; Williams, Leigh J; Evans, Helen; Barber, Paul R; Prise, Vivien E; Vojnovic, Borivoj; Kanthou, Chryso; Tozer, Gillian M

    2013-12-01

    Antiangiogenic therapy based on blocking the actions of vascular endothelial growth factor-A (VEGF) can lead to "normalization" of blood vessels in both animal and human tumors. Differential expression of VEGF isoforms affects tumor vascular maturity, which could influence the normalization process and response to subsequent treatment. Fibrosarcoma cells expressing only VEGF120 or VEGF188 isoforms were implanted either subcutaneously (s.c.) or in dorsal skin-fold "window" chambers in SCID mice. VEGF120 was associated with vascular fragility and hemorrhage. Tumor-bearing mice were treated with repeat doses of SU5416, an indolinone receptor tyrosine kinase inhibitor with activity against VEGFR-2 and proven preclinical ability to induce tumor vascular normalization. SU5416 reduced vascularization in s.c. implants of both VEGF120 and VEGF188 tumors. However, in the window chamber, SU5416 treatment increased red cell velocity in VEGF120 (representing vascular normalization) but not VEGF188 tumors. SU5416 treatment had no effect on growth or necrosis levels in either tumor type but tended to counteract the increase in interstitial fluid pressure seen with growth of VEGF120 tumors. SU5416 pretreatment resulted in the normally fragile blood vessels in VEGF120-expressing tumors becoming resistant to the vascular damaging effects of the tubulin-binding vascular disrupting agent (VDA), combretastatin A4 3-O-phosphate (CA4P). Thus, vascular normalization induced by antiangiogenic treatment can reduce the efficacy of subsequent VDA treatment. Expression of VEGF120 made tumors particularly susceptible to vascular normalization by SU5416, which in turn made them resistant to CA4P. Therefore, VEGF isoform expression may be useful for predicting response to both antiangiogenic and vascular-disrupting therapy. Copyright © 2013 UICC.

  14. Membrane-bound versus soluble major histocompatibility complex Class I-related chain A and major histocompatibility complex Class I-related chain B differential expression: Mechanisms of tumor eradication versus evasion and current drug development strategies

    Directory of Open Access Journals (Sweden)

    P K Suresh

    2016-01-01

    Full Text Available Major histocompatibility complex Class I-related chain A/chain B (MICA/MICB is stress-inducible, highly polymorphic ligands whose expression at the transcript level has been detected in all tissues except the central nervous system. However, their restricted protein expression is due to their regulation at the posttranslational level. Its levels are elevated in virally infected and neoplastically transformed cells. Membrane expression of this NKG2DL marks the aberrant cells for elimination by those immune effector cells that express the cognate NKG2D receptor. Among the evasion strategies developed by tumors, the metalloprotease-dependent shedding of MICA/MICB from tumors (either the free or the exosome form can contribute to the inhibition of cytolysis by the immune effector cells (all NK cells, most NKT cells; γδ CD8+ T cells and αβ CD8+ T cells, as well as some αβ CD4+ T cells. There are micro-RNA clusters that regulate surface expression and shedding. Polymorphic variants can be used as susceptibility/associative markers and can also possibly be used to correlate with tumor survival as well as staging/grading of tumors. Variations in the expression level require quantification of this marker for diagnostic/prognostic and therapeutic purposes. Mechanism-based studies would provide a better tumor-specific understanding of their relative roles in the processes of tumor cell elimination versus growth and progression. Last but not least, conventional, interlaboratory validated assays (for, e.g., antibody-based methods should be replaced by robust, reproducible, feasible biophysics-based methods using tumor biopsies. Further, correlative DNA polymorphism-based studies can be done using biological fluids (for, e.g., human saliva that can be sampled by minimally invasive means.

  15. Membrane-bound versus soluble major histocompatibility complex Class I-related chain A and major histocompatibility complex Class I-related chain B differential expression: Mechanisms of tumor eradication versus evasion and current drug development strategies.

    Science.gov (United States)

    Suresh, P K

    2016-01-01

    Major histocompatibility complex Class I-related chain A/chain B (MICA/MICB) is stress-inducible, highly polymorphic ligands whose expression at the transcript level has been detected in all tissues except the central nervous system. However, their restricted protein expression is due to their regulation at the posttranslational level. Its levels are elevated in virally infected and neoplastically transformed cells. Membrane expression of this NKG2DL marks the aberrant cells for elimination by those immune effector cells that express the cognate NKG2D receptor. Among the evasion strategies developed by tumors, the metalloprotease-dependent shedding of MICA/MICB from tumors (either the free or the exosome form) can contribute to the inhibition of cytolysis by the immune effector cells (all NK cells, most NKT cells; γδ CD8+ T cells and αβ CD8+ T cells, as well as some αβ CD4+ T cells). There are micro-RNA clusters that regulate surface expression and shedding. Polymorphic variants can be used as susceptibility/associative markers and can also possibly be used to correlate with tumor survival as well as staging/grading of tumors. Variations in the expression level require quantification of this marker for diagnostic/prognostic and therapeutic purposes. Mechanism-based studies would provide a better tumor-specific understanding of their relative roles in the processes of tumor cell elimination versus growth and progression. Last but not least, conventional, interlaboratory validated assays (for, e.g., antibody-based methods) should be replaced by robust, reproducible, feasible biophysics-based methods using tumor biopsies. Further, correlative DNA polymorphism-based studies can be done using biological fluids (for, e.g., human saliva) that can be sampled by minimally invasive means.

  16. Modulating the Tumor Microenvironment to Enhance Tumor Nanomedicine Delivery

    Directory of Open Access Journals (Sweden)

    Bo Zhang

    2017-12-01

    Full Text Available Nanomedicines including liposomes, micelles, and nanoparticles based on the enhanced permeability and retention (EPR effect have become the mainstream for tumor treatment owing to their superiority over conventional anticancer agents. Advanced design of nanomedicine including active targeting nanomedicine, tumor-responsive nanomedicine, and optimization of physicochemical properties to enable highly effective delivery of nanomedicine to tumors has further improved their therapeutic benefits. However, these strategies still could not conquer the delivery barriers of a tumor microenvironment such as heterogeneous blood flow, dense extracellular matrix, abundant stroma cells, and high interstitial fluid pressure, which severely impaired vascular transport of nanomedicines, hindered their effective extravasation, and impeded their interstitial transport to realize uniform distribution inside tumors. Therefore, modulation of tumor microenvironment has now emerged as an important strategy to improve nanomedicine delivery to tumors. Here, we review the existing strategies and approaches for tumor microenvironment modulation to improve tumor perfusion for helping more nanomedicines to reach the tumor site, to facilitate nanomedicine extravasation for enhancing transvascular transport, and to improve interstitial transport for optimizing the distribution of nanomedicines. These strategies may provide an avenue for the development of new combination chemotherapeutic regimens and reassessment of previously suboptimal agents.

  17. Modulating the Tumor Microenvironment to Enhance Tumor Nanomedicine Delivery

    Science.gov (United States)

    Zhang, Bo; Hu, Yu; Pang, Zhiqing

    2017-01-01

    Nanomedicines including liposomes, micelles, and nanoparticles based on the enhanced permeability and retention (EPR) effect have become the mainstream for tumor treatment owing to their superiority over conventional anticancer agents. Advanced design of nanomedicine including active targeting nanomedicine, tumor-responsive nanomedicine, and optimization of physicochemical properties to enable highly effective delivery of nanomedicine to tumors has further improved their therapeutic benefits. However, these strategies still could not conquer the delivery barriers of a tumor microenvironment such as heterogeneous blood flow, dense extracellular matrix, abundant stroma cells, and high interstitial fluid pressure, which severely impaired vascular transport of nanomedicines, hindered their effective extravasation, and impeded their interstitial transport to realize uniform distribution inside tumors. Therefore, modulation of tumor microenvironment has now emerged as an important strategy to improve nanomedicine delivery to tumors. Here, we review the existing strategies and approaches for tumor microenvironment modulation to improve tumor perfusion for helping more nanomedicines to reach the tumor site, to facilitate nanomedicine extravasation for enhancing transvascular transport, and to improve interstitial transport for optimizing the distribution of nanomedicines. These strategies may provide an avenue for the development of new combination chemotherapeutic regimens and reassessment of previously suboptimal agents. PMID:29311946

  18. MicroRNA-661 Enhances TRAIL or STS Induced Osteosarcoma Cell Apoptosis by Modulating the Expression of Cytochrome c1

    Directory of Open Access Journals (Sweden)

    Lin Fan

    2017-04-01

    Full Text Available Aim: Osteosarcoma (OS is an aggressive bone malignancy that affects rapidly growing bones and is associated with a poor prognosis. Our previous study showed that cytochrome c1 (CYC1, a subunit of the cytochrome bc1 complex (complex III of the mitochondrial electron chain, is overexpressed in human OS tissues and cell lines and its silencing induces apoptosis in vitro and inhibits tumor growth in vivo. Here, we investigated the mechanism underlying the modulation of CYC1 expression in OS and its role in the resistance of OS to apoptosis. Methods: qRT-PCR, luciferase reporter assay, western blotting, fow cytometry, and animal experiments were performed in this study. Results: MicroRNA (miR-661 was identified as a downregulated miRNA in OS tissues and cells and shown to directly target CYC1. Ectopically expressed miR-661 inhibited OS cell growth, promoted apoptosis, and reduced the activity of mitochondrial complex III. miR-661 overexpression enhanced TRAIL or STS induced apoptosis and promoted the release of cytochrome c into the cytosol, which induced caspase-9 activation, and these effects were abolished by a caspase-3 inhibitor. Overexpression of CYC1 rescued the effects of miR-661 on sensitizing OS cells to TRAIL or STS induced apoptosis, indicating that the antitumor effect of miR-661 is mediated by the downregulation of CYC1. In vivo, miR-661 overexpression sensitized tumors to TRAIL or STS induced apoptosis in a xenograft mouse model, and these effects were attenuated by co-expression of CYC1. Conclusion: Taken together, our results indicate that miR-661 plays a tumor suppressor role in OS mediated by the downregulation of CYC1, suggesting a potential mechanism underlying cell death resistance in OS.

  19. Trailing edge noise estimation by tomographic Particle Image Velocimetry

    Science.gov (United States)

    Pröbsting, Stefan; Tuinstra, Marthijn; Scarano, Fulvio

    2015-06-01

    The feasibility of estimating broadband trailing edge noise with high-speed tomographic Particle Image Velocimetry (PIV) measurements is studied. A thin plate terminating in a sharp trailing edge provides a generic test case for turbulent boundary layer trailing edge interaction noise. Far-field noise is linked to the wavenumber-frequency spectrum of the surface pressure fluctuations in proximity of the trailing edge through diffraction theory. High-speed tomographic PIV measurements return volumetric and time-resolved information about all velocity components for the resolved spatio-temporal scales and can therefore provide the required statistical quantities. For the turbulent boundary layer interacting with the trailing edge, these statistics include the auto-spectral density, spanwise correlation length, and convection velocity of the unsteady surface pressure, which are thus estimated. Acoustic phased array measurements in an anechoic environment provide a reference for comparison. Over the resolved frequency band, PIV based noise estimation results compare favorably with the reference measurements. Especially at lower frequencies, where existing, empirical models for the unsteady surface pressure spectrum are not accurate, tomographic PIV can offer an alternative approach to complex and intrusive model instrumentation for assessing the relevant statistical quantities.

  20. 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.

  1. 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.

  2. Bortezomib sensitizes primary human astrocytoma cells of WHO grades I to IV for tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis

    NARCIS (Netherlands)

    Koschny, Ronald; Holland, Heidrun; Sykora, Jaromir; Haas, Tobias L.; Sprick, Martin R.; Ganten, Tom M.; Krupp, Wolfgang; Bauer, Manfred; Ahnert, Peter; Meixensberger, Jürgen; Walczak, Henning

    2007-01-01

    Malignant gliomas are the most aggressive human brain tumors without any curative treatment. The antitumor effect of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in gliomas has thus far only been thoroughly established in tumor cell lines. In the present study, we investigated the

  3. Trails Management at LANL - A Presentation to the Los Alamos County Parks and Recreation Board

    Energy Technology Data Exchange (ETDEWEB)

    Pava, Daniel Seth [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2015-05-12

    Los Alamos National Laboratory’s (LANL) trail management program goals include reduce risk of damage and injury to property, human life, and health, and sensitive natural and cultural resources from social trail use at LANL, facilitate the establishment of a safe viable network of linked trails, maintain security of LANL operations, and many more, respect the wishes of local Pueblos, adapt trail use to changing conditions in a responsive manner, and maintain the recreational functionality of the DOE lands. There are approximately 30 miles of LANL trails. Some are open to the public and allow bicycles, horses, hikers, and runners. Know the rules of the trails to stay safe.

  4. TRAIL Activates a Caspase 9/7-Dependent Pathway in Caspase 8/10-Defective SK-N-SH Neuroblastoma Cells with Two Functional End Points: Induction of Apoptosis and PGE2 Release

    Directory of Open Access Journals (Sweden)

    Giorgio Zauli

    2003-09-01

    Full Text Available Most neuroblastoma cell lines do not express apical caspases 8 and 10, which play a key role in mediating tumor necrosis factor-related apoptosis-inducing ligand (TRAIL cytotoxicity in a variety of malignant cell types. In this study, we demonstrated that TRAIL induced a moderate but significant increase of apoptosis in the caspase 8/10-deficient SK-N-SH neuroblastoma cell line, through activation of a novel caspase 9/7 pathway. Concomitant to the induction of apoptosis, TRAIL also promoted a significant increase of prostaglandin E2 (PGE2 release by SKN-SH cells. Moreover, coadministration of TRAIL plus indomethacin, a pharmacological inhibitor of cyclooxygenase (COX, showed an additive effect on SKN-SH cell death. In spite of the ability of TRAIL to promote the phosphorylation of both ERKi/2 and p38/MAPK, which have been involved in the control of COX expression/activity, neither PD98059 nor SB203580, pharmacological inhibitors of the ERKi/2 and p38/MAPK pathways, respectively, affected either PGE2 production or apoptosis induced by TRAIL. Finally, both induction of apoptosis and PGE2 release were completely abrogated by the broad caspase inhibitor z-VAD4mk, suggesting that both biologic end points were regulated in SK-N-SH cells through a caspase 9/7-dependent pathway.

  5. Wake-Induced Aerodynamics on a Trailing Aircraft

    Science.gov (United States)

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

    2016-01-01

    NASA conducted flight tests to measure the exhaust products from alternative fuels using a DC-8 transport aircraft and a Falcon business jet. An independent analysis of the maximum vortex-induced loads on the Falcon in the DC-8 wake was conducted for pre-flight safety analysis and to define safe trail distances for the flight tests. Static and dynamic vortex-induced aerodynamic loads on the Falcon were predicted at a matrix of locations aft of the DC-8 under flight-test conditions, and the maximum loads were compared with design limit loads to assess aircraft safety. Trajectory simulations for the Falcon during close encounters with the DC-8 wake were made to study the vortex-induced loads during traverses of the DC-8 primary trailing vortex. A parametric study of flight traverses through the trailing vortex was conducted to assess Falcon flight behavior and motion characteristics.

  6. Trail Trees: Living Artifacts (Vivifacts of Eastern North America

    Directory of Open Access Journals (Sweden)

    Nicholas C. Kawa

    2015-09-01

    Full Text Available Living trees historically modified by human populations, oftentimes referred to as “culturally modified trees” (CMTs, are found throughout the North American landscape. In eastern North America specifically, indigenous populations bent thousands of trees to mark trails, and some of these still exist in the region today. In this article, we present a synthesis of current knowledge on trail trees, including their speculated functions, formation, and selection. We also examine the theoretical implications of these living artifacts (or vivifacts and how they may open new avenues for investigation by archaeologists, environmental historians, and ethnobiologists. To conclude, we make a call for expanded public recognition and documentation of trail trees, discussing the need for their incorporation into forest and park management plans.

  7. 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.

  8. 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.

  9. 78 FR 25762 - Notice of Availability of the Final Trail Management Plan/Final Environmental Impact Statement...

    Science.gov (United States)

    2013-05-02

    ... includes the addition of 37 miles of trails, including 10 miles of trails for off-road bicycle use... the restoration and sustainability of the trail system for the future. Of the actions that are...

  10. 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.

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

    DEFF Research Database (Denmark)

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

    2009-01-01

    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 hea...... 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....

  12. Microstructure analysis of snail trails in photovoltaic modules

    Science.gov (United States)

    Tao, J.; Shi, Z. X.; Chen, S. Y.; Kong, J. X.; Huang, Q. S.; Gou, X. Fg

    2018-01-01

    Snail trails on photovoltaic modules are a source of enormous concern to the solar industry as few scientific reports on the mechanisms producing this global phenomenon were previously available. The samples surface were treated with CH3OH/CH2Cl2 and used the SEM and Raman for material analysis. The size of the discoloration silver grid is about 80-200 nm. From the Raman spectroscopy can be seen snail trails and the surrounding discoloration of silver on the Ag2CO3 generation.

  13. 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)

  14. 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...

  15. Failures in trailing edge bondlines of wind turbine blades

    DEFF Research Database (Denmark)

    Jensen, Find Mølholt; Sørensen, John Dalsgaard; Nielsen, Per Hørlyk

    2011-01-01

    constitute a significant part of the cost per kWh produced. However, the wind turbine industy is reluctant to share statistical values for damages, and this makes it more difficult to assess the reliability. Instead of analyzing the joint and reinforce the connection, research at Risø DTU has shown......, that it possible to reduce the deformation of the trailing edge panels and thereby reduce the peeling stresses in the trailing edge joint. A basic solution patented by Risø DTU is presented. The research is based on a combination of numerical analysis and full-scale testing. The research has shown the need...

  16. Peran Layanan Jasa Search Engine Optimization untuk Meningkatkan Daya Saing pada Bisnis Startup (Studi pada Kaldera Trail and Jeep Adventure Malang

    Directory of Open Access Journals (Sweden)

    Wira Bharata

    2016-12-01

    Full Text Available This study aimed to investigate the role of SEO as a strategic competitive advantage. This study uses a qualitative approach with case studies are used as a research design. Researchers in the interviews to the owner Caldera Trail & Jeep Adventure. The results of this study indicate that the role of SEO to optimize the website proved successful in the company’s competitive advantage strategy Caldera Trail & Jeep Adventure. The results showed online marketing is done through Facebook, Twitter, Instagram and website have a positive impact on sales in their services. Applying marketing strategies using social media-based social networks and websites are very efficient because of much greater use conventional marketing strategies. This study also emphasizes the social media as online advertising that can be used as a marketing strategy in today’s digital era.

  17. Osteoprotegerin rich tumor microenvironment: implications in breast cancer.

    Science.gov (United States)

    Goswami, Sudeshna; Sharma-Walia, Neelam

    2016-07-05

    Osteoprotegerin (OPG) is a soluble decoy receptor for tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL). It belongs to the tumor necrosis factor receptor superfamily (TNFRSF). OPG was initially discovered to contribute to homeostasis of bone turnover due to its capability of binding to receptor activator of nuclear factor-kappaB (NF-kB). However, apart from bone turnover, OPG plays important and diverse role(s) in many biological functions. Besides having anti-osteoclastic activity, OPG is thought to exert a protective anti-apoptotic action in OPG-expressing tumors by overcoming the physiologic mechanism of tumor surveillance exerted by TRAIL. Along with inhibiting TRAIL induced apoptosis, it can induce proliferation by binding to various cell surface receptors and thus turning on the canonical cell survival and proliferative pathways. OPG also induces angiogenesis, one of the hallmarks of cancer, thus facilitating tumor growth. Recently, the understanding of OPG and its different roles has been augmented substantially. This review is aimed at providing a very informative overview as to how OPG affects cancer progression especially breast cancer.

  18. Modulating TRAIL-Mediated Apoptosis in Prostate Cancer Using Synthetic Triterpenoids

    National Research Council Canada - National Science Library

    Hyer, Marc L

    2005-01-01

    .... Concomitant treatment with CDDO or CDDO-Im reverses the TRAIL-resistant phenotype, leading to rapid induction of TRAIL-mediated apoptosis, while having no adverse effects on normal human mammary epithelial cells (HMEC...

  19. 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...

  20. Water-Solubilizing Hydrophobic ZnAgInSe/ZnS QDs with Tumor-Targeted cRGD-Sulfobetaine-PIMA-Histamine Ligands via a Self-Assembly Strategy for Bioimaging.

    Science.gov (United States)

    Deng, Tao; Peng, Yanan; Zhang, Rong; Wang, Jie; Zhang, Jie; Gu, Yueqing; Huang, Dechun; Deng, Dawei

    2017-04-05

    Exploring the organic-to-aqueous phase transfer of quantum dots (QDs) is significant for achieving their versatile applications in biomedical fields. In this thematic issue, surface modification, size control, and biocompatibility of QDs and QDs-based nanocomposites are core problems. Herein, the new highly fluorescent tumor-targeted QDs-clusters consisting of ZnAgInSe/ZnS (ZAISe/ZnS) QDs and sulfobetaine-PIMA-histamine (SPH) polymer with the α ν β 3 integrin receptor cyclic RGD (c-RGD) were developed via ligand exchange and an accompanying self-assembly process. It was found that the structure of RGD-SPH QDs-clusters was propitious to reduce the capture of reticulo-endothelial system (RES) in virtue of external stealth ligands, and benefit to selectively accumulate at the tumor site after intravenous injection via active tumor targeting cooperated with the enhanced permeability and retention (EPR) effect. In the meantime, those clusters also recognized and enriched the cell surface when cocultured with the α ν β 3 integrin receptor overexpressed malignant cells (U87MG tumor). On the basis of the results, fabricating mutil-functional nanocomposites integrated with the long-term circulation and dual-targeting effects should be an interesting strategy for imaging cancer in vitro and in vivo.

  1. Tumors markers

    International Nuclear Information System (INIS)

    Yamaguchi-Mizumoto, N.H.

    1989-01-01

    In order to study blood and cell components alterations (named tumor markers) that may indicate the presence of a tumor, several methods are presented. Aspects as diagnostic, prognostic, therapeutic value and clinical evaluation are discussed. (M.A.C.)

  2. Mammary tumors

    International Nuclear Information System (INIS)

    Weller, R.E.

    1988-10-01

    Mammary neoplasia is one of the more common malignancies affecting domestic species. Despite their importance, they are often over- diagnosed, undertreated and subject to several misconceptions propagated by veterinarians and pet owners alike. Mammary neoplasia is the most frequent tumor type encountered in the female accounting for almost half of all malignancies reported. The canine has the highest incidence of mammary tumors of all domestic species. In the dog, about 65 percent of mammary tumors are benign mixed tumors, and 25 percent are carcinomas. The rest are adenomas, myoepitheliomas, and malignant mixed tumors. The age distribution of mammary tumors closely follows the age distribution of most tumors in the dog. Mammary tumors are rare in dogs 2 years old, but incidence begins to increase sharply at approximately 6 years of age. Median age at diagnosis is about 10 years. No breed predilection has been consistently reported

  3. 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◦....

  4. Mucus trail tracking in a predatory snail: olfactory processing retooled to serve a novel sensory modality

    OpenAIRE

    Patel, Kinjal; Shaheen, Nagma; Witherspoon, Jessica; Robinson, Natallia; Harrington, Melissa A

    2013-01-01

    Introduction The rosy wolfsnail (Euglandina rosea), a predatory land snail, finds prey snails and potential mates by following their mucus trails. Euglandina have evolved unique, mobile lip extensions that detect mucus and aid in following trails. Currently, little is known of the neural substrates of the trail-following behavior. Methods To investigate the neural correlates of trail following we used tract-tracing experiments in which nerves were backfilled with either nickel-lysine or Lucif...

  5. Different modulation of TRAIL-induced apoptosis by inhibition of pro-survival pathways in TRAIL-sensitive and TRAIL-resistant colon cancer cells

    Czech Academy of Sciences Publication Activity Database

    Vaculová, Alena; Hofmanová, Jiřina; Souček, Karel; Kozubík, Alois

    2006-01-01

    Roč. 580, č. 28-29 (2006), s. 6565-6569 ISSN 0014-5793 R&D Projects: GA ČR(CZ) GA524/04/0895; GA AV ČR(CZ) 1QS500040507 Institutional research plan: CEZ:AV0Z50040507 Keywords : TRAIL * apoptosis * Mc1-1 Subject RIV: BO - Biophysics Impact factor: 3.372, year: 2006

  6. Spinal tumors

    International Nuclear Information System (INIS)

    Goethem, J.W.M. van; Hauwe, L. van den; Oezsarlak, Oe.; Schepper, A.M.A. de; Parizel, P.M.

    2004-01-01

    Spinal tumors are uncommon lesions but may cause significant morbidity in terms of limb dysfunction. In establishing the differential diagnosis for a spinal lesion, location is the most important feature, but the clinical presentation and the patient's age and gender are also important. Magnetic resonance (MR) imaging plays a central role in the imaging of spinal tumors, easily allowing tumors to be classified as extradural, intradural-extramedullary or intramedullary, which is very useful in tumor characterization. In the evaluation of lesions of the osseous spine both computed tomography (CT) and MR are important. We describe the most common spinal tumors in detail. In general, extradural lesions are the most common with metastasis being the most frequent. Intradural tumors are rare, and the majority is extramedullary, with meningiomas and nerve sheath tumors being the most frequent. Intramedullary tumors are uncommon spinal tumors. Astrocytomas and ependymomas comprise the majority of the intramedullary tumors. The most important tumors are documented with appropriate high quality CT or MR images and the characteristics of these tumors are also summarized in a comprehensive table. Finally we illustrate the use of the new World Health Organization (WHO) classification of neoplasms affecting the central nervous system

  7. Urogenital tumors

    Energy Technology Data Exchange (ETDEWEB)

    Weller, R.E.

    1994-03-01

    An overview is provided for veterinary care of urogenital tumors in companion animals, especially the dog. Neoplasms discussed include tumors of the kidney, urinary bladder, prostate, testis, ovary, vagina, vulva and the canine transmissible venereal tumor. Topics addressed include description, diagnosis and treatment.

  8. Brain Tumors

    Science.gov (United States)

    A brain tumor is a growth of abnormal cells in the tissues of the brain. Brain tumors can be benign, with no cancer cells, ... cancer cells that grow quickly. Some are primary brain tumors, which start in the brain. Others are ...

  9. Trail pheromone of the Argentine ant, Linepithema humile (Mayr) (Hymenoptera: Formicidae).

    Science.gov (United States)

    Choe, Dong-Hwan; Villafuerte, David B; Tsutsui, Neil D

    2012-01-01

    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.

  10. 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.

  11. Trails in an Urban Setting (Chicago Circle Campus, University of Illinois, March 21, 1970).

    Science.gov (United States)

    Open Lands Project, Chicago, IL.

    Concerned with developing a master plan for interlinking recreational trails throughout Cook County, Illinois, this document consists primarily of proceedings of a conference on trails in an urban setting. Presentations are Urban Trails: A Tremendous Recreation Opportunity; Legal Considerations; Development; Utilities; Planning; Getting Started;…

  12. Material matters: Controllable rubber trailing edge flap regulates load on wind turbine blades

    DEFF Research Database (Denmark)

    Aagaard Madsen, Helge

    2010-01-01

    trailing edge flap, known as CRTEF. The trailing edge blade design is expected to help mitigate localized loading, and its molded rubber design, the sharp trailing edge, produces less noise and greater output. With CRTEF, the blade automatically has a completely sharp edge. The elastic flap tested...

  13. 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

  14. 76 FR 8992 - National Trails System Act and Railroad Rights-of-Way

    Science.gov (United States)

    2011-02-16

    ... continued interim trail use is subject to possible future restoration of the right-of-way and reactivation...-of-way for interim trail use and rail banking. (a) * * * (2) A statement indicating the trail sponsor... described in paragraph (a)(2) of this section, and subject to possible future reconstruction and...

  15. Evaluation of the Cross Alert system on the Virginia Capital Trail in James City County.

    Science.gov (United States)

    2008-01-01

    The Virginia Capital Trail is a bicycle and pedestrian trail that connects Virginia's past and present capitals of Jamestown, Williamsburg, and Richmond along the scenic Route 5 highway corridor. The trail crosses Route 5, a two-lane roadway with a 5...

  16. 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...

  17. Trail Pheromone of the Argentine Ant, Linepithema humile (Mayr) (Hymenoptera: Formicidae)

    Science.gov (United States)

    Choe, Dong-Hwan; Villafuerte, David B.; Tsutsui, Neil D.

    2012-01-01

    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. PMID:23028739

  18. Epidemiological features of brain tumors

    Directory of Open Access Journals (Sweden)

    Živković Nenad

    2013-01-01

    Full Text Available Brain tumors account for 1.4% of all cancers and 2.4% of all cancer-related deaths. The incidence of brain tumors varies and it is higher in developed countries of Western Europe, North America, Australia and New Zealand. In Serbia, according to data from 2009, malignant brain tumors account for 2. 2 of all tumors, and from all cancer­related deaths, 3.2% is caused by malignant brain tumors. According to recent statistical reports, an overall incidence of brain tumors for benign and malignant tumors combined is 18.71 per 100,000 persons/year. The most common benign brain tumor in adults is meningioma, which is most present in women, and the most common malignant tumor is glioblastoma, which is most present in adult men. Due to high mortality, especially in patients diagnosed with glioblastoma and significant brain tumor morbidity, there is a constant interest in understanding its etiology in order to possibly prevent tumor occurrence in future and enable more efficient treatment strategies for this fatal brain disease. Despite the continuously growing number of epidemiological studies on possible factors of tumor incidence, the etiology remains unclear. The only established environmental risk factor of gliomas is ionizing radiation exposure. Exposure to radiofrequency electromagnetic fields via cell phone use has gained a lot of attention as a potential risk factor of brain tumor development. However, studies have been inconsistent and inconclusive, so more definite results are still expected.

  19. Operative management of skull base malignant tumors arising from the nasal cavity and paranasal sinus. Recent strategies used in 25 cases

    International Nuclear Information System (INIS)

    Jimbo, Hiroyuki; Kamata, Shinetsu; Miura, Kouki; Asamoto, Shunji; Tada, Shinichiro; Endo, Takahiro; Masubuchi, Tatsuo; Nakamura, Narihiro; Fushimi, Chihiro

    2010-01-01

    Cancers of the paranasal sinuses and nasal cavity are the most common malignant tumors of the anterior and anterolateral skull base. The treatment of these tumors affecting the skull base is complex due to the significant anatomical features. We examined 25 patients, 17 males and 8 females with mean age 61±2 years. En bloc resections using anterior skull base resection, orbital resection, middle fossa resection, and combined procedures of these three resections were performed. Using a combination of adjuvant radiation and chemotherapy, we have achieved a 2-year disease-free survival rate of 90% in these cases. However, potential complications include cerebrospinal fluid leakage, meningitis, abscess formation, pneumocephalus, frontal brain contusion, trismus, and dysphagia as a functional complication. We believe that the optimal management of such malignant tumors involves a multimodal and multidisciplinary team approach. Here we present our recent institutional experience and treatment policy employed during the past 3 years. (author)

  20. 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...

  1. 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 an...

  2. Subcomponent testing of trailing edge panels in wind turbine blades

    DEFF Research Database (Denmark)

    Branner, Kim; Berring, Peter; Haselbach, Philipp Ulrich

    2016-01-01

    This paper proposes a static subcomponent test method designed to check the compressive strength of the trailing edge region in wind turbine blades under a simplified loading. The paper presents numerical simulations using the proposed subcomponent test method and discusses its ability to be used...

  3. 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...

  4. A Contingent Trip Model for Estimating Rail-trail Demand

    Science.gov (United States)

    Carter J. Betz; John C. Bergstrom; J. Michael Bowker

    2003-01-01

    The authors develop a contingent trip model to estimate the recreation demand for and value of a potential rail-trail site in north-east Georgia. The contingent trip model is an alternative to travel cost modelling useful for ex ante evaluation of proposed recreation resources or management alternatives. The authors estimate the empirical demand for trips using a...

  5. Design methodology for trailing-edge high-lift mechanisms

    NARCIS (Netherlands)

    Zaccai, D; Bertels, F.G.A.; Vos, R.

    2016-01-01

    A new methodology has been developed that integrates the preliminary wing design with trailing edge high-lift systems and accounts for three-dimensional flap kinematics. The high-lift system in the developed application includes the kinematic synthesis of four common mechanisms (dropped-hinge,

  6. 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

    The development of a morphing trailing edge system for wind turbines, also called a flap system, is presented. The functionality is simple as the flap deflection is controlled by pressurized air or a fluid in a number of voids in the flap made of an elastic material. It is thus a robust system...

  7. 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…

  8. Cohort Profile Update : The TRacking Adolescents' Individual Lives Survey (TRAILS)

    NARCIS (Netherlands)

    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

    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

  9. 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.

  10. What Happened to Hyakutake? On the Trail of a Comet

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 1; Issue 6. What Happened to Hyakutake? On the Trail of a Comet. B S Shylaja. General Article Volume 1 Issue 6 June 1996 pp 50-57. Fulltext. Click here to view fulltext PDF. Permanent link: http://www.ias.ac.in/article/fulltext/reso/001/06/0050-0057 ...

  11. Dispersion of meteor trails in the geomagnetic field.

    Science.gov (United States)

    Robson, R E

    2001-02-01

    A meteor trail is modeled by a long column of weakly ionized plasma, whose dispersion is controlled by the geomagnetic field and the requirement to maintain effective space charge neutrality. First we consider scattering of a radar signal from an underdense trail and derive an expression for the amplitude of the backscattered signal as a function of time. Then, starting from the basic momentum balance equations for electrons and ions in a partially ionized plasma, we require divergences of ion and electron fluxes to be equal, plus assume equality of the flux components along the magnetic field direction. The analysis is really applicable to a whole range of plasma problems, although we focus upon meteor trails for now. It is found that charged particle densities satisfy a diffusion equation and we obtain an expression for the ambipolar diffusion tensor and expressions for the ambipolar electric field, valid for arbitrary relative orientations of the magnetic field and meteor trail axis. Results are somewhat different from previous analyses in the meteor literature.

  12. 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…

  13. 30 CFR 75.828 - Trailing cable pulling.

    Science.gov (United States)

    2010-07-01

    ... MANDATORY SAFETY STANDARDS-UNDERGROUND COAL MINES Underground High-Voltage Distribution High-Voltage... any equipment other than the continuous mining machine. The cable manufacturer's recommended pulling procedures must be followed when pulling the trailing cable with equipment other than the continuous mining...

  14. Inca Trail porters: the health of local tourism employees as a challenge for travel medicine.

    Science.gov (United States)

    Bauer, Irmgard L

    2003-01-01

    Trekking is an activity that forms part of the increasing adventure and outdoor tourism. High altitude trekking in the Himalayas or Andes has been popular for some time. For longer treks, porters are employed to carry necessary equipment. Porters' working conditions are unfortunate and subsequent health problems considerable. Although Himalayan porters have received some attention in the press and research literature, porters on the popular Inca Trail in Peru have been neglected. In light of the growing awareness of health problems of local tourism employees, the purpose of this study was to describe Inca Trail porters' working conditions and their reports on their related health status to provide baseline information for further research and strategies for improvement. For this descriptive study, 101 Inca Trail porters were interviewed (August/September 2001) using a structured interview schedule. Porters were between 17 and 68 years old; estimated body weight ranged from 50 kg to 76 kg. The usual portering job lasts for 4 days with 9 to 10 hours of carrying per day. Estimated weight of loads ranged from 20 kg to 45 kg. Major concerns were lack of fuel, clothes, shelter, and equipment but foremost the lack of sufficient food provisions. A third described their general health as poor or very poor and attributed this to work. Health complaints included respiratory infections, kidney problems, or rheumatism. Thirty-eight porters recalled injuries while on the trail and over 90% had fallen ill on the job with cold, "majurki," and stomach pain due to lack of food or cold food being named most often. Porters' demands for improvement included increased pay and appropriate and sufficient food. The porters' working conditions and subsequent health problems need to be addressed. A range of stakeholders is responsible for the porters' conditions and are in a position to improve current situations. Specific responsibility for health care lies with travel health professionals

  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. Strategy; Strategies

    Energy Technology Data Exchange (ETDEWEB)

    Anon.

    2005-07-15

    Francois Loos, Minister of Industry, explains the French energy policy in the frame of Europe. ONERC is a French public body in charge of defining a national strategy against climate changes. It submits its first strategic elements to the Government. (authors)

  17. Determinates of tumor response to radiation: Tumor cells, tumor stroma and permanent local control

    International Nuclear Information System (INIS)

    Li, Wende; Huang, Peigen; Chen, David J.; Gerweck, Leo E.

    2014-01-01

    Background and purpose: The causes of tumor response variation to radiation remain obscure, thus hampering the development of predictive assays and strategies to decrease resistance. The present study evaluates the impact of host tumor stromal elements and the in vivo environment on tumor cell kill, and relationship between tumor cell radiosensitivity and the tumor control dose. Material and methods: Five endpoints were evaluated and compared in a radiosensitive DNA double-strand break repair-defective (DNA-PKcs −/− ) tumor line, and its DNA-PKcs repair competent transfected counterpart. In vitro colony formation assays were performed on in vitro cultured cells, on cells obtained directly from tumors, and on cells irradiated in situ. Permanent local control was assessed by the TCD 50 assay. Vascular effects were evaluated by functional vascular density assays. Results: The fraction of repair competent and repair deficient tumor cells surviving radiation did not substantially differ whether irradiated in vitro, i.e., in the absence of host stromal elements and factors, from the fraction of cells killed following in vivo irradiation. Additionally, the altered tumor cell sensitivity resulted in a proportional change in the dose required to achieve permanent local control. The estimated number of tumor cells per tumor, their cloning efficiency and radiosensitivity, all assessed by in vitro assays, were used to predict successfully, the measured tumor control doses. Conclusion: The number of clonogens per tumor and their radiosensitivity govern the permanent local control dose

  18. Tumor immunology

    International Nuclear Information System (INIS)

    Otter, W. den

    1987-01-01

    Tumor immunology, the use of immunological techniques for tumor diagnosis and approaches to immunotherapy of cancer are topics covered in this multi-author volume. Part A, 'Tumor Immunology', deals with present views on tumor-associated antigens, the initiation of immune reactions of tumor cells, effector cell killing, tumor cells and suppression of antitumor immunity, and one chapter dealing with the application of mathematical models in tumor immunology. Part B, 'Tumor Diagnosis and Imaging', concerns the use of markers to locate the tumor in vivo, for the histological diagnosis, and for the monitoring of tumor growth. In Part C, 'Immunotherapy', various experimental approaches to immunotherapy are described, such as the use of monoclonal antibodies to target drugs, the use of interleukin-2 and the use of drugs inhibiting suppression. In the final section, the evaluation, a pathologist and a clinician evaluate the possibilities and limitations of tumor immunology and the extent to which it is useful for diagnosis and therapy. refs.; figs.; tabs

  19. Aerodynamic noise from rigid trailing edges with finite porous extensions

    Science.gov (United States)

    Kisil, A.; Ayton, L. J.

    2018-02-01

    This paper investigates the effects of finite flat porous extensions to semi-infinite impermeable flat plates in an attempt to control trailing-edge noise through bio-inspired adaptations. Specifically the problem of sound generated by a gust convecting in uniform mean steady flow scattering off the trailing edge and permeable-impermeable junction is considered. This setup supposes that any realistic trailing-edge adaptation to a blade would be sufficiently small so that the turbulent boundary layer encapsulates both the porous edge and the permeable-impermeable junction, and therefore the interaction of acoustics generated at these two discontinuous boundaries is important. The acoustic problem is tackled analytically through use of the Wiener-Hopf method. A two-dimensional matrix Wiener-Hopf problem arises due to the two interaction points (the trailing edge and the permeable-impermeable junction). This paper discusses a new iterative method for solving this matrix Wiener-Hopf equation which extends to further two-dimensional problems in particular those involving analytic terms that exponentially grow in the upper or lower half planes. This method is an extension of the commonly used "pole removal" technique and avoids the needs for full matrix factorisation. Convergence of this iterative method to an exact solution is shown to be particularly fast when terms neglected in the second step are formally smaller than all other terms retained. The final acoustic solution highlights the effects of the permeable-impermeable junction on the generated noise, in particular how this junction affects the far-field noise generated by high-frequency gusts by creating an interference to typical trailing-edge scattering. This effect results in partially porous plates predicting a lower noise reduction than fully porous plates when compared to fully impermeable plates.

  20. 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.

  1. 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.

  2. Estratégias auxiliares para graduação dos tumores astrocíticos segundo os critérios histopatológicos estabelecidos pela OMS Auxiliary strategies for astrocytic tumor graduation according to histopathological criteria established by WHO

    Directory of Open Access Journals (Sweden)

    Mário Henrique Girão Faria

    2006-10-01

    aimed to develop auxiliary strategies for astrocytic tumor graduation according to histological criteria established by WHO. MATERIAL AND METHOD: A clinical and epidemiological analysis and a histopathological evaluation were performed in 55 astrocytomas of different graduations (13 grade I, 14 grade II, seven grade III, 21 grade IV and five samples of non-tumor tissue (control group. RESULTS: The distribution by age, sex, and tumor localization of astrocytomas in patients reproduced, in a general way, worldwide trends. The presence of multinucleated cells and gemistocytes was associated with tumoral malignancy. The histopathological findings evaluated through semi-quantitative criteria and CART modeling confirmed the primary classification, reaffirming their applicability and reproducibility. CONCLUSION: These results indicate the CART decision tree and the totality of semi-quantitative scores as practical and auxiliary strategies for astrocytoma graduation as stated by WHO criteria.

  3. 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

  4. 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.

  5. 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

  6. 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.

  7. Tumor vaccines:

    OpenAIRE

    Frank, Mojca; Ihan, Alojz

    2006-01-01

    Tumor vaccines have several potential advantages over standard anticancer regirrcents. They represent highly specific anticancer therapy. Inducing tumor-specific memory T-lymphocytes, they have potential for long-lived antitumor effects. However, clinical trials, in which cancer patients were vaccinated with tccmor aaccines, have been so far mainly disappointing. There are many reasons for the inefficiency of tumor vaccines. Most cancer antigens are normal self-molecules to which imrrtune tol...

  8. Proteomics informed by transcriptomics reveals Hendra virus sensitizes bat cells to TRAIL-mediated apoptosis.

    Science.gov (United States)

    Wynne, James W; Shiell, Brian J; Marsh, Glenn A; Boyd, Victoria; Harper, Jennifer A; Heesom, Kate; Monaghan, Paul; Zhou, Peng; Payne, Jean; Klein, Reuben; Todd, Shawn; Mok, Lawrence; Green, Diane; Bingham, John; Tachedjian, Mary; Baker, Michelle L; Matthews, David; Wang, Lin-Fa

    2014-01-01

    Bats are a major reservoir of emerging infectious viruses. Many of these viruses are highly pathogenic to humans however bats remain asymptomatic. The mechanism by which bats control viral replication is unknown. Here we utilize an integrated approach of proteomics informed by transcriptomics to compare the response of immortalized bat and human cells following infection with the highly pathogenic bat-borne Hendra virus (HeV). The host response between the cell lines was significantly different at both the mRNA and protein levels. Human cells demonstrated minimal response eight hours post infection, followed by a global suppression of mRNA and protein abundance. Bat cells demonstrated a robust immune response eight hours post infection, which led to the up-regulation of apoptosis pathways, mediated through the tumor necrosis factor-related apoptosis inducing ligand (TRAIL). HeV sensitized bat cells to TRAIL-mediated apoptosis, by up-regulating death receptor transcripts. At 48 and 72 hours post infection, bat cells demonstrated a significant increase in apoptotic cell death. This is the first study to comprehensively compare the response of bat and human cells to a highly pathogenic zoonotic virus. An early induction of innate immune processes followed by apoptosis of virally infected bat cells highlights the possible involvement of programmed cell death in the host response. Our study shows for the first time a side-by-side high-throughput analysis of a dangerous zoonotic virus in cell lines derived from humans and the natural bat host. This enables a way to search for divergent mechanisms at a molecular level that may influence host pathogenesis.

  9. Bypassing the need for pre-sensitization of cancer cells for anticancer TRAIL therapy with secretion of novel cell penetrable form of Smac from hA-MSCs as cellular delivery vehicle.

    Science.gov (United States)

    Khorashadizadeh, Mohsen; Soleimani, Masoud; Khanahmad, Hossein; Fallah, Ali; Naderi, Mahmood; Khorramizadeh, Mohammadreza

    2015-06-01

    TNF-related apoptosis inducing ligand (TRAIL) is a novel anticancer agent with selective apoptosis-inducing activity on cancer cells. However, many malignant tumors still remain unresponsive. Although cells can bypass apoptosis by different functions, the defect in the blocking role of second mitochondria-derived activator of caspase (Smac) on X-linked inhibitor of apoptosis protein (XIAP) is known to be an important hub for immortal characteristic of malignant cells. Actually, XIAP is known as an apoptosis inhibitor. To date, the sensitization of cancerous cells to TRAIL was successfully performed with different protocols, mainly through blocking XIAP with Smac administration. However, all these sensitization methodologies need to be performed prior to TRAIL administration on cancerous cells which in turn limit their practical application in clinics. Therefore, we hypothesized that concurrent expression of Smac and TRAIL on human adipose-derived mesenchymal stem cells (hA-MSC-ST) could both sensitize and destroy cancerous cells. To this aim, we generated hA-MSC-ST, secreting a novel cell penetrable form of Smac and a trimeric form of TRAIL. Indeed, the cell penetrable form of Smac obviates the need for any pretreatment of cancerous cells. Our data depicted that individual overexpression of TRAIL or Smac in different breast cancer cell types induced limited or no apoptosis, respectively. Conversely, their concomitant overexpression markedly increased cell death even for a resistant type of breast cancer cells, MCF-7. Notably, we observed no cytotoxicity of our methodology on normal cells. In summary, this is the first demonstration that a dual approach using simultaneous overexpression of a cell penetrable form of Smac and TRAIL sensitize and promote apoptotic process even in resistant breast cancer cells.

  10. Captopril improves tumor nanomedicine delivery by increasing tumor blood perfusion and enlarging endothelial gaps in tumor blood vessels.

    Science.gov (United States)

    Zhang, Bo; Jiang, Ting; Tuo, Yanyan; Jin, Kai; Luo, Zimiao; Shi, Wei; Mei, Heng; Hu, Yu; Pang, Zhiqing; Jiang, Xinguo

    2017-12-01

    Poor tumor perfusion and unfavorable vessel permeability compromise nanomedicine drug delivery to tumors. Captopril dilates blood vessels, reducing blood pressure clinically and bradykinin, as the downstream signaling moiety of captopril, is capable of dilating blood vessels and effectively increasing vessel permeability. The hypothesis behind this study was that captopril can dilate tumor blood vessels, improving tumor perfusion and simultaneously enlarge the endothelial gaps of tumor vessels, therefore enhancing nanomedicine drug delivery for tumor therapy. Using the U87 tumor xenograft with abundant blood vessels as the tumor model, tumor perfusion experiments were carried out using laser Doppler imaging and lectin-labeling experiments. A single treatment of captopril at a dose of 100 mg/kg significantly increased the percentage of functional vessels in tumor tissues and improved tumor blood perfusion. Scanning electron microscopy of tumor vessels also indicated that the endothelial gaps of tumor vessels were enlarged after captopril treatment. Immunofluorescence-staining of tumor slices demonstrated that captopril significantly increased bradykinin expression, possibly explaining tumor perfusion improvements and endothelial gap enlargement. Additionally, imaging in vivo, imaging ex vivo and nanoparticle distribution in tumor slices indicated that after a single treatment with captopril, the accumulation of 115-nm nanoparticles in tumors had increased 2.81-fold with a more homogeneous distribution pattern in comparison to non-captopril treated controls. Finally, pharmacodynamics experiments demonstrated that captopril combined with paclitaxel-loaded nanoparticles resulted in the greatest tumor shrinkage and the most extensive necrosis in tumor tissues among all treatment groups. Taken together, the data from the present study suggest a novel strategy for improving tumor perfusion and enlarging blood vessel permeability simultaneously in order to improve

  11. Approach for Structurally Clearing an Adaptive Compliant Trailing Edge Flap for Flight

    Science.gov (United States)

    Miller, Eric J.; Lokos, William A.; Cruz, Josue; Crampton, Glen; Stephens, Craig A.; Kota, Sridhar; Ervin, Gregory; Flick, Pete

    2015-01-01

    The Adaptive Compliant Trailing Edge (ACTE) flap was flown on the National Aeronautics and Space Administration (NASA) Gulfstream GIII testbed at the NASA Armstrong Flight Research Center. This smoothly curving flap replaced the existing Fowler flaps creating a seamless control surface. This compliant structure, developed by FlexSys Inc. in partnership with the Air Force Research Laboratory, supported NASA objectives for airframe structural noise reduction, aerodynamic efficiency, and wing weight reduction through gust load alleviation. A thorough structures airworthiness approach was developed to move this project safely to flight. A combination of industry and NASA standard practice require various structural analyses, ground testing, and health monitoring techniques for showing an airworthy structure. This paper provides an overview of compliant structures design, the structural ground testing leading up to flight, and the flight envelope expansion and monitoring strategy. Flight data will be presented, and lessons learned along the way will be highlighted.

  12. Using external data sources to improve audit trail analysis.

    Science.gov (United States)

    Herting, R L; Asaro, P V; Roth, A C; Barnes, M R

    1999-01-01

    Audit trail analysis is the primary means of detection of inappropriate use of the medical record. While audit logs contain large amounts of information, the information required to determine useful user-patient relationships is often not present. Adequate information isn't present because most audit trail analysis systems rely on the limited information available within the medical record system. We report a feature of the STAR (System for Text Archive and Retrieval) audit analysis system where information available in the medical record is augmented with external information sources such as: database sources, Light-weight Directory Access Protocol (LDAP) server sources, and World Wide Web (WWW) database sources. We discuss several issues that arise when combining the information from each of these disparate information sources. Furthermore, we explain how the enhanced person specific information obtained can be used to determine user-patient relationships that might signify a motive for inappropriately accessing a patient's medical record.

  13. The organized nature of a turbulent trailing vortex

    Science.gov (United States)

    Bandyopadhyay, Promode R.; Ash, Robert L.; Stead, Daniel J.

    1990-01-01

    The turbulence structure of a trailing vortex produced at the juncture of a flow aligned cylinder and a pair of oppositely loaded airfoils is analyzed. The freestream turbulence intensity in this study varies from 0.32 to 1.48 percent, the vortex Reynold number varies from 15000 to 25000, and the Rossby number varies from 0.65 to 0.81. Within this parameter range, it is shown that the screens, but not the freestream turbulence level, are able to produce significant variations in the turbulence structure of the vortex, and that the turbulent structure is determined by the Rossby number and not the vortex Reynolds number. It is noted that the core is dynamic and an organized exchange of momentum takes place between the outer flow and the core region of the vortex. The vortex structure in the trailing vortex having the lowest Rossby number is considered.

  14. 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.

  15. 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.

  16. Design, manufacturing and testing of Controllable Rubber Trailing Edge Flaps

    DEFF Research Database (Denmark)

    Løgstrup Andersen, Tom; Aagaard Madsen, Helge; Barlas, Thanasis K

    The overall goal for the INDUFLAP project was realization of a test facility for development and test of Controllable Rubber Trailing Edge Flaps (CRTEF) for wind turbines. This report covers experimental work at DTU Wind Energy including design, manufacture and test of different configurations of...... of flaps with voids in chord- or spanwise direction. Development of rubber flaps has involved further design improvements. Non-metallic spring elements and solutions for sealing of continuous extruded rubber profiles have been investigated....

  17. Tramping Trail with Elroy in the Early Years of CELP

    Science.gov (United States)

    O'Krafka, Karen

    2010-01-01

    The author is sipping tea on the eve of a week-long winter trip--over a decade since she first tramped trail with Mike Elrick into the winter wilderness. This evening holds for her the same electricity that it did in 1997--anxiety and excitement--when Elroy guided a motley crew of teens (his gang) into the woods and frozen waters of Algonquin…

  18. 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.

  19. 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

  20. Tumoral tracers

    International Nuclear Information System (INIS)

    Camargo, E.E.

    1979-01-01

    Direct tumor tracers are subdivided in the following categories:metabolite tracers, antitumoral tracers, radioactive proteins and cations. Use of 67 Ga-citrate as a clinically important tumoral tracer is emphasized and gallium-67 whole-body scintigraphy is discussed in detail. (M.A.) [pt

  1. Carcinoid Tumors

    Science.gov (United States)

    ... spread to other parts of the body. Doctors don't know what causes the mutations that can lead to carcinoid tumors. But they know that carcinoid tumors develop in neuroendocrine cells. Neuroendocrine cells are found in various organs throughout the body. They perform some nerve cell ...

  2. 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.

  3. 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 <1% of the initial mass, while the rest of the object possessed a low durability of 1 MPa [4]. Moreover, Fe3+ hydroxyls were discovered in meteorite samples, the formation of which required water [5]. The glow at the head of the bolide trail, lasting 8 seconds after the flight of the object, and the development of the cloud trail indicate that the celestial body carried water. The Chinese weather satellite 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.

  4. 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.

  5. Looking for dark matter trails in colliding galaxy clusters

    Science.gov (United States)

    Harvey, David; Robertson, Andrew; Massey, Richard; Kneib, Jean-Paul

    2017-02-01

    If dark matter interacts, even weakly, via non-gravitational forces, simulations predict that it will be preferentially scattered towards the trailing edge of the halo during collisions between galaxy clusters. This will temporarily create a non-symmetric mass profile, with a trailing overdensity along the direction of motion. To test this hypothesis, we fit (and subtract) symmetric haloes to the weak gravitational data of 72 merging galaxy clusters observed with the Hubble Space Telescope. We convert the shear directly into excess κ and project in to a one-dimensional profile. We generate numerical simulations and find that the one-dimensional profile is well described with simple Gaussian approximations. We detect the weak lensing signal of trailing gas at a 4σ confidence, finding a mean gas fraction of Mgas/Mdm = 0.13 ± 0.035. We find no evidence for scattered dark matter particles with an estimated scattering fraction of f = 0.03 ± 0.05. Finally, we find that if we can reduce the statistical error on the positional estimate of a single dark matter halo to <2.5 arcsec, then we will be able to detect a scattering fraction of 10 per cent at the 3σ level with current surveys. This potentially interesting new method can provide an important independent test for other complimentary studies of the self-interaction cross-section of dark matter.

  6. Ant trail pheromone biosynthesis is triggered by a neuropeptide hormone.

    Directory of Open Access Journals (Sweden)

    Man-Yeon Choi

    Full Text Available Our understanding of insect chemical communication including pheromone identification, synthesis, and their role in behavior has advanced tremendously over the last half-century. However, endocrine regulation of pheromone biosynthesis has progressed slowly due to the complexity of direct and/or indirect hormonal activation of the biosynthetic cascades resulting in insect pheromones. Over 20 years ago, a neurohormone, pheromone biosynthesis activating neuropeptide (PBAN was identified that stimulated sex pheromone biosynthesis in a lepidopteran moth. Since then, the physiological role, target site, and signal transduction of PBAN has become well understood for sex pheromone biosynthesis in moths. Despite that PBAN-like peptides (∼200 have been identified from various insect Orders, their role in pheromone regulation had not expanded to the other insect groups except for Lepidoptera. Here, we report that trail pheromone biosynthesis in the Dufour's gland (DG of the fire ant, Solenopsis invicta, is regulated by PBAN. RNAi knock down of PBAN gene (in subesophageal ganglia or PBAN receptor gene (in DG expression inhibited trail pheromone biosynthesis. Reduced trail pheromone was documented analytically and through a behavioral bioassay. Extension of PBAN's role in pheromone biosynthesis to a new target insect, mode of action, and behavioral function will renew research efforts on the involvement of PBAN in pheromone biosynthesis in Insecta.

  7. The iron chelator, deferasirox, as a novel strategy for cancer treatment: oral activity against human lung tumor xenografts and molecular mechanism of action.

    Science.gov (United States)

    Lui, Goldie Y L; Obeidy, Peyman; Ford, Samuel J; Tselepis, Chris; Sharp, Danae M; Jansson, Patric J; Kalinowski, Danuta S; Kovacevic, Zaklina; Lovejoy, David B; Richardson, Des R

    2013-01-01

    Deferasirox is an orally effective iron (Fe) chelator currently used for the treatment of iron-overload disease and has been implemented as an alternative to the gold standard chelator, desferrioxamine (DFO). Earlier studies demonstrated that DFO exhibits anticancer activity due to its ability to deplete cancer cells of iron. In this investigation, we examined the in vitro and in vivo activity of deferasirox against cells from human solid tumors. To date, there have been no studies to investigate the effect of deferasirox on these types of tumors in vivo. Deferasirox demonstrated similar activity at inhibiting proliferation of DMS-53 lung carcinoma and SK-N-MC neuroepithelioma cell lines compared with DFO. Furthermore, deferasirox was generally similar or slightly more effective than DFO at mobilizing cellular (59)Fe and inhibiting iron uptake from human transferrin depending on the cell type. However, deferasirox potently inhibited DMS-53 xenograft growth in nude mice when given by oral gavage, with no marked alterations in normal tissue histology. To understand the antitumor activity of deferasirox, we investigated its effect on the expression of molecules that play key roles in metastasis, cell cycle control, and apoptosis. We demonstrated that deferasirox increased expression of the metastasis suppressor protein N-myc downstream-regulated gene 1 and upregulated the cyclin-dependent kinase inhibitor p21(CIP1/WAF1) while decreasing cyclin D1 levels. Moreover, this agent increased the expression of apoptosis markers, including cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase 1. Collectively, we demonstrate that deferasirox is an orally effective antitumor agent against solid tumors.

  8. Animal tumors

    International Nuclear Information System (INIS)

    Gillette, E.L.

    1983-01-01

    There are few trained veterinary radiation oncologists and the expense of facilities has limited the extent to which this modality is used. In recent years, a few cobalt teletherapy units and megavoltage x-ray units have been employed in larger veterinary institutions. In addition, some radiation oncologists of human medical institutions are interested and willing to cooperate with veterinarians in the treatment of animal tumors. Carefully designed studies of the response of animal tumors to new modalities serve two valuable purposes. First, these studies may lead to improved tumor control in companion animals. Second, these studies may have important implications to the improvement of therapy of human tumors. Much remains to be learned of animal tumor biology so that appropriate model systems can be described for such studies. Many of the latter studies can be sponsored by agencies interested in the improvement of cancer management

  9. 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

  10. 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

  11. 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

  12. 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

  13. Technical innovation in dynamic contrast-enhanced magnetic resonance imaging of musculoskeletal tumors: an MR angiographic sequence using a sparse k-space sampling strategy.

    Science.gov (United States)

    Fayad, Laura M; Mugera, Charles; Soldatos, Theodoros; Flammang, Aaron; del Grande, Filippo

    2013-07-01

    We demonstrate the clinical use of an MR angiography sequence performed with sparse k-space sampling (MRA), as a method for dynamic contrast-enhanced (DCE)-MRI, and apply it to the assessment of sarcomas for treatment response. Three subjects with sarcomas (2 with osteosarcoma, 1 with high-grade soft tissue sarcomas) underwent MRI after neoadjuvant therapy/prior to surgery, with conventional MRI (T1-weighted, fluid-sensitive, static post-contrast T1-weighted sequences) and DCE-MRI (MRA, time resolution = 7-10 s, TR/TE 2.4/0.9 ms, FOV 40 cm(2)). Images were reviewed by two observers in consensus who recorded image quality (1 = diagnostic, no significant artifacts, 2 = diagnostic, 75 % with good response, >75 % with poor response). DCE-MRI findings were concordant with histological response (arterial enhancement with poor response, no arterial enhancement with good response). Unlike conventional DCE-MRI sequences, an MRA sequence with sparse k-space sampling is easily integrated into a routine musculoskeletal tumor MRI protocol, with high diagnostic quality. In this preliminary work, tumor enhancement characteristics by DCE-MRI were used to assess treatment response.

  14. Transporter-Mediated Drug Interaction Strategy for 5-Aminolevulinic Acid (ALA-Based Photodynamic Diagnosis of Malignant Brain Tumor: Molecular Design of ABCG2 Inhibitors

    Directory of Open Access Journals (Sweden)

    Toshihisa Ishikawa

    2011-09-01

    Full Text Available Photodynamic diagnosis (PDD is a practical tool currently used in surgical operation of aggressive brain tumors, such as glioblastoma. PDD is achieved by a photon-induced physicochemical reaction which is induced by excitation of protoporphyrin IX (PpIX exposed to light. Fluorescence-guided gross-total resection has recently been developed in PDD, where 5-aminolevulinic acid (ALA or its ester is administered as the precursor of PpIX. ALA induces the accumulation of PpIX, a natural photo-sensitizer, in cancer cells. Recent studies provide evidence that adenosine triphosphate (ATP-binding cassette (ABC transporter ABCG2 plays a pivotal role in regulating the cellular accumulation of porphyrins in cancer cells and thereby affects the efficacy of PDD. Protein kinase inhibitors are suggested to potentially enhance the PDD efficacy by blocking ABCG2-mediated porphyrin efflux from cancer cells. It is of great interest to develop potent ABCG2-inhibitors that can be applied to PDD for brain tumor therapy. This review article addresses a pivotal role of human ABC transporter ABCG2 in PDD as well as a new approach of quantitative structure-activity relationship (QSAR analysis to design potent ABCG2-inhibitors.

  15. Technical innovation in dynamic contrast-enhanced magnetic resonance imaging of musculoskeletal tumors: an MR angiographic sequence using a sparse k-space sampling strategy

    International Nuclear Information System (INIS)

    Fayad, Laura M.; Mugera, Charles; Grande, Filippo del; Soldatos, Theodoros; Flammang, Aaron

    2013-01-01

    We demonstrate the clinical use of an MR angiography sequence performed with sparse k-space sampling (MRA), as a method for dynamic contrast-enhanced (DCE)-MRI, and apply it to the assessment of sarcomas for treatment response. Three subjects with sarcomas (2 with osteosarcoma, 1 with high-grade soft tissue sarcomas) underwent MRI after neoadjuvant therapy/prior to surgery, with conventional MRI (T1-weighted, fluid-sensitive, static post-contrast T1-weighted sequences) and DCE-MRI (MRA, time resolution = 7-10 s, TR/TE 2.4/0.9 ms, FOV 40 cm 2 ). Images were reviewed by two observers in consensus who recorded image quality (1 = diagnostic, no significant artifacts, 2 = diagnostic, 75 % with good response, >75 % with poor response). DCE-MRI findings were concordant with histological response (arterial enhancement with poor response, no arterial enhancement with good response). Unlike conventional DCE-MRI sequences, an MRA sequence with sparse k-space sampling is easily integrated into a routine musculoskeletal tumor MRI protocol, with high diagnostic quality. In this preliminary work, tumor enhancement characteristics by DCE-MRI were used to assess treatment response. (orig.)

  16. Mediastinal tumors. Update 1995

    International Nuclear Information System (INIS)

    Wood, D.E.; Thomas, C.R. Jr.

    1995-01-01

    This volume represents the premier work devoted solely to the complex myriad of mediastinal tumors. The contributors to the state-of-the-art text are clinical investigators of international renown. The diagnosis, natural history, and therapeutic strategies in respect of all mediastinal tumors are thoroughly addressed in a concise and logical manner. An emphasis on the multidisciplinary nature of mediastinal tumors is thematic throughout the text. Moreover, the combined-modality treatment schemes that have been increasingly developed worldwide are analyzed. This textbook will prove of value to all general surgeons, thoracic surgeons, medical oncologists, radiation oncologists, pulmonologists, and endocrinologists, as well as to nursing and medical students, residents and fellows-in training. (orig.). 55 figs., 21 tabs

  17. 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.

  18. TRAIL-deficiency accelerates vascular calcification in atherosclerosis via modulation of RANKL.

    Directory of Open Access Journals (Sweden)

    Belinda A Di Bartolo

    Full Text Available The osteoprotegerin (OPG and receptor activator of nuclear factor-κB ligand (RANKL cytokine system, not only controls bone homeostasis, but has been implicated in regulating vascular calcification. TNF-related apoptosis-inducing ligand (TRAIL is a second ligand for OPG, and although its effect in vascular calcification in vitro is controversial, its role in vivo is not yet established. This study aimed to investigate the role of TRAIL in vascular calcification in vitro using vascular smooth muscle cells (VSMCs isolated from TRAIL(-/- and wild-type mice, as well as in vivo, in advanced atherosclerotic lesions of TRAIL(-/-ApoE(-/- mice. The involvement of OPG and RANKL in this process was also examined. TRAIL dose-dependently inhibited calcium-induced calcification of human VSMCs, while TRAIL(-/- VSMCs demonstrated accelerated calcification induced by multiple concentrations of calcium compared to wild-type cells. Consistent with this, RANKL mRNA was significantly elevated with 24 h calcium treatment, while OPG and TRAIL expression in human VSMCs was inhibited. Brachiocephalic arteries from TRAIL(-/-ApoE(-/- and ApoE(-/- mice fed a high fat diet for 12 w demonstrated increased chondrocyte-like cells in atherosclerotic plaque, as well as increased aortic collagen II mRNA expression in TRAIL(-/-ApoE(-/- mice, with significant increases in calcification observed at 20 w. TRAIL(-/-ApoE(-/- aortas also had significantly elevated RANKL, BMP-2, IL-1β, and PPAR-γ expression at 12 w. Our data provides the first evidence that TRAIL deficiency results in accelerated cartilaginous metaplasia and calcification in atherosclerosis, and that TRAIL plays an important role in the regulation of RANKL and inflammatory markers mediating bone turn over in the vasculature.

  19. 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.

  20. Tumor Markers

    Science.gov (United States)

    ... only a small number of people will test positive for the disease who do not have it—in other words, it will result in very few false-positive results. Although tumor markers are extremely useful in ...

  1. Tumor Grade

    Science.gov (United States)

    ... Peer Review and Funding Outcomes Step 4: Award Negotiation & Issuance Manage Your Award Grants Management Contacts Monitoring ... may require immediate or more aggressive treatment. The importance of tumor grade in planning treatment and determining ...

  2. Prognostic significance of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor expression in patients with breast cancer.

    Science.gov (United States)

    Ganten, Tom M; Sykora, Jaromir; Koschny, Ronald; Batke, Emanuela; Aulmann, Sebastian; Mansmann, Ulrich; Stremmel, Wolfgang; Sinn, Hans-Peter; Walczak, Henning

    2009-10-01

    TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis upon binding to TRAIL receptors 1 and 2 (TRAIL-R1/DR4 and TRAIL-R2/DR5). TRAIL-R3 (DcR1) and TRAIL-R4 (DcR2) have no or only a truncated cytoplasmic death domain. Consequently, they cannot induce apoptosis and instead have been proposed to inhibit apoptosis induction by TRAIL. Agonists for the apoptosis-inducing TRAIL-R1 and TRAIL-R2 are currently tested in clinical trials. To determine the expression pattern of all surface-bound TRAIL receptors and their prognostic clinical value, we investigated tumour samples of 311 patients with breast cancer by immunohistochemistry. TRAIL receptor expression profiles were correlated with clinico-pathological data, disease-free survival and overall survival. TRAIL-R1 was more strongly expressed in better differentiated tumours, and correlated positively with surrogate markers of a better prognosis (hormone receptor status, Bcl-2, negative nodal status), but negatively with the expression of Her2/neu and the proliferation marker Ki67. In contrast, TRAIL-R2 and TRAIL-R4 expression correlated with higher tumour grades, higher Ki67 index, higher Her2/neu expression and a positive nodal status at the time of diagnosis, but with lower expression of Bcl-2. Thus, the TRAIL receptor expression pattern was predictive of nodal status. Patients with grade 1 and 2 tumours, who had TRAIL-R2 but no TRAIL-R1, showed a positive lymph node status in 47% of the cases. Vice versa, only 19% had a positive nodal status with high TRAIL-R1 but low TRAIL-R2. Most strikingly, TRAIL-R4 and -R2 expression negatively correlated with overall survival of breast cancer patients. Although TRAIL-R2 correlated with more aggressive tumour behaviour, mammary carcinoma could be sensitised to TRAIL-R2-induced apoptosis, suggesting that TRAIL-R2 might therefore be used to therapeutically target such tumours. Hence, determination of the TRAIL receptor expression profile may aid in defining which breast

  3. In Vitro Efficient Expansion of Tumor Cells Deriving from Different Types of Human Tumor Samples

    Directory of Open Access Journals (Sweden)

    Ilaria Turin

    2014-03-01

    Full Text Available Obtaining human tumor cell lines from fresh tumors is essential to advance our understanding of antitumor immune surveillance mechanisms and to develop new ex vivo strategies to generate an efficient anti-tumor response. The present study delineates a simple and rapid method for efficiently establishing primary cultures starting from tumor samples of different types, while maintaining the immuno-histochemical characteristics of the original tumor. We compared two different strategies to disaggregate tumor specimens. After short or long term in vitro expansion, cells analyzed for the presence of malignant cells demonstrated their neoplastic origin. Considering that tumor cells may be isolated in a closed system with high efficiency, we propose this methodology for the ex vivo expansion of tumor cells to be used to evaluate suitable new drugs or to generate tumor-specific cytotoxic T lymphocytes or vaccines.

  4. A normative study of the Trail Making Test in Korean elders.

    Science.gov (United States)

    Seo, Eun Hyun; Lee, Dong Young; Kim, Ki Woong; Lee, Jung Hie; Jhoo, Jin Hyeong; Youn, Jong Choul; Choo, Il Han; Ha, Jin; Woo, Jong Inn

    2006-09-01

    The purpose of this study was to explore the effects of age, education and gender on the performance of the Trail Making Test (TMT) and provide normative information in Korean elders. The TMT was administered to 997 community-dwelling volunteers aged 60-90. People with serious neurological, medical and psychiatric disorders, including dementia, were excluded. Education and age had significant effects on both parts of the TMT. Gender also had an effect on part A of the TMT (Trail A). Based on these results, the norms of Trail A stratified by age (four overlapping tables), education (four strata) and gender, and the norms of part B of TMT (Trail B) stratified by age (four overlapping tables) and education (three strata). Age and educational level had a considerable influence on both Trail A and B. Our normative information on the Trail A will be useful in the elders with poor educational attainment and can be utilized for cross-cultural comparison of the Trail A performance. The fact that a large number of elders fail to complete Trail B indicates a limited applicability of Trail B in elderly population, particularly with poor educational background. Copyright (c) 2006 John Wiley & Sons, Ltd.

  5. 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.

  6. 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

    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...... 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...

  7. 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.

  8. 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.

  9. Aeroelastic Response of the Adaptive Compliant Trailing Edge Transtition Section

    Science.gov (United States)

    Herrera, Claudia Y.; Spivey, Natalie D.; Lung, Shun-fat

    2016-01-01

    The Adaptive Compliant Trailing Edge demonstrator was a joint task under the Environmentally Responsible Aviation Project in partnership with the Air Force Research Laboratory and FlexSys, Inc. (Ann Arbor, Michigan), chartered by the National Aeronautics and Space Administration to develop advanced technologies that enable environmentally friendly aircraft, such as continuous mold-line technologies. The Adaptive Compliant Trailing Edge demonstrator encompassed replacing the Fowler flaps on the SubsoniC Aircraft Testbed, a Gulfstream III (Gulfstream Aerospace, Savannah, Georgia) aircraft, with control surfaces developed by FlexSys, Inc., a pair of uniquely-designed, unconventional flaps to be used as lifting surfaces during flight-testing to substantiate their structural effectiveness. The unconventional flaps consisted of a main flap section and two transition sections, inboard and outboard, which demonstrated the continuous mold-line technology. Unique characteristics of the transition sections provided a challenge to the airworthiness assessment for this part of the structure. A series of build-up tests and analyses were conducted to ensure the data required to support the airworthiness assessment were acquired and applied accurately. The transition sections were analyzed both as individual components and as part of the flight-test article assembly. Instrumentation was installed in the transition sections based on the analysis to best capture the in-flight aeroelastic response. Flight-testing was conducted and flight data were acquired to validate the analyses. This paper documents the details of the aeroelastic assessment and in-flight response of the transition sections of the unconventional Adaptive Compliant Trailing Edge flaps.

  10. 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.

  11. Immunization Strategies Producing a Humoral IgG Immune Response against Devil Facial Tumor Disease in the Majority of Tasmanian Devils Destined for Wild Release

    Directory of Open Access Journals (Sweden)

    Ruth Pye

    2018-02-01

    Full Text Available Devil facial tumor disease (DFTD is renowned for its successful evasion of the host immune system. Down regulation of the major histocompatabilty complex class I molecule (MHC-I on the DFTD cells is a primary mechanism of immune escape. Immunization trials on captive Tasmanian devils have previously demonstrated that an immune response against DFTD can be induced, and that immune-mediated tumor regression can occur. However, these trials were limited by their small sample sizes. Here, we describe the results of two DFTD immunization trials on cohorts of devils prior to their wild release as part of the Tasmanian Government’s Wild Devil Recovery project. 95% of the devils developed anti-DFTD antibody responses. Given the relatively large sample sizes of the trials (N = 19 and N = 33, these responses are likely to reflect those of the general devil population. DFTD cells manipulated to express MHC-I were used as the antigenic basis of the immunizations in both trials. Although the adjuvant composition and number of immunizations differed between trials, similar anti-DFTD antibody levels were obtained. The first trial comprised DFTD cells and the adjuvant combination of ISCOMATRIX™, polyIC, and CpG with up to four immunizations given at monthly intervals. This compared to the second trial whereby two immunizations comprising DFTD cells and the adjuvant combination ISCOMATRIX™, polyICLC (Hiltonol® and imiquimod were given a month apart, providing a shorter and, therefore, more practical protocol. Both trials incorporated a booster immunization given up to 5 months after the primary course. A key finding was that devils in the second trial responded more quickly and maintained their antibody levels for longer compared to devils in the first trial. The different adjuvant combination incorporating the RNAase resistant polyICLC and imiquimod used in the second trial is likely to be responsible. The seroconversion in the majority of

  12. Tumor Types: Understanding Brain Tumors

    Science.gov (United States)

    Search Menu Facebook Twitter YouTube Flickr Instagram LinkedIn Brain Tumor Information | News & Blog Our Mission Our History Mission Leadership & Staff Financials Careers News & Blog Contact Us Donate Now Our Impact Our Impact Recent News News & ...

  13. 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

  14. 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

  15. 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...... noise emission, trying at the same time to preserve some of its aerodynamic and geometric characteristics. The new designs are characterized by less cambered airfoils and flatter suction sides. The resulting noise reductions seem to be mainly achieved by a reduction in the turbulent kinetic energy...

  16. 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.

  17. Automatic Search for Differential Trails in ARX Ciphers

    OpenAIRE

    Biryukov, Alex; Velichkov, Vesselin

    2014-01-01

    We propose a tool for automatic search for differential trails in ARX ciphers. By introducing the concept of a partial difference distribution table (pDDT) we extend Matsui's algorithm, originally proposed for DES-like ciphers, to the class of ARX ciphers. To the best of our knowledge this is the first application of Matsui's algorithm to ciphers that do not have S-boxes. The tool is applied to the block ciphers TEA, XTEA, SPECK and RAIDEN. For RAIDEN we find an iterative characteristic on al...

  18. Influence of free stream turbulence on a trailing line vortex

    Science.gov (United States)

    Ash, Robert L.; Stead, Daniel J.

    1990-01-01

    Low-speed wind tunnel experiments have been conducted to investigate the influence of free stream turbulence on the mean behavior of a trailing line vortex. Perforated plates and screens were used to produce turbulence levels ranging between 0.03 percent and 5 percent of the free stream velocity in the vicinity of the vortex generator. Smoke was used to provide a visual image of the vortex and photographic and videotape records were taken. Experiments have shown that high turbulence levels cause vortices to meander but with little evidence of structural change. At lower turbulence intensities, some types of vortex oscillations were observed which suggest possible instabilities.

  19. TRAIL pathway is associated with inhibition of colon cancer by protopanaxadiol

    Directory of Open Access Journals (Sweden)

    Zhiyu Zhang

    2015-01-01

    Full Text Available Among important components of American ginseng, protopanaxadiol (PPD showed more active anticancer potential than other triterpenoid saponins. In this study, we determined the in vivo effects of PPD in a mouse cancer model first. Then, using human colorectal cancer cell lines, we observed significant cancer cell growth inhibition by promoting G1 cell cycle redistribution and apoptosis. Subsequently, we characterized the downstream genes targeted by PPD in HCT-116 cancer cells. Using Affymetrix high density GeneChips, we obtained the gene expression profile of the cells. Microarray data indicated that the expression levels of 76 genes were changed over two-fold after PPD, of which 52 were upregulated while the remaining 24 were downregulated. Ingenuity pathway analysis of top functions affected was carried out. Data suggested that by regulating the interactions between p53 and DR4/DR5, the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL pathway played a key role in the action of PPD, a promising colon cancer inhibitory compound.

  20. TRAIL pathway is associated with inhibition of colon cancer by protopanaxadiol.

    Science.gov (United States)

    Zhang, Zhiyu; Li, Zejuan; Wu, Xiaohui; Zhang, Chun-Feng; Calway, Tyler; He, Tong-Chuan; Du, Wei; Chen, Jianjun; Wang, Chong-Zhi; Yuan, Chun-Su

    2015-01-01

    Among important components of American ginseng, protopanaxadiol (PPD) showed more active anticancer potential than other triterpenoid saponins. In this study, we determined the in vivo effects of PPD in a mouse cancer model first. Then, using human colorectal cancer cell lines, we observed significant cancer cell growth inhibition by promoting G1 cell cycle redistribution and apoptosis. Subsequently, we characterized the downstream genes targeted by PPD in HCT-116 cancer cells. Using Affymetrix high density GeneChips, we obtained the gene expression profile of the cells. Microarray data indicated that the expression levels of 76 genes were changed over two-fold after PPD, of which 52 were upregulated while the remaining 24 were downregulated. Ingenuity pathway analysis of top functions affected was carried out. Data suggested that by regulating the interactions between p53 and DR4/DR5, the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway played a key role in the action of PPD, a promising colon cancer inhibitory compound. Copyright © 2014 Japanese Pharmacological Society. Production and hosting by Elsevier B.V. All rights reserved.

  1. Mediastinal tumors

    International Nuclear Information System (INIS)

    Canizares, Claudio; Araujo, Ivan; Rodriguez, Amparo; Robles, Wilson; Simba, Catalina

    2005-01-01

    In our practice the mediastinal tumors are infrequent. The mediastinum is the portion of the thoracic cavity that contains numerous organs and structures which makes a crossroad for the diagnostic process. Within which congenital cysts, inflammatory and benign tumors, malignant neoplasms may develop. In the superior compartment are found: thymoma and thymic cysts, germ cell tumors, thyroid lesions, parathyroid adenomas, malignant lymphomas, paragangliomas, hemangiomas, lipomas, and inflammatory lesions such as fibrosing mediastinitis. In the middle portion: pericardial cysts, bronchial cysts, malignant lymphomas. In the posterior region: neurogenic tumors such as Shawnomas, neurofibromas, ganglioneuroblastomas, neuroblastomas, paragangliomas, and gastro enteric cysts. We describe two cases. One of a female patient with a prominent tumor in the anterior compartment of the mediastinum, detected by the x-ray films. Initially a cardiac lesion was excluded by echographic, angiographic studies. The biopsy exhibited a prominent fibrosis that suggested fibrosing mediastinitis (sclerosing). Whoever the immunohistochemical phenotype was positive for lambda chains, determining the diagnosis of lymphoma. The other case is of a young male with a thymoma associated to a pure red cell aplasia, which was the initial clinical symptom. Computerized tomography and thyroid scintigraphy was used. (The author)

  2. Phosphoinositide 3-kinase accelerates postoperative tumor growth by inhibiting apoptosis and enhancing resistance to chemotherapy-induced apoptosis. Novel role for an old enemy.

    LENUS (Irish Health Repository)

    Coffey, J Calvin

    2012-02-03

    Tumor removal remains the principal treatment modality in the management of solid tumors. The process of tumor removal may potentiate the resurgent growth of residual neoplastic tissue. Herein, we describe a novel murine model in which flank tumor cytoreduction is followed by accelerated local tumor recurrence. This model held for primary and recurrent tumors generated using a panel of human and murine (LS174T, DU145, SW480, SW640, and 3LL) cell lines and replicated accelerated tumor growth following excisional surgery. In investigating this further, epithelial cells were purified from LS174T primary and corresponding recurrent tumors for comparison. Baseline as well as tumor necrosis factor apoptosis-inducing ligand (TRAIL)-induced apoptosis were significantly reduced in recurrent tumor epithelia. Primary and recurrent tumor gene expression profiles were then compared. This identified an increase and reduction in the expression of p110gamma and p85alpha class Ia phosphoinositide 3-kinase (PI3K) subunits in recurrent tumor epithelia. These changes were further confirmed at the protein level. The targeting of PI3K ex vivo, using LY294002, restored sensitivity to TRAIL in recurrent tumor epithelia. In vivo, adjuvant LY294002 prolonged survival and significantly attenuated recurrent tumor growth by greatly enhancing apoptosis levels. Hence, PI3K plays a role in generating the antiapoptotic and chemoresistant phenotype associated with accelerated local tumor recurrence.

  3. Imaging of brain tumors

    International Nuclear Information System (INIS)

    Gaensler, E.H.L.

    1995-01-01

    The contents are diagnostic approaches, general features of tumors -hydrocephalus, edema, attenuation and/or intensity value, hemorrhage, fat, contrast enhancement, intra-axial supratentorial tumors - tumors of glial origin, oligodendrogliomas, ependymomas, subependymomas, subependymal giant cell astrocytomas, choroid plexus papilloma; midline tumors - colloid cysts, craniopharyngiomas; pineal region tumors and miscellaneous tumors i.e. primary intracerebral lymphoma, primitive neuroectodermal tumors, hemangioblastomas; extraaxial tumors - meningiomas; nerve sheath tumors -schwannomas, epidermoids, dermoids, lipomas, arachnoid cysts; metastatic tumors (8 refs.)

  4. Enhanced presentation of MHC class Ia, Ib and class II-restricted peptides encapsulated in biodegradable nanoparticles: a promising strategy for tumor immunotherapy

    Directory of Open Access Journals (Sweden)

    Schroter Stephanie

    2011-03-01

    Full Text Available Abstract Background Many peptide-based cancer vaccines have been tested in clinical trials with a limited success, mostly due to difficulties associated with peptide stability and delivery, resulting in inefficient antigen presentation. Therefore, the development of suitable and efficient vaccine carrier systems remains a major challenge. Methods To address this issue, we have engineered polylactic-co-glycolic acid (PLGA nanoparticles incorporating: (i two MHC class I-restricted clinically-relevant peptides, (ii a MHC class II-binding peptide, and (iii a non-classical MHC class I-binding peptide. We formulated the nanoparticles utilizing a double emulsion-solvent evaporation technique and characterized their surface morphology, size, zeta potential and peptide content. We also loaded human and murine dendritic cells (DC with the peptide-containing nanoparticles and determined their ability to present the encapsulated peptide antigens and to induce tumor-specific cytotoxic T lymphocytes (CTL in vitro. Results We confirmed that the nanoparticles are not toxic to either mouse or human dendritic cells, and do not have any effect on the DC maturation. We also demonstrated a significantly enhanced presentation of the encapsulated peptides upon internalization of the nanoparticles by DC, and confirmed that the improved peptide presentation is actually associated with more efficient generation of peptide-specific CTL and T helper cell responses. Conclusion Encapsulating antigens in PLGA nanoparticles offers unique advantages such as higher efficiency of antigen loading, prolonged presentation of the antigens, prevention of peptide degradation, specific targeting of antigens to antigen presenting cells, improved shelf life of the antigens, and easy scale up for pharmaceutical production. Therefore, these findings are highly significant to the development of synthetic vaccines, and the induction of CTL for adoptive immunotherapy.

  5. Trail communication regulated by two trail pheromone components in the fungus-growing termite Odontotermes formosanus (Shiraki.

    Directory of Open Access Journals (Sweden)

    Ping Wen

    Full Text Available 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

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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 Reloadable Packages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115 17.5 Wrapping Command-line tools . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 17.6 Interfacing with the VisTrails Menu... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 17.12 For System Administrators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130 18 Command-line Arguments 131 18.1 Starting VisTrails via the Command Line...

  11. 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.

  12. 75 FR 29359 - Draft Environmental Impact Statement for the Tamiami Trail Modifications: Next Steps Project...

    Science.gov (United States)

    2010-05-25

    ... of a Draft Environmental Impact Statement (DEIS) for the Tamiami Trail (U.S. Highway 41.... Army Corps of Engineers (USACE) to construct modifications to U.S. Highway 41 (Tamiami Trail) that were... within the Park and the ecological connectivity between the Park and the Water Conservation Areas'' (2009...

  13. A volatile trail Pheromone of the Leaf-Cutting Ant, Atta Texana

    Science.gov (United States)

    J. H. Tumlinson; John C. Moser; R. M. Silverstein; R. G. Brownlee; J. M. Ruth

    1972-01-01

    The major volatile trail-marking pheromone of the Texas leaf-cutting Ant, Atta texana, was isolated, identified as methyl 4-methylpyrrole-2-carboxylate, and synthesized. The synthesized pheromone elicited strong trail-following response from workers in the laboratory and field.

  14. 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...

  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. 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…

  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. 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...

  19. Bortezomib and TRAIL : A perfect match for apoptotic elimination of tumour cells?

    NARCIS (Netherlands)

    de Wilt, L. H. A. M.; Kroon, J.; Jansen, G.; de Jong, S.; Peters, G. J.; Kruyt, F. A. E.

    Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine that selectively eradicates tumour cells via specific cell surface receptors and is intensively explored for use as a novel anticancer approach. To enhance the efficacy of TRAIL receptor agonists the proteasome inhibitor

  20. Up the Garden Path: A Chemical Trail through the Cambridge University Botanic Garden

    Science.gov (United States)

    Battle, Gary M.; Kyd, Gwenda O.; Groom, Colin R.; Allen, Frank H.; Day, Juliet; Upson, Timothy

    2012-01-01

    The living world is a rich source of chemicals with many medicines, dyes, flavorings, and foodstuffs having their origins in compounds produced by plants. We describe a chemical trail through the plant holdings of the Cambridge University Botanic Gardens. Visitors to the gardens are provided with a laminated trail guide with 22 stopping points…

  1. Arginylglycylaspartic Acid-Surface-Functionalized Doxorubicin-Loaded Lipid-Core Nanocapsules as a Strategy to Target Alpha(V Beta(3 Integrin Expressed on Tumor Cells

    Directory of Open Access Journals (Sweden)

    Michelli B. Antonow

    2017-12-01

    Full Text Available Doxorubicin (Dox clinical use is limited by dose-related cardiomyopathy, becoming more prevalent with increasing cumulative doses. Previously, we developed Dox-loaded lipid-core nanocapsules (Dox-LNC and, in this study, we hypothesized that self-assembling and interfacial reactions could be used to obtain arginylglycylaspartic acid (RGD-surface-functionalized-Dox-LNC, which could target tumoral cells overexpressing αvβ3 integrin. Human breast adenocarcinoma cell line (MCF-7 and human glioblastoma astrocytoma (U87MG expressing different levels of αvβ3 integrin were studied. RGD-functionalized Dox-LNC were prepared with Dox at 100 and 500 mg·mL−1 (RGD-MCMN (Dox100 and RGD-MCMN (Dox500. Blank formulation (RGD-MCMN had z-average diameter of 162 ± 6 nm, polydispersity index of 0.11 ± 0.04, zeta potential of +13.2 ± 1.9 mV and (6.2 ± 1.1 × 1011 particles mL−1, while RGD-MCMN (Dox100 and RGD-MCMN (Dox500 showed respectively 146 ± 20 and 215 ± 25 nm, 0.10 ± 0.01 and 0.09 ± 0.03, +13.8 ± 2.3 and +16.4 ± 1.5 mV and (6.9 ± 0.6 × 1011 and (6.1 ± 1.0 × 1011 particles mL−1. RGD complexation was 7.73 × 104 molecules per nanocapsule and Dox loading were 1.51 × 104 and 7.64 × 104 molecules per nanocapsule, respectively. RGD-functionalized nanocapsules had an improved uptake capacity by U87MG cells. Pareto chart showed that the cell viability was mainly affected by the Dox concentration and the period of treatment in both MCF-7 and U87MG. The influence of RGD-functionalization on cell viability was a determinant factor exclusively to U87MG.

  2. New Strategies in Cancer Nanomedicine.

    Science.gov (United States)

    Tong, Rong; Kohane, Daniel S

    2016-01-01

    We review recent progress in cancer nanomedicine, including stimulus-responsive drug delivery systems and nanoparticles responding to light for phototherapy or tumor imaging. In addition, several new strategies to improve the circulation of nanoparticles in vivo, tumor penetration, and tumor targeting are discussed. The application of nanomedicine in cancer immunology, a relatively new type of cancer therapy, is also highlighted.

  3. 75 FR 53735 - Notice of Final Federal Agency Actions on East Lake Sammamish Master Plan Trail in King County, WA

    Science.gov (United States)

    2010-09-01

    ... Final Federal Agency Actions on East Lake Sammamish Master Plan Trail in King County, WA AGENCY: Federal... 11-mile-long paved trail, providing an alternative non- motorized transportation corridor and...

  4. Pituitary Tumors

    Science.gov (United States)

    ... nursing, or cause a man to lose his sex drive or lower his sperm count. Pituitary tumors often go undiagnosed because their symptoms resemble those of so many other more common diseases. × Definition The pituitary is a small, bean-sized gland ...

  5. Nephrogenic tumors

    International Nuclear Information System (INIS)

    Wiesbauer, P.

    2008-01-01

    Nephroblastomas are the most common malignant renal tumors in childhood. According to the guidelines of the SIOP (Societe Internationale d'Oncologie Pediatrique) and GPOH (Gesellschaft fuer Paediatrische Onkologie und Haematologie) pre-operative chemotherapy can be started without histological confirmation and thus initial imaging studies, in particular ultrasound, play an outstanding role for diagnostic purposes

  6. The use of bispecific antibodies in tumor cell and tumor vasculature directed immunotherapy

    NARCIS (Netherlands)

    Molema, G; Kroesen, BJ; Helfrich, W; Meijer, DKF; de Leij, LFMH

    2000-01-01

    To overcome dose limiting toxicities and to increase efficacy of immunotherapy of cancer, a number of strategies are under development for selectively redirecting effector cells/molecules towards tumor cells. Many of these strategies exploit the specificity of tumor associated antigen recognition by

  7. Adjoint-based optimization of flapping plates hinged with a trailing-edge flap

    Directory of Open Access Journals (Sweden)

    Min Xu

    2015-01-01

    Full Text Available It is important to understand the impact of wing-morphing on aerodynamic performance in the study of flapping-wing flight of birds and insects. We use a flapping plate hinged with a trailing-edge flap as a simplified model for flexible/morphing wings in hovering. The trailing-edge flapping motion is optimized by an adjoint-based approach. The optimized configuration suggests that the trailing-edge flap can substantially enhance the overall lift. Further analysis indicates that the lift enhancement by the trailing-edge flapping is from the change of circulation in two ways: the local circulation change by the rotational motion of the flap, and the modification of vortex shedding process by the relative location between the trailing-edge flap and leading-edge main plate.

  8. Bioassay-Guided Isolation of Compounds from Datura stramonium with TRAIL-Resistance Overcoming Activity.

    Science.gov (United States)

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

    2016-02-01

    TRAIL is a potent inducer of apoptosis in most cancer cells, but not in normal cells, and therefore has deserved intense interest as a promising agent for cancer therapy. In the search for bioactive natural products for overcoming TRAIL-resistance, we previously reported a number of active compounds. In our screening program on natural resources targeting overcoming TRAIL-resistance, activity-guided fractionation of the MeOH extract of Datura stramonium leaves led to the isolation of three alkaloids--scopolamine (1), trigonelline (2), and tyramine (3). Compounds 1, 2, and 3 exhibited TRAIL-resistance overcoming activity at 50, 150, and 100 µM, respectively in TRAIL-resistant AGS cells.

  9. Behaviour of nitric oxide trails deposited in the mesosphere and stratosphere

    Science.gov (United States)

    Eberstein, I. J.; Aikin, A. C.

    1975-01-01

    The transient behavior of a nitric oxide trail deposited at approximately 60 km altitude is studied by the solution of the appropriate multidimensional diffusion equation which includes terms representing the effects of wind shear. Similar analysis is then carried out for the situation in the stratosphere. Trail behavior is found to be relatively independent of altitude and background ozone, but strongly dependent on the magnitude of eddy diffusity and the initial nitric oxide concentration. The nitric oxide trail reacts with ambient ozone to form nitrogen dioxide. For a trail 100 m initial radius, an ozone hole will form to a maximum size in 4 to 6 hours and then decay. The overall recovery time of the atmosphere following the creation of the trail is less than 12 hours.

  10. Effect of Trailing Edge Damage on Full-Scale Wind Turbine Blade Failure

    DEFF Research Database (Denmark)

    Haselbach, Philipp Ulrich; Branner, Kim

    2015-01-01

    of trailing edge failure is very complex and can arise from manufacturing flaws, damages during transportation and erection as well as under general and extreme operational conditions. The focus in this study is put on the geometrical nonlinear buckling effect of the trailing edge under combined loading...... where the load bearing structure is connected to the shells and at the joints of the upper and lower shells, usually at the leading and trailing edges. Maintenance inspections of wind turbines show that cracks in the vicinity of the trailing edge are typically occurring forms of damage. The cause...... and how it affects the ultimate strength of a holistic blade. For this reason a 34m long blade was studied experimentally and numerically under ultimate load until blade collapse. The interaction between trailing edge buckling on damage onset and sandwich panel failure was studied in detail. Numerically...

  11. 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.

  12. Laboratory investigations of the trail-following responses of four species of leaf-cutting ants with notes on the specificity of a trail pheromone of Atta texana (Buckley)

    Science.gov (United States)

    S. W. Robinson; John C. Moser; M. S. Blum; E. Amante

    1974-01-01

    Interspecific trail following activity of poison sac contents from four species of leaf-cutting ants was investigated. with only one exception, all the species teste followed trails made from each others poison sac contents. however when the ants were given a choice of following one of two separate trails, clear differences were shown in the poison sac contents of the...

  13. Optimization of the tumor microenvironment and nanomedicine properties simultaneously to improve tumor therapy.

    Science.gov (United States)

    Zhang, Bo; Shi, Wei; Jiang, Ting; Wang, Lanting; Mei, Heng; Lu, Heng; Hu, Yu; Pang, Zhiqing

    2016-09-20

    Effective delivery of nanomedicines to tumor tissues depends on both the tumor microenvironment and nanomedicine properties. Accordingly, tumor microenvironment modification or advanced design of nanomedicine was emerging to improve nanomedicine delivery to tumors. However, few studies have emphasized the necessity to optimize the tumor microenvironment and nanomedicine properties simultaneously to improve tumor treatment. In the present study, imatinib mesylate (IMA) was used to normalize the tumor microenvironment including platelet-derived growth factor receptor-β expression inhibition, tumor vessel normalization, and tumor perfusion improvement as demonstrated by immunofluorescence staining. In addition, the effect of tumor microenvironment normalization on tumor delivery of nanomedicines with different sizes was carefully investigated. It was shown that IMA treatment significantly reduced the accumulation of nanoparticles (NPs) around 110 nm but enhanced the accumulation of micelles around 23 nm by in vivo fluorescence imaging experiment. Furthermore, IMA treatment limited the distribution of NPs inside tumors but increased that of micelles with a more homogeneous pattern. Finally, the anti-tumor efficacy study displayed that IMA pretreatment could significantly increase the therapeutic effects of paclitaxel-loaded micelles. All-together, a new strategy to improve nanomedicine delivery to tumor was provided by optimizing both nanomedicine size and the tumor microenvironment simultaneously, and it will have great potential in clinics for tumor treatment.

  14. 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 (particleserosion. Particular attention is paid to how the creation of a new trail 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.

  15. Experimental aerodynamics of mesoscale trailing-edge actuators

    Science.gov (United States)

    Solovitz, Stephen Adam

    Uninhabited air vehicles (UAVs) are commonly designed with high-aspect ratio wings, which can be susceptible to significant aeroelastic vibrations. These modes can result in a loss of control or structural failure, and new techniques are necessary to alleviate them. A multidisciplinary effort at Stanford developed a distributed flow control method that used small trailing-edge actuators to alter the aerodynamic loads at specific spanwise locations along an airplane wing. This involved design and production of the actuators, computational and experimental study of their characteristics, and application to a flexible wing. This project focused on the experimental response. The actuators were based on a Gurney flap, which is a trailing-edge flap of small size and large deflection, typically about 2% of the chord and 90 degrees, respectively. Because of the large deflection, there is a significant change to the wing camber, increasing the lift. However, due to the small size, the drag does not increase substantially, and the performance is actually improved for high lift conditions. For this project, a 1.5% flap was divided into small span segments (5.2% of the chord), each individually controllable. These devices are termed microflaps or Micro Trailing-edge Effectors (MiTEs). The aerodynamic response was examined to determine the effects of small flap span, the influence of the device structure, and the transient response to relatively rapid MiTE actuation. Measurements included integrated loads, pressure profiles, wake surveys, and near-wake studies using particle image velocimetry. The basic response was similar to a Gurney flap, as full-span actuation of the devices produced a lift increment of about +0.25 when applied towards the pressure surface. For partial actuated spans, the load increment was approximately linear with the actuated span, regardless of configuration. The primary effects occurred within two device spans, indicating that most of the load was

  16. Perceptions of public forest managers concerning trail use by off-highway vehicle riders in the northeast United States

    Science.gov (United States)

    Diane M. Kuehn; Valerie A. Luzadis; Robert W. Malmsheimer; Rudolph M. Schuster

    2012-01-01

    This research provides information about natural resource managers' perceptions of off-highway vehicle (OHV) riders' attitudes towards two OHV riding behaviors: (1) the use of trails on which OHVs are prohibited; and (2) the development and/or use of unauthorized trails (i.e., trails not authorized or created by a public land management agency). In the spring...

  17. Research for the development of best management practices for minimizing horse trail impacts on the Hoosier National Forest

    Science.gov (United States)

    Aust, M.W.; Marion, J.L.; Kyle, K.

    2005-01-01

    This research investigates horse trail impacts to gain an improved understanding of the relationship between various levels of horse use, horse trail management alternatives, and subsequent horse trail degradation. A survey of existing horse trails on the Hoosier National Forest was used to collect data on use-related, environmental and management factors to model horse trail impacts. Results are analyzed to identify which factors are most easily manipulated by managers to effectively avoid and minimize horse trail impacts. A specific focus includes evaluating the relative effect of trail use level, surfacing, grade, and water control on indices of erosion and trafficability such as trail cross sectional area, estimated erosion, muddiness, and incision. Overall, the Hoosier National Forest horse trails could be significantly improved by relocating or closing inherited trails that directly ascend slope or are excessively steep, reducing the distance between water control structures, and by applying gravel to harden trail surfaces and reduce soil erosion. A set of Best Management Practices for trails are included as a product of this work, with recommendations based on this research.

  18. Adequate antigen availability: a key issue for novel approaches to tumor vaccination and tumor immunotherapy.

    Science.gov (United States)

    Accolla, Roberto S; Tosi, Giovanna

    2013-03-01

    A crucial parameter for activation of the anti-tumor immune response is an adequate antigen availability (AAA) defined here as the optimal tumor antigen dose and related antigen processing and MHC-II-restricted presentation necessary to efficiently trigger tumor-specific TH cells. We will discuss two distinct experimental systems: a) a preventive anti-tumor vaccination system; b) a therapy-induced anti-tumor vaccination approach. In the first case tumor cells are rendered constitutively MHC-II+ by transfecting them with the MHC-II transcriptional activator CIITA. Here AAA is generated by the function of tumor's newly expressed MHC-II molecules to present tumor-associated antigens to tumor-specific TH cells. In the second case, AAA is generated by treating established tumors with neovasculature-targeted TNFα. In conjuction with Melphalan, targeted TNFα delivery produces extensive areas of tumor necrosis that generate AAA capable of optimally activate tumor-specific TH cells which in turn activate CTL immune effectors. In both experimental systems tumor rejection and persistent and long-lived TH cell anti-tumor memory, responsible of defending the animals from subsequent challenges with tumor cells, are achieved. Based on these and other investigators' results we propose that AAA is a key element for triggering adaptive immune functions resulting in subversion from a pro-tumor to an anti-tumor microenvironment, tumor rejection and acquisition of anti-tumor immune memory. Hypotheses of neuro-immune networks involved in these approaches are discussed. These considerations are important also for the comprehension of how chemotherapy and/or radiation therapies may help to block and/or to eradicate the tumor and for the construction of suitable anti-tumor vaccine strategies.

  19. 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

  20. TRAIL: a Tokamak Rail Gun Limiter for fusion reactors

    Energy Technology Data Exchange (ETDEWEB)

    Powell, J R; Yu, W S; Fillo, J A; Usher, J L

    1980-01-01

    An attractive new limiter concept is investigated. The Tokamak Rail Gun Limiter (TRAIL) 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 in an E-M mass accelerator. Heat fluxes of approx. 30,000 W/cm/sup 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.