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Sample records for costimulates tumor-antigen specific

  1. Antigen specific T-cell responses against tumor antigens are controlled by regulatory T cells in patients with prostate cancer.

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    Hadaschik, Boris; Su, Yun; Huter, Eva; Ge, Yingzi; Hohenfellner, Markus; Beckhove, Philipp

    2012-04-01

    Immunotherapy is a promising approach in an effort to control castration resistant prostate cancer. We characterized tumor antigen reactive T cells in patients with prostate cancer and analyzed the suppression of antitumor responses by regulatory T cells. Peripheral blood samples were collected from 57 patients with histologically confirmed prostate cancer, 8 patients with benign prostatic hyperplasia and 16 healthy donors. Peripheral blood mononuclear cells were isolated and antigen specific interferon-γ secretion of isolated T cells was analyzed by enzyme-linked immunospot assay. T cells were functionally characterized and T-cell responses before and after regulatory T-cell depletion were compared. As test tumor antigens, a panel of 11 long synthetic peptides derived from a total of 8 tumor antigens was used, including prostate specific antigen and prostatic acid phosphatase. In patients with prostate cancer we noted a 74.5% effector T-cell response rate compared with only 25% in patients with benign prostatic hyperplasia and 31% in healthy donors. In most patients 2 or 3 tumor antigens were recognized. Comparing various disease stages there was a clear increase in the immune response against prostate specific antigens from intermediate to high risk tumors and castration resistant disease. Regulatory T-cell depletion led to a significant boost in effector T-cell responses against prostate specific antigen and prostatic acid phosphatase. Tumor specific effector T cells were detected in most patients with prostate cancer, especially those with castration resistant prostate cancer. Since effector T-cell responses against prostate specific antigens strongly increased after regulatory T-cell depletion, our results indicate that immunotherapy efficacy could be enhanced by decreasing regulatory T cells. Copyright © 2012 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  2. Adoptive Immunotherapy for Hematological Malignancies Using T Cells Gene-Modified to Express Tumor Antigen-Specific Receptors

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    Hiroshi Fujiwara

    2014-12-01

    Full Text Available Accumulating clinical evidence suggests that adoptive T-cell immunotherapy could be a promising option for control of cancer; evident examples include the graft-vs-leukemia effect mediated by donor lymphocyte infusion (DLI and therapeutic infusion of ex vivo-expanded tumor-infiltrating lymphocytes (TIL for melanoma. Currently, along with advances in synthetic immunology, gene-modified T cells retargeted to defined tumor antigens have been introduced as “cellular drugs”. As the functional properties of the adoptive immune response mediated by T lymphocytes are decisively regulated by their T-cell receptors (TCRs, transfer of genes encoding target antigen-specific receptors should enable polyclonal T cells to be uniformly redirected toward cancer cells. Clinically, anticancer adoptive immunotherapy using genetically engineered T cells has an impressive track record. Notable examples include the dramatic benefit of chimeric antigen receptor (CAR gene-modified T cells redirected towards CD19 in patients with B-cell malignancy, and the encouraging results obtained with TCR gene-modified T cells redirected towards NY-ESO-1, a cancer-testis antigen, in patients with advanced melanoma and synovial cell sarcoma. This article overviews the current status of this treatment option, and discusses challenging issues that still restrain the full effectiveness of this strategy, especially in the context of hematological malignancy.

  3. Generation of Tumor Antigen-Specific iPSC-Derived Thymic Emigrants Using a 3D Thymic Culture System

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    Raul Vizcardo

    2018-03-01

    Full Text Available Summary: Induced pluripotent stem cell (iPSC-derived T cells may provide future therapies for cancer patients, but those generated by current methods, such as the OP9/DLL1 system, have shown abnormalities that pose major barriers for clinical translation. Our data indicate that these iPSC-derived CD8 single-positive T cells are more like CD4+CD8+ double-positive T cells than mature naive T cells because they display phenotypic markers of developmental arrest and an innate-like phenotype after stimulation. We developed a 3D thymic culture system to avoid these aberrant developmental fates, generating a homogeneous subset of CD8αβ+ antigen-specific T cells, designated iPSC-derived thymic emigrants (iTEs. iTEs exhibit phenotypic and functional similarities to naive T cells both in vitro and in vivo, including the capacity for expansion, memory formation, and tumor suppression. These data illustrate the limitations of current methods and provide a tool to develop the next generation of iPSC-based antigen-specific immunotherapies. : A barrier for clinical application of iPSC-derived CD8 T cells using OP9/DLL1 is their abnormal biology. Vizcardo et al. show that a 3D thymic culture system enables the generation of a homogeneous antigen-specific T cell subset, named iTEs, which closely mimics naive T cells and exhibits potent anti-tumor activity. Keywords: thymopoiesis, T cell differentiation, iPSC differentiation, adoptive cell transfer, naïve T cell, recent rhymic emigrants, fetal thymus organ culture, immunotherapy, 3D culture, tumor antigen specific T cell

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

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    Shashi Ashok Gujar

    2014-04-01

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

  5. [Detection of fps tumor antigen with mono-specific anti-fps serum in tumors induced by acute transforming ALV].

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    Wang, Yixin; Chen, Hao; Zhao, Peng; Li, Jianliang; Cui, Zhizhong

    2013-03-04

    To prepare anti-fps mono-specific serum, and detect the fps antigen in tumors induced by acute transforming avian leukosis/sarcoma virus containing v-fps oncogene. Two part of v-fps gene was amplified by RT-PCR using the Fu-J viral RNA as the template. Mono-specific serum was prepared by immuning Kunming white mouse with both two recombinant infusion proteins expressed by the prokaryotic expression system. Indirect immunofluorescent assay was used to detect fps antigen in tumor tissue suspension cells and CEF infected by sarcoma supernatant. Immunohistochemical method was used to detect fps antigen in tumor tissue. The mouse mono-specific serum was specific as it had no cross reaction with classical ALV-J strains. The result reveals that the tumor tissue suspension cells, the CEF infected by sarcoma supernatant, and the slice immunohistochemistry of the sarcoma showed positive results. The anti-fps mono-specific serum was prepared, and the detection method was established, which laid the foundation for the study of viral biological characteristics and mechanism of tumourgenesis of acute transforming avian leukosis/sarcoma virus containing v-fps oncogene.

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

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    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.

  7. In vivo programming of tumor antigen-specific T lymphocytes from pluripotent stem cells to promote cancer immunosurveillance.

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    Lei, Fengyang; Zhao, Baohua; Haque, Rizwanul; Xiong, Xiaofang; Budgeon, Lynn; Christensen, Neil D; Wu, Yuzhang; Song, Jianxun

    2011-07-15

    Adoptive T-cell immunotherapy has garnered wide attention, but its effective use is limited by the need of multiple ex vivo manipulations and infusions that are complex and expensive. In this study, we show how highly reactive antigen (Ag)-specific CTLs can be generated from induced pluripotent stem (iPS) cells to provide an unlimited source of functional CTLs for adoptive immunotherapy. iPS cell-derived T cells can offer the advantages of avoiding possible immune rejection and circumventing ethical and practical issues associated with other stem cell types. iPS cells can be differentiated into progenitor T cells in vitro by stimulation with the Notch ligand Delta-like 1 (DL1) overexpressed on bone marrow stromal cells, with complete maturation occurring upon adoptive transfer into Rag1-deficient mice. Here, we report that these iPS cells can be differentiated in vivo into functional CTLs after overexpression of MHC I-restricted Ag-specific T-cell receptors (TCR). In this study, we generated murine iPS cells genetically modified with ovalbumin (OVA)-specific and MHC-I restricted TCR (OT-I) by retrovirus-mediated transduction. After their adoptive transfer into recipient mice, the majority of OT-I/iPS cells underwent differentiation into CD8+ CTLs. TCR-transduced iPS cells developed in vivo responded in vitro to peptide stimulation by secreting interleukin 2 and IFN-γ. Most importantly, adoptive transfer of TCR-transduced iPS cells triggered infiltration of OVA-reactive CTLs into tumor tissues and protected animals from tumor challenge. Taken together, our findings offer proof of concept for a potentially more efficient approach to generate Ag-specific T lymphocytes for adoptive immunotherapy. ©2011 AACR.

  8. Differential Patterns of Large Tumor Antigen-Specific Immune Responsiveness in Patients with BK Polyomavirus-Positive Prostate Cancer or Benign Prostatic Hyperplasia

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    Sais, Giovanni; Wyler, Stephen; Hudolin, Tvrtko; Banzola, Irina; Mengus, Chantal; Bubendorf, Lukas; Wild, Peter J.; Hirsch, Hans H.; Sulser, Tullio; Spagnoli, Giulio C.

    2012-01-01

    The role of the polyomavirus BK (BKV) large tumor antigen (L-Tag) as a target of immune response in patients with prostate cancer (PCa) has not been investigated thus far. In this study, we comparatively analyzed humoral and cellular L-Tag-specific responsiveness in age-matched patients bearing PCa or benign prostatic hyperplasia, expressing or not expressing BKV L-Tag-specific sequences in their tissue specimens, and in non-age-matched healthy individuals. Furthermore, results from patients with PCa were correlated to 5-year follow-up clinical data focusing on evidence of biochemical recurrence (BR) after surgery (prostate specific antigen level of ≥0.2 ng/ml). In peripheral blood mononuclear cells (PBMC) from patients with PCa with evidence of BR and BKV L-Tag-positive tumors, stimulation with peptides derived from the BKV L-Tag but not those derived from Epstein-Barr virus, influenza virus, or cytomegalovirus induced a peculiar cytokine gene expression profile, characterized by high expression of interleukin-10 (IL-10) and transforming growth factor β1 and low expression of gamma interferon genes. This pattern was confirmed by protein secretion data and correlated with high levels of anti-BKV L-Tag IgG. Furthermore, in PBMC from these PCa-bearing patients, L-Tag-derived peptides significantly expanded an IL-10-secreting CD4+ CD25+(high) CD127− FoxP3+ T cell population with an effector memory phenotype (CD103+) capable of inhibiting proliferation of autologous anti-CD3/CD28-triggered CD4+ CD25− T cells. Collectively, our findings indicate that potentially tolerogenic features of L-Tag-specific immune response are significantly associated with tumor progression in patients with BKV+ PCa. PMID:22647697

  9. Harnessing Dendritic Cells for Tumor Antigen Presentation

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    Nierkens, Stefan [Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Geert Grooteplein 28, Nijmegen 6525 GA (Netherlands); Janssen, Edith M., E-mail: edith.janssen@cchmc.org [Division of Molecular Immunology, Cincinnati Children' s Hospital Research Foundation, University of Cincinnati College of Medicine, 3333 Burnet Avenue, Cincinnati, OH 45229 (United States)

    2011-04-26

    Dendritic cells (DC) are professional antigen presenting cells that are crucial for the induction of anti-tumor T cell responses. As a consequence, research has focused on the harnessing of DCs for therapeutic interventions. Although current strategies employing ex vivo-generated and tumor-antigen loaded DCs have been proven feasible, there are still many obstacles to overcome in order to improve clinical trial successes and offset the cost and complexity of customized cell therapy. This review focuses on one of these obstacles and a pivotal step for the priming of tumor-specific CD8{sup +} and CD4{sup +} T cells; the in vitro loading of DCs with tumor antigens.

  10. Role of CD28 co-stimulation in generation and maintenance of virus-specific T cells

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    Christensen, Jeanette Erbo; Christensen, Jan P; Kristensen, Nanna N

    2002-01-01

    Efficient induction of T cell responses is normally assumed to require both TCR-mediated signaling and engagement of co-stimulatory molecules, in particular CD28. However, the importance of CD28 co-stimulation in induction and maintenance of antiviral T cell responses is not clearly established....... For this reason antiviral CD4(+) and CD8(+) T cell responses in CD28-deficient mice were studied using two different viruses [vesicular stomatitis virus and lymphocytic choriomeningitis virus (LCMV)]. Intracellular cytokine staining and/or MHC-peptide tetramers were used to enumerate antigen-specific T cells...

  11. Radioimmunoassay for tumor antigen of human cervical squamous cell carcinoma

    International Nuclear Information System (INIS)

    Kato, H.; Torigoe, T.

    1977-01-01

    A heterologous antiserum for human cervical squamous cell carcinoma was prepared and specificity determined by Ouchterlony immunodiffusion and immunofluorescence studies. With this antiserum, a tumor antigen was purified from human cervical squamous cell carcinoma tissue. The specificities of the antigen and the antiserum were then re-examined by a radioimmunoassay method using 125 I-labeled purified antigen. Although normal cervical tissue extract showed a moderate cross-reactivity in the radioimmunoassay, the circulating antigen activity could not be detected in normal women or in several patients with other carcinomas, whereas 27 of 35 patients with cervical squamous cell carcinoma showed detectable serum antigen activity. All patients with advanced stages of cervical squamous cell carcinoma showed detectable antigen levels. These results indicate that there is a quantitative abnormality, at least, of this tumor antigen in patients with cervical squamous cell carcinoma and that the radioimmunoassay for the antigen is a potentially useful tool in clinical care

  12. Characterization of highly frequent epitope-specific CD45RA+/CCR7+/- T lymphocyte responses against p53-binding domains of the human polyomavirus BK large tumor antigen in HLA-A*0201+ BKV-seropositive donors

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    Zajac Paul

    2006-11-01

    Full Text Available Abstract Human polyomavirus BK (BKV has been implicated in oncogenic transformation. Its ability to replicate is determined by the binding of its large tumor antigen (LTag to products of tumor-suppressor genes regulating cell cycle, as specifically p53. We investigated CD8+ T immune responses to BKV LTag portions involved in p53 binding in HLA-A*0201+ BKV LTag experienced individuals. Peptides selected from either p53-binding region (LTag351–450 and LTag533–626 by current algorithms and capacity to bind HLA-A*0201 molecule were used to stimulate CD8+ T responses, as assessed by IFN-γ gene expression ex vivo and detected by cytotoxicity assays following in vitro culture. We observed epitope-specific immune responses in all HLA-A*0201+ BKV LTag experienced individuals tested. At least one epitope, LTag579–587; LLLIWFRPV, was naturally processed in non professional antigen presenting cells and induced cytotoxic responses with CTL precursor frequencies in the order of 1/20'000. Antigen specific CD8+ T cells were only detectable in the CD45RA+ subset, in both CCR7+ and CCR7- subpopulations. These data indicate that widespread cellular immune responses against epitopes within BKV LTag-p53 binding regions exist and question their roles in immunosurveillance against tumors possibly associated with BKV infection.

  13. The Prognostic, Diagnostic, and Therapeutic Potential of Tumor Antigens

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    Olsen, Lars Rønn

    or abundance in cancer cells is often unique and their roles and functions in tumorigenesis are, in many cases, studied extensively. They, therefore, have the potential to be highly specific biomarkers as well as therapeutic targets, but complex analysis combining basic science, high-throughput methods...... of genomics and proteomics, and clinical studies need to be combined. These analyses produce large amounts of data that require advanced bioinformatics methods for collection, management, integration and interpretation. In this thesis, I have explored the potential of tumor antigens as biomarkers...... and therapeutic agents, by developing and implementing several computational tools and databases for immunotherapy target discovery, and have analyzed the potential of tumor antigens as proteogenomic biomarkers in invasive ductal carcinomas. In this analysis I have shown that the combination of proteomics...

  14. Application of Adoptive T-Cell Therapy Using Tumor Antigen-Specific T-Cell Receptor Gene Transfer for the Treatment of Human Leukemia

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    Toshiki Ochi

    2010-01-01

    Full Text Available The last decade has seen great strides in the field of cancer immunotherapy, especially the treatment of melanoma. Beginning with the identification of cancer antigens, followed by the clinical application of anti-cancer peptide vaccination, it has now been proven that adoptive T-cell therapy (ACT using cancer antigen-specific T cells is the most effective option. Despite the apparent clinical efficacy of ACT, the timely preparation of a sufficient number of cancer antigen-specific T cells for each patient has been recognized as its biggest limitation. Currently, therefore, attention is being focused on ACT with engineered T cells produced using cancer antigen-specific T-cell receptor (TCR gene transfer. With regard to human leukemia, ACT using engineered T cells bearing the leukemia antigen-specific TCR gene still remains in its infancy. However, several reports have provided preclinical data on TCR gene transfer using Wilms' tumor gene product 1 (WT1, and also preclinical and clinical data on TCR gene transfer involving minor histocompatibility antigen, both of which have been suggested to provide additional clinical benefit. In this review, we examine the current status of anti-leukemia ACT with engineered T cells carrying the leukemia antigen-specific TCR gene, and discuss the existing barriers to progress in this area.

  15. NOG-hIL-4-Tg, a new humanized mouse model for producing tumor antigen-specific IgG antibody by peptide vaccination.

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    Yoshie Kametani

    Full Text Available Immunodeficient mice transplanted with human peripheral blood mononuclear cells (PBMCs are promising tools to evaluate human immune responses to vaccines. However, these mice usually develop severe graft-versus-host disease (GVHD, which makes estimation of antigen-specific IgG production after antigen immunization difficult. To evaluate antigen-specific IgG responses in PBMC-transplanted immunodeficient mice, we developed a novel NOD/Shi-scid-IL2rγnull (NOG mouse strain that systemically expresses the human IL-4 gene (NOG-hIL-4-Tg. After human PBMC transplantation, GVHD symptoms were significantly suppressed in NOG-hIL-4-Tg compared to conventional NOG mice. In kinetic analyses of human leukocytes, long-term engraftment of human T cells has been observed in peripheral blood of NOG-hIL-4-Tg, followed by dominant CD4+ T rather than CD8+ T cell proliferation. Furthermore, these CD4+ T cells shifted to type 2 helper (Th2 cells, resulting in long-term suppression of GVHD. Most of the human B cells detected in the transplanted mice had a plasmablast phenotype. Vaccination with HER2 multiple antigen peptide (CH401MAP or keyhole limpet hemocyanin (KLH successfully induced antigen-specific IgG production in PBMC-transplanted NOG-hIL-4-Tg. The HLA haplotype of donor PBMCs might not be relevant to the antibody secretion ability after immunization. These results suggest that the human PBMC-transplanted NOG-hIL-4-Tg mouse is an effective tool to evaluate the production of antigen-specific IgG antibodies.

  16. Co-stimulatory signaling determines tumor antigen sensitivity and persistence of CAR T cells targeting PSCA+ metastatic prostate cancer.

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    Priceman, Saul J; Gerdts, Ethan A; Tilakawardane, Dileshni; Kennewick, Kelly T; Murad, John P; Park, Anthony K; Jeang, Brook; Yamaguchi, Yukiko; Yang, Xin; Urak, Ryan; Weng, Lihong; Chang, Wen-Chung; Wright, Sarah; Pal, Sumanta; Reiter, Robert E; Wu, Anna M; Brown, Christine E; Forman, Stephen J

    2018-01-01

    Advancing chimeric antigen receptor (CAR)-engineered adoptive T cells for the treatment of solid cancers is a major focus in the field of immunotherapy, given impressive recent clinical responses in hematological malignancies. Prostate cancer may be amenable to T cell-based immunotherapy since several tumor antigens, including prostate stem-cell antigen (PSCA), are widely over-expressed in metastatic disease. While antigen selectivity of CARs for solid cancers is crucial, it is problematic due to the absence of truly restricted tumor antigen expression and potential safety concerns with "on-target off-tumor" activity. Here, we show that the intracellular co-stimulatory signaling domain can determine a CAR's sensitivity for tumor antigen expression. A 4-1BB intracellular co-stimulatory signaling domain in PSCA-CARs confers improved selectivity for higher tumor antigen density, reduced T cell exhaustion phenotype, and equivalent tumor killing ability compared to PSCA-CARs containing the CD28 co-stimulatory signaling domain. PSCA-CARs exhibit robust in vivo anti-tumor activity in patient-derived bone-metastatic prostate cancer xenograft models, and 4-1BB-containing CARs show superior T cell persistence and control of disease compared with CD28-containing CARs. Our study demonstrates the importance of co-stimulation in defining an optimal CAR T cell, and also highlights the significance of clinically relevant models in developing solid cancer CAR T cell therapies.

  17. Co-stimulatory signaling determines tumor antigen sensitivity and persistence of CAR T cells targeting PSCA+ metastatic prostate cancer

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    Priceman, Saul J.; Gerdts, Ethan A.; Tilakawardane, Dileshni; Kennewick, Kelly T.; Murad, John P.; Park, Anthony K.; Jeang, Brook; Yamaguchi, Yukiko; Urak, Ryan; Weng, Lihong; Chang, Wen-Chung; Wright, Sarah; Pal, Sumanta; Reiter, Robert E.; Brown, Christine E.; Forman, Stephen J.

    2018-01-01

    ABSTRACT Advancing chimeric antigen receptor (CAR)-engineered adoptive T cells for the treatment of solid cancers is a major focus in the field of immunotherapy, given impressive recent clinical responses in hematological malignancies. Prostate cancer may be amenable to T cell-based immunotherapy since several tumor antigens, including prostate stem-cell antigen (PSCA), are widely over-expressed in metastatic disease. While antigen selectivity of CARs for solid cancers is crucial, it is problematic due to the absence of truly restricted tumor antigen expression and potential safety concerns with “on-target off-tumor” activity. Here, we show that the intracellular co-stimulatory signaling domain can determine a CAR's sensitivity for tumor antigen expression. A 4-1BB intracellular co-stimulatory signaling domain in PSCA-CARs confers improved selectivity for higher tumor antigen density, reduced T cell exhaustion phenotype, and equivalent tumor killing ability compared to PSCA-CARs containing the CD28 co-stimulatory signaling domain. PSCA-CARs exhibit robust in vivo anti-tumor activity in patient-derived bone-metastatic prostate cancer xenograft models, and 4-1BB-containing CARs show superior T cell persistence and control of disease compared with CD28-containing CARs. Our study demonstrates the importance of co-stimulation in defining an optimal CAR T cell, and also highlights the significance of clinically relevant models in developing solid cancer CAR T cell therapies. PMID:29308300

  18. Therapeutic efficacy of MUC1-specific cytotoxic T lymphocytes and CD137 co-stimulation in a spontaneous breast cancer model.

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    Mukherjee, Pinku; Tinder, Teresa L; Basu, Gargi D; Pathangey, Latha B; Chen, Lieping; Gendler, Sandra J

    2004-01-01

    To study immunology in breast tumors, we have utilized a mammary gland adenocarcinoma model in which mice develop spontaneous tumors of the mammary gland which are initiated at puberty and express a human tumor antigen, MUC1. MUC1 (CD227) is over-expressed in 90% of human breast cancers and its glycosylation status and pattern of expression in cancer cells is altered. Humoral and cellular responses to MUC1 have been reported in breast cancer patients and therefore, MUC1 is being evaluated as a target for immune intervention. This mouse model of spontaneous breast cancer allows the evaluation of anti-MUC1 immune responses at all stages of the disease. In this report, we review the model as it pertains to a) the development of the tumor, b) MUC1 expression, and the native immune responses against MUC1 as tumors progress, and c) the immune suppressive microenvironment within the developing tumor. Finally, we report our latest findings describing the therapeutic efficacy of adoptively transferred MUC1-specific cytotoxic T lymphocytes (MUC1-CTL) in these mice and discuss ways to increase their effectiveness by agonistic monoclonal antibody against CD137 T cell costimulatory molecule.

  19. Human Tumor Antigens Yesterday, Today, and Tomorrow.

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    Finn, Olivera J

    2017-05-01

    The question of whether human tumors express antigens that can be recognized by the immune system has been answered with a resounding YES. Most were identified through spontaneous antitumor humoral and cellular immune responses found in cancer patients and include peptides, glycopeptides, phosphopeptides, viral peptides, and peptides resulting from common mutations in oncogenes and tumor-suppressor genes, or common gene fusion events. Many have been extensively tested as candidates for anticancer vaccines. More recently, attention has been focused on the potentially large number of unique tumor antigens, mutated neoantigens, that are the predicted products of the numerous mutations revealed by exome sequencing of primary tumors. Only a few have been confirmed as targets of spontaneous immunity and immunosurveillance, and even fewer have been tested in preclinical and clinical settings. The field has been divided for a long time on the relative importance of shared versus mutated antigens in tumor surveillance and as candidates for vaccines. This question will eventually need to be answered in a head to head comparison in well-designed clinical trials. One advantage that shared antigens have over mutated antigens is their potential to be used in vaccines for primary cancer prevention. Cancer Immunol Res; 5(5); 347-54. ©2017 AACR . ©2017 American Association for Cancer Research.

  20. Targeting tumor antigens to secreted membrane vesicles in vivo induces efficient antitumor immune responses.

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    Zeelenberg, Ingrid S; Ostrowski, Matias; Krumeich, Sophie; Bobrie, Angélique; Jancic, Carolina; Boissonnas, Alexandre; Delcayre, Alain; Le Pecq, Jean-Bernard; Combadière, Béhazine; Amigorena, Sebastian; Théry, Clotilde

    2008-02-15

    Expression of non-self antigens by tumors can induce activation of T cells in vivo, although this activation can lead to either immunity or tolerance. CD8+ T-cell activation can be direct (if the tumor expresses MHC class I molecules) or indirect (after the capture and cross-presentation of tumor antigens by dendritic cells). The modes of tumor antigen capture by dendritic cells in vivo remain unclear. Here we examine the immunogenicity of the same model antigen secreted by live tumors either in association with membrane vesicles (exosomes) or as a soluble protein. We have artificially addressed the antigen to secreted vesicles by coupling it to the factor VIII-like C1C2 domain of milk fat globule epidermal growth factor-factor VIII (MFG-E8)/lactadherin. We show that murine fibrosarcoma tumor cells that secrete vesicle-bound antigen grow slower than tumors that secrete soluble antigen in immunocompetent, but not in immunodeficient, host mice. This growth difference is due to the induction of a more potent antigen-specific antitumor immune response in vivo by the vesicle-bound than by the soluble antigen. Finally, in vivo secretion of the vesicle-bound antigen either by tumors or by vaccination with naked DNA protects against soluble antigen-secreting tumors. We conclude that the mode of secretion can determine the immunogenicity of tumor antigens and that manipulation of the mode of antigen secretion may be used to optimize antitumor vaccination protocols.

  1. The role and mechanics of dendritic cells in tumor antigen acquisition and presentation following laser immunotherapy

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    Laverty, Sean M.; Dawkins, Bryan A.; Chen, Wei R.

    2018-02-01

    We extend our model of the antitumor immune response initiated by laser-immunotherapy treatment to more closely examine key steps in the immune response 1) tumor antigen acquisition by antigen-presenting dendritic cells (DCs) and 2) cytotoxic T cell (CTL) priming by lymphatic DCs. Specifically we explore the formation of DC-CTL complexes that lead to CTL priming. We find that the bias in the dissociation rate of the complex influences the outcome of treatment. In particular, a bias towards priming favors a rapid activated CTL response and the clearance of tumors.

  2. State of the Art in Tumor Antigen and Biomarker Discovery

    International Nuclear Information System (INIS)

    Even-Desrumeaux, Klervi; Baty, Daniel; Chames, Patrick

    2011-01-01

    Our knowledge of tumor immunology has resulted in multiple approaches for the treatment of cancer. However, a gap between research of new tumors markers and development of immunotherapy has been established and very few markers exist that can be used for treatment. The challenge is now to discover new targets for active and passive immunotherapy. This review aims at describing recent advances in biomarkers and tumor antigen discovery in terms of antigen nature and localization, and is highlighting the most recent approaches used for their discovery including “omics” technology

  3. Tumor antigens as proteogenomic biomarkers in invasive ductal carcinomas

    DEFF Research Database (Denmark)

    Olsen, Lars Rønn; Campos, Benito; Winther, Ole

    2014-01-01

    directly linked to the hallmarks of cancer. The results found by proteogenomic analysis of the 32 tumor antigens studied here, capture largely the same pathway irregularities as those elucidated from large-scale screening of genomics analyses, where several thousands of genes are often found......Background: The majority of genetic biomarkers for human cancers are defined by statistical screening of high-throughput genomics data. While a large number of genetic biomarkers have been proposed for diagnostic and prognostic applications, only a small number have been applied in the clinic....... Similarly, the use of proteomics methods for the discovery of cancer biomarkers is increasing. The emerging field of proteogenomics seeks to enrich the value of genomics and proteomics approaches by studying the intersection of genomics and proteomics data. This task is challenging due to the complex nature...

  4. p56Lck and p59Fyn Regulate CD28 Binding to Phosphatidylinositol 3-Kinase, Growth Factor Receptor-Bound Protein GRB-2, and T Cell-Specific Protein-Tyrosine Kinase ITK: Implications for T-Cell Costimulation

    Science.gov (United States)

    Raab, Monika; Cai, Yun-Cai; Bunnell, Stephen C.; Heyeck, Stephanie D.; Berg, Leslie J.; Rudd, Christopher E.

    1995-09-01

    T-cell activation requires cooperative signals generated by the T-cell antigen receptor ξ-chain complex (TCRξ-CD3) and the costimulatory antigen CD28. CD28 interacts with three intracellular proteins-phosphatidylinositol 3-kinase (PI 3-kinase), T cell-specific protein-tyrosine kinase ITK (formerly TSK or EMT), and the complex between growth factor receptor-bound protein 2 and son of sevenless guanine nucleotide exchange protein (GRB-2-SOS). PI 3-kinase and GRB-2 bind to the CD28 phosphotyrosine-based Tyr-Met-Asn-Met motif by means of intrinsic Src-homology 2 (SH2) domains. The requirement for tyrosine phosphorylation of the Tyr-Met-Asn-Met motif for SH2 domain binding implicates an intervening protein-tyrosine kinase in the recruitment of PI 3-kinase and GRB-2 by CD28. Candidate kinases include p56Lck, p59Fyn, ξ-chain-associated 70-kDa protein (ZAP-70), and ITK. In this study, we demonstrate in coexpression studies that p56Lck and p59Fyn phosphorylate CD28 primarily at Tyr-191 of the Tyr-Met-Asn-Met motif, inducing a 3- to 8-fold increase in p85 (subunit of PI 3-kinase) and GRB-2 SH2 binding to CD28. Phosphatase digestion of CD28 eliminated binding. In contrast to Src kinases, ZAP-70 and ITK failed to induce these events. Further, ITK binding to CD28 was dependent on the presence of p56Lck and is thus likely to act downstream of p56Lck/p59Fyn in a signaling cascade. p56Lck is therefore likely to be a central switch in T-cell activation, with the dual function of regulating CD28-mediated costimulation as well as TCR-CD3-CD4 signaling.

  5. The Advantages of Multi-Epitope Tumor Antigens as an Approach to Treating Breast Cancer

    National Research Council Canada - National Science Library

    Kiertscher, Sylvia

    1999-01-01

    .... We hypothesized that the processing and presentation of multiple tumor antigen epitopes by DC is a more efficient and effective way of stimulating T cell responses than current HLA-restricted peptide-based methods...

  6. EVIR: chimeric receptors that enhance dendritic cell cross-dressing with tumor antigens.

    Science.gov (United States)

    Squadrito, Mario Leonardo; Cianciaruso, Chiara; Hansen, Sarah K; De Palma, Michele

    2018-03-01

    We describe a lentivirus-encoded chimeric receptor, termed extracellular vesicle (EV)-internalizing receptor (EVIR), which enables the selective uptake of cancer-cell-derived EVs by dendritic cells (DCs). The EVIR enhances DC presentation of EV-associated tumor antigens to CD8 + T cells primarily through MHCI recycling and cross-dressing. EVIRs should facilitate exploring the mechanisms and implications of horizontal transfer of tumor antigens to antigen-presenting cells.

  7. Whole tumor antigen vaccination using dendritic cells: Comparison of RNA electroporation and pulsing with UV-irradiated tumor cells

    Directory of Open Access Journals (Sweden)

    Benencia Fabian

    2008-04-01

    Full Text Available Abstract Because of the lack of full characterization of tumor associated antigens for solid tumors, whole antigen use is a convenient approach to tumor vaccination. Tumor RNA and apoptotic tumor cells have been used as a source of whole tumor antigen to prepare dendritic cell (DC based tumor vaccines, but their efficacy has not been directly compared. Here we compare directly RNA electroporation and pulsing of DCs with whole tumor cells killed by ultraviolet (UV B radiation using a convenient tumor model expressing human papilloma virus (HPV E6 and E7 oncogenes. Although both approaches led to DCs presenting tumor antigen, electroporation with tumor cell total RNA induced a significantly higher frequency of tumor-reactive IFN-gamma secreting T cells, and E7-specific CD8+ lymphocytes compared to pulsing with UV-irradiated tumor cells. DCs electroporated with tumor cell RNA induced a larger tumor infiltration by T cells and produced a significantly stronger delay in tumor growth compared to DCs pulsed with UV-irradiated tumor cells. We conclude that electroporation with whole tumor cell RNA and pulsing with UV-irradiated tumor cells are both effective in eliciting antitumor immune response, but RNA electroporation results in more potent tumor vaccination under the examined experimental conditions.

  8. Real-time PCR analysis of genes encoding tumor antigens in esophageal tumors and a cancer vaccine

    NARCIS (Netherlands)

    Weinert, Brian T.; Krishnadath, Kausilia K.; Milano, Francesca; Pedersen, Ayako W.; Claesson, Mogens H.; Zocca, Mai-Britt

    2009-01-01

    Tumor antigens are the primary target of therapeutic cancer vaccines. We set out to define and compare the expression pattern of tumor antigen genes in esophagus carcinoma biopsies and in an allogeneic tumor lysate-based cancer vaccine, MelCancerVac. Cells used for vaccine production were treated

  9. T Cell Receptors that Recognize the Tyrosinase Tumor Antigen | NCI Technology Transfer Center | TTC

    Science.gov (United States)

    The National Cancer Institute, Surgery Branch, Tumor Immunology Section, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize T Cells Attacking Cancer: T Cell Receptors that Recognize the Tyrosinase Tumor Antigen

  10. Real-time PCR analysis of genes encoding tumor antigens in esophageal tumors and a cancer vaccine

    DEFF Research Database (Denmark)

    Weinert, Brian T; Krishnadath, Kausilia K; Milano, Francesca

    2009-01-01

    Tumor antigens are the primary target of therapeutic cancer vaccines. We set out to define and compare the expression pattern of tumor antigen genes in esophagus carcinoma biopsies and in an allogeneic tumor lysate-based cancer vaccine, MelCancerVac. Cells used for vaccine production were treated...... in the production of the vaccine. Quantitative PCR was used to assay 74 tumor antigen genes in patients with squamous cell carcinoma of the esophagus. 81% (13/16) of tumors expressed more than five cancer/testis (CT) antigens. A total of 96 genes were assayed in the tumor cell clone (DDM1.7) used to make tumor cell...

  11. Connective tissue growth factor linked to the E7 tumor antigen generates potent antitumor immune responses mediated by an antiapoptotic mechanism.

    Science.gov (United States)

    Cheng, W-F; Chang, M-C; Sun, W-Z; Lee, C-N; Lin, H-W; Su, Y-N; Hsieh, C-Y; Chen, C-A

    2008-07-01

    A novel method for generating an antigen-specific cancer vaccine and immunotherapy has emerged using a DNA vaccine. However, antigen-presenting cells (APCs) have a limited life span, which hinders their long-term ability to prime antigen-specific T cells. Connective tissue growth factor (CTGF) has a role in cell survival. This study explored the intradermal administration of DNA encoding CTGF with a model tumor antigen, human papilloma virus type 16 E7. Mice vaccinated with CTGF/E7 DNA exhibited a dramatic increase in E7-specific CD4(+) and CD8(+) T-cell precursors. They also showed an impressive antitumor effect against E7-expressing tumors compared with mice vaccinated with the wild-type E7 DNA. The delivery of DNA encoding CTGF and E7 or CTGF alone could prolong the survival of transduced dendritic cells (DCs) in vivo. In addition, CTGF/E7-transduced DCs could enhance a higher number of E7-specific CD8(+) T cells than E7-transduced DCs. By prolonging the survival of APCs, DNA vaccine encoding CTGF linked to a tumor antigen represents an innovative approach to enhance DNA vaccine potency and holds promise for cancer prophylaxis and immunotherapy.

  12. Recombinant heat shock protein 70 in combination with radiotherapy as a source of tumor antigens to improve dendritic cell immunotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Yu-Shan [Department of Radiation Therapy and Oncology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan (China); Department of Animal Science, National Ilan University, Ilan, Taiwan (China); Liu, Shih-Jen [Vaccine Research and Development Center, National Health Research Institutes, Miaoli, Taiwan (China); Huang, Su-Chen; Chang, Chao-Chun; Huang, Yi-Chun; Fong, Weng-Lam; Chi, Mau-Shin [Department of Radiation Therapy and Oncology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan (China); Chi, Kwan-Hwa, E-mail: m006565@ms.skh.org.tw [Department of Radiation Therapy and Oncology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan (China); School of Medicine and Institute of Radiation Science and Image Research, National Yang-Ming Medical University, Taipei, Taiwan (China)

    2012-10-29

    Local radiotherapy (RT) plus intratumoral dendritic cell (DC) injection can mediate immunological response. We hypothesized that co-injection of exogenous recombinant heat shock protein 70 (rHsp70) in combination with RT-DC could be as effective as co-injection of HSP-peptide for evoking specific immune response. rHsp70-prostate-specific antigen (rHSP70C′-PSA) and α-fetoprotein (rHSP70C′-AFP) were used to compare specific response. Growth inhibition of the tumor and the systemic anti-tumor immune response were measured on CT26/PSA and CT26/AFP mice model. Intratumoral co-injection of rHsp70 and DC into the irradiated tumor site induced a more potent anti-tumor immune response than injection of DC alone. rHsp70 was as effective as rHsp70C′-PSA or rHsp70C′-AFP in inducing a tumor-specific cytotoxic T lymphocyte response or tumor growth delay. These results demonstrate that co-administration with rHsp70 and RT could be a simple and effective source of tumor antigens to achieve RT-DC immunotherapy protocol and easy to apply in clinical use.

  13. Recombinant heat shock protein 70 in combination with radiotherapy as a source of tumor antigens to improve dendritic cell immunotherapy

    International Nuclear Information System (INIS)

    Wang, Yu-Shan; Liu, Shih-Jen; Huang, Su-Chen; Chang, Chao-Chun; Huang, Yi-Chun; Fong, Weng-Lam; Chi, Mau-Shin; Chi, Kwan-Hwa

    2012-01-01

    Local radiotherapy (RT) plus intratumoral dendritic cell (DC) injection can mediate immunological response. We hypothesized that co-injection of exogenous recombinant heat shock protein 70 (rHsp70) in combination with RT-DC could be as effective as co-injection of HSP-peptide for evoking specific immune response. rHsp70-prostate-specific antigen (rHSP70C′-PSA) and α-fetoprotein (rHSP70C′-AFP) were used to compare specific response. Growth inhibition of the tumor and the systemic anti-tumor immune response were measured on CT26/PSA and CT26/AFP mice model. Intratumoral co-injection of rHsp70 and DC into the irradiated tumor site induced a more potent anti-tumor immune response than injection of DC alone. rHsp70 was as effective as rHsp70C′-PSA or rHsp70C′-AFP in inducing a tumor-specific cytotoxic T lymphocyte response or tumor growth delay. These results demonstrate that co-administration with rHsp70 and RT could be a simple and effective source of tumor antigens to achieve RT-DC immunotherapy protocol and easy to apply in clinical use.

  14. Increased projection of MHC and tumor antigens in murine B16-BL6 melanoma induced by hydrostatic pressure and chemical crosslinking.

    Science.gov (United States)

    Ramakrishna, V; Eisenthal, A; Skornick, Y; Shinitzky, M

    1993-05-01

    The B16-BL6 melanoma, like most spontaneously arising tumors, is poorly immunogenic and expresses low levels of major histocompatibility complex (MHC) antigens. Treatment of cells of this tumor in vitro by hydrostatic pressure in the presence of adenosine 2',3'-dialdehyde (oxAdo), a membrane-impermeant crosslinker, caused elevated projection of MHC and a specific tumor antigen as demonstrated by flow-cytometric analysis. Maximum projection of both the MHC and the tumor antigens could be reached by application of 1200 atm for 15 min in the presence of 20 mM oxAdo. It is not yet clear whether this passive increase in availability of antigens on the cell surface originated from a dormant pool of antigens in the plasma membrane or from pressure-induced fusion of antigen-rich intracellular organelles (e.g. the endoplasmic reticulum). The immunogenic properties of the antigen-enriched B16-BL6 cells are described in the following paper.

  15. 用单因子血清识别急性致瘤性ALV诱发肿瘤组织中的fps肿瘤抗原%Detection of fps tumor antigen with mono-specific anti-fps serum in tumors induced by acute transforming ALV

    Institute of Scientific and Technical Information of China (English)

    王一新; 陈浩; 赵鹏; 李建亮; 崔治中

    2013-01-01

    [目的]制备鼠抗fps单因子血清,检测急性致瘤性ALV诱发肉瘤组织中的fps肿瘤抗原.[方法]以J亚群相关禽白血病/肉瘤病毒Fu-J株RNA为模板,分两段扩增v-fps肿瘤基因,利用大肠杆菌表达系统表达这两段蛋白,纯化后将两种蛋白同时免疫小鼠,获得抗血清,间接免疫荧光试验检测肉瘤组织滤过液感染的CEF和肿瘤细胞中的fps抗原,免疫组织化学方法检测肿瘤组织中的fps抗原.[结果]该单因子血清具有较好特异性,不与经典ALV-J发生交叉反应.被感染的CEF细胞、肿瘤细胞及纤维肉瘤组织切片均显示阳性.[结论]该实验制备了鼠抗fps单因子血清,建立了fps肿瘤抗原的检测方法,为进一步研究该病毒的生物学特性及其致瘤机制奠定了基础.%[Objective] To prepare anti-fps mono-specific serum, and detect the fps antigen in tumors induced by acute transforming avian leukosis/sarcoma virus containing v-fps oncogene.[Methods] Two part of v-fps gene was amplified by RT-PCR using the Fu-J viral RNA as the template.Mono-specific serum was prepared by immuning Kunming white mouse with both two recombinant infusion proteins expressed by the prokaryotic expression system.Indirect immunofluorescent assay was used to detect fps antigen in tumor tissue suspension cells and CEF infected by sarcoma supernatant.Immunohistochemical method was used to detect fps antigen in tumor tissue.[Results] The mouse mono-specific serum was specific as it had no cross reaction with classical ALV-J strains.The result reveals that the tumor tissue suspension cells, the CEF infected by sarcoma supernatant, and the slice immunohistochemistry of the sarcoma showed positive results.[Conclusion] The anti-fps mono-specific serum was prepared, and the detection method was established, which laid the foundation for the study of viral biological characteristics and mechanism of tumourgenesis of acute transforming avian leukosis/sarcoma virus containing v

  16. Highly efficient gene delivery by mRNA electroporation in human hematopoietic cells: superiority to lipofection and passive pulsing of mRNA and to electroporation of plasmid cDNA for tumor antigen loading of dendritic cells.

    Science.gov (United States)

    Van Tendeloo, V F; Ponsaerts, P; Lardon, F; Nijs, G; Lenjou, M; Van Broeckhoven, C; Van Bockstaele, D R; Berneman, Z N

    2001-07-01

    Designing effective strategies to load human dendritic cells (DCs) with tumor antigens is a challenging approach for DC-based tumor vaccines. Here, a cytoplasmic expression system based on mRNA electroporation to efficiently introduce tumor antigens into DCs is described. Preliminary experiments in K562 cells using an enhanced green fluorescent protein (EGFP) reporter gene revealed that mRNA electroporation as compared with plasmid DNA electroporation showed a markedly improved transfection efficiency (89% versus 40% EGFP(+) cells, respectively) and induced a strikingly lower cell toxicity (15% death rate with mRNA versus 51% with plasmid DNA). Next, mRNA electroporation was applied for nonviral transfection of different types of human DCs, including monocyte-derived DCs (Mo-DCs), CD34(+) progenitor-derived DCs (34-DCs) and Langerhans cells (34-LCs). High-level transgene expression by mRNA electroporation was obtained in more than 50% of all DC types. mRNA-electroporated DCs retained their phenotype and maturational potential. Importantly, DCs electroporated with mRNA-encoding Melan-A strongly activated a Melan-A-specific cytotoxic T lymphocyte (CTL) clone in an HLA-restricted manner and were superior to mRNA-lipofected or -pulsed DCs. Optimal stimulation of the CTL occurred when Mo-DCs underwent maturation following mRNA transfection. Strikingly, a nonspecific stimulation of CTL was observed when DCs were transfected with plasmid DNA. The data clearly demonstrate that Mo-DCs electroporated with mRNA efficiently present functional antigenic peptides to cytotoxic T cells. Therefore, electroporation of mRNA-encoding tumor antigens is a powerful technique to charge human dendritic cells with tumor antigens and could serve applications in future DC-based tumor vaccines.

  17. Antigen-specific immunotherapy in ovarian cancer and p53 as tumor antigen

    NARCIS (Netherlands)

    Vermeij, Renee; Leffers, Ninke; Melief, Cornelis J.; Daemen, Toos; Nijman, Hans W.

    This review discusses the results of different immunization strategies, identifies possible drawbacks in study design and provides potential solutions for augmentation of clinical efficacy. A potential target for cancer immunotherapy is p53, as approximately 50% of ovarian cancer cells carry p53

  18. Detection of polyomavirus simian virus 40 tumor antigen DNA in AIDS-related systemic non-Hodgkin lymphoma

    Science.gov (United States)

    Vilchez, Regis A.; Lednicky, John A.; Halvorson, Steven J.; White, Zoe S.; Kozinetz, Claudia A.; Butel, Janet S.

    2002-01-01

    Systemic non-Hodgkin lymphoma (S-NHL) is a common malignancy during HIV infection, and it is hypothesized that infectious agents may be involved in the etiology. Epstein-Barr virus DNA is found in <40% of patients with AIDS-related S-NHL, suggesting that other oncogenic viruses, such as polyomaviruses, may play a role in pathogenesis. We analyzed AIDS-related S-NHL samples, NHL samples from HIV-negative patients, peripheral blood leukocytes from HIV-infected and -uninfected patients without NHL, and lymph nodes without tumors from HIV-infected patients. Specimens were examined by polymerase chain reaction analysis with use of primers specific for an N-terminal region of the oncoprotein large tumor antigen ( T-ag ) gene conserved among all three polyomaviruses (simian virus 40 [SV40], JC virus, and BK virus). Polyomavirus T-ag DNA sequences, proven to be SV40-specific, were detected more frequently in AIDS-related S-NHL samples (6 of 26) than in peripheral blood leukocytes from HIV-infected patients (6 of 26 vs. 0 of 69; p =.0001), NHL samples from HIV-negative patients (6 of 26 vs. 0 of 10; p =.09), or lymph nodes (6 of 26 vs. 0 of 7; p =.16). Sequences of C-terminal T-ag DNA from SV40 were amplified from two AIDS-related S-NHL samples. Epstein-Barr virus DNA sequences were detected in 38% (10 of 26) AIDS-related S-NHL samples, 50% (5 of 10) HIV-negative S-NHL samples, and 57% (4 of 7) lymph nodes. None of the S-NHL samples were positive for both Epstein-Barr virus DNA and SV40 DNA. Further studies of the possible role of SV40 in the pathogenesis of S-NHL are warranted.

  19. The raccoon polyomavirus genome and tumor antigen transcription are stable and abundant in neuroglial tumors.

    Science.gov (United States)

    Brostoff, Terza; Dela Cruz, Florante N; Church, Molly E; Woolard, Kevin D; Pesavento, Patricia A

    2014-11-01

    Raccoon polyomavirus (RacPyV) is associated with 100% of neuroglial tumors in free-ranging raccoons. Other tumor-associated polyomaviruses (PyVs), including simian virus 40 (SV40), murine PyV, and Merkel cell PyV, are found integrated in the host genome in neoplastic cells, where they constitutively express splice variants of the tumor antigen (TAg) gene. We have previously reported that RacPyV exists only as an episome (nonintegrated) in neuroglial tumors. Here, we have investigated TAg transcription in primary tumor tissue by transcriptome analysis, and we identified the alternatively spliced TAg transcripts for RacPyV. We also determined that TAg was highly transcribed relative to host cellular genes. We further colocalized TAg DNA and mRNA by in situ hybridization and found that the majority of tumor cells showed positive staining. Lastly, we examined the stability of the viral genome and TAg transcription by quantitative reverse transcriptase PCR in cultured tumor cells in vitro and in a mouse xenograft model. When tumor cells were cultured in vitro, TAg transcription increased nearly 2 log-fold over that of parental tumor tissue by passage 17. Both episomal viral genome and TAg transcription were faithfully maintained in culture and in tumors arising from xenotransplantation of cultured cells in mice. This study represents a minimal criterion for RacPyV's association with neuroglial tumors and a novel mechanism of stability for a polyomavirus in cancer. The natural cycle of polyomaviruses in mammals is to persist in the host without causing disease, but they can cause cancer in humans or in other animals. Because this is an unpredictable and rare event, the oncogenic potential of polyomavirus is primarily evaluated in laboratory animal models. Recently, raccoon polyomavirus (RacPyV) was identified in neuroglial tumors of free-ranging raccoons. Viral copy number was consistently high in these tumors but was low or undetectable in nontumor tissue or in

  20. In silico and cell-based analyses reveal strong divergence between prediction and observation of T-cell-recognized tumor antigen T-cell epitopes.

    Science.gov (United States)

    Schmidt, Julien; Guillaume, Philippe; Dojcinovic, Danijel; Karbach, Julia; Coukos, George; Luescher, Immanuel

    2017-07-14

    Tumor exomes provide comprehensive information on mutated, overexpressed genes and aberrant splicing, which can be exploited for personalized cancer immunotherapy. Of particular interest are mutated tumor antigen T-cell epitopes, because neoepitope-specific T cells often are tumoricidal. However, identifying tumor-specific T-cell epitopes is a major challenge. A widely used strategy relies on initial prediction of human leukocyte antigen-binding peptides by in silico algorithms, but the predictive power of this approach is unclear. Here, we used the human tumor antigen NY-ESO-1 (ESO) and the human leukocyte antigen variant HLA-A*0201 (A2) as a model and predicted in silico the 41 highest-affinity, A2-binding 8-11-mer peptides and assessed their binding, kinetic complex stability, and immunogenicity in A2-transgenic mice and on peripheral blood mononuclear cells from ESO-vaccinated melanoma patients. We found that 19 of the peptides strongly bound to A2, 10 of which formed stable A2-peptide complexes and induced CD8 + T cells in A2-transgenic mice. However, only 5 of the peptides induced cognate T cells in humans; these peptides exhibited strong binding and complex stability and contained multiple large hydrophobic and aromatic amino acids. These results were not predicted by in silico algorithms and provide new clues to improving T-cell epitope identification. In conclusion, our findings indicate that only a small fraction of in silico -predicted A2-binding ESO peptides are immunogenic in humans, namely those that have high peptide-binding strength and complex stability. This observation highlights the need for improving in silico predictions of peptide immunogenicity. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  1. Direct identification of an HPV-16 tumor antigen from cervical cancer biopsy specimens

    Directory of Open Access Journals (Sweden)

    Derin B Keskin

    2011-12-01

    Full Text Available Persistent infection with high-risk human papilloma viruses (HPV is the worldwide cause of many cancers, including cervical, anal, vulval, vaginal, penile and oropharyngeal. Since T cells naturally eliminate the majority of chronic HPV infections by recognizing epitopes displayed on virally altered epithelium, we exploited Poisson detection mass spectrometry (MS3 to identify those epitopes and inform future T cell-based vaccine design. Nine cervical cancer biopsies from HPV-16 positive HLA-A*02 patients were obtained, histopathology determined, and E7 oncogene PCR-amplified from tumor DNA and sequenced. Conservation of E7 oncogene coding segments was found in all tumors. MS3 analysis of HLA-A*02 immunoprecipitates detected E711-19 peptide (YMLDLQPET in seven of the nine tumor biopsies. The remaining two samples were E711-19 negative and lacked the HLA-A*02 binding GILT thioreductase peptide despite possessing binding-competent HLA-A*02 alleles. Thus, the conserved E711-19 peptide is a dominant HLA-A*02 binding tumor antigen in HPV-16 transformed cervical squamous and adenocarcinomas. Findings that a minority of HLA-A*02:01 tumors lack expression of both E711-19 and a peptide from a thioreductase important in processing of cysteine-rich proteins like E7 underscore the value of physical detection, define a potential additional tumor escape mechanism and have implications for therapeutic cancer vaccine development.

  2. The role of B cell-mediated T cell costimulation in the efficacy of the T cell retargeting bispecific antibody BIS20x3

    NARCIS (Netherlands)

    Stel, AJ; Kroesen, BJ; Jacobs, Susan; Groen, H; de Leij, LFMH; Kluin-Nelemans, HC; Withoff, S

    2004-01-01

    In this study, we investigated the role of the naturally occurring B cell-mediated T cell costimulation in the antitumor efficacy of the bispecific Ab BIS20x3. BIS20x3 has a dual specificity for both CD20 and CD3 and has previously been shown to effectively direct the lytic potential of cytolytic T

  3. Lung cancer-associated tumor antigens and the present status of immunotherapy against non-small-cell lung cancer

    International Nuclear Information System (INIS)

    Yasumoto, Kosei; Hanagiri, Takeshi; Takenoyama, Mitsuhiro

    2009-01-01

    Despite recent advances in surgery, irradiation, and chemotherapy, the prognosis of patients with lung cancer is still poor. Therefore, the development and application of new therapeutic strategies are essential for improving the prognosis of this disease. Significant progress in our understanding of tumor immunology and molecular biology has allowed us to identify the tumor-associated antigens recognized by cytotoxic T lymphocytes. Immune responses and tumor-associated antigens against not only malignant melanoma but also lung cancer have been elucidated at the molecular level. In a theoretical sense, tumor eradication is considered possible through antigen-based immunotherapy against such diseases. However, many clinical trials of cancer vaccination with defined tumor antigens have resulted in objective clinical responses in only a small number of patients. Tumor escape mechanisms from host immune surveillance remain a major obstacle for cancer immunotherapy. A better understanding of the immune escape mechanisms employed by tumor cells is necessary before we can develop a more effective immunotherapeutic approach to lung cancer. We review recent studies regarding the identification of tumor antigens in lung cancer, tumor immune escape mechanisms, and clinical vaccine trials in lung cancer. (author)

  4. CD28 co-stimulation down regulates Th17 development.

    Directory of Open Access Journals (Sweden)

    Salim Bouguermouh

    Full Text Available Th17 cells are implicated in host defence and autoimmune diseases. CD28/B7 co-stimulation is involved in the induction and progression of autoimmune diseases, but its role in controlling murine Th17 cell fate remains to be clarified. We here report that soluble anti-CD28 mAb suppressed the differentiation of anti-CD3-stimulated naïve CD4(+ T cells into IL-17-producing cells. CD28 co-stimulation reduced the frequency of proliferating cells that produce IL-17. We provide evidence for an IL-2 and IFN-gamma-dependent mechanism of CD28-mediated IL-17 suppression. CD28 blockade of Th17 development was correlated with a decrease rather than an increase in the percentage of Foxp3(+ T cells. In APC/T cell co-cultures, mature dendritic cells (DC were less efficient than immature DC in their ability to support Th17 cell differentiation, while CTLA4-Ig, an agent blocking CD28/B7 and CTLA4/B7 interactions, facilitated both murine and human Th17 differentiation. This study identifies the importance of B7 co-stimulatory molecules in the negative regulation of Th17 development. These unexpected results caution targeting the CD28/B7 pathways in the treatment of human autoimmune diseases.

  5. EGFRvIII mCAR-modified T-cell therapy cures mice with established intracerebral glioma and generates host immunity against tumor-antigen loss.

    Science.gov (United States)

    Sampson, John H; Choi, Bryan D; Sanchez-Perez, Luis; Suryadevara, Carter M; Snyder, David J; Flores, Catherine T; Schmittling, Robert J; Nair, Smita K; Reap, Elizabeth A; Norberg, Pamela K; Herndon, James E; Kuan, Chien-Tsun; Morgan, Richard A; Rosenberg, Steven A; Johnson, Laura A

    2014-02-15

    Chimeric antigen receptor (CAR) transduced T cells represent a promising immune therapy that has been shown to successfully treat cancers in mice and humans. However, CARs targeting antigens expressed in both tumors and normal tissues have led to significant toxicity. Preclinical studies have been limited by the use of xenograft models that do not adequately recapitulate the immune system of a clinically relevant host. A constitutively activated mutant of the naturally occurring epidermal growth factor receptor (EGFRvIII) is antigenically identical in both human and mouse glioma, but is also completely absent from any normal tissues. We developed a third-generation, EGFRvIII-specific murine CAR (mCAR), and performed tests to determine its efficacy in a fully immunocompetent mouse model of malignant glioma. At elevated doses, infusion with EGFRvIII mCAR T cells led to cures in all mice with brain tumors. In addition, antitumor efficacy was found to be dependent on lymphodepletive host conditioning. Selective blockade with EGFRvIII soluble peptide significantly abrogated the activity of EGFRvIII mCAR T cells in vitro and in vivo, and may offer a novel strategy to enhance the safety profile for CAR-based therapy. Finally, mCAR-treated, cured mice were resistant to rechallenge with EGFRvIII(NEG) tumors, suggesting generation of host immunity against additional tumor antigens. All together, these data support that third-generation, EGFRvIII-specific mCARs are effective against gliomas in the brain and highlight the importance of syngeneic, immunocompetent models in the preclinical evaluation of tumor immunotherapies. ©2013 AACR

  6. CD28 Costimulation of T Helper 1 Cells Enhances Cytokine Release In Vivo

    Directory of Open Access Journals (Sweden)

    Daniela Langenhorst

    2018-05-01

    Full Text Available Compared to naive T cells, differentiated T cells are thought to be less dependent on CD28 costimulation for full activation. To revisit the role of CD28 costimulation in mouse T cell recall responses, we adoptively transferred in vitro generated OT-II T helper (Th 1 cells into C57BL/6 mice (Thy1.2+ and then either blocked CD28–ligand interactions with Fab fragments of the anti-CD28 monoclonal antibody (mAb E18 or deleted CD28 expression using inducible CD28 knock-out OT-II mice as T cell donors. After injection of ovalbumin protein in adjuvant into the recipient mice we observed that systemic interferon (IFNγ release strongly depended on CD28 costimulation of the Th1 cells, while secondary clonal expansion was not reduced in the absence of CD28 costimulation. For human memory CD4+ T cell responses we also noted that cytokine release was reduced upon inhibition of CD28 costimulation. Together, our data highlight the so far underestimated role of CD28 costimulation for the reactivation of fully differentiated CD4+ T cells.

  7. GITR ligand-costimulation activates effector and regulatory functions of CD4+ T cells

    International Nuclear Information System (INIS)

    Igarashi, Hanna; Cao, Yujia; Iwai, Hideyuki; Piao, Jinhua; Kamimura, Yosuke; Hashiguchi, Masaaki; Amagasa, Teruo; Azuma, Miyuki

    2008-01-01

    Engagement of glucocorticoid-induced TNFR-related protein (GITR) enables the costimulation of both CD25 - CD4 + effector (Teff) and CD25 + CD4 + regulatory (Treg) cells; however, the effects of GITR-costimulation on Treg function remain controversial. In this study, we examined the effects of GITR ligand (GITRL) binding on the respective functions of CD4 + T cells. GITRL-P815 transfectants efficiently augmented anti-CD3-induced proliferation and cytokine production by Teff cells. Proliferation and IL-10 production in Treg were also enhanced by GITRL transfectants when exogenous IL-2 and stronger CD3 stimulation was provided. Concomitant GITRL-costimulation of Teff and Treg converted the anergic state of Treg into a proliferating state, maintaining and augmenting their function. Thus, GITRL-costimulation augments both effector and regulatory functions of CD4 + T cells. Our results suggest that highly activated and increased ratios of Treg reverse the immune-enhancing effects of GITRL-costimulation in Teff, which may be problematic for therapeutic applications using strong GITR agonists

  8. CD5 costimulation induces stable Th17 development by promoting IL-23R expression and sustained STAT3 activation

    NARCIS (Netherlands)

    de Wit, Jelle; Souwer, Yuri; van Beelen, Astrid J.; de Groot, Rosa; Muller, Femke J. M.; Klaasse Bos, Hanny; Jorritsma, Tineke; Kapsenberg, Martien L.; de Jong, Esther C.; van Ham, S. Marieke

    2011-01-01

    IL-17-producing CD4(+) T helper (Th17) cells are important for immunity against extracellular pathogens and in autoimmune diseases. The factors that drive Th17 development in human remain a matter of debate. Here we show that, compared with classic CD28 costimulation, alternative costimulation via

  9. Induction of IgG3 to LPS via Toll-like receptor 4 co-stimulation.

    Directory of Open Access Journals (Sweden)

    Francisco J Quintana

    Full Text Available B-cells integrate antigen-specific signals transduced via the B-cell receptor (BCR and antigen non-specific co-stimulatory signals provided by cytokines and CD40 ligation in order to produce IgG antibodies. Toll-like receptors (TLRs also provide co-stimulation, but the requirement for TLRs to generate T-cell independent and T-cell dependent antigen specific antibody responses is debated. Little is known about the role of B-cell expressed TLRs in inducing antigen-specific antibodies to antigens that also activate TLR signaling. We found that mice lacking functional TLR4 or its adaptor molecule MyD88 harbored significantly less IgG3 natural antibodies to LPS, and required higher amounts of LPS to induce anti-LPS IgG3. In vitro, BCR and TLR4 signaling synergized, lowering the threshold for production of T-cell independent IgG3 and IL-10. Moreover, BCR and TLR4 directly associate through the transmembrane domain of TLR4. Thus, in vivo, BCR/TLR synergism could facilitate the induction of IgG3 antibodies against microbial antigens that engage both innate and adaptive B-cell receptors. Vaccines might exploit BCR/TLR synergism to rapidly induce antigen-specific antibodies before significant T-cell responses arise.

  10. A short CD3/CD28 costimulation combined with IL-21 enhance the generation of human memory stem T cells for adoptive immunotherapy.

    Science.gov (United States)

    Alvarez-Fernández, C; Escribà-Garcia, L; Vidal, S; Sierra, J; Briones, J

    2016-07-19

    Immunotherapy based on the adoptive transfer of gene modified T cells is an emerging approach for the induction of tumor-specific immune responses. Memory stem T cells, due to their enhanced antitumor and self-renewal capacity, have become potential candidate for adoptive T cell therapy of cancer. Methods to generate memory stem T cells ex vivo rely on CD3/CD28 costimulation and the use of cytokines such as IL-7 and IL-15 during the entire culture period. However, a strong costimulation may induce differentiation of memory stem T cells to effector memory T cells. Here we show that manipulation of the length of the costimulation and addition of IL-21 enhance the ex vivo expansion of memory stem T cells. Purified naïve T cells from healthy donors were cultured in the presence of anti-CD3/CD28 coated beads, IL-7, IL-15 and/or IL-21 (25 ng/ml). T cells phenotype from the different memory and effector subpopulations were analyzed by multiparametric flow cytometry. A short anti-CD3/CD28 costimulation of naïve T cells, combined with IL-7 and IL-15 significantly increased the frequencies of CD4(+) and CD8(+) memory stem T cells ex vivo, compared to a prolonged costimulation (34.6 ± 4.4 % vs 15.6 ± 4.24 % in CD4(+); p = 0.008, and 20.5 ± 4.00 % vs 7.7 ± 2.53 % in CD8(+); p = 0.02). Moreover, the addition of IL-21 to this condition further enhanced the enrichment and expansion of CD4(+) and CD8(+) memory stem T cells with an increase in the absolute numbers (0.7 × 10(6) ± 0.1 vs 0.26 × 10(6) ± 0.1 cells for CD4(+); p = 0.002 and 1.1 × 10(6) ± 0.1 vs 0.27 × 10(6) ± 0.1 cells for CD8(+); p = 0.0002; short + IL-21 vs long). These new in vitro conditions increase the frequencies and expansion of memory stem T cells and may have relevant clinical implications for the generation of this memory T cell subset for adoptive cell therapy of patients with cancer.

  11. Increasing the ex vivo antigen-specific IFN-γ production in subpopulations of T cells and NKp46+ cells by anti-CD28, anti-CD49d and recombinant IL-12 costimulation in cattle vaccinated with recombinant proteins from Mycobacterium avium subspecies paratuberculosis

    DEFF Research Database (Denmark)

    Thakur, Aneesh; Riber, Ulla; Davis, William C.

    2013-01-01

    -γ secretion by CD4, CD8, γδ T cells and NK cells. Age matched male jersey calves, experimentally infected with Mycobacterium avium subsp. paratuberculosis (MAP), were vaccinated with a cocktail of recombinant MAP proteins or left unvaccinated. Vaccine induced ex vivo recall responses were measured through Ag......T cells, which encounter specific antigen (Ag), require additional signals to mount a functional immune response. Here, we demonstrate activation of signal 2, by anti-CD28 mAb (aCD28) and other costimulatory molecules (aCD49d, aCD5), and signal 3, by recombinant IL-12, enhance Ag-specific IFN...

  12. OSCAR is a collagen receptor that costimulates osteoclastogenesis in DAP12-deficient humans and mice

    DEFF Research Database (Denmark)

    Barrow, Alexander David; Raynal, Nicolas; Levin Andersen, Thomas

    2011-01-01

    by preosteoclasts in vitro, but OSCAR lacks a cognate ligand and its role in vivo has been unclear. Using samples from mice and patients deficient in various ITAM signaling pathways, we show here that OSCAR costimulates one of the major FcRγ-associated pathways required for osteoclastogenesis in vivo. Furthermore...... to signaling that increased numbers of osteoclasts in culture. Thus, our results suggest that ITAM-containing receptors can respond to exposed ligands in collagen, leading to the functional differentiation of leukocytes, which provides what we believe to be a new concept for ITAM regulation of cytokine...

  13. CXCL12 Mediates Aberrant Costimulation of B Lymphocytes in Warts, Hypogammaglobulinemia, Infections, Myelokathexis Immunodeficiency

    Directory of Open Access Journals (Sweden)

    Giuliana Roselli

    2017-09-01

    Full Text Available The Warts, Hypogammaglobulinemia, Infections, Myelokathexis (WHIM syndrome is an immunodeficiency caused by mutations in chemokine receptor CXCR4. WHIM patient adaptive immunity defects remain largely unexplained. We have previously shown that WHIM-mutant T cells form unstable immunological synapses, affecting T cell activation. Here, we show that, in WHIM patients and WHIM CXCR4 knock-in mice, B cells are more apoptosis prone. Intriguingly, WHIM-mutant B cells were also characterized by spontaneous activation. Searching for a mechanistic explanation for these observations, we uncovered a novel costimulatory effect of CXCL12, the CXCR4 ligand, on WHIM-mutant but not wild-type B cells. The WHIM CXCR4-mediated costimulation led to increased B-cell activation, possibly involving mTOR, albeit without concurrently promoting survival. A reduction in antigenic load during immunization in the mouse was able to circumvent the adaptive immunity defects. These results suggest that WHIM-mutant CXCR4 may lead to spontaneous aberrant B-cell activation, via CXCL12-mediated costimulation, impairing B-cell survival and thus possibly contributing to the WHIM syndrome defects in adaptive immunity.

  14. CXCL12 Mediates Aberrant Costimulation of B Lymphocytes in Warts, Hypogammaglobulinemia, Infections, Myelokathexis Immunodeficiency

    Science.gov (United States)

    Roselli, Giuliana; Martini, Elisa; Lougaris, Vassilios; Badolato, Raffaele; Viola, Antonella; Kallikourdis, Marinos

    2017-01-01

    The Warts, Hypogammaglobulinemia, Infections, Myelokathexis (WHIM) syndrome is an immunodeficiency caused by mutations in chemokine receptor CXCR4. WHIM patient adaptive immunity defects remain largely unexplained. We have previously shown that WHIM-mutant T cells form unstable immunological synapses, affecting T cell activation. Here, we show that, in WHIM patients and WHIM CXCR4 knock-in mice, B cells are more apoptosis prone. Intriguingly, WHIM-mutant B cells were also characterized by spontaneous activation. Searching for a mechanistic explanation for these observations, we uncovered a novel costimulatory effect of CXCL12, the CXCR4 ligand, on WHIM-mutant but not wild-type B cells. The WHIM CXCR4-mediated costimulation led to increased B-cell activation, possibly involving mTOR, albeit without concurrently promoting survival. A reduction in antigenic load during immunization in the mouse was able to circumvent the adaptive immunity defects. These results suggest that WHIM-mutant CXCR4 may lead to spontaneous aberrant B-cell activation, via CXCL12-mediated costimulation, impairing B-cell survival and thus possibly contributing to the WHIM syndrome defects in adaptive immunity. PMID:28928741

  15. The Role of Costimulation Blockade in Solid Organ and Islet Xenotransplantation

    Directory of Open Access Journals (Sweden)

    Kannan P. Samy

    2017-01-01

    Full Text Available Pig-to-human xenotransplantation offers a potential bridge to the growing disparity between patients with end-stage organ failure and graft availability. Early studies attempting to overcome cross-species barriers demonstrated robust humoral immune responses to discordant xenoantigens. Recent advances have led to highly efficient and targeted genomic editing, drastically altering the playing field towards rapid production of less immunogenic porcine tissues and even the discussion of human xenotransplantation trials. However, as these humoral immune barriers to cross-species transplantation are overcome with advanced transgenics, cellular immunity to these novel xenografts remains an outstanding issue. Therefore, understanding and optimizing immunomodulation will be paramount for successful clinical xenotransplantation. Costimulation blockade agents have been introduced in xenotransplantation research in 2000 with anti-CD154mAb. Most recently, prolonged survival has been achieved in solid organ (kidney xenograft survival > 400 days with anti-CD154mAb, heart xenograft survival > 900 days, and liver xenograft survival 29 days with anti-CD40mAb and islet xenotransplantation (>600 days with anti-CD154mAb with the use of these potent experimental agents. As the development of novel genetic modifications and costimulation blocking agents converges, we review their impact thus far on preclinical xenotransplantation and the potential for future application.

  16. B7h-expressing dendritic cells and plasma B cells mediate distinct outcomes of ICOS costimulation in T cell-dependent antibody responses

    Directory of Open Access Journals (Sweden)

    Larimore Kevin

    2012-06-01

    Full Text Available Abstract Background The ICOS-B7h costimulatory receptor-ligand pair is required for germinal center formation, the production of isotype-switched antibodies, and antibody affinity maturation in response to T cell-dependent antigens. However, the potentially distinct roles of regulated B7h expression on B cells and dendritic cells in T cell-dependent antibody responses have not been defined. Results We generated transgenic mice with lineage-restricted B7h expression to assess the cell-type specific roles of B7h expression on B cells and dendritic cells in regulating T cell-dependent antibody responses. Our results show that endogenous B7h expression is reduced on B cells after activation in vitro and is also reduced in vivo on antibody-secreting plasma B cells in comparison to both naïve and germinal center B cells from which they are derived. Increasing the level of B7h expression on activated and plasma B cells in B-B7hTg mice led to an increase in the number of antibody-secreting plasma cells generated after immunization and a corresponding increase in the concentration of antigen-specific high affinity serum IgG antibodies of all isotypes, without affecting the number of responding germinal center B cells. In contrast, ICOS costimulation mediated by dendritic cells in DC-B7hTg mice contributed to germinal center formation and selectively increased IgG2a production without affecting the overall magnitude of antibody responses. Conclusions Using transgenic mice with lineage-restricted B7h expression, we have revealed distinct roles of ICOS costimulation mediated by dendritic cells and B cells in the regulation of T cell-dependent antibody responses.

  17. Isolation of scFv antibody fragments against HER2 and CEA tumor antigens from combinatorial antibody libraries derived from cancer patients.

    Science.gov (United States)

    Ayat, Hoda; Burrone, Oscar R; Sadghizadeh, Majid; Jahanzad, Eissa; Rastgou, Nasrin; Moghadasi, Sarrira; Arbabi, Mehdi

    2013-11-01

    Tumor cells expressing HER-2/neu and CEA antigens are potentially ideal targets for antibody-targeted therapy. In this study, two large human combinatorial libraries have been generated from the lymph nodes of breast cancer patients that express HER2 and CEA antigens in their tumors. These 'immune' libraries have been constructed in two different formats of scFv, differing in the length of the peptide linker connecting the two variable VH and VL domains. Libraries derived from these patients may contain a larger pool of anti-tumor antigen antibodies and are useful repertoire for isolating scFvs against any tumor markers. The results of this study showed that we were successful in obtaining human scFvs against HER-2/neu and CEA. For HER-2, cell-panning strategy was performed and resulted in two scFv binders that detected the complete HER-2 receptor on the cell membrane and internalized to the cells. Also, preliminary ELISA data showed that several anti-CEA scFv binders were isolated by panning. Copyright © 2013 The International Alliance for Biological Standardization. All rights reserved.

  18. Comparison of Vaccine-Induced Effector CD8 T Cell Responses Directed against Self- and Non-Self-Tumor Antigens

    DEFF Research Database (Denmark)

    Pedersen, Sara R; Sørensen, Maria R; Buus, Søren

    2013-01-01

    It is generally accepted that CD8 T cells play a major role in tumor control, yet vaccination aimed at eliciting potent CD8 T cell responses are rarely efficient in clinical trials. To try and understand why this is so, we have generated potent adenoviral vectors encoding the endogenous tumor Ags...... that low avidity of the self-TA-specific CD8 T cells may represent a major obstacle for efficient immunotherapy of cancer....

  19. Costimulation blockade and regulatory T-cells in a non-human primate model of kidney allograft transplantation

    NARCIS (Netherlands)

    Haanstra, Krista Geraldine

    2008-01-01

    Successful tolerance induction therapies in rodents are for the most part unsuccessful in larger primates. Costimulation blockade by anti-CD40 or anti-CD40 + anti-CD86 in the life-supporting kidney allograft model in the rhesus monkey prevented graft rejection during treatment but did not induce

  20. Radiation and chemical effects on viral transformation and tumor antigen expression. Annual progress report, August 1, 1978--May 1, 1979

    International Nuclear Information System (INIS)

    Coggin, J.H. Jr.

    1979-01-01

    Studies aimed at the biological, biochemical, and immunologic characterization of fetal antigens (EA) in hamsters and mice and locating and determining the distribution of fetal antigens in tumor tissues and in developing fetuses have been underway for several months. Progress has been made in isolating embryonic or fetal antigens from fetuses and from tumor cells. We have developed and reported a reliable lymphocyte transformation assay (LTA) which meets our needs in routinely assaying cell free tumor associated antigen (TAA) preparations from fetal and tumor cells. The assay correlated with transplantation resistance assays and has appropriate specificity. We have also developed the staph-A protein binding assay utilizing anti-serum derived against embryonic antigens present on SV40 tumor cells. In other studies, we have reported increases and perturbations in thymocytes during viral and chemical oncogenesis in hamsters, have developed a simple technique for preserving functional lymphocytes sensitized against TAA by freezing for use in our model system work, have reported the cross-reactivity of tranplantation resistance antigen on a spectrum of chemically induced tumors previously believed to only contain individually specific TSTAs and have recently reported the cross-reactivity of papovavirus induced transplantation resistance antigen in sarcoma cells induced by different viruses. We have concluded our studies of glycosyltransferases in the membranes of developing fetuses and noted no differences in their levels with advancing days of gestation using whold embryo cell populations

  1. Monoclonal antibodies reactive with common tumor antigens on UV-induced tumors also react with hyperplastic UV-irradiated skin

    International Nuclear Information System (INIS)

    Spellman, C.W.; Beauchamp, D.A.

    1986-01-01

    Most murine skin tumors induced by ultraviolet light (UVB, 280-340 nm) can be successfully transplanted only into syngeneic hosts that have received subcarcinogenic doses of UVB. The tumor susceptible state is long-lived and mediated by T suppressor cells that control effector responses against common antigens on UV-induced tumors. Because antigen specific suppression arises prior to the appearance of a tumor, questions arise about the source of the original antigen. They have previously reported transplantation studies indicating that UV-irradiated skin is antigenically cross-reactive with UV-induced tumors. They now report on flow cytometry analyses showing that a series of MoAb reactive with common antigens expressed by UV-induced tumors are also reactive on cells from UV-irradiated skin. Various antigens appear at different times in the UV irradiation scheme, and some persist while others are transient. They speculate that the common antigens detected may be the ones to which functional suppression is directed. If true, these results suggest that successful tumors need not escape host defenses to emerge. Rather, tumors may arise and grow progressively if they express antigens that cross-react with specificities to which the host has previously mounted a suppressive response

  2. The role of CD27-CD70-mediated T cell co-stimulation in vasculogenesis, arteriogenesis and angiogenesis.

    Science.gov (United States)

    Simons, K H; Aref, Z; Peters, H A B; Welten, S P; Nossent, A Y; Jukema, J W; Hamming, J F; Arens, R; de Vries, M R; Quax, P H A

    2018-06-01

    T cells have a distinctive role in neovascularization, which consists of arteriogenesis and angiogenesis under pathological conditions and vasculogenesis under physiological conditions. However, the role of co-stimulation in T cell activation in neovascularization has yet to be established. The aim of this study was to investigate the role T cell co-stimulation and inhibition in angiogenesis, arteriogenesis and vasculogenesis. Hind limb ischemia was induced by double ligation of the left femoral artery in mice and blood flow recovery was measured with Laser Doppler Perfusion Imaging in control, CD70 -/- , CD80/86 -/- , CD70/80/86 -/- and CTLA4 +/- mice. Blood flow recovery was significantly impaired in mice lacking CD70 compared to control mice, but was similar in CD80/86 -/- , CTLA4 +/- and control mice. Mice lacking CD70 showed impaired vasculogenesis, since the number of pre-existing collaterals was reduced as observed in the pia mater compared to control mice. In vitro an impaired capability of vascular smooth muscle cells (VSMC) to activate T cells was observed in VSMC lacking CD70. Furthermore, CD70 -/- , CD80/86 -/- and CD70/80/86 -/- mice showed reduced angiogenesis in the soleus muscle 10 days after ligation. Arteriogenesis was also decreased in CD70 -/- compared to control mice 10 and 28 days after surgery. The present study is the first to describe an important role for T cell activation via co-stimulation in angiogenesis, arteriogenesis and vasculogenesis, where the CD27-CD70 T cell co-stimulation pathway appears to be the most important co-stimulation pathway in pre-existing collateral formation and post-ischemic blood flow recovery, by arteriogenesis and angiogenesis. Copyright © 2018 Elsevier B.V. All rights reserved.

  3. Optimization of Diagnostic Elisa - Based Tests for the Detection of Auto-Antibodies Against Tumor Antigens in Human Serum

    Directory of Open Access Journals (Sweden)

    Daria Štefatić

    2008-08-01

    Full Text Available Colorectal cancer is one of the most common cancer types worldwide and it continues to be a serious public health problem. Early detection and diagnosis are of great importance in cancer management. At present, diagnostic blood tests are based on the detection of tumor-associated markers such as carcinoembryonic antigen (CEA, the cancer antigen CA19-9 for gastrointestinal cancer, CA15-3 for breast cancer or CA125 for ovarian cancer. The lack of sensitivity and specificity of these markers prevents their general use in cancer screening of an average risk population. Therefore, new cancer biomarkers or better screening methods are necessary to improve the diagnostics of the disease. This study was directed to the optimization of a diagnostic, enzyme linked immunosorbent assay (ELISA based test to identify and validate new serum markers, such as extracellular Protein Kinase A (ecPKA and Nicotinamide A-Meth- yltransferase (NNMT. In this type of assay, the cancer antigens are quantified indirectly - by detecting the presence of auto-antibodies against tumor proteins in human serum. The result of the optimization and validation process was in the case of ecPKA a reproducible and stable assay. In case of NNMT the assay was probably not sensitive enough.

  4. CARbodies: Human Antibodies Against Cell Surface Tumor Antigens Selected From Repertoires Displayed on T Cell Chimeric Antigen Receptors

    Directory of Open Access Journals (Sweden)

    Vanesa Alonso-Camino

    2013-01-01

    Full Text Available A human single-chain variable fragment (scFv antibody library was expressed on the surface of human T cells after transduction with lentiviral vectors (LVs. The repertoire was fused to a first-generation T cell receptor ζ (TCRζ-based chimeric antigen receptor (CAR. We used this library to isolate antibodies termed CARbodies that recognize antigens expressed on the tumor cell surface in a proof-of-principle system. After three rounds of activation-selection there was a clear repertoire restriction, with the emergence dominant clones. The CARbodies were purified from bacterial cultures as soluble and active proteins. Furthermore, to validate its potential application for adoptive cell therapy, human T cells were transduced with a LV encoding a second-generation costimulatory CAR (CARv2 bearing the selected CARbodies. Transduced human primary T cells expressed significant levels of the CARbodies-based CARv2 fusion protein on the cell surface, and importantly could be specifically activated, after stimulation with tumor cells. This approach is a promising tool for the generation of antibodies fully adapted to the display format (CAR and the selection context (cell synapse, which could extend the scope of current adoptive cell therapy strategies with CAR-redirected T cells.

  5. TCRs Used in Cancer Gene Therapy Cross-React with MART-1/Melan-A Tumor Antigens via Distinct Mechanisms

    Energy Technology Data Exchange (ETDEWEB)

    Borbulevych, Oleg Y.; Santhanagopolan, Sujatha M.; Hossain, Moushumi; Baker, Brian M. (Notre)

    2013-09-18

    T cells engineered to express TCRs specific for tumor Ags can drive cancer regression. The first TCRs used in cancer gene therapy, DMF4 and DMF5, recognize two structurally distinct peptide epitopes of the melanoma-associated MART-1/Melan-A protein, both presented by the class I MHC protein HLA-A*0201. To help understand the mechanisms of TCR cross-reactivity and provide a foundation for the further development of immunotherapy, we determined the crystallographic structures of DMF4 and DMF5 in complex with both of the MART-1/Melan-A epitopes. The two TCRs use different mechanisms to accommodate the two ligands. Although DMF4 binds the two with a different orientation, altering its position over the peptide/MHC, DMF5 binds them both identically. The simpler mode of cross-reactivity by DMF5 is associated with higher affinity toward both ligands, consistent with the superior functional avidity of DMF5. More generally, the observation of two diverging mechanisms of cross-reactivity with the same Ags and the finding that TCR-binding orientation can be determined by peptide alone extend our understanding of the mechanisms underlying TCR cross-reactivity.

  6. Effector/memory CD8+ T cells synergize with co-stimulation competent macrophages to trigger autoimmune peripheral neuropathy.

    Science.gov (United States)

    Yang, Mu; Shi, Xiang Qun; Peyret, Corentin; Oladiran, Oladayo; Wu, Sonia; Chambon, Julien; Fournier, Sylvie; Zhang, Ji

    2018-04-05

    Autoimmune peripheral neuropathy (APN) such as Guillain Barre Syndrome (GBS) is a debilitating illness and sometimes life threatening. The molecular and cellular mechanisms remain elusive but exposure to environmental factors including viral/bacterial infection and injury is highly associated with disease incidence. We demonstrated previously that both male and female B7.2 (CD86) transgenic L31 and L31/CD4KO mice develop spontaneous APN. Here we further reveal that CD8 + T cells in these mice exhibit an effector/memory phenotype, which bears a resemblance to the CD8 + T cell response following persistent cytomegalovirus (CMV) infection in humans and mice, whilst CMV has been considered as one of the most relevant pathogens in APN development. These activated, peripheral myelin Ag specific CD8 + T cells are required for the disease initiation. While an injury to a peripheral nerve results in Wallerian degeneration in control littermates, the same injury accelerates the development of APN in other non-injured nerves of L31 mice which have a predisposed inflammatory background consisting of effector/memory CD8 + T (CD8 + T EM ) cells. However, CD8 + T EM cells alone are not sufficient. A certain threshold of B7.2 expression on nerve macrophages is an additional requisite. Our findings reveal that indeed, the synergism between CD8 + T EM cells and co-stimulation competent macrophages is crucial in inducing autoimmune-mediated peripheral neuropathy. The identification of decisive molecular/cellular players connecting environmental triggers and the occurrence of APN provides opportunities to prevent disease onset, reduce relapses and develop new therapeutic strategies. Crown Copyright © 2018. Published by Elsevier Inc. All rights reserved.

  7. Control of Memory CD8+ T Cell Differentiation by CD80/CD86-CD28 Costimulation and Restoration by IL-2 during the Recall Response1

    OpenAIRE

    Fuse, Shinichiro; Zhang, Weijun; Usherwood, Edward J.

    2008-01-01

    Memory CD8+ T cell responses have been considered to be independent of CD80/CD86-CD28 costimulation. However, recall responses are often severely blunted in CD28−/− mice. Whether this impairment represents a requirement for CD28 costimulation for proper memory CD8+ T cell development or a requirement during the recall response is unknown. Furthermore, how CD28 costimulation affects the phenotype and function of memory CD8+ T cells has not been characterized in detail. In this study, we invest...

  8. Functional dichotomy between NKG2D and CD28-mediated co-stimulation in human CD8+ T cells.

    Directory of Open Access Journals (Sweden)

    Kamalakannan Rajasekaran

    2010-09-01

    Full Text Available Both CD28 and NKG2D can function as co-stimulatory receptors in human CD8+ T cells. However, their independent functional contributions in distinct CD8+ T cell subsets are not well understood. In this study, CD8+ T cells in human peripheral blood- and lung-derived lymphocytes were analyzed for CD28 and NKG2D expression and function. We found a higher level of CD28 expression in PBMC-derived naïve (CD45RA+CD27+ and memory (CD45RA-CD27+ CD8+ T cells (CD28Hi, while its expression was significantly lower in effector (CD45RA+CD27- CD8+ T cells (CD28Lo. Irrespective of the differences in the CD28 levels, NKG2D expression was comparable in all three CD8+ T cell subsets. CD28 and NKG2D expressions followed similar patterns in human lung-resident GILGFVFTL/HLA-A2-pentamer positive CD8+ T cells. Co-stimulation of CD28Lo effector T cells via NKG2D significantly increased IFN-γ and TNF-α levels. On the contrary, irrespective of its comparable levels, NKG2D-mediated co-stimulation failed to augment IFN-γ and TNF-α production in CD28Hi naïve/memory T cells. Additionally, CD28-mediated co-stimulation was obligatory for IL-2 generation and thereby its production was limited only to the CD28Hi naïve/memory subsets. MICA, a ligand for NKG2D was abundantly expressed in the tracheal epithelial cells, validating the use of NKG2D as the major co-stimulatory receptor by tissue-resident CD8+ effector T cells. Based on these findings, we conclude that NKG2D may provide an expanded level of co-stimulation to tissue-residing effector CD8+ T cells. Thus, incorporation of co-stimulation via NKG2D in addition to CD28 is essential to activate tumor or tissue-infiltrating effector CD8+ T cells. However, boosting a recall immune response via memory CD8+ T cells or vaccination to stimulate naïve CD8+ T cells would require CD28-mediated co-stimulation.

  9. Costimulation of N-methyl-d-aspartate and muscarinic neuronal receptors modulates gap junctional communication in striatal astrocytes

    OpenAIRE

    Rouach, N.; Tencé, M.; Glowinski, J.; Giaume, C.

    2002-01-01

    Cocultures of neurons and astrocytes from the rat striatum were used to determine whether the stimulation of neuronal receptors could affect the level of intercellular communication mediated by gap junctions in astrocytes. The costimulation of N-methyl-D-asparte (NMDA) and muscarinic receptors led to a prominent reduction of astrocyte gap junctional communication (GJC) in coculture. This treatment was not effective in astrocyte cultures, these cells being devoid of NMDA receptors. Both types ...

  10. Electrical and optical co-stimulation in the deaf white cat

    Science.gov (United States)

    Cao, Zhiping; Xu, Yingyue; Tan, Xiaodong; Suematsu, Naofumi; Robinson, Alan; Richter, Claus-Peter

    2018-02-01

    Spatial selectivity of neural stimulation with photons, such as infrared neural stimulation (INS) is higher than the selectivity obtained with electrical stimulation. To obtain more independent channels for stimulation in neural prostheses, INS may be implemented to better restore the fidelity of the damaged neural system. However, irradiation with infrared light also bares the risk of heat accumulation in the target tissue with subsequent neural damage. Lowering the threshold for stimulation could reduce the amount of heat delivered to the tissue and the risk for subsequent tissue damage. It has been shown in the rat sciatic nerve that simultaneous irradiation with infrared light and the delivery of biphasic sub-threshold electrical pulses can reduce the threshold for INS [1]. In this study, deaf white cats have been used to test whether opto-electrical co-stimulation can reduce the stimulation threshold for INS in the auditory system too. The cochleae of the deaf white cats have largely reduced spiral ganglion neuron counts and significant degeneration of the organ of Corti and do not respond to acoustic stimuli. Combined electrical and optical stimulation was used to demonstrate that simultaneous stimulation with infrared light and biphasic electrical pulses can reduce the threshold for stimulation.

  11. Mixed Signals: Co-Stimulation in Invariant Natural Killer T Cell-Mediated Cancer Immunotherapy

    Directory of Open Access Journals (Sweden)

    Susannah C. Shissler

    2017-11-01

    Full Text Available Invariant natural killer T (iNKT cells are an integral component of the immune system and play an important role in antitumor immunity. Upon activation, iNKT cells can directly kill malignant cells as well as rapidly produce cytokines that stimulate other immune cells, making them a front line defense against tumorigenesis. Unfortunately, iNKT cell number and activity are reduced in multiple cancer types. This anergy is often associated with upregulation of co-inhibitory markers such as programmed death-1. Similar to conventional T cells, iNKT cells are influenced by the conditions of their activation. Conventional T cells receive signals through the following three types of receptors: (1 T cell receptor (TCR, (2 co-stimulation molecules, and (3 cytokine receptors. Unlike conventional T cells, which recognize peptide antigen presented by MHC class I or II, the TCRs of iNKT cells recognize lipid antigen in the context of the antigen presentation molecule CD1d (Signal 1. Co-stimulatory molecules can positively and negatively influence iNKT cell activation and function and skew the immune response (Signal 2. This study will review the background of iNKT cells and their co-stimulatory requirements for general function and in antitumor immunity. We will explore the impact of monoclonal antibody administration for both blocking inhibitory pathways and engaging stimulatory pathways on iNKT cell-mediated antitumor immunity. This review will highlight the incorporation of co-stimulatory molecules in antitumor dendritic cell vaccine strategies. The use of co-stimulatory intracellular signaling domains in chimeric antigen receptor-iNKT therapy will be assessed. Finally, we will explore the influence of innate-like receptors and modification of immunosuppressive cytokines (Signal 3 on cancer immunotherapy.

  12. T helper-independent activation of human CD8+ cells: the role of CD28 costimulation.

    Science.gov (United States)

    Van Gool, S W; Zhang, Y; Kasran, A; de Boer, M; Ceuppens, J L

    1996-07-01

    The concept that activation of MHC class I-restricted CD8+ cells entirely depends on help from MHC class II-restricted CD4+ T cells has recently been supplemented with an alternative model in which CD8+ cells can directly be activated by MHC class I-expressing professional antigen-presenting cells (APC), which are able to deliver an accessory signal. The authors analysed the role of CD28-mediated costimulation for T helper cell-independent activation of purified human CD8+ T cells in two different in vitro models. Freshly isolated CD8+ cells could be activated (proliferation, IL-2 production and cytotoxic activity) by anti-CD3-presenting Fc gamma R+ mouse cells transfected with the human CD28 ligand, CD80, as the only accessory signal. On the other hand, activation of CD8+ cells by allogeneic MHC class I on EBV-transformed B cells, which express two different CD28 ligands, CD80 and CD86, also proceeded very efficiently (proliferation, cytotoxic activity and CD25 expression), but was either not, or only partially, blocked by anti-CD80 and anti-CD86 MoAb or CTLA-4Ig. This indicates that other costimulatory signals are also effective, and that CD28 triggering is not absolutely required for initial T-cell activation. CsA and CD80/CD86-blocking agents were synergistic in completely inhibiting activation of CD8+ cells in the MLR with allogeneic B-cell lines. This combination also induced non-responsiveness of CD8+ cells upon restimulation in the absence of blocking agents. Therefore, although professional APC can apparently provide multiple costimulatory signals for direct activation of CD8+ T cells, the signal derived from CD80/CD86 is unique in providing CsA-resistance.

  13. Minor Antigen Disparities Impede Induction of Long Lasting Chimerism and Tolerance through Bone Marrow Transplantation with Costimulation Blockade

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    Sinda Bigenzahn

    2016-01-01

    Full Text Available Mixed chimerism and tolerance can be successfully induced in rodents through allogeneic bone marrow transplantation (BMT with costimulation blockade (CB, but varying success rates have been reported with distinct models and protocols. We therefore investigated the impact of minor antigen disparities on the induction of mixed chimerism and tolerance. C57BL/6 (H2b mice received nonmyeloablative total body irradiation (3 Gy, costimulation blockade (anti-CD40L mAb and CTLA4Ig, and 2×107 bone marrow cells (BMC from either of three donor strains: Balb/c (H2d (MHC plus multiple minor histocompatibility antigen (mHAg mismatched, B10.D2 (H2d or B10.A (H2a (both MHC mismatched, but mHAg matched. Macrochimerism was followed over time by flow cytometry and tolerance was tested by skin grafting. 20 of 21 recipients of B10.D2 BMC but only 13 of 18 of Balb/c BMC and 13 of 20 of B10.A BMC developed stable long-term multilineage chimerism (p<0.05 for each donor strain versus B10.D2. Significantly superior donor skin graft survival was observed in successfully established long-term chimeras after mHAg matched BMT compared to mHAg mismatched BMT (p<0.05. Both minor and major antigen disparities pose a substantial barrier for the induction of chimerism while the maintenance of tolerance after nonmyeloablative BMT and costimulation blockade is negatively influenced by minor antigen disparities.

  14. Inducible Costimulator Expressing T Cells Promote Parasitic Growth During Blood Stage Plasmodium berghei ANKA Infection

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    Gajendra M. Jogdand

    2018-05-01

    Full Text Available The lethality of blood stage Plasmodium berghei ANKA (PbA infection is associated with the expression of T-bet and production of cytokine IFN-γ. Expression of inducible costimulator (ICOS and its downstream signaling has been shown to play a critical role in the T-bet expression and IFN-γ production. Although earlier studies have examined the role of ICOS in the control of acute blood-stage infection of Plasmodium chabaudi chabaudi AS (a non-lethal model of malaria infection, its significance in the lethal blood-stage of PbA infection remains unclear. Thus, to address the seminal role of ICOS in lethal blood-stage of PbA infection, we treated PbA-infected mice with anti-ICOS antibody and observed that these mice survived longer than their infected counterparts with significantly lower parasitemia. Anti-ICOS treatment notably depleted ICOS expressing CD4+ and CD8+ T cells with a concurrent reduction in plasma IFN-γ, which strongly indicated that ICOS expressing T cells are major IFN-γ producers. Interestingly, we observed that while ICOS expressing CD4+ and CD8+ T cells produced IFN-γ, ICOS−CD8+ T cells were also found to be producers of IFN-γ. However, we report that ICOS+CD8+ T cells were higher producers of IFN-γ than ICOS−CD8+ T cells. Moreover, correlation of ICOS expression with IFN-γ production in ICOS+IFN-γ+ T cell population (CD4+ and CD8+ T cells suggested that ICOS and IFN-γ could positively regulate each other. Further, master transcription factor T-bet importantly involved in regulating IFN-γ production was also found to be expressed by ICOS expressing CD4+ and CD8+ T cells during PbA infection. As noted above with IFN-γ and ICOS, a positive correlation of expression of ICOS with the transcription factor T-bet suggested that both of them could regulate each other. Taken together, our results depicted the importance of ICOS expressing CD4+ and CD8+ T cells in malaria parasite growth and lethality through IFN

  15. Genetic disassociation of autoimmunity and resistance to costimulation blockade-induced transplantation tolerance in nonobese diabetic mice.

    Science.gov (United States)

    Pearson, Todd; Markees, Thomas G; Serreze, David V; Pierce, Melissa A; Marron, Michele P; Wicker, Linda S; Peterson, Laurence B; Shultz, Leonard D; Mordes, John P; Rossini, Aldo A; Greiner, Dale L

    2003-07-01

    Curing type 1 diabetes by islet transplantation requires overcoming both allorejection and recurrent autoimmunity. This has been achieved with systemic immunosuppression, but tolerance induction would be preferable. Most islet allotransplant tolerance induction protocols have been tested in nonobese diabetic (NOD) mice, and most have failed. Failure has been attributed to the underlying autoimmunity, assuming that autoimmunity and resistance to transplantation tolerance have a common basis. Out of concern that NOD biology could be misleading in this regard, we tested the hypothesis that autoimmunity and resistance to transplantation tolerance in NOD mice are distinct phenotypes. Unexpectedly, we observed that (NOD x C57BL/6)F(1) mice, which have no diabetes, nonetheless resist prolongation of skin allografts by costimulation blockade. Further analyses revealed that the F(1) mice shared the dendritic cell maturation defects and abnormal CD4(+) T cell responses of the NOD but had lost its defects in macrophage maturation and NK cell activity. We conclude that resistance to allograft tolerance induction in the NOD mouse is not a direct consequence of overt autoimmunity and that autoimmunity and resistance to costimulation blockade-induced transplantation tolerance phenotypes in NOD mice can be dissociated genetically. The outcomes of tolerance induction protocols tested in NOD mice may not accurately predict outcomes in human subjects.

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

    DEFF Research Database (Denmark)

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

    2009-01-01

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

  17. Naturally Induced Secretions of the Potato Cyst Nematode Co-stimulate the Proliferation of Both Tobacco Leaf Protoplasts and Human Peripheral Blood Mononuclear Cells

    NARCIS (Netherlands)

    Goverse, A.; Rouppe van der Voort, J.N.A.M.; Rouppe van der voort, C.; Kavelaars, A.; Smant, G.; Schots, A.; Bakker, J.; Helder, J.

    1999-01-01

    Naturally induced secretions from infective juveniles of the potato cyst nematode Globodera rostochiensis co-stimulate the proliferation of tobacco leaf protoplasts in the presence of the synthetic phytohormones α-naphthaleneacetic acid (NAA) and 6-benzylaminopurine (BAP). With the use of a

  18. Type 2 innate lymphoid cell suppression by regulatory T cells attenuates airway hyperreactivity and requires inducible T-cell costimulator-inducible T-cell costimulator ligand interaction.

    Science.gov (United States)

    Rigas, Diamanda; Lewis, Gavin; Aron, Jennifer L; Wang, Bowen; Banie, Homayon; Sankaranarayanan, Ishwarya; Galle-Treger, Lauriane; Maazi, Hadi; Lo, Richard; Freeman, Gordon J; Sharpe, Arlene H; Soroosh, Pejman; Akbari, Omid

    2017-05-01

    Atopic diseases, including asthma, exacerbate type 2 immune responses and involve a number of immune cell types, including regulatory T (Treg) cells and the emerging type 2 innate lymphoid cells (ILC2s). Although ILC2s are potent producers of type 2 cytokines, the regulation of ILC2 activation and function is not well understood. In the present study, for the first time, we evaluate how Treg cells interact with pulmonary ILC2s and control their function. ILC2s and Treg cells were evaluated by using in vitro suppression assays, cell-contact assays, and gene expression panels. Also, human ILC2s and Treg cells were adoptively transferred into NOD SCID γC-deficient mice, which were given isotype or anti-inducible T-cell costimulator ligand (ICOSL) antibodies and then challenged with IL-33 and assessed for airway hyperreactivity. We show that induced Treg cells, but not natural Treg cells, effectively suppress the production of the ILC2-driven proinflammatory cytokines IL-5 and IL-13 both in vitro and in vivo. Mechanistically, our data reveal the necessity of inducible T-cell costimulator (ICOS)-ICOS ligand cell contact for Treg cell-mediated ILC2 suppression alongside the suppressive cytokines TGF-β and IL-10. Using a translational approach, we then demonstrate that human induced Treg cells suppress syngeneic human ILC2s through ICOSL to control airway inflammation in a humanized ILC2 mouse model. These findings suggest that peripheral expansion of induced Treg cells can serve as a promising therapeutic target against ILC2-dependent asthma. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  19. Targeting CD28, CTLA-4 and PD-L1 costimulation differentially controls immune synapses and function of human regulatory and conventional T-cells.

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    Nahzli Dilek

    Full Text Available CD28, CTLA-4 and PD-L1, the three identified ligands for CD80/86, are pivotal positive and negative costimulatory molecules that, among other functions, control T cell motility and formation of immune synapse between T cells and antigen-presenting cells (APCs. What remains incompletely understood is how CD28 leads to the activation of effector T cells (Teff but inhibition of suppression by regulatory T cells (Tregs, while CTLA-4 and PD-L1 inhibit Teff function but are crucial for the suppressive function of Tregs. Using alloreactive human T cells and blocking antibodies, we show here by live cell dynamic microscopy that CD28, CTLA-4, and PD-L1 differentially control velocity, motility and immune synapse formation in activated Teff versus Tregs. Selectively antagonizing CD28 costimulation increased Treg dwell time with APCs and induced calcium mobilization which translated in increased Treg suppressive activity, in contrast with the dampening effect on Teff responses. The increase in Treg suppressive activity after CD28 blockade was also confirmed with polyclonal Tregs. Whereas CTLA-4 played a critical role in Teff by reversing TCR-induced STOP signals, it failed to affect motility in Tregs but was essential for formation of the Treg immune synapse. Furthermore, we identified a novel role for PD-L1-CD80 interactions in suppressing motility specifically in Tregs. Thus, our findings reveal that the three identified ligands of CD80/86, CD28, CTLA-4 and PD-L1, differentially control immune synapse formation and function of the human Teff and Treg cells analyzed here. Individually targeting CD28, CTLA-4 and PD-L1 might therefore represent a valuable therapeutic strategy to treat immune disorders where effector and regulatory T cell functions need to be differentially targeted.

  20. Heat shock protein 90-mediated peptide-selective presentation of cytosolic tumor antigen for direct recognition of tumors by CD4(+) T cells.

    Science.gov (United States)

    Tsuji, Takemasa; Matsuzaki, Junko; Caballero, Otavia L; Jungbluth, Achim A; Ritter, Gerd; Odunsi, Kunle; Old, Lloyd J; Gnjatic, Sacha

    2012-04-15

    Tumor Ag-specific CD4(+) T cells play important functions in tumor immunosurveillance, and in certain cases they can directly recognize HLA class II-expressing tumor cells. However, the underlying mechanism of intracellular Ag presentation to CD4(+) T cells by tumor cells has not yet been well characterized. We analyzed two naturally occurring human CD4(+) T cell lines specific for different peptides from cytosolic tumor Ag NY-ESO-1. Whereas both lines had the same HLA restriction and a similar ability to recognize exogenous NY-ESO-1 protein, only one CD4(+) T cell line recognized NY-ESO-1(+) HLA class II-expressing melanoma cells. Modulation of Ag processing in melanoma cells using specific molecular inhibitors and small interfering RNA revealed a previously undescribed peptide-selective Ag-presentation pathway by HLA class II(+) melanoma cells. The presentation required both proteasome and endosomal protease-dependent processing mechanisms, as well as cytosolic heat shock protein 90-mediated chaperoning. Such tumor-specific pathway of endogenous HLA class II Ag presentation is expected to play an important role in immunosurveillance or immunosuppression mediated by various subsets of CD4(+) T cells at the tumor local site. Furthermore, targeted activation of tumor-recognizing CD4(+) T cells by vaccination or adoptive transfer could be a suitable strategy for enhancing the efficacy of tumor immunotherapy.

  1. The IgV domain of human B7-2 (CD86) is sufficient to co-stimulate T lymphocytes and induce cytokine secretion.

    Science.gov (United States)

    Rennert, P; Furlong, K; Jellis, C; Greenfield, E; Freeman, G J; Ueda, Y; Levine, B; June, C H; Gray, G S

    1997-06-01

    B7-1 (CD80) and B7-2 (CD86) are genetically and structurally related molecules expressed on antigen-presenting cells. Both bind CD28 to co-stimulate T lymphocytes, resulting in proliferation and cytokine production. The extracellular portions of B7-1 and B7-2 which bind to CD28 and CTLA-4 are related to Ig variable (V) and Ig constant (C) domain sequences. Recent reports have described splice variant forms of B7 proteins which occur in vivo and are of unknown function. Here we describe soluble recombinant forms of B7-1 and B7-2 containing either both of the Ig-like extracellular domains or the individual IgV or IgC domains coupled to an Ig Fc tail. Soluble B7-1 and B7-2 bind to CD28 and CTLA-4, and effectively co-stimulate T lymphocytes resulting in their proliferation and the secretion of cytokines. Furthermore, the IgV domain of B7-2 binds CD28 and CTLA-4, competes with B7-1 and B7-2 for binding to these receptors, and co-stimulates T lymphocytes. Cross-linked soluble B7-2v was the most potent co-stimulatory molecule tested and was active at a concentration approximately 100-fold lower than cross-linked soluble B7-1 or B7-2 proteins. When bound to tosyl-activated beads, B7-2v was capable of sustaining multiple rounds of T cell expansion. These data complement the description of naturally occurring variants to suggest that T cell co-stimulation in vivo may be regulated by soluble or truncated forms of B7 proteins.

  2. Numerical simulation of Class 3 hydrate reservoirs exploiting using horizontal well by depressurization and thermal co-stimulation

    International Nuclear Information System (INIS)

    Yang, Shengwen; Lang, Xuemei; Wang, Yanhong; Wen, Yonggang; Fan, Shuanshi

    2014-01-01

    Highlights: • Depressurization and thermal co-stimulation using horizontal well were proposed. • 3D stimulation showed that gas release rate was 3 × 10 5 m 3 per day within 450 days. • 2D stimulation showed that Class 3 hydrates could be dissociated within 8500 days. • 2D Simulation showed that heat flow was 1620 W lasting 1500 days, and decreased fast. • 1.1× 10 5 kg water was collected within 2000 days and then no more water was produced. - Abstract: Class 3 hydrate reservoirs exploiting using horizontal well by depressurization and thermal co-stimulation was simulated using the HydarteResSim code. Results showed that more than 20% of hydrates in the reservoirs had been dissociated within 450 days at the well temperature of 42 °C and well pressure of 0.1P 0 , 0.2P 0 (P 0 is the initial pressure of the reservoirs, simplifying 42 °C and 0.1P 0 , 42 °C and 0.2P 0 ). While the production behavior of 42 °C and 0.5P 0 , 42 °C and 0.8P 0 were not so exciting. In order to understand the production character of the well in long term, the cross section of 1 m length reservoirs was simulated. Simulation results showed that 4.5 × 10 5 m 3 gas would be collected within 4500 days and 1.1 × 10 6 kg water could be produced within 1500 days in the well at 42 °C and 0.1P 0 . 3.5 × 10 5 m 3 gas would be collected within 8500 days and 1.1 × 10 6 kg water could be produced within 1500 days in the well at 42 °C and 0.2P 0 . The heat flow was 1620 W at the beginning and then decreased rapidly in the two cases. For reservoirs of 1495.2 m in length, about 6.7 × 10 8 m 3 and 5.3 × 10 8 m 3 gas would be collected in the well corresponding to conditions of 42 °C and 0.1P 0 , and 42 °C and 0.2P 0

  3. Identification of Tumor Antigen AF20 as Glycosylated Transferrin Receptor 1 in Complex with Heat Shock Protein 90 and/or Transporting ATPase.

    Directory of Open Access Journals (Sweden)

    Jason M Shapiro

    Full Text Available We previously isolated AF20, a murine monoclonal antibody that recognizes a cell surface glycoprotein of approximately 90-110 kDa. The AF20 antigen is specifically expressed in human hepatoma and colon cancer cell lines, and thus could serve as a cancer biomarker. To uncover the molecular identity of the AF20 antigen, a combination of ion-exchange chromatography, immunoprecipitation, and SDS-polyacrylamide gel electrophoresis was employed to purify the AF20 antigen followed by trypsin digestion and mass spectrometry. Surprisingly, three host proteins were thus purified from human hepatoma and colon cancer cell lines: transferrin receptor 1 (TFR1, heat shock protein 90 (HSP90, and Na+/K+ ATPase or Mg++ ATPase. Co-immunoprecipitation followed by Western blot analysis confirmed interaction among the three proteins. However, only the cDNA encoding TFR1 conferred strong cell surface staining by the AF20 antibody following its transient transfection into a cell line lacking endogenous AF20. In support of the molecular identity of AF20 as TFR1, diferric but not iron-free transferrin could prevent AF20 antigen-antibody interaction during immunoprecipitation. Moreover, very similar patterns of AF20 and TFR1 overexpression was documented in colon cancer tissues. In conclusion, AF20 is glycosylated TFR1. This finding could explain the molecular structure of AF20, its cell surface localization, as well as overexpression in cancer cells. Glycosylated TFR1 should serve as a usefulness target for anti-cancer therapy, or a vehicle for delivery of anti-tumor drugs with high affinity and specificity. The biological significance of the complex formation between TFR1, HSP90, and/or transporting ATPase warrants further investigation.

  4. IL-2-Mediated In Vivo Expansion of Regulatory T Cells Combined with CD154–CD40 Co-Stimulation Blockade but Not CTLA-4 Ig Prolongs Allograft Survival in Naive and Sensitized Mice

    Directory of Open Access Journals (Sweden)

    Dela Golshayan

    2017-04-01

    Full Text Available In recent years, regulatory T cells (Treg-based immunotherapy has emerged as a promising strategy to promote operational tolerance after solid organ transplantation (SOT. However, a main hurdle for the therapeutic use of Treg in transplantation is their low frequency, particularly in non-lymphopenic hosts. We aimed to expand Treg directly in vivo and determine their efficacy in promoting donor-specific tolerance, using a stringent experimental model. Administration of the IL-2/JES6-1 immune complex at the time of transplantation resulted in significant expansion of donor-specific Treg, which suppressed alloreactive T cells. IL-2-mediated Treg expansion in combination with short-term CD154–CD40 co-stimulation blockade, but not CTLA-4 Ig or rapamycin, led to tolerance to MHC-mismatched skin grafts in non-lymphopenic mice, mainly by hindering alloreactive CD8+ effector T cells and the production of alloantibodies. Importantly, this treatment also allowed prolonged survival of allografts in the presence of either donor-specific or cross-reactive memory cells. However, late rejection occurred in sensitized hosts, partly mediated by activated B cells. Overall, these data illustrate the potential but also some important limitations of Treg-based therapy in clinical SOT as well as the importance of concomitant immunomodulatory strategies in particular in sensitized hosts.

  5. Tonic 4-1BB Costimulation in Chimeric Antigen Receptors Impedes T Cell Survival and Is Vector-Dependent

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    Diogo Gomes-Silva

    2017-10-01

    Full Text Available Antigen-independent tonic signaling by chimeric antigen receptors (CARs can increase differentiation and exhaustion of T cells, limiting their potency. Incorporating 4-1BB costimulation in CARs may enable T cells to resist this functional exhaustion; however, the potential ramifications of tonic 4-1BB signaling in CAR T cells remain unclear. Here, we found that tonic CAR-derived 4-1BB signaling can produce toxicity in T cells via continuous TRAF2-dependent activation of the nuclear factor κB (NF-κB pathway and augmented FAS-dependent cell death. This mechanism was amplified in a non-self-inactivating gammaretroviral vector through positive feedback on the long terminal repeat (LTR promoter, further enhancing CAR expression and tonic signaling. Attenuating CAR expression by substitution with a self-inactivating lentiviral vector minimized tonic signaling and improved T cell expansion and anti-tumor function. These studies illuminate the interaction between tonic CAR signaling and the chosen expression platform and identify inhibitory properties of the 4-1BB costimulatory domain that have direct implications for rational CAR design.

  6. Id1 expression promotes peripheral CD4{sup +} T cell proliferation and survival upon TCR activation without co-stimulation

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Chen; Jin, Rong [Department of Immunology, Peking University Health Science Center, Beijing (China); Wang, Hong-Cheng [Oklahoma Medical Research Foundation, Oklahoma City, OK (United States); Tang, Hui; Liu, Yuan-Feng; Qian, Xiao-Ping; Sun, Xiu-Yuan; Ge, Qing [Department of Immunology, Peking University Health Science Center, Beijing (China); Sun, Xiao-Hong, E-mail: sunx@omrf.org [Oklahoma Medical Research Foundation, Oklahoma City, OK (United States); Zhang, Yu, E-mail: zhangyu007@bjmu.edu.cn [Department of Immunology, Peking University Health Science Center, Beijing (China)

    2013-06-21

    Highlights: •Id1 expression enables naïve T cell proliferation without anti-CD28 co-stimulation. •Id1 expression facilitates T cells survival when stimulated with anti-CD3. •Elevation of IL-2 production by Id1 contributes increased proliferation and survival. •Id1 potentiates NF-κB activation by anti-CD3 stimulation. -- Abstract: Although the role of E proteins in the thymocyte development is well documented, much less is known about their function in peripheral T cells. Here we demonstrated that CD4 promoter-driven transgenic expression of Id1, a naturally occurring dominant-negative inhibitor of E proteins, can substitute for the co-stimulatory signal delivered by CD28 to facilitate the proliferation and survival of naïve CD4{sup +} cells upon anti-CD3 stimulation. We next discovered that IL-2 production and NF-κB activity after anti-CD3 stimulation were significantly elevated in Id1-expressing cells, which may be, at least in part, responsible for the augmentation of their proliferation and survival. Taken together, results from this study suggest an important role of E and Id proteins in peripheral T cell activation. The ability of Id proteins to by-pass co-stimulatory signals to enable T cell activation has significant implications in regulating T cell immunity.

  7. c-MPL provides tumor-targeted T-cell receptor-transgenic T cells with costimulation and cytokine signals.

    Science.gov (United States)

    Nishimura, Christopher D; Brenner, Daniel A; Mukherjee, Malini; Hirsch, Rachel A; Ott, Leah; Wu, Meng-Fen; Liu, Hao; Dakhova, Olga; Orange, Jordan S; Brenner, Malcolm K; Lin, Charles Y; Arber, Caroline

    2017-12-21

    Adoptively transferred T-cell receptor (TCR)-engineered T cells depend on host-derived costimulation and cytokine signals for their full and sustained activation. However, in patients with cancer, both signals are frequently impaired. Hence, we developed a novel strategy that combines both essential signals in 1 transgene by expressing the nonlymphoid hematopoietic growth factor receptor c-MPL (myeloproliferative leukemia), the receptor for thrombopoietin (TPO), in T cells. c-MPL signaling activates pathways shared with conventional costimulatory and cytokine receptor signaling. Thus, we hypothesized that host-derived TPO, present in the tumor microenvironment, or pharmacological c-MPL agonists approved by the US Food and Drug Administration could deliver both signals to c-MPL-engineered TCR-transgenic T cells. We found that c-MPL + polyclonal T cells expand and proliferate in response to TPO, and persist longer after adoptive transfer in immunodeficient human TPO-transgenic mice. In TCR-transgenic T cells, c-MPL activation enhances antitumor function, T-cell expansion, and cytokine production and preserves a central memory phenotype. c-MPL signaling also enables sequential tumor cell killing, enhances the formation of effective immune synapses, and improves antileukemic activity in vivo in a leukemia xenograft model. We identify the type 1 interferon pathway as a molecular mechanism by which c-MPL mediates immune stimulation in T cells. In conclusion, we present a novel immunotherapeutic strategy using c-MPL-enhanced transgenic T cells responding to either endogenously produced TPO (a microenvironment factor in hematologic malignancies) or c-MPL-targeted pharmacological agents. © 2017 by The American Society of Hematology.

  8. Mechanism for initiation of food allergy: Dependence on skin barrier mutations and environmental allergen costimulation.

    Science.gov (United States)

    Walker, Matthew T; Green, Jeremy E; Ferrie, Ryan P; Queener, Ashley M; Kaplan, Mark H; Cook-Mills, Joan M

    2018-02-15

    Mechanisms for the development of food allergy in neonates are unknown but clearly linked in patient populations to a genetic predisposition to skin barrier defects. Whether skin barrier defects contribute functionally to development of food allergy is unknown. The purpose of the study was to determine whether skin barrier mutations, which are primarily heterozygous in patient populations, contribute to the development of food allergy. Mice heterozygous for the filaggrin (Flg) ft and Tmem79 ma mutations were skin sensitized with environmental and food allergens. After sensitization, mice received oral challenge with food allergen, and then inflammation, inflammatory mediators, and anaphylaxis were measured. We define development of inflammation, inflammatory mediators, and food allergen-induced anaphylaxis in neonatal mice with skin barrier mutations after brief concurrent cutaneous exposure to food and environmental allergens. Moreover, neonates of allergic mothers have increased responses to suboptimal sensitization with food allergens. Importantly, responses to food allergens by these neonatal mice were dependent on genetic defects in skin barrier function and on exposure to environmental allergens. ST2 blockade during skin sensitization inhibited the development of anaphylaxis, antigen-specific IgE, and inflammatory mediators. Neonatal anaphylactic responses and antigen-specific IgE were also inhibited by oral pre-exposure to food allergen, but interestingly, this was blunted by concurrent pre-exposure of the skin to environmental allergen. These studies uncover mechanisms for food allergy sensitization and anaphylaxis in neonatal mice that are consistent with features of human early-life exposures and genetics in patients with clinical food allergy and demonstrate that changes in barrier function drive development of anaphylaxis to food allergen. Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  9. Naturally induced secretions of the potato cyst nematode co-stimulate the proliferation of both tobacco leaf protoplasts and human peripheral blood mononuclear cells.

    Science.gov (United States)

    Goverse, A; Rouppe van der Voort, J; Roppe van der Voort, C; Kavelaars, A; Smant, G; Schots, A; Bakker, J; Helder, J

    1999-10-01

    Naturally induced secretions from infective juveniles of the potato cyst nematode Globodera rostochiensis co-stimulate the proliferation of tobacco leaf protoplasts in the presence of the synthetic phytohormones alpha-naphthaleneacetic acid (NAA) and 6-benzylaminopurine (BAP). With the use of a protoplast-based bioassay, a low-molecular-weight peptide(s) (cyst nematode secretions also co-stimulated mitogenesis in human peripheral blood mononuclear cells (PBMC). The stimulation of plant cells isolated from nontarget tissue--these nematodes normally invade the roots of potato plants--suggests the activation of a general signal transduction mechanism(s) by an oligopeptide(s) secreted by the nematode. Whether a similar oligopeptide-induced mechanism underlies human PBMC activation remains to be investigated. Reactivation of the cell cycle is a crucial event in feeding cell formation by cyst nematodes. The secretion of a mitogenic low-molecular-weight peptide(s) by infective juveniles of the potato cyst nematode could contribute to the redifferentiation of plant cells into such a feeding cell.

  10. T cell ignorance is bliss: T cells are not tolerized by Langerhans cells presenting human papillomavirus antigens in the absence of costimulation

    Directory of Open Access Journals (Sweden)

    Andrew W. Woodham

    2016-12-01

    Full Text Available Human papillomavirus type 16 (HPV16 infections are intra-epithelial, and thus, HPV16 is known to interact with Langerhans cells (LCs, the resident epithelial antigen-presenting cells (APCs. The current paradigm for APC-mediated induction of T cell anergy is through delivery of T cell receptor signals via peptides on MHC molecules (signal 1, but without costimulation (signal 2. We previously demonstrated that LCs exposed to HPV16 in vitro present HPV antigens to T cells without costimulation, but it remained uncertain if such T cells would remain ignorant, become anergic, or in the case of CD4+ T cells, differentiate into Tregs. Here we demonstrate that Tregs were not induced by LCs presenting only signal 1, and through a series of in vitro immunizations show that CD8+ T cells receiving signal 1+2 from LCs weeks after consistently receiving signal 1 are capable of robust effector functions. Importantly, this indicates that T cells are not tolerized but instead remain ignorant to HPV, and are activated given the proper signals. Keywords: T cell anergy, T cell ignorance, Immune tolerance, Human papillomavirus, HPV16, Langerhans cells

  11. The C-type lectin OCILRP2 costimulates EL4 T cell activation via the DAP12-Raf-MAP kinase pathway.

    Science.gov (United States)

    Lou, Qiang; Zhang, Wei; Liu, Guangchao; Ma, Yuanfang

    2014-01-01

    OCILRP2 is a typical Type-II transmembrane protein that is selectively expressed in activated T lymphocytes, dendritic cells, and B cells and functions as a novel co-stimulator of T cell activation. However, the signaling pathways underlying OCILRP2 in T cell activation are still not completely understood. In this study, we found that the knockdown of OCILRP2 expression with shRNA or the blockage of its activity by an anti-OCILRP2 antagonist antibody reduced CD3/CD28-costimulated EL4 T cell viability and IL-2 production, inhibit Raf1, MAPK3, and MAPK8 activation, and impair NFAT and NF-κB transcriptional activities. Furthermore, immunoprecipitation results indicated that OCILRP2 could interact with the DAP12 protein, an adaptor containing an intracellular ITAM motif that can transduce signals to induce MAP kinase activation for T cell activation. Our data reveal that after binding with DAP12, OCILRP2 activates the Raf-MAP kinase pathways, resulting in T cell activation.

  12. The C-type lectin OCILRP2 costimulates EL4 T cell activation via the DAP12-Raf-MAP kinase pathway.

    Directory of Open Access Journals (Sweden)

    Qiang Lou

    Full Text Available OCILRP2 is a typical Type-II transmembrane protein that is selectively expressed in activated T lymphocytes, dendritic cells, and B cells and functions as a novel co-stimulator of T cell activation. However, the signaling pathways underlying OCILRP2 in T cell activation are still not completely understood. In this study, we found that the knockdown of OCILRP2 expression with shRNA or the blockage of its activity by an anti-OCILRP2 antagonist antibody reduced CD3/CD28-costimulated EL4 T cell viability and IL-2 production, inhibit Raf1, MAPK3, and MAPK8 activation, and impair NFAT and NF-κB transcriptional activities. Furthermore, immunoprecipitation results indicated that OCILRP2 could interact with the DAP12 protein, an adaptor containing an intracellular ITAM motif that can transduce signals to induce MAP kinase activation for T cell activation. Our data reveal that after binding with DAP12, OCILRP2 activates the Raf-MAP kinase pathways, resulting in T cell activation.

  13. EXPERIENCE OF TREATMENT WITH INHIBITOR OF T-LYMPHOCYTES CO-STIMULATION ABATACEPT IN PATIENT WITH POLYARTICULAR TYPE OF JUVENILE RHEUMATOID ARTHRITIS

    Directory of Open Access Journals (Sweden)

    T.M. Bzarova

    2010-01-01

    Full Text Available The article presents a case report of recurrent clinical course of polyarticular type of juvenile rheumatoid arthritis, which is characterized with rapid development of disability, low quality of life, high index of functional insufficiency, torpid flow. The disease developed with intolerance to metotrexate and presence of contra-indications to blockers of tumor necrotizing factor _. Authors describe successful treatment with inhibitor of T-lymphocytes co-stimulation abatacept. The dose of drug was 10 mg/kg of body weight during 24 weeks. In two weeks after the beginning of treatment pain and exudative lesions in joints were lessened, joint range of motions significantly increased. The quality of life of patient and her family increased in 4 weeks of treatment with abatacept. The drug induced clinical and laboratory remission in 24 weeks.Key words: children, juvenile rheumatoid arthritis, abatacept, treatment.(Voprosy sovremennoi pediatrii — Current Pediatrics. – 2010;9(4:147-154

  14. The role of CD80/CD86 in generation and maintenance of functional virus-specific CD8+ T cells in mice infected with lymphocytic choriomeningitis virus

    DEFF Research Database (Denmark)

    Grujic, Mirjana; Bartholdy, Christina; Remy, Melissa

    2010-01-01

    Lymphocytic choriomeningitis virus (LCMV)-specific CD8(+) T cell responses are considered to be independent of CD28-B7 costimulation. However, the LCMV-specific response has never been evaluated in B7.1/B7.2(-/-) mice. For this reason, we decided to study the T cell response in B7.1/B7.2(-/-) mice......, but no chronic infection. Taken together, these results indicate that B7 costimulation is required for induction and maintenance of LCMV-specific CD8(+) T cell memory, irrespective of the LCMV strain used for priming. However, the erosion of CD8(+) T cell memory in B7.1/B7.2(-/-) mice was more pronounced...

  15. T cell costimulation blockade promotes transplantation tolerance in combination with sirolimus and post-transplantation cyclophosphamide for haploidentical transplantation in children with severe aplastic anemia.

    Science.gov (United States)

    Jaiswal, Sarita Rani; Bhakuni, Prakash; Zaman, Shamsuz; Bansal, Satish; Bharadwaj, Priyanka; Bhargava, Sneh; Chakrabarti, Suparno

    2017-08-01

    We conducted a pilot study employing extended T cell costimulation blockade (COSBL) with Abatacept along with sirolimus and post-transplantation cyclophosphamide (PTCy) in 10 patients (median age 12) with severe aplastic anemia (SAA). Nine patients engrafted in the COSBL group, compared to all 10 patients (median 14 vs 13days) treated on PTCy protocols without abatacept (CONTROL group). The incidence of acute graft-versus-host disease (GVHD) was 10.5% in the COSBL group compared to 50% in the CONTROL group (p=0.04). Chronic GVHD (12.5% vs 56%, p=0.02) and CMV reactivation (30% vs 80%, p=0.03) were also reduced in the COSBL group. T and NK cell subset analysis revealed higher CD56 bright CD16 - NK cells in the CONTROL group (p=0.004), but similar CD56 dim CD16 + NK cells in both groups at day+30. Tregs (CD4 + CD25 + CD127 dim/- FoxP3+) were markedly higher in the COSBL group at day+30 (8.4% vs 1.1%) and the trend was maintained through day+90 (p<0.01). The GVHD and Disease-free survival at one year in the COSBL group was 80% vs. 30% in the CONTROL group (p=0.05). Our preliminary findings suggest that COSBL in combination with PTCy and sirolimus might augment transplantation tolerance in children with SAA, probably due to synergistic effect on early recovery of Tregs. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Association of Inducible T Cell Costimulator Polymorphisms with Susceptibility and Outcome of Hepatitis B Virus Infection in a Chinese Han Population.

    Science.gov (United States)

    Hu, J; Li, Q-L; Hou, S-H; Peng, H; Guo, J-J

    2015-09-01

    Inducible T cell costimulator (ICOS) functions to regulate cell-cell signalling, immune responses and cell proliferation. ICOS single nucleotide polymorphism (SNP) may affect protein expression and functions. This study investigated the association of ICOS SNPs with hepatitis B virus (HBV) infection and outcome in a Chinese population. A total of 1290 Chinese Han individuals were enrolled, including 63 asymptomatic HBV carriers, 220 chronic hepatitis B patients (CHB), 249 HBV-related liver cirrhosis patients (LC), 108 patients with HBV-related hepatocellular carcinoma (HCC), 338 patients with natural HBV clearance and 312 healthy subjects (as controls). DNA samples from these subjects were genotyped for four ICOS SNPs (rs11883722, rs10932029, rs1559931 and rs4675379) using TaqMan SNP Genotyping Assay and analysed. The data showed that genotype and allele frequencies of ICOS SNPs in cases and controls followed the Hardy-Weinberg distribution. The CC genotype of rs4675379 was higher in patients with HBV infection (including AC, CHB, LC and HCC) than in patients with HBV clearance (P = 0.006). Furthermore, the genotype 'GA' and the minor allele 'A' of rs1559931 were associated with a decreased HCC susceptibility (P a lower frequency in patients than in HBV-cleared subjects (P = 0.034), although its overall frequency was only 1.6%. Our study found that ICOS rs1559931 SNP was associated with decreased HBV-related HCC risk in the studied Chinese Han population, except for patients with natural clearance of HBV. © 2015 The Foundation for the Scandinavian Journal of Immunology.

  17. PD-L1 peptide co-stimulation increases immunogenicity of a dendritic cell-based cancer vaccine

    DEFF Research Database (Denmark)

    Munir Ahmad, Shamaila; Martinenaite, Evelina; Hansen, Morten

    2016-01-01

    elicited by the DC vaccine even further. Consequently, we observed a significant increase in the number of vaccine-reacting T cells in vitro. In conclusion, activation of PD-L1-specific T cells may directly modulate immunogenicity of DC vaccines. Addition of PD-L1 epitopes may thus be an easily applicable...... and attractive option to augment the effectiveness of cancer vaccines and other immunotherapeutic agents....

  18. PRMT5-Mediated Methylation of NF-κB p65 at Arg174 Is Required for Endothelial CXCL11 Gene Induction in Response to TNF-α and IFN-γ Costimulation.

    Directory of Open Access Journals (Sweden)

    Daniel P Harris

    Full Text Available Inflammatory agonists differentially activate gene expression of the chemokine family of proteins in endothelial cells (EC. TNF is a weak inducer of the chemokine CXCL11, while TNF and IFN-γ costimulation results in potent CXCL11 induction. The molecular mechanisms underlying TNF plus IFN-γ-mediated CXCL11 induction are not fully understood. We have previously reported that the protein arginine methyltransferase PRMT5 catalyzes symmetrical dimethylation of the NF-κB subunit p65 in EC at multiple arginine residues. Methylation of Arg30 and Arg35 on p65 is critical for TNF induction of CXCL10 in EC. Here we show that PRMT5-mediated methylation of p65 at Arg174 is required for induction of CXCL11 when EC are costimulated with TNF and IFN-γ. Knockdown of PRMT5 by RNAi reduced CXCL11 mRNA and protein levels in costimulated cells. Reconstitution of p65 Arg174Ala or Arg174Lys mutants into EC that were depleted of endogenous p65 blunted TNF plus IFN-γ-mediated CXCL11 induction. Mass spectrometric analyses showed that p65 Arg174 arginine methylation is enhanced by TNF plus IFN-γ costimulation, and is catalyzed by PRMT5. Chromatin immunoprecipitation assays (ChIP demonstrated that PRMT5 is necessary for p65 association with the CXCL11 promoter in response to TNF plus IFN-γ. Further, reconstitution of p65 Arg174Lys mutant in EC abrogated this p65 association with the CXCL11 promoter. Finally, ChIP and Re-ChIP assays revealed that symmetrical dimethylarginine-containing proteins complexed with the CXCL11 promoter were diminished in p65 Arg174Lys-reconstituted EC stimulated with TNF and IFN-γ. In total, these results indicate that PRMT5-mediated p65 methylation at Arg174 is essential for TNF plus IFN-γ-mediated CXCL11 gene induction. We therefore suggest that the use of recently developed small molecule inhibitors of PRMT5 may present a therapeutic approach to moderating chronic inflammatory pathologies.

  19. Co-stimulation by anti-immunoglobulin is required for B cell activation by CD40Llow T cells

    DEFF Research Database (Denmark)

    Poudrier, J; Owens, T

    1994-01-01

    cell Ag specificity by using anti-CD3/T cell receptor (TcR) monoclonal antibodies (mAb) to activate T cells. To study the role of sIg engagement in the responsiveness of B cells to T help, we pre-treated small resting B cells with soluble anti-kappa mAb prior to contact with an activated Th1 clone...... strongly. Low buoyant density B cells also responded to CD40Llow Th cells. There was no B cell response to resting Th cells. mAb against CD54/intercellular adhesion molecule-1 or major histocompatibility complex (MHC) class II completely inhibited B cell responses to CD40Llow Th1 cells, equivalent...

  20. Human Langerhans cells use an IL-15R-α/IL-15/pSTAT5-dependent mechanism to break T-cell tolerance against the self-differentiation tumor antigen WT1.

    Science.gov (United States)

    Romano, Emanuela; Cotari, Jesse W; Barreira da Silva, Rosa; Betts, Brian C; Chung, David J; Avogadri, Francesca; Fink, Mitsu J; St Angelo, Erin T; Mehrara, Babak; Heller, Glenn; Münz, Christian; Altan-Bonnet, Gregoire; Young, James W

    2012-05-31

    Human CD34(+) progenitor-derived Langerhans-type dendritic cells (LCs) are more potent stimulators of T-cell immunity against tumor and viral antigens in vitro than are monocyte-derived DCs (moDCs). The exact mechanisms have remained elusive until now, however. LCs synthesize the highest amounts of IL-15R-α mRNA and protein, which binds IL-15 for presentation to responder lymphocytes, thereby signaling the phosphorylation of signal transducer and activator of transcription 5 (pSTAT5). LCs electroporated with Wilms tumor 1 (WT1) mRNA achieve sufficiently sustained presentation of antigenic peptides, which together with IL-15R-α/IL-15, break tolerance against WT1 by stimulating robust autologous, WT1-specific cytolytic T-lymphocytes (CTLs). These CTLs develop from healthy persons after only 7 days' stimulation without exogenous cytokines and lyse MHC-restricted tumor targets, which include primary WT1(+) leukemic blasts. In contrast, moDCs require exogenous rhuIL-15 to phosphorylate STAT5 and attain stimulatory capacity comparable to LCs. LCs therefore provide a more potent costimulatory cytokine milieu for T-cell activation than do moDCs, thus accounting for their superior stimulation of MHC-restricted Ag-specific CTLs without need for exogenous cytokines. These data support the use of mRNA-electroporated LCs, or moDCs supplemented with exogenous rhuIL-15, as vaccines for cancer immunotherapy to break tolerance against self-differentiation antigens shared by tumors.

  1. Immunostimulatory CpG-oligonucleotides induce functional high affinity IL-2 receptors on B-CLL cells: costimulation with IL-2 results in a highly immunogenic phenotype.

    Science.gov (United States)

    Decker, T; Schneller, F; Kronschnabl, M; Dechow, T; Lipford, G B; Wagner, H; Peschel, C

    2000-05-01

    CpG-oligodeoxynucleotides (CpG-ODN) have been shown to induce proliferation, cytokine production, and surface molecule regulation in normal and malignant human B cells. In the present study, we investigated the potential of CpG-ODN to induce functional high-affinity receptors in leukemic and normal B cells and the effects of costimulation with IL-2 on proliferation, cytokine secretion, and surface molecule regulation. Highly purified B cells from B-CLL patients and normal controls were stimulated with CpG-ODN with or without IL-2. Expression of CD25 was determined using FACS, and the presence of high-affinity IL-2 receptors was determined by scatchard analysis. Costimulatory effects of IL-2 and CpG-ODN were investigated using proliferation assays, ELISA (IL-6, TNF-alpha), and FACS analysis (CD80, CD86 expression). Reactivity of autologous and allogeneic T cells toward activated B-CLL cells was determined in mixed lymphocyte reactions and Interferon-gamma Elispot assays. The CpG-ODN DSP30 caused a significantly stronger induction of the IL-2 receptor alpha chain in malignant as compared with normal B cells (p = 0.03). This resulted in the expression of functional high-affinity IL-2 receptors in B-CLL cells, but fewer numbers of receptors with less affinity were expressed in normal B cells. Although addition of IL-2 to CpG-ODN-stimulated cells augmented proliferation in both normal B cells and B-CLL cells, no costimulatory effect on cytokine production or surface molecule expression could be observed in normal B cells. In contrast, TNF-alpha and IL-6 production was increased in B-CLL cells, and the expression of CD80 and CD86 was further enhanced when IL-2 was used as a costimulus. Autologous and allogeneic immune recognition of B-CLL cells stimulated with CpG-ODN and IL-2 was increased compared with B-CLL cells stimulated with CpG-ODN alone. Stimulation of B-CLL cells with CpG-ODN and IL-2 might be an attractive strategy for potential immunotherapies for B

  2. Serum and Urinary Cytokeratin 19 and Bladder Tumor Antigen in ...

    African Journals Online (AJOL)

    Conclusion Urinary CYFRA 21-1 and BTA stat are valuable non-invasive urinary markers for the detection of bladder cancer with a high sensitivity compared to urine cytology. Key Words cytokeratin, complement H, BTA, CYFRA 21-1, BTA stat. Résumé Cytokeratin 19 Sérique et Urinaire et Antigen Tumoral Vésical dans le ...

  3. Adoptively transferred human lung tumor specific cytotoxic T cells can control autologous tumor growth and shape tumor phenotype in a SCID mouse xenograft model

    Directory of Open Access Journals (Sweden)

    Ferrone Soldano

    2007-06-01

    Full Text Available Abstract Background The anti-tumor efficacy of human immune effector cells, such as cytolytic T lymphocytes (CTLs, has been difficult to study in lung cancer patients in the clinical setting. Improved experimental models for the study of lung tumor-immune cell interaction as well as for evaluating the efficacy of adoptive transfer of immune effector cells are needed. Methods To address questions related to the in vivo interaction of human lung tumor cells and immune effector cells, we obtained an HLA class I + lung tumor cell line from a fresh surgical specimen, and using the infiltrating immune cells, isolated and characterized tumor antigen-specific, CD8+ CTLs. We then established a SCID mouse-human tumor xenograft model with the tumor cell line and used it to study the function of the autologous CTLs provided via adoptive transfer. Results The tumor antigen specific CTLs isolated from the tumor were found to have an activated memory phenotype and able to kill tumor cells in an antigen specific manner in vitro. Additionally, the tumor antigen-specific CTLs were fully capable of homing to and killing autologous tumors in vivo, and expressing IFN-γ, each in an antigen-dependent manner. A single injection of these CTLs was able to provide significant but temporary control of the growth of autologous tumors in vivo without the need for IL-2. The timing of injection of CTLs played an essential role in the outcome of tumor growth control. Moreover, immunohistochemical analysis of surviving tumor cells following CTL treatment indicated that the surviving tumor cells expressed reduced MHC class I antigens on their surface. Conclusion These studies confirm and extend previous studies and provide additional information regarding the characteristics of CTLs which can be found within a patient's tumor. Moreover, the in vivo model described here provides a unique window for observing events that may also occur in patients undergoing adoptive cellular

  4. SA-4-1BBL costimulation inhibits conversion of conventional CD4+ T cells into CD4+ FoxP3+ T regulatory cells by production of IFN-γ.

    Directory of Open Access Journals (Sweden)

    Shravan Madireddi

    Full Text Available Tumors convert conventional CD4(+ T cells into induced CD4(+CD25(+FoxP3(+ T regulatory (iTreg cells that serve as an effective means of immune evasion. Therefore, the blockade of conventional CD4(+ T cell conversion into iTreg cells represents an attractive target for improving the efficacy of various immunotherapeutic approaches. Using a novel form of 4-1BBL molecule, SA-4-1BBL, we previously demonstrated that costimulation via 4-1BB receptor renders both CD4(+and CD8(+ T effector (Teff cells refractory to inhibition by Treg cells and increased intratumoral Teff/Treg cell ratio that correlated with therapeutic efficacy in various preclinical tumor models. Building on these studies, we herein show for the first time, to our knowledge, that signaling through 4-1BB inhibits antigen- and TGF-β-driven conversion of naïve CD4(+FoxP3(- T cells into iTreg cells via stimulation of IFN-γ production by CD4(+FoxP3(- T cells. Importantly, treatment with SA-4-1BBL blocked the conversion of CD4(+FoxP3(- T cells into Treg cells by EG.7 tumors. Taken together with our previous studies, these results show that 4-1BB signaling negatively modulate Treg cells by two distinct mechanisms: i inhibiting the conversion of CD4(+FoxP3(- T cells into iTreg cells and ii endowing Teff cells refractory to inhibition by Treg cells. Given the dominant role of Treg cells in tumor immune evasion mechanisms, 4-1BB signaling represents an attractive target for favorably tipping the Teff:Treg balance toward Teff cells with important implications for cancer immunotherapy.

  5. NKG2D performs two functions in invariant NKT cells: direct TCR-independent activation of NK-like cytolysis and co-stimulation of activation by CD1d.

    Science.gov (United States)

    Kuylenstierna, Carlotta; Björkström, Niklas K; Andersson, Sofia K; Sahlström, Peter; Bosnjak, Lidija; Paquin-Proulx, Dominic; Malmberg, Karl-Johan; Ljunggren, Hans-Gustaf; Moll, Markus; Sandberg, Johan K

    2011-07-01

    Invariant NKT cells are important in the activation and regulation of immune responses. They can also function as CD1d-restricted killer cells. However, the role of activating innate NK-cell receptors expressed on NKT cells in triggering cytolytic function is poorly characterized. Here, we initially confirmed that the cellular stress-ligand receptor NKG2D is expressed on CD4- NKT cells, whereas most CD4+ NKT cells lack this receptor. Interestingly, NKG2D+ NKT cells frequently expressed perforin, and both NKG2D and perforin localized at the site of contact with NKG2D ligand-expressing target cells. CD4- NKT cells degranulated in response to NKG2D engagement in a redirected activation assay independent of stimulation via their invariant TCR. NKT cells killed P815 cells coated with anti-NKG2D mAb and CD1d-negative K562 tumor target cells in an NKG2D-dependent manner. Furthermore, NKG2D engagement co-stimulated TCR-mediated NKT-cell activation in response to endogenous CD1d-presented ligands or suboptimal levels of anti-CD3 triggering. These data indicate that the CD4- subset of human NKT cells can mediate direct lysis of target cells via NKG2D engagement independent of CD1d, and that NKG2D also functions as a co-stimulatory receptor in these cells. NKG2D thus plays both a direct and a co-stimulatory role in the activation of NKT cells. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. Donor-Derived Regulatory Dendritic Cell Infusion Maintains Donor-Reactive CD4+CTLA4hi T Cells in Non-Human Primate Renal Allograft Recipients Treated with CD28 Co-Stimulation Blockade.

    Science.gov (United States)

    Ezzelarab, Mohamed B; Lu, Lien; Shufesky, William F; Morelli, Adrian E; Thomson, Angus W

    2018-01-01

    Donor-derived regulatory dendritic cell (DCreg) infusion before transplantation, significantly prolongs renal allograft survival in non-human primates. This is associated with enhanced expression of the immunoregulatory molecules cytotoxic T-lymphocyte-associated antigen (Ag) 4 (CTLA4) and programmed cell death protein 1 (PD1) by host donor-reactive T cells. In rodents and humans, CD28 co-stimulatory pathway blockade with the fusion protein CTLA4:Ig (CTLA4Ig) is associated with reduced differentiation and development of regulatory T cells (Treg). We hypothesized that upregulation of CTLA4 by donor-reactive CD4 + T cells in DCreg-infused recipients treated with CTLA4Ig, might be associated with higher incidences of donor-reactive CD4 + T cells with a Treg phenotype. In normal rhesus monkeys, allo-stimulated CD4 + CTLA4 hi , but not CD4 + CTLA4 med/lo T cells exhibited a regulatory phenotype, irrespective of PD1 expression. CTLA4Ig significantly reduced the incidence of CD4 + CTLA4 hi , but not CD4 + CTLA4 med/lo T cells following allo-stimulation, associated with a significant reduction in the CD4 + CTLA4 hi /CD4 + CTLA4 med/lo T cell ratio. In CTLA4Ig-treated renal allograft recipient monkeys, there was a marked reduction in circulating donor-reactive CD4 + CTLA4 hi T cells. In contrast, in CTLA4Ig-treated monkeys with DCreg infusion, no such reduction was observed. In parallel, the donor-reactive CD4 + CTLA4 hi /CD4 + CTLA4 med/lo T cell ratio was reduced significantly in graft recipients without DCreg infusion, but increased in those given DCreg. These observations suggest that pre-transplant DCreg infusion promotes and maintains donor-reactive CD4 + CTLA4 hi T cells with a regulatory phenotype after transplantation, even in the presence of CD28 co-stimulation blockade.

  7. Co-delivery of antigen and IL-12 by Venezuelan equine encephalitis virus replicon particles enhances antigen-specific immune responses and anti-tumor effects

    Science.gov (United States)

    Osada, Takuya; Berglund, Peter; Morse, Michael A.; Hubby, Bolyn; Lewis, Whitney; Niedzwiecki, Donna; Hobeika, Amy; Burnett, Bruce; Devi, Gayathri R.; Clay, Timothy M.; Smith, Jonathan; Lyerly, H. Kim

    2013-01-01

    We recently demonstrated that Venezuelan equine encephalitis (VEE) virus-based replicon particles (VRP) encoding tumor antigens could break tolerance in the immunomodulatory environment of advanced cancer. We hypothesized that local injection of VRP expressing Interleukin-12 (IL-12) at the site of injections of VRP-based cancer vaccines would enhance the tumor-antigen-specific T cell and antibody responses and anti-tumor efficacy. Mice were immunized with VRP encoding the human tumor-associated antigen, carcinoembryonic antigen (CEA) (VRP-CEA(6D)) and VRP-IL-12 was also administered at the same site or at a distant location. CEA-specific T cell and antibody responses were measured. To determine antitumor activity, mice were implanted with MC38-CEA-2 cells and immunized with VRP-CEA with and without VRP-IL-12 and tumor growth and mouse survival were measured. VRP-IL-12 greatly enhanced CEA-specific T cell and antibody responses when combined with VRP-CEA(6D) vaccination. VRP IL-12 was superior to IL-12 protein at enhancing immune responses. Vaccination with VRP-CEA(6D) plus VRP-IL-12 was superior to VRP-CEA(6D) or VRP-IL-12 alone in inducing anti-tumor activity and prolonging survival in tumor-bearing mice. Importantly, local injection of VRP-IL-12 at the VRP-CEA(6D) injection site provided more potent activation of CEA-specific immune responses than VRP-IL-12 injected at a distant site from the VRP-CEA injections. Together, this study shows that VRP-IL-12 enhances vaccination with VRP-CEA(6D) and was more effective at activating CEA-specific T cell responses when locally expressed at the vaccine site. Clinical trials evaluating the adjuvant effect of VRP-IL-12 at enhancing the immunogenicity of cancer vaccines are warranted. PMID:22488274

  8. Tumor Immunology meets…Immunology: Modified cancer cells as professional APC for priming naïve tumor-specific CD4+ T cells.

    Science.gov (United States)

    Bou Nasser Eddine, Farah; Ramia, Elise; Tosi, Giovanna; Forlani, Greta; Accolla, Roberto S

    2017-01-01

    Although recent therapeutic approaches have revitalized the enthusiasm of the immunological way to combat cancer, still the comprehension of immunity against tumors is largely incomplete. Due to their specific function, CD8+ T cells with cytolytic activity (CTL) have attracted the attention of most investigators because CTL are considered the main effectors against tumor cells. Nevertheless, CTL activity and persistence is largely dependent on the action of CD4+ T helper cells (TH). Thus establishment of tumor-specific TH cell response is key to the optimal response against cancer. Here we describe emerging new strategies to increase the TH cell recognition of tumor antigens. In particular, we review recent data indicating that tumor cells themselves can act as surrogate antigen presenting cells for triggering TH response and how these findings can help in constructing immunotherapeutic protocols for anti-cancer vaccine development.

  9. Donor-Derived Regulatory Dendritic Cell Infusion Maintains Donor-Reactive CD4+CTLA4hi T Cells in Non-Human Primate Renal Allograft Recipients Treated with CD28 Co-Stimulation Blockade

    Directory of Open Access Journals (Sweden)

    Mohamed B. Ezzelarab

    2018-02-01

    Full Text Available Donor-derived regulatory dendritic cell (DCreg infusion before transplantation, significantly prolongs renal allograft survival in non-human primates. This is associated with enhanced expression of the immunoregulatory molecules cytotoxic T-lymphocyte-associated antigen (Ag 4 (CTLA4 and programmed cell death protein 1 (PD1 by host donor-reactive T cells. In rodents and humans, CD28 co-stimulatory pathway blockade with the fusion protein CTLA4:Ig (CTLA4Ig is associated with reduced differentiation and development of regulatory T cells (Treg. We hypothesized that upregulation of CTLA4 by donor-reactive CD4+ T cells in DCreg-infused recipients treated with CTLA4Ig, might be associated with higher incidences of donor-reactive CD4+ T cells with a Treg phenotype. In normal rhesus monkeys, allo-stimulated CD4+CTLA4hi, but not CD4+CTLA4med/lo T cells exhibited a regulatory phenotype, irrespective of PD1 expression. CTLA4Ig significantly reduced the incidence of CD4+CTLA4hi, but not CD4+CTLA4med/lo T cells following allo-stimulation, associated with a significant reduction in the CD4+CTLA4hi/CD4+CTLA4med/lo T cell ratio. In CTLA4Ig-treated renal allograft recipient monkeys, there was a marked reduction in circulating donor-reactive CD4+CTLA4hi T cells. In contrast, in CTLA4Ig-treated monkeys with DCreg infusion, no such reduction was observed. In parallel, the donor-reactive CD4+CTLA4hi/CD4+CTLA4med/lo T cell ratio was reduced significantly in graft recipients without DCreg infusion, but increased in those given DCreg. These observations suggest that pre-transplant DCreg infusion promotes and maintains donor-reactive CD4+CTLA4hi T cells with a regulatory phenotype after transplantation, even in the presence of CD28 co-stimulation blockade.

  10. Cancer Patient T Cells Genetically Targeted to Prostate-Specific Membrane Antigen Specifically Lyse Prostate Cancer Cells and Release Cytokines in Response to Prostate-Specific Membrane Antigen

    Directory of Open Access Journals (Sweden)

    Michael C. Gong

    1999-06-01

    Full Text Available The expression of immunoglobulin-based artificial receptors in normal T lymphocytes provides a means to target lymphocytes to cell surface antigens independently of major histocompatibility complex restriction. Such artificial receptors have been previously shown to confer antigen-specific tumoricidal properties in murine T cells. We constructed a novel ζ chain fusion receptor specific for prostate-specific membrane antigen (PSMA termed Pz-1. PSMA is a cell-surface glycoprotein expressed on prostate cancer cells and the neovascular endothelium of multiple carcinomas. We show that primary T cells harvested from five of five patients with different stages of prostate cancer and transduced with the Pz-1 receptor readily lyse prostate cancer cells. Having established a culture system using fibroblasts that express PSMA, we next show that T cells expressing the Pz-1 receptor release cytokines in response to cell-bound PSMA. Furthermore, we show that the cytokine release is greatly augmented by B7.1-mediated costimulation. Thus, our findings support the feasibility of adoptive cell therapy by using genetically engineered T cells in prostate cancer patients and suggest that both CD4+ and CD8+ T lymphocyte functions can be synergistically targeted against tumor cells.

  11. PET-based compartmental modeling of {sup 124}I-A33 antibody: quantitative characterization of patient-specific tumor targeting in colorectal cancer

    Energy Technology Data Exchange (ETDEWEB)

    Zanzonico, Pat; O' Donoghue, Joseph A.; Humm, John L. [Memorial Sloan Kettering Cancer Center, Department of Medical Physics, New York, NY (United States); Carrasquillo, Jorge A.; Pandit-Taskar, Neeta; Ruan, Shutian; Larson, Steven M. [Memorial Sloan Kettering Cancer Center, Department of Radiology, New York, NY (United States); Smith-Jones, Peter [Memorial Sloan Kettering Cancer Center, Department of Radiology, New York, NY (United States); Stony Brook School of Medicine, Departments of Psychiatry and Radiology, Stony Brook, NY (United States); Divgi, Chaitanya [Columbia University Medical Center, New York, NY (United States); Scott, Andrew M. [La Trobe University, Olivia Newton-John Cancer Research Institute, Melbourne (Australia); Kemeny, Nancy E.; Wong, Douglas; Scheinberg, David [Memorial Sloan Kettering Cancer Center, Department of Medicine, New York, NY (United States); Fong, Yuman [Memorial Sloan Kettering Cancer Center, Department of Surgery, New York, NY (United States); City of Hope, Department of Surgery, Duarte, CA (United States); Ritter, Gerd; Jungbluth, Achem; Old, Lloyd J. [Memorial Sloan Kettering Cancer Center, Ludwig Institute for Cancer Research, New York, NY (United States)

    2015-10-15

    The molecular specificity of monoclonal antibodies (mAbs) directed against tumor antigens has proven effective for targeted therapy of human cancers, as shown by a growing list of successful antibody-based drug products. We describe a novel, nonlinear compartmental model using PET-derived data to determine the ''best-fit'' parameters and model-derived quantities for optimizing biodistribution of intravenously injected {sup 124}I-labeled antitumor antibodies. As an example of this paradigm, quantitative image and kinetic analyses of anti-A33 humanized mAb (also known as ''A33'') were performed in 11 colorectal cancer patients. Serial whole-body PET scans of {sup 124}I-labeled A33 and blood samples were acquired and the resulting tissue time-activity data for each patient were fit to a nonlinear compartmental model using the SAAM II computer code. Excellent agreement was observed between fitted and measured parameters of tumor uptake, ''off-target'' uptake in bowel mucosa, blood clearance, tumor antigen levels, and percent antigen occupancy. This approach should be generally applicable to antibody-antigen systems in human tumors for which the masses of antigen-expressing tumor and of normal tissues can be estimated and for which antibody kinetics can be measured with PET. Ultimately, based on each patient's resulting ''best-fit'' nonlinear model, a patient-specific optimum mAb dose (in micromoles, for example) may be derived. (orig.)

  12. Administration of sulfosuccinimidyl-4-[N-maleimidomethyl] cyclohexane-1-carboxylate conjugated GP10025–33 peptide-coupled spleen cells effectively mounts antigen-specific immune response against mouse melanoma

    International Nuclear Information System (INIS)

    Chang, Xiaoli; Xia, Chang-Qing

    2015-01-01

    It remains a top research priority to develop immunotherapeutic approaches to induce potent antigen-specific immune responses against tumors. However, in spite of some promising results, most strategies are ineffective because they generate low numbers of tumor-reactive cytotoxic T lymphocytes (CTLs). Here we designed a strategy to enhance antigen-specific immune response via administering sulfosuccinimidyl-4-[N-maleimidomethyl] cyclohexane-1-carboxylate (sulfo-SMCC)-conjugated melanoma tumor antigen GP100 25–33 peptide-coupled syngeneic spleen cells in a mouse model of melanoma. We found that infusion of GP100 25–33 peptide-coupled spleen cells significantly attenuated the growth of melanoma in prophylactic and therapeutic immunizations. Consistent with these findings, the adoptive transfer of spleen cells from immunized mice to naïve syngeneic mice was able to transfer anti-tumor effect, suggesting that GP100 25–33 peptide-specific immune response was induced. Further studies showed that, CD8+ T cell proliferation and the frequency of interferon (IFN)-γ-producing CD8+ T cells upon ex vivo stimulation by GP100 25–33 were significantly increased compared to control groups. Tumor antigen, GP100 25–23 specific immune response was also confirmed by ELISpot and GP100-tetramer assays. This approach is simple, easy-handled, and efficiently delivering antigens to lymphoid tissues. Our study offers an opportunity for clinically translating this approach into tumor immunotherapy. - Highlights: • Infusion of GP100 25–33 -coupled spleen cells leads to potent anti-melanoma immunity. • GP100 25–33 -coupled spleen cell treatment induces antigen-specific IFN-γ-producing CD8 T cells. • This approach takes advantage of homing nature of immune cells.

  13. Administration of sulfosuccinimidyl-4-[N-maleimidomethyl] cyclohexane-1-carboxylate conjugated GP100{sub 25–33} peptide-coupled spleen cells effectively mounts antigen-specific immune response against mouse melanoma

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Xiaoli [Department of Hematology, Xuanwu Hospital, Capital Medical University, Beijing (China); Xia, Chang-Qing, E-mail: cqx65@yahoo.com [Department of Hematology, Xuanwu Hospital, Capital Medical University, Beijing (China); Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL32610 (United States)

    2015-12-04

    It remains a top research priority to develop immunotherapeutic approaches to induce potent antigen-specific immune responses against tumors. However, in spite of some promising results, most strategies are ineffective because they generate low numbers of tumor-reactive cytotoxic T lymphocytes (CTLs). Here we designed a strategy to enhance antigen-specific immune response via administering sulfosuccinimidyl-4-[N-maleimidomethyl] cyclohexane-1-carboxylate (sulfo-SMCC)-conjugated melanoma tumor antigen GP100{sub 25–33} peptide-coupled syngeneic spleen cells in a mouse model of melanoma. We found that infusion of GP100{sub 25–33} peptide-coupled spleen cells significantly attenuated the growth of melanoma in prophylactic and therapeutic immunizations. Consistent with these findings, the adoptive transfer of spleen cells from immunized mice to naïve syngeneic mice was able to transfer anti-tumor effect, suggesting that GP100{sub 25–33} peptide-specific immune response was induced. Further studies showed that, CD8+ T cell proliferation and the frequency of interferon (IFN)-γ-producing CD8+ T cells upon ex vivo stimulation by GP100{sub 25–33} were significantly increased compared to control groups. Tumor antigen, GP100{sub 25–23} specific immune response was also confirmed by ELISpot and GP100-tetramer assays. This approach is simple, easy-handled, and efficiently delivering antigens to lymphoid tissues. Our study offers an opportunity for clinically translating this approach into tumor immunotherapy. - Highlights: • Infusion of GP100{sub 25–33}-coupled spleen cells leads to potent anti-melanoma immunity. • GP100{sub 25–33}-coupled spleen cell treatment induces antigen-specific IFN-γ-producing CD8 T cells. • This approach takes advantage of homing nature of immune cells.

  14. A proteomic view at T cell costimulation.

    Directory of Open Access Journals (Sweden)

    Rudolf Lichtenfels

    Full Text Available The "two-signal paradigm" in T cell activation predicts that the cooperation of "signal 1," provided by the T cell receptor (TCR through engagement of major histocompatility complex (MHC-presented peptide, with "signal 2″ provided by costimulatory molecules, the prototype of which is CD28, is required to induce T cell effector functions. While the individual signalling pathways are well understood, little is known about global changes in the proteome pattern during TCR/CD28-mediated activation. Therefore, comparative 2-DE-based proteome analyses of CD3(+ CD69(- resting T cells versus cells incubated with (i the agonistic anti-CD3 antibody OKT3 mimicking signal 1 in absence or presence of IL-2 and/or with (ii the agonistic antibody 15E8 triggering CD28-mediated signaling were performed. Differentially regulated spots were defined leading to the identification of proteins involved in the regulation of the metabolism, shaping and maintenance of the cytoskeleton and signal transduction. Representative members of the differentially expressed protein families, such as calmodulin (CALM, glyceraldehyde-3-phosphate dehydrogenase (GAPDH, L-lactate dehydrogenase (LDH, Rho GDP-dissociation inhibitor 2 (GDIR2, and platelet basic protein (CXCL7, were independently verified by flow cytometry. Data provide a detailed map of individual protein alterations at the global proteome level in response to TCR/CD28-mediated T cell activation.

  15. L1 Cell Adhesion Molecule-Specific Chimeric Antigen Receptor-Redirected Human T Cells Exhibit Specific and Efficient Antitumor Activity against Human Ovarian Cancer in Mice.

    Directory of Open Access Journals (Sweden)

    Hao Hong

    Full Text Available New therapeutic modalities are needed for ovarian cancer, the most lethal gynecologic malignancy. Recent clinical trials have demonstrated the impressive therapeutic potential of adoptive therapy using chimeric antigen receptor (CAR-redirected T cells to target hematological cancers, and emerging studies suggest a similar impact may be achieved for solid cancers. We sought determine whether genetically-modified T cells targeting the CE7-epitope of L1-CAM, a cell adhesion molecule aberrantly expressed in several cancers, have promise as an immunotherapy for ovarian cancer, first demonstrating that L1-CAM was highly over-expressed on a panel of ovarian cancer cell lines, primary ovarian tumor tissue specimens, and ascites-derived primary cancer cells. Human central memory derived T cells (TCM were then genetically modified to express an anti-L1-CAM CAR (CE7R, which directed effector function upon tumor antigen stimulation as assessed by in vitro cytokine secretion and cytotoxicity assays. We also found that CE7R+ T cells were able to target primary ovarian cancer cells. Intraperitoneal (i.p. administration of CE7R+ TCM induced a significant regression of i.p. established SK-OV-3 xenograft tumors in mice, inhibited ascites formation, and conferred a significant survival advantage compared with control-treated animals. Taken together, these studies indicate that adoptive transfer of L1-CAM-specific CE7R+ T cells may offer a novel and effective immunotherapy strategy for advanced ovarian cancer.

  16. Specific inhibition of cytotoxic memory cells produced against uv-induced tumors in uv-irradiation mice

    International Nuclear Information System (INIS)

    Thorn, R.M.

    1978-01-01

    Cytotoxic responses of uv-irradiated mice against syngeneic uv-induced tumors were measured by using a 51 Cr-release assay to determine if uv treatment induced a specific reduction of cytotoxic activity. The in vivo and in vitro primary responses against syngeneic tumors and allogeneic cells were unaffected, as was the ''memory'' response (in vivo stimulation, in vitro restimulation) against alloantigens. In contrast, the memory response of uv-treated mice against syngeneic, uv-induced tumors was consistently and significantly depressed. The cytotoxicity generated by tumor cell stimulation in vivo or in vitro was tumor-specific and T cell-dependent. Since the primary response against syngeneic uv-induced tumors produces apparently normal amounts of tumor-specific cytotoxic activity, uv-treated mice may not reject transplanted syngeneic tumors because of too few T effector memory cells. These results imply that, at least in this system, tumor rejection depends mostly on the secondary responses against tumor antigens and that at least one carcinogen can, indirectly, specifically regulate immune responses

  17. His-tag ELISA for the detection of humoral tumor-specific immunity

    Directory of Open Access Journals (Sweden)

    Disis Mary L

    2008-05-01

    Full Text Available Abstract Background The application of high throughput molecular techniques such as SEREX are resulting in the identification of a multitude of tumor associated antigens. As newly identified antigens are incorporated into a variety of clinical trials, standardization of immunologic monitoring methods becomes increasingly important. We questioned whether mammalian cell expression of a histadine-linked human protein could be used to produce antigen suitable for detecting tumor-specific humoral immunity and whether such an assay could be amenable to standardization for clinical use. Methods We designed a his-tagged capture ELISA based on lysate from genetically engineered CHO cells for detection of antibodies to insulin-like growth factor binding protein 2, a novel tumor antigen. We performed technical and preliminary clinical validation studies, including comparison to a standard indirect ELISA based on commercially prepared recombinant antigen. Results The his-tagged capture ELISA could be standardized. Precision experiments resulted in CVs 2 values of 0.99. In comparison to Western blot analysis, his-tag and indirect ELISA accurately identified 88% and 93% of samples, respectively. Sample concordance between capture and indirect assays was highly significant (p = 0.003. Furthermore, significantly greater levels of IGFBP-2 antibody immunity were found in cancer patients compared to normal controls (p = 0.008. Conclusion A genetically engineered cell lysate based ELISA can be amenable to standardization and can detect increased levels of antibody immunity to tumor-associated antigen in cancer patients compared to non tumor-bearing healthy controls.

  18. Therapeutic targeting of regulatory T cells enhances tumor-specific CD8+ T cell responses in Epstein–Barr virus associated nasopharyngeal carcinoma

    International Nuclear Information System (INIS)

    Fogg, Mark; Murphy, John R.; Lorch, Jochen; Posner, Marshall; Wang, Fred

    2013-01-01

    Epstein–Barr virus (EBV) is associated with multiple malignancies including nasopharyngeal carcinoma (NPC). In nasopharynx cancer, CD8+ T cells specific for EBV Nuclear Antigen-1 (EBNA-1) and Latent Membrane Protein 2 (LMP2) are important components of anti-tumor immunity since both are consistently expressed in NPC. We have previously shown that EBNA-1-specific CD8+ T cell responses were suppressed in NPC patients compared to healthy controls. We now find that CD8+ T cell responses specific for LMP2 are also abnormal in NPC patients, and both EBNA-1- and LMP2-specific responses are suppressed by regulatory T cells (Treg). EBNA-1 and LMP2-specific CD8+ T cell responses, as well as immune control of EBV-infected cells in vitro, could be restored by the depletion of Tregs and by use of a clinically approved drug targeting Tregs. Thus, in vivo modulation of Tregs may be an effective means of enhancing these anti-tumor immune responses in NPC patients. - Highlights: • Viral proteins are tumor antigens in Epstein–Barr virus associated Nasopharyngeal Carcinoma. • CD8+ T cell responses against EBV proteins EBNA-1 and LMP2 are suppressed in NPC patients. • T regulatory cells are responsible for suppressing EBV immunity in NPC patients. • Depletion of Tregs with Ontak can rescue EBV-specific CD8+ T cell responses in NPC patients. • This clinically approved drug may be effective for enhancing anti-tumor immunity in NPC patients

  19. Therapeutic targeting of regulatory T cells enhances tumor-specific CD8+ T cell responses in Epstein–Barr virus associated nasopharyngeal carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Fogg, Mark [Department of Medicine, Brigham and Women' s Hospital (United States); Murphy, John R. [Departments of Medicine and Microbiology, Boston University School of Medicine, Boston, MA 02118 (United States); Lorch, Jochen; Posner, Marshall [Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115 (United States); Wang, Fred, E-mail: fwang@research.bwh.harvard.edu [Department of Medicine, Brigham and Women' s Hospital (United States); Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115 (United States)

    2013-07-05

    Epstein–Barr virus (EBV) is associated with multiple malignancies including nasopharyngeal carcinoma (NPC). In nasopharynx cancer, CD8+ T cells specific for EBV Nuclear Antigen-1 (EBNA-1) and Latent Membrane Protein 2 (LMP2) are important components of anti-tumor immunity since both are consistently expressed in NPC. We have previously shown that EBNA-1-specific CD8+ T cell responses were suppressed in NPC patients compared to healthy controls. We now find that CD8+ T cell responses specific for LMP2 are also abnormal in NPC patients, and both EBNA-1- and LMP2-specific responses are suppressed by regulatory T cells (Treg). EBNA-1 and LMP2-specific CD8+ T cell responses, as well as immune control of EBV-infected cells in vitro, could be restored by the depletion of Tregs and by use of a clinically approved drug targeting Tregs. Thus, in vivo modulation of Tregs may be an effective means of enhancing these anti-tumor immune responses in NPC patients. - Highlights: • Viral proteins are tumor antigens in Epstein–Barr virus associated Nasopharyngeal Carcinoma. • CD8+ T cell responses against EBV proteins EBNA-1 and LMP2 are suppressed in NPC patients. • T regulatory cells are responsible for suppressing EBV immunity in NPC patients. • Depletion of Tregs with Ontak can rescue EBV-specific CD8+ T cell responses in NPC patients. • This clinically approved drug may be effective for enhancing anti-tumor immunity in NPC patients.

  20. Metastatic tumor antigen 3 is a direct corepressor of the Wnt4 pathway

    OpenAIRE

    Zhang, Hao; Singh, Rajesh R.; Talukder, Amjad H.; Kumar, Rakesh

    2006-01-01

    Here we show that expression of MTA3 inhibits ductal branching in virgin and pregnant murine transgenic mammary glands. MTA3 also suppresses the Wnt4 pathway and, thus, these findings parallel phenotypic changes in Wnt4-null mice. MTA3 represses Wnt4 transcription and Wnt4 secretion, inhibiting Wnt-target genes in mammary epithelial cells. Accordingly, knockdown of endogenous MTA3 stimulates Wnt4 expression and Wnt cellular targets. The MTA3–NuRD (nucleosome remodeling and deacetylase) comple...

  1. Role of the adenovirus early region 1B tumor antigens in transformation and lytic infection

    NARCIS (Netherlands)

    Bernards, R.A.; Leeuw, M.G.W. de; Houweling, A.; Eb, A.J. van der

    1986-01-01

    We have investigated the contribution of each of the two adenovirus type 5 (Ad5) major early region lb (Elb) proteins in cell transformation and in lytic infection. An Ad5 El plasmid, in which the reading frame for the 19-kDa Elb protein was abolished by a stop codon close to the initiation codon,

  2. Identification of Four-Jointed Box 1 (FJX1-Specific Peptides for Immunotherapy of Nasopharyngeal Carcinoma.

    Directory of Open Access Journals (Sweden)

    San Jiun Chai

    Full Text Available Nasopharyngeal carcinoma (NPC is highly prevalent in South East Asia and China. The poor outcome is due to late presentation, recurrence, distant metastasis and limited therapeutic options. For improved treatment outcome, immunotherapeutic approaches focusing on dendritic and autologous cytotoxic T-cell based therapies have been developed, but cost and infrastructure remain barriers for implementing these in low-resource settings. As our prior observations had found that four-jointed box 1 (FJX1, a tumor antigen, is overexpressed in NPCs, we investigated if short 9-20 amino acid sequence specific peptides matching to FJX1 requiring only intramuscular immunization to train host immune systems would be a better treatment option for this disease. Thus, we designed 8 FJX1-specific peptides and implemented an assay system to first, assess the binding of these peptides to HLA-A2 molecules on T2 cells. After, ELISPOT assays were used to determine the peptides immunogenicity and ability to induce potential cytotoxicity activity towards cancer cells. Also, T-cell proliferation assay was used to evaluate the potential of MHC class II peptides to stimulate the expansion of isolated T-cells. Our results demonstrate that these peptides are immunogenic and peptide stimulated T-cells were able to induce peptide-specific cytolytic activity specifically against FJX1-expressing cancer cells. In addition, we demonstrated that the MHC class II peptides were capable of inducing T-cell proliferation. Our results suggest that these peptides are capable of inducing specific cytotoxic cytokines secretion against FJX1-expressing cancer cells and serve as a potential vaccine-based therapy for NPC patients.

  3. Identification of Four-Jointed Box 1 (FJX1)-Specific Peptides for Immunotherapy of Nasopharyngeal Carcinoma

    Science.gov (United States)

    Chai, San Jiun; Yap, Yoke Yeow; Foo, Yoke Ching; Yap, Lee Fah; Ponniah, Sathibalan; Teo, Soo Hwang; Cheong, Sok Ching; Patel, Vyomesh; Lim, Kue Peng

    2015-01-01

    Nasopharyngeal carcinoma (NPC) is highly prevalent in South East Asia and China. The poor outcome is due to late presentation, recurrence, distant metastasis and limited therapeutic options. For improved treatment outcome, immunotherapeutic approaches focusing on dendritic and autologous cytotoxic T-cell based therapies have been developed, but cost and infrastructure remain barriers for implementing these in low-resource settings. As our prior observations had found that four-jointed box 1 (FJX1), a tumor antigen, is overexpressed in NPCs, we investigated if short 9–20 amino acid sequence specific peptides matching to FJX1 requiring only intramuscular immunization to train host immune systems would be a better treatment option for this disease. Thus, we designed 8 FJX1-specific peptides and implemented an assay system to first, assess the binding of these peptides to HLA-A2 molecules on T2 cells. After, ELISPOT assays were used to determine the peptides immunogenicity and ability to induce potential cytotoxicity activity towards cancer cells. Also, T-cell proliferation assay was used to evaluate the potential of MHC class II peptides to stimulate the expansion of isolated T-cells. Our results demonstrate that these peptides are immunogenic and peptide stimulated T-cells were able to induce peptide-specific cytolytic activity specifically against FJX1-expressing cancer cells. In addition, we demonstrated that the MHC class II peptides were capable of inducing T-cell proliferation. Our results suggest that these peptides are capable of inducing specific cytotoxic cytokines secretion against FJX1-expressing cancer cells and serve as a potential vaccine-based therapy for NPC patients. PMID:26536470

  4. Identification of NY-BR-1-specific CD4(+) T cell epitopes using HLA-transgenic mice.

    Science.gov (United States)

    Gardyan, Adriane; Osen, Wolfram; Zörnig, Inka; Podola, Lilli; Agarwal, Maria; Aulmann, Sebastian; Ruggiero, Eliana; Schmidt, Manfred; Halama, Niels; Leuchs, Barbara; von Kalle, Christof; Beckhove, Philipp; Schneeweiss, Andreas; Jäger, Dirk; Eichmüller, Stefan B

    2015-06-01

    Breast cancer represents the second most common cancer type worldwide and has remained the leading cause of cancer-related deaths among women. The differentiation antigen NY-BR-1 appears overexpressed in invasive mammary carcinomas compared to healthy breast tissue, thus representing a promising target antigen for T cell based tumor immunotherapy approaches. Since efficient immune attack of tumors depends on the activity of tumor antigen-specific CD4(+) effector T cells, NY-BR-1 was screened for the presence of HLA-restricted CD4(+) T cell epitopes that could be included in immunological treatment approaches. Upon NY-BR-1-specific DNA immunization of HLA-transgenic mice and functional ex vivo analysis, a panel of NY-BR-1-derived library peptides was determined that specifically stimulated IFNγ secretion among splenocytes of immunized mice. Following in silico analyses, four candidate epitopes were determined which were successfully used for peptide immunization to establish NY-BR-1-specific, HLA-DRB1*0301- or HLA-DRB1*0401-restricted CD4(+) T cell lines from splenocytes of peptide immunized HLA-transgenic mice. Notably, all four CD4(+) T cell lines recognized human HLA-DR-matched dendritic cells (DC) pulsed with lysates of NY-BR-1 expressing human tumor cells, demonstrating natural processing of these epitopes also within the human system. Finally, CD4(+) T cells specific for all four CD4(+) T cell epitopes were detectable among PBMC of breast cancer patients, showing that CD4(+) T cell responses against the new epitopes are not deleted nor inactivated by self-tolerance mechanisms. Our results present the first NY-BR-1-specific HLA-DRB1*0301- and HLA-DRB1*0401-restricted T cell epitopes that could be exploited for therapeutic intervention against breast cancer. © 2014 UICC.

  5. Correlation of antigen-specific IFN-γ responses of fresh blood samples from Mycobacterium avium subsp. paratuberculosis infected heifers with responses of day-old samples co-cultured with IL-12 or anti-IL-10 antibodies

    DEFF Research Database (Denmark)

    Mikkelsen, Heidi; Aagaard, Claus; Nielsen, Søren Saxmose

    2012-01-01

    Paratuberculosis is a chronic infection of the intestine of ruminants caused by Mycobacterium avium subsp. paratuberculosis (MAP). Early stage MAP infection can be detected by measuring cell-mediated immune responses using the interferon gamma (IFN-γ) assay. Whole blood samples are cultured...... to enhance IFN-γ responses of cultures stimulated with Johnin purified protein derivative (PPDj). Here we examined the correlation of IFN-γ production in response to PPDj and 15 recombinant antigens in day-old blood samples from heifers 10–21 months of age from a MAP infected herd with addition of either...... overnight with specific MAP antigens followed by quantification of IFN-γ by ELISA. It is recommended that the time interval from sampling to culture does not exceed eight hours but addition of the co-stimulating cytokine interleukin 12 (IL-12) or anti-IL-10 antibodies to culture have been demonstrated...

  6. Mechanism study of tumor-specific immune responses induced by laser immunotherapy

    Science.gov (United States)

    Li, Xiaosong; Zhou, Feifan; Le, Henry; Wolf, Roman F.; Howard, Eric; Nordquist, Robert E.; Hode, Tomas; Liu, Hong; Chen, Wei R.

    2011-03-01

    Laser immunotherapy (LIT) has shown its efficacy against late-stage, metastatic cancers, both in pre-clinical studies and clinical pilot trials. However, the possible mechanism of LIT is still not fully understood. In our previous studies, we have shown that LIT induces tumor-specific antibodies that strongly bind to the target tumors. Tumor resistance in cured animals demonstrated long-term immunological effect of LIT. Successful transfer of adoptive immunity using spleen cells from LIT-cured animals indicated a long-term immunological memory of the host system. In clinical trials for the treatment of late-stage melanoma patients and breast cancer patients, the similar long-term, systemic effects have also been observed. To further study the immunological mechanism of LIT, immuno-histochemical analysis of patient tumor samples has performed before and after LIT treatment. Our results showed strong evidence that LIT significantly increases the infiltration of immune cells in the target tumors. Specifically, LIT appeared to drive the infiltrating immune cell populations in the direction of CD4, CD8 and CD68 T-cells. It is possible that activation and enhancement of both humeral and cellular arms of the host immune system are achievable by the treatment of LIT. These special features of LIT have contributed to the success of patient treatment. The underlying mechanism of LIT appears to be an in-situ autologous whole-cell cancer vaccination, using all components of tumors as sources of tumor antigens. Our preliminary mechanistic studies and future in-depth studies will contribute to the understanding and development of LIT as an effective modality for the treatment of late stage cancer patients who are facing severely limited options.

  7. Mucin 1-specific immunotherapy in a mouse model of spontaneous breast cancer.

    Science.gov (United States)

    Mukherjee, Pinku; Madsen, Cathy S; Ginardi, Amelia R; Tinder, Teresa L; Jacobs, Fred; Parker, Joanne; Agrawal, Babita; Longenecker, B Michael; Gendler, Sandra J

    2003-01-01

    Human mucin 1 (MUC1) is an epithelial mucin glycoprotein that is overexpressed in 90% of all adenocarcinomas including breast, lung, pancreas, prostate, stomach, colon, and ovary. MUC1 is a target for immune intervention, because, in patients with solid adenocarcinomas, low-level cellular and humoral immune responses to MUC1 have been observed, which are not sufficiently strong to eradicate the growing tumor. The hypothesis for this study is that enhancing MUC1-specific immunity will result in antitumor immunity. To test this, the authors have developed a clinically relevant breast cancer model that demonstrates peripheral and central tolerance to MUC1 and develops spontaneous tumors of the mammary gland. In these mice, the authors tested a vaccine formulation comprised of liposomal-MUC1 lipopeptide and human recombinant interleukin-2. Results indicate that when compared with untreated mice, immunized mice develop T cells that express intracellular IFN-gamma, are reactive with MHC class I H-2Db/MUC1 tetramer, and are cytotoxic against MUC1-expressing tumor cells in vitro. The presence of MUC1-specific CTL did not translate into a clinical response as measured by time of tumor onset, tumor burden, and survival. The authors demonstrate that some of the immune-evasion mechanisms used by the tumor cells include downregulation of MHC-class I molecule, expression of TGF-beta2, and decrease in IFN-gamma -expressing effector T cells as tumors progress. Finally, utilizing an injectable breast cancer model, the authors show that targeting a single tumor antigen may not be an effective antitumor treatment, but that immunization with dendritic cells fed with whole tumor lysate is effective in breaking tolerance and protecting mice from subsequent tumor challenge. A physiologically relevant spontaneous breast cancer model has been developed to test improved immunotherapeutic approaches.

  8. Specifying Specification.

    Science.gov (United States)

    Paulo, Norbert

    2016-03-01

    This paper tackles the accusation that applied ethics is no serious academic enterprise because it lacks theoretical bracing. It does so in two steps. In the first step I introduce and discuss a highly acclaimed method to guarantee stability in ethical theories: Henry Richardson's specification. The discussion shows how seriously ethicists take the stability of the connection between the foundational parts of their theories and their further development as well as their "application" to particular problems or cases. A detailed scrutiny of specification leads to the second step, where I use insights from legal theory to inform the debate around stability from that point of view. This view reveals some of specification's limitations. I suggest that, once specification is sufficiently specified, it appears astonishingly similar to deduction as used in legal theory. Legal theory also provides valuable insight into the functional range of deduction and its relation to other forms of reasoning. This leads to a richer understanding of stability in normative theories and to a smart division of labor between deduction and other forms of reasoning. The comparison to legal theory thereby provides a framework for how different methods such as specification, deduction, balancing, and analogy relate to one another.

  9. Probe specificity

    International Nuclear Information System (INIS)

    Laget, J.M.

    1986-11-01

    Specificity and complementarity of hadron and electron probes must be systematically developed to answer three questions currently asked in intermediate energy nuclear physics: what is nucleus structure at short distances, what is nature of short range correlations, what is three body force nature [fr

  10. Endogenous collagen peptide activation of CD1d-restricted NKT cells ameliorates tissue-specific inflammation in mice

    DEFF Research Database (Denmark)

    Liu, Yawei; Teige, Anna; Mondoc, Emma

    2011-01-01

    NKT cells in the mouse recognize antigen in the context of the MHC class I-like molecule CD1d and play an important role in peripheral tolerance and protection against autoimmune and other diseases. NKT cells are usually activated by CD1d-presented lipid antigens. However, peptide recognition...... in the context of CD1 has also been documented, although no self-peptide ligands have been reported to date. Here, we have identified an endogenous peptide that is presented by CD1d to activate mouse NKT cells. This peptide, the immunodominant epitope from mouse collagen type II (mCII707-721), was not associated...... with either MHC class I or II. Activation of CD1d-restricted mCII707-721-specific NKT cells was induced via TCR signaling and classical costimulation. In addition, mCII707-721-specific NKT cells induced T cell death through Fas/FasL, in an IL-17A-independent fashion. Moreover, mCII707-721-specific NKT cells...

  11. A novel and effective cancer immunotherapy mouse model using antigen-specific B cells selected in vitro.

    Directory of Open Access Journals (Sweden)

    Tatsuya Moutai

    Full Text Available Immunotherapies such as adoptive transfer of T cells or natural killer cells, or monoclonal antibody (MoAb treatment have recently been recognized as effective means to treat cancer patients. However, adoptive transfer of B cells or plasma cells producing tumor-specific antibodies has not been applied as a therapy because long-term culture and selective expansion of antigen-specific B cells has been technically very difficult. Here, we describe a novel cancer immunotherapy that uses B-cell adoptive transfer. We demonstrate that germinal-center-like B cells (iGB cells induced in vitro from mouse naïve B cells become plasma cells and produce IgG antibodies for more than a month in the bone marrow of non-irradiated recipient mice. When transferred into mice, iGB cells producing antibody against a surrogate tumor antigen suppressed lung metastasis and growth of mouse melanoma cells expressing the same antigen and prolonged survival of the recipients. In addition, we have developed a novel culture system called FAIS to selectively expand antigen-specific iGB cells utilizing the fact that iGB cells are sensitive to Fas-induced cell death unless their antigen receptors are ligated by membrane-bound antigens. The selected iGB cells efficiently suppressed lung metastasis of melanoma cells in the adoptive immunotherapy model. As human blood B cells can be propagated as iGB cells using culture conditions similar to the mouse iGB cell cultures, our data suggest that it will be possible to treat cancer-bearing patients by the adoptive transfer of cancer-antigen-specific iGB cells selected in vitro. This new adoptive immunotherapy should be an alternative to the laborious development of MoAb drugs against cancers for which no effective treatments currently exist.

  12. Profound tumor-specific Th2 bias in patients with malignant glioma

    International Nuclear Information System (INIS)

    Shimato, Shinji; Maier, Lisa M; Maier, Richard; Bruce, Jeffrey N; Anderson, Richard CE; Anderson, David E

    2012-01-01

    Vaccination against tumor-associated antigens is one promising approach to immunotherapy against malignant gliomas. While previous vaccine efforts have focused exclusively on HLA class I-restricted peptides, class II-restricted peptides are necessary to induce CD4 + helper T cells and sustain effective anti-tumor immunity. In this report we investigated the ability of five candidate peptide epitopes derived from glioma-associated antigens MAGE and IL-13 receptor α2 to detect and characterize CD4 + helper T cell responses in the peripheral blood of patients with malignant gliomas. Primary T cell responses were determined by stimulating freshly isolated PBMCs from patients with primary glioblastoma (GBM) (n = 8), recurrent GBM (n = 5), meningioma (n = 7), and healthy controls (n = 6) with each candidate peptide, as well as anti-CD3 monoclonal antibody (mAb) and an immunodominant peptide epitope derived from myelin basic protein (MBP) serving as positive and negative controls, respectively. ELISA was used to measure IFN-γ and IL-5 levels, and the ratio of IFN-γ/IL-5 was used to determine whether the response had a predominant Th1 or Th2 bias. We demonstrate that novel HLA Class-II restricted MAGE-A3 and IL-13Rα2 peptides can detect T cell responses in patients with GBMs as well as in healthy subjects. Stimulation with a variety of peptide antigens over-expressed by gliomas is associated with a profound reduction in the IFN-γ/IL-5 ratio in GBM patients relative to healthy subjects. This bias is more pronounced in patients with recurrent GBMs. Therapeutic vaccine strategies to shift tumor antigen-specific T cell response to a more immunostimulatory Th1 bias may be needed for immunotherapeutic trials to be more successful clinically

  13. Co-stimulation through 4-1BB/CD137 improves the expansion and function of CD8(+ melanoma tumor-infiltrating lymphocytes for adoptive T-cell therapy.

    Directory of Open Access Journals (Sweden)

    Jessica Ann Chacon

    Full Text Available Adoptive T-cell therapy (ACT using tumor-infiltrating lymphocytes (TIL can induce tumor regression in up to 50% or more of patients with unresectable metastatic melanoma. However, current methods to expand melanoma TIL, especially the "rapid expansion protocol" (REP were not designed to enhance the generation of optimal effector-memory CD8(+ T cells for infusion. One approach to this problem is to manipulate specific co-stimulatory signaling pathways to enhance CD8(+ effector-memory T-cell expansion. In this study, we determined the effects of activating the TNF-R family member 4-1BB/CD137, specifically induced in activated CD8(+ T cells, on the yield, phenotype, and functional activity of expanded CD8(+ T cells during the REP. We found that CD8(+ TIL up-regulate 4-1BB expression early during the REP after initial TCR stimulation, but neither the PBMC feeder cells in the REP or the activated TIL expressed 4-1BB ligand. However, addition of an exogenous agonistic anti-4-1BB IgG4 (BMS 663513 to the REP significantly enhanced the frequency and total yield of CD8(+ T cells as well as their maintenance of CD28 and increased their anti-tumor CTL activity. Gene expression analysis found an increase in bcl-2 and survivin expression induced by 4-1BB that was associated with an enhanced survival capability of CD8(+ post-REP TIL when re-cultured in the absence or presence of cytokines. Our findings suggest that adding an agonistic anti-4-1BB antibody during the time of TIL REP initiation produces a CD8(+ T cell population capable of improved effector function and survival. This may greatly improve TIL persistence and anti-tumor activity in vivo after adoptive transfer into patients.

  14. HRT Specification

    CERN Document Server

    Möller, M

    1996-01-01

    In the context of the AIS Project (Advanced Informatics Systems for administration and management) a study has been conducted that resulted in the definition of a high level information systems model. Thirteen proposed systems were defined for detailed analysis. The Finance, Foundation, Human Resources, Logistics and Purchasing areas have been studied in detail. These studies have lead to the purchase and implementation of the ORIAC and SIRIAC packages, the Foundation database, the Oracle HR package, the Triton package and EDH and BHT. This specification describes the Human Resources Toolkit (HRT) intended to be used for accessing data in the HR and Foundation systems. This toolkit should help the divisions carry out their Human Resource management, planning and follow-up. It will have extensive report generation capabilities and offer a variety of standard graphs. It should have an easy-to-use graphical user interface and run on the CERN standard desktop platforms.

  15. Epitope diversification driven by non-tumor epitope-specific Th1 and Th17 mediates potent antitumor reactivity.

    Science.gov (United States)

    Ichikawa, Kosuke; Kagamu, Hiroshi; Koyama, Kenichi; Miyabayashi, Takao; Koshio, Jun; Miura, Satoru; Watanabe, Satoshi; Yoshizawa, Hirohisa; Narita, Ichiei

    2012-09-21

    MHC class I-restricted peptide-based vaccination therapies have been conducted to treat cancer patients, because CD8⁺ CTL can efficiently induce apoptosis of tumor cells in an MHC class I-restricted epitope-specific manner. Interestingly, clinical responders are known to demonstrate reactivity to epitopes other than those used for vaccination; however, the mechanism underlying how antitumor T cells with diverse specificity are induced is unclear. In this study, we demonstrated that dendritic cells (DCs) that engulfed apoptotic tumor cells in the presence of non-tumor MHC class II-restricted epitope peptides, OVA(323-339), efficiently presented tumor-associated antigens upon effector-dominant CD4⁺ T cell balance against regulatory T cells (Treg) for the OVA(323-339) epitope. Th1 and Th17 induced tumor-associated antigens presentation of DC, while Th2 ameliorated tumor-antigen presentation for CD8⁺ T cells. Blocking experiments with anti-IL-23p19 antibody and anti-IL-23 receptor indicated that an autocrine mechanism of IL-23 likely mediated the diverted tumor-associated antigens presentation of DC. Tumor-associated antigens presentation of DC induced by OVA(323-339) epitope-specific CD4⁺ T cells resulted in facilitated antitumor immunity in both priming and effector phase in vivo. Notably, this immunotherapy did not require pretreatment to reduce Treg induced by tumor. This strategy may have clinical implications for designing effective antitumor immunotherapies. Copyright © 2012 Elsevier Ltd. All rights reserved.

  16. In Vivo Expansion of Melanoma-Specific T Cells Using Microneedle Arrays Coated with Immune-Polyelectrolyte Multilayers.

    Science.gov (United States)

    Zeng, Qin; Gammon, Joshua M; Tostanoski, Lisa H; Chiu, Yu-Chieh; Jewell, Christopher M

    2017-02-13

    Microneedles (MNs) are micron-scale polymeric or metallic structures that offer distinct advantages for vaccines by efficiently targeting skin-resident immune cells, eliminating injection-associated pain, and improving patient compliance. These advantages, along with recent studies showing therapeutic benefits achieved using traditional intradermal injections in human cancer patients, suggest MN delivery might enhance cancer vaccines and immunotherapies. We recently developed a new class of polyelectrolyte multilayers based on the self-assembly of model peptide antigens and molecular toll-like receptor agonists (TLRa) into ultrathin, conformal coatings. Here, we reasoned that these immune polyelectrolyte multilayers (iPEMs) might be a useful platform for assembling cancer vaccine components on MN arrays for intradermal delivery from these substrates. Using conserved human melanoma antigens and a potent TLRa vaccine adjuvant, CpG, we show that iPEMs can be assembled on MNs in an automated fashion. These films, prepared with up to 128 layers, are approximately 200 nm thick but provide cancer vaccine cargo loading >225 μg/cm 2 . In cell culture, iPEM cargo released from MNs is internalized by primary dendritic cells, promotes activation of these cells, and expands T cells during coculture. In mice, application of iPEM-coated MNs results in the codelivery of tumor antigen and CpG through the skin, expanding tumor-specific T cells during initial MN applications and resulting in larger memory recall responses during a subsequent booster MN application. This study support MNs coated with PEMs built from tumor vaccine components as a well-defined, modular system for generating tumor-specific immune responses, enabling new approaches that can be explored in combination with checkpoint blockade or other combination cancer therapies.

  17. MUC1-specific CTLs are non-functional within a pancreatic tumor microenvironment.

    Science.gov (United States)

    Mukherjee, P; Ginardi, A R; Madsen, C S; Tinder, T L; Jacobs, F; Parker, J; Agrawal, B; Longenecker, B M; Gendler, S J

    2001-01-01

    Pancreatic cancer is a highly aggressive, treatment refractory disease and is the fourth leading cause of death in the United States. In humans, 90% of pancreatic adenocarcinomas over-express altered forms of a tumor-associated antigen, MUC1 (an epithelial mucin glycoprotein), which is a target for immunotherapy. Using a clinically relevant mouse model of pancreas cancer that demonstrates peripheral and central tolerance to human MUC1 and develops spontaneous tumors of the pancreas, we have previously reported the presence of functionally active, low affinity, MUC1-specific precursor cytotoxic T cells (pCTLs). Hypothesis for this study is that MUC1-based immunization may enhance the low level MUC1-specific immunity that may lead to an effective anti-tumor response. Data demonstrate that MUC1 peptide-based immunization elicits mature MUC1-specific CTLs in the peripheral lymphoid organs. The mature CTLs secrete IFN-gamma and are cytolytic against MUC1-expressing tumor cells in vitro. However, active CTLs that infiltrate the pancreas tumor microenvironment become cytolytically anergic and are tolerized to MUC1 antigen, allowing the tumor to grow. We demonstrate that the CTL tolerance could be reversed at least in vitro with the use of anti-CD40 co-stimulation. The pancreas tumor cells secrete immunosuppressive cytokines, including IL-10 and TGF-beta that are partly responsible for the down-regulation of CTL activity. In addition, they down-regulate their MHC class I molecules to avoid immune recognition. CD4+ CD25+ T regulatory cells, which secrete IL-10, were also found in the tumor environment. Together these data indicate the use of several immune evasion mechanisms by tumor cells to evade CTL killing. Thus altering the tumor microenvironment to make it more conducive to CTL killing may be key in developing a successful anti-cancer immunotherapy.

  18. Identification of a novel dendritic cell surface antigen defined by carbohydrate specific CD24 antibody cross-reactivity.

    Science.gov (United States)

    Williams, L A; McLellan, A D; Summers, K L; Sorg, R V; Fearnley, D B; Hart, D N

    1996-01-01

    Dendritic cells (DC) are characterized as leucocytes that lack mature lineage specific markers and stimulate naive T-lymphocyte proliferation in vitro and in vivo. The mouse heat stable antigen (HSA) participates in T lymphocyte co-stimulation and is expressed by DC isolated from thymus, skin and spleen. The human HSA homologue, CD24, is predominantly expressed by B lymphocytes and granulocytes, but its expression on DC has not been studied in detail. CD24 clearly participates in B-lymphocyte signalling but co-stimulatory activity for T lymphocytes has not yet been described. We have examined the expression of CD24 on human peripheral blood DC populations isolated directly or following in vitro culture. The CD24 antigen was absent from blood DC however, cross-reactive sialylated carbohydrate epitopes were detected on DC with some CD24 monoclonal antibodies (mAb). These CD24 mAb define a protein surface antigen, which is expressed by an immature or resting subpopulation of peripheral blood DC and is down-regulated following activation differentiation in vitro. PMID:8911149

  19. Induction of CML28-specific cytotoxic T cell responses using co-transfected dendritic cells with CML28 DNA vaccine and SOCS1 small interfering RNA expression vector

    International Nuclear Information System (INIS)

    Zhou Hongsheng; Zhang Donghua; Wang Yaya; Dai Ming; Zhang Lu; Liu Wenli; Liu Dan; Tan Huo; Huang Zhenqian

    2006-01-01

    CML28 is an attractive target for antigen-specific immunotherapy. SOCS1 represents an inhibitory control mechanism for DC antigen presentation and the magnitude of adaptive immunity. In this study, we evaluated the potential for inducing CML28-specific cytotoxic T lymphocytes (CTL) responses by dendritic cells (DCs)-based vaccination. We constructed a CML28 DNA vaccine and a SOCS1 siRNA vector and then cotransfect monocyte-derived DCs. Flow cytometry analysis showed gene silencing of SOCS1 resulted in higher expressions of costimulative moleculars in DCs. Mixed lymphocyte reaction (MLR) indicated downregulation of SOCS1 stronger capability to stimulate proliferation of responder cell in DCs. The CTL assay revealed transfected DCs effectively induced autologous CML28-specific CTL responses and the lytic activities induced by SOCS1-silenced DCs were significantly higher compared with those induced by SOCS1-expressing DCs. These results in our study indicates gene silencing of SOCS1 remarkably enhanced the cytotoxicity efficiency of CML28 DNA vaccine in DCs

  20. Molecular mechanisms underlying CD27-CD70 costimulation

    NARCIS (Netherlands)

    Peperzak, L.

    2010-01-01

    We are in a constant state of war, threatened by both exogenous enemies in the form of killing pathogens, or enemies from within in the form of tumor cells. The key for survival of our species amongst an overwhelming amount and diversity of microorganisms, such as viruses, bacteria and parasites is

  1. Stable Skin-specific Overexpression of Human CTLA4-Ig in Transgenic Mice through Seven Generations

    Institute of Scientific and Technical Information of China (English)

    Yong WANG; Yong NI; Hong WEI; Feng-Chao WANG; Liang-Peng GE; Xiang GAO

    2006-01-01

    Skin graft rejection is a typical cellular immune response, mainly mediated by T cells. Cytotoxic T lymphocyte associated antigen 4-immunoglobin (CTLA4-Ig) extends graft survival by blocking the T cell co-stimulation pathway and inhibiting T cell activation. To investigate the efficacy of CTLA4-Ig in prolonging skin graft survival, human CTLA4-Ig (hCTLA4-Ig) was engineered to overexpress in mouse skin by transgenesis using the K14 promoter. Reverse transcription-polymerase chain reaction (RT-PCR) and Western blot assay indicated that the expression of CTLA4-Ig remained skin-specific and relatively constant compared to the internal control protein, AKT, through seven generations. The presence and concentration of the hCTLA4-Ig protein in transgenic mouse sera was determined by enzyme-linked immunosorbent assay (ELISA), and the results indicated that the serum CTLA4-Ig concentration also remained constant through generations. Survival of transgenic mouse skins grafted onto rat wounds was remarkably prolonged compared to that of wild-type skins from the same mouse strain, and remained comparable among all seven generations. This suggested that the bioactive hCTLA4-Ig protein was stably expressed in transgenical mice through at least seven generations, which was consistent with the stable skin-specific CTLA4-Ig expression.The results demonstrated that the transgenic expression of hCTLA4-Ig in skin driven by the K14 promoter remained constant through generations, and a transgenic line can be established to provide transgenic skin with extended survival reproducibly.

  2.   A rationally designed tyrosine hydroxylase DNA vaccine induces specific antineuroblastoma immunity

    DEFF Research Database (Denmark)

    Huebener, Nicole; Fest, Stefan; Strandsby, Anne Bystrup

    2008-01-01

    Therapeutic vaccination against tumor antigens without induction of autoimmunity remains a major challenge in cancer immunotherapy. Here, we show for the first time effective therapeutic vaccination followed by suppression of established spontaneous neuroblastoma metastases using a tyrosine...... show effective therapeutic vaccination against neuroblastoma with a novel rationally designed TH minigene vaccine without induction of autoimmunity providing an important baseline for future clinical application of this strategy....

  3. Therapeutic limitations in tumor-specific CD8+ memory T cell engraftment

    International Nuclear Information System (INIS)

    Bathe, Oliver F; Dalyot-Herman, Nava; Malek, Thomas R

    2003-01-01

    Adoptive immunotherapy with cytotoxic T lymphocytes (CTL) represents an alternative approach to treating solid tumors. Ideally, this would confer long-term protection against tumor. We previously demonstrated that in vitro-generated tumor-specific CTL from the ovalbumin (OVA)-specific OT-I T cell receptor transgenic mouse persisted long after adoptive transfer as memory T cells. When recipient mice were challenged with the OVA-expressing E.G7 thymoma, tumor growth was delayed and sometimes prevented. The reasons for therapeutic failures were not clear. OT-I CTL were adoptively transferred to C57BL/6 mice 21 – 28 days prior to tumor challenge. At this time, the donor cells had the phenotypical and functional characteristics of memory CD8+ T cells. Recipients which developed tumor despite adoptive immunotherapy were analyzed to evaluate the reason(s) for therapeutic failure. Dose-response studies demonstrated that the degree of tumor protection was directly proportional to the number of OT-I CTL adoptively transferred. At a low dose of OT-I CTL, therapeutic failure was attributed to insufficient numbers of OT-I T cells that persisted in vivo, rather than mechanisms that actively suppressed or anergized the OT-I T cells. In recipients of high numbers of OT-I CTL, the E.G7 tumor that developed was shown to be resistant to fresh OT-I CTL when examined ex vivo. Furthermore, these same tumor cells no longer secreted a detectable level of OVA. In this case, resistance to immunotherapy was secondary to selection of clones of E.G7 that expressed a lower level of tumor antigen. Memory engraftment with tumor-specific CTL provides long-term protection against tumor. However, there are several limitations to this immunotherapeutic strategy, especially when targeting a single antigen. This study illustrates the importance of administering large numbers of effectors to engraft sufficiently efficacious immunologic memory. It also demonstrates the importance of targeting several

  4. Simultaneous targeting of prostate stem cell antigen and prostate-specific membrane antigen improves the killing of prostate cancer cells using a novel modular T cell-retargeting system.

    Science.gov (United States)

    Arndt, Claudia; Feldmann, Anja; Koristka, Stefanie; Cartellieri, Marc; Dimmel, Maria; Ehninger, Armin; Ehninger, Gerhard; Bachmann, Michael

    2014-09-01

    Recently, we described a novel modular platform technology in which T cell-recruitment and tumor-targeting domains of conventional bispecific antibodies are split to independent components, a universal effector module (EM) and replaceable monospecific/monovalent target modules (TMs) that form highly efficient T cell-retargeting complexes. Theoretically, our unique strategy should allow us to simultaneously retarget T cells to different tumor antigens by combining the EM with two or more different monovalent/monospecific TMs or even with bivalent/bispecific TMs, thereby overcoming limitations of a monospecific treatment such as the selection of target-negative tumor escape variants. In order to advance our recently introduced prostate stem cell antigen (PSCA)-specific modular system for a dual-targeting of prostate cancer cells, two additional TMs were constructed: a monovalent/monospecific TM directed against the prostate-specific membrane antigen (PSMA) and a bivalent/bispecific TM (bsTM) with specificity for PSMA and PSCA. The functionality of the novel dual-targeting strategies was analyzed by performing T cell activation and chromium release assays. Similar to the PSCA-specific modular system, the novel PSMA-specific modular system mediates an efficient target-dependent and -specific tumor cell lysis at low E:T ratios and picomolar Ab concentrations. Moreover, by combination of the EM with either the bispecific TM directed to PSMA and PSCA or both monospecifc TMs directed to either PSCA or PSMA, dual-specific targeting complexes were formed which allowed us to kill potential escape variants expressing only one or the other target antigen. Overall, the novel modular system represents a promising tool for multiple tumor targeting. © 2014 Wiley Periodicals, Inc.

  5. A novel system of artificial antigen-presenting cells efficiently stimulates Flu peptide-specific cytotoxic T cells in vitro

    International Nuclear Information System (INIS)

    Han, Hui; Peng, Ji-Run; Chen, Peng-Cheng; Gong, Lei; Qiao, Shi-Shi; Wang, Wen-Zhen; Cui, Zhu-Qingqing; Yu, Xin; Wei, Yu-Hua; Leng, Xi-Sheng

    2011-01-01

    Highlights: → Adoptive immunotherapy depends on relevant numbers of cytolytic T lymphocytes. → An ideal artificial APCs system was successfully prepared in vivo. → Controlled release of IL-2 leads to much more T-cell expansion. → This system is better than general cellular APCs on T-cell expansion. -- Abstract: Therapeutic numbers of antigen-specific cytotoxic T lymphocytes (CTLs) are key effectors in successful adoptive immunotherapy. However, efficient and reproducible methods to meet the qualification remain poor. To address this issue, we designed the artificial antigen-presenting cell (aAPC) system based on poly(lactic-co-glycolic acid) (PLGA). A modified emulsion method was used for the preparation of PLGA particles encapsulating interleukin-2 (IL-2). Biotinylated molecular ligands for recognition and co-stimulation of T cells were attached to the particle surface through the binding of avidin-biotin. These formed the aAPC system. The function of aAPCs in the proliferation of specific CTLs against human Flu antigen was detected by enzyme-linked immunospot assay (ELISPOT) and MTT staining methods. Finally, we successfully prepared this suitable aAPC system. The results show that IL-2 is released from aAPCs in a sustained manner over 30 days. This dramatically improves the stimulatory capacity of this system as compared to the effect of exogenous addition of cytokine. In addition, our aAPCs promote the proliferation of Flu antigen-specific CTLs more effectively than the autologous cellular APCs. Here, this aAPC platform is proved to be suitable for expansion of human antigen-specific T cells.

  6. Endogenous collagen peptide activation of CD1d-restricted NKT cells ameliorates tissue-specific inflammation in mice.

    Science.gov (United States)

    Liu, Yawei; Teige, Anna; Mondoc, Emma; Ibrahim, Saleh; Holmdahl, Rikard; Issazadeh-Navikas, Shohreh

    2011-01-01

    NKT cells in the mouse recognize antigen in the context of the MHC class I-like molecule CD1d and play an important role in peripheral tolerance and protection against autoimmune and other diseases. NKT cells are usually activated by CD1d-presented lipid antigens. However, peptide recognition in the context of CD1 has also been documented, although no self-peptide ligands have been reported to date. Here, we have identified an endogenous peptide that is presented by CD1d to activate mouse NKT cells. This peptide, the immunodominant epitope from mouse collagen type II (mCII707-721), was not associated with either MHC class I or II. Activation of CD1d-restricted mCII707-721-specific NKT cells was induced via TCR signaling and classical costimulation. In addition, mCII707-721-specific NKT cells induced T cell death through Fas/FasL, in an IL-17A-independent fashion. Moreover, mCII707-721-specific NKT cells suppressed a range of in vivo inflammatory conditions, including delayed-type hypersensitivity, antigen-induced airway inflammation, collagen-induced arthritis, and EAE, which were all ameliorated by mCII707-721 vaccination. The findings presented here offer new insight into the intrinsic roles of NKT cells in health and disease. Given the results, endogenous collagen peptide activators of NKT cells may offer promise as novel therapeutics in tissue-specific autoimmune and inflammatory diseases.

  7. A novel system of artificial antigen-presenting cells efficiently stimulates Flu peptide-specific cytotoxic T cells in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Han, Hui [Department of Hepatobiliary Surgery, Peking University People' s Hospital, Beijing 100044 (China); Peng, Ji-Run, E-mail: pengjr@medmail.com.cn [Department of Hepatobiliary Surgery, Peking University People' s Hospital, Beijing 100044 (China); Chen, Peng-Cheng; Gong, Lei [Department of Hepatobiliary Surgery, Peking University People' s Hospital, Beijing 100044 (China); Qiao, Shi-Shi [Department of Hepatobiliary Surgery, The First Affiliated Hospital, Zhengzhou University, Zhengzhou 450052 (China); Wang, Wen-Zhen; Cui, Zhu-Qingqing; Yu, Xin; Wei, Yu-Hua [Department of Hepatobiliary Surgery, Peking University People' s Hospital, Beijing 100044 (China); Leng, Xi-Sheng, E-mail: lengxs2003@yahoo.com.cn [Department of Hepatobiliary Surgery, Peking University People' s Hospital, Beijing 100044 (China)

    2011-08-05

    Highlights: {yields} Adoptive immunotherapy depends on relevant numbers of cytolytic T lymphocytes. {yields} An ideal artificial APCs system was successfully prepared in vivo. {yields} Controlled release of IL-2 leads to much more T-cell expansion. {yields} This system is better than general cellular APCs on T-cell expansion. -- Abstract: Therapeutic numbers of antigen-specific cytotoxic T lymphocytes (CTLs) are key effectors in successful adoptive immunotherapy. However, efficient and reproducible methods to meet the qualification remain poor. To address this issue, we designed the artificial antigen-presenting cell (aAPC) system based on poly(lactic-co-glycolic acid) (PLGA). A modified emulsion method was used for the preparation of PLGA particles encapsulating interleukin-2 (IL-2). Biotinylated molecular ligands for recognition and co-stimulation of T cells were attached to the particle surface through the binding of avidin-biotin. These formed the aAPC system. The function of aAPCs in the proliferation of specific CTLs against human Flu antigen was detected by enzyme-linked immunospot assay (ELISPOT) and MTT staining methods. Finally, we successfully prepared this suitable aAPC system. The results show that IL-2 is released from aAPCs in a sustained manner over 30 days. This dramatically improves the stimulatory capacity of this system as compared to the effect of exogenous addition of cytokine. In addition, our aAPCs promote the proliferation of Flu antigen-specific CTLs more effectively than the autologous cellular APCs. Here, this aAPC platform is proved to be suitable for expansion of human antigen-specific T cells.

  8. The possible role of tumor antigen CA 15-3, CEA and ferritin in malignant and benign disease

    OpenAIRE

    Nafija Serdarević; Samira Mehanović

    2012-01-01

    Introduction: Serum CA15-3 has been one of the most reliable tumor markers used in monitoring of breast cancer patients. To increase its sensitivity, the combined measurement of other tumor markers (CEA and ferritin) with CA15-3 was investigated. The aim of this study was determination of CA 15-3, CEA and ferritin in female patients with breast cancer, lung cancer and mastitisMethods: 300 patients with carcinoma, hospitalized at Department of Gynecologic Oncology and Department for Oncology a...

  9. Molecular Characteristics of Carcinoembryonic Antigen and Nonspecific Cross-reacting Antigen(Clinical Application of Tumor Antigen)

    OpenAIRE

    内山, 一晃; Uchiyama, Kazuaki

    1990-01-01

    Carcinoembryonic antigen (CEA) is one of the most famous laboratory tests of tumor markers. CEA was first reported in 1965, but molecular structure of CEA was not clear untill recent years. Amino acid sequence of CEA was reported in 1987, by the success of cDNA clonig of CEA. The CEA molecule is composed of five major domains, called domain N, I, II, III, C from the -NH_2 terminal. But sugar chains of CEA are complicated and have much variety, so there are few informations about them. If CEA ...

  10. The possible role of tumor antigen CA 15-3, CEA and ferritin in malignant and benign disease

    Directory of Open Access Journals (Sweden)

    Nafija Serdarević

    2012-09-01

    Full Text Available Introduction: Serum CA15-3 has been one of the most reliable tumor markers used in monitoring of breast cancer patients. To increase its sensitivity, the combined measurement of other tumor markers (CEA and ferritin with CA15-3 was investigated. The aim of this study was determination of CA 15-3, CEA and ferritin in female patients with breast cancer, lung cancer and mastitisMethods: 300 patients with carcinoma, hospitalized at Department of Gynecologic Oncology and Department for Oncology at the University Clinics Center of Sarajevo and 200 healthy subjects were compared.Results: In patients with breast cancer the mean value of tumor markers were CEA 155.61 ng/mL, CA 15-3 106.38 U/mL and ferritin 197.03 ng/mL. In patients with lung cancer CEA was 58.97 ng/ml, CA 15-3 40.62 U/mL and ferritin 544.16 ng/mL. Patients with mastitis had CEA 5.17 ng/mL, CA 15-3 112.67 U/mL and ferritin 174.92 ng/mL. The control group had values of tumor markers CEA 1.62 ng/mL, CA 15-3 11.72 U/mL and ferritin 85.35 ng/mL. We found good correlation between CA 15-3 and CEA correlation coeffi cient was r = 0.750. There was a low correlation between CA 15-3 and ferritin with correlation coeffi cient r = 0.274.Conclusions: The CA 15-3 and CEA are useful markers in patients with confi rmed diagnosis of breast and lung cancers. The ferritin concentration has not increased in patients with breast cancer but it increased inlung patients. The future study has to make investigations of tumor markers and ferritin in different stage of breast cancer.

  11. Endolysosomal‐escape nanovaccines through adjuvant‐induced tumor antigen assembly for enhanced effector CD8+ T cell activation

    Czech Academy of Sciences Publication Activity Database

    Qiu, L.; Valente, M.; Dolen, Y.; Jäger, Eliezer; ter Beest, M.; Zheng, L.; Figdor, C. G.; Verdoes, M.

    2018-01-01

    Roč. 14, č. 15 (2018), s. 1-11, č. článku 1703539. ISSN 1613-6810 Grant - others:AV ČR(CZ) MSM200501602 Program:Program na podporu mezinárodní spolupráce začínajících výzkumných pracovníků Institutional support: RVO:61389013 Keywords : antigen/adjuvant codelivery * cancer nanovaccines * cross-presentation Subject RIV: CD - Macromolecular Chemistry OBOR OECD: Polymer science Impact factor: 8.643, year: 2016

  12. Ionizing radiation affects generation of MART-1-specific cytotoxic T cell responses by dendritic cells

    International Nuclear Information System (INIS)

    Liao, Y.P.; Wang, C.-C.; McBride, W.H.

    2003-01-01

    Full text: The human MART-1/Melan-A (MART-1) melanoma tumor antigen is known to be recognized by cytotoxic T lymphocytes (CTLs) and several groups are using this target for clinical immunotherapy. Most approaches use dendritic cells (DCs) that are potent antigen presentation cells for initiating CTL responses. In order for CTL recognition to occur, DCs must display 9-residue antigenic peptides on MHC class I molecules. These peptides are generated by proteasome degradation and then transported through the endoplasmic reticulum to the cell surface where they stabilize MHC class I expression. Our previous data showed that irradiation inhibits proteasome function and, therefore, we hypothesized that irradiation may inhibit antigen processing and CTL activation, as has been shown for proteasome inhibitors. To study the importance of irradiation effects on DCs, we studied the generation MART-1-specific CTL responses. Preliminary data showed that irradiation of murine bone marrow derived DCs did not affect expression of MHC class I, II, CD80, or CD86, as assessed by flow cytometric analyses 24-hour after irradiation. The effect of irradiation on MART-1 antigen processing by DCs was evaluated using DC transduced with adenovirus MART-1 (AdVMART1). C57BL/6 mice were immunized with AdVMART1 transduced DCs, with and without prior irradiation. IFN-γ production was measured by ELISPOT assays after 10-14 days of immunization. Prior radiation treatment resulted in a significant decrease in MART-1-specific T cell responses. The ability of irradiated and non-irradiated AdVMART1/DC vaccines to protect mice against growth of murine B16 tumors, which endogenously express murine MART-1, was also examined. AdVMART1/DC vaccination protected C57BL/6 mice against challenge with viable B16 melanoma cells while DCs irradiated (10 Gy) prior to AdVMART1 transduction abrogated protection. These results suggest that proteasome inhibition in DCs by irradiation may be a possible pathway in

  13. Myositis specific autoantibodies; specificity and clinical applications.

    NARCIS (Netherlands)

    Hengstman, G.J.D.

    2005-01-01

    The sera of about half of the patients with myositis contain autoantibodies that are specific for this group of diseases compared to other inflammatory connective tissue disorders. In a recent study we showed that these myositis specific autoantibodies (MSAs) are also specific for myositis as

  14. Detection of a novel specificity (CTLA-4) in ATG/TMG globulins and sera from ATG-treated leukemic patients.

    Science.gov (United States)

    Pistillo, Maria Pia; Tazzari, Pier Luigi; Bonifazi, Francesca; Bandini, Giuseppe; Kato, Tomohiro; Matsui, Toshihiro; Nishioka, Kusuki; Conte, Roberto; Ferrara, Giovanni Battista

    2002-04-27

    T-cell costimulation has been shown to provide positive signals for T-cell activation and generation of effector activity. In this study, we analyzed the presence of antibodies (Abs) against the T-lymphocyte costimulatory molecules CD28, CTLA-4, CD80, and CD86 in anti-T-lymphocyte (ATG) and antithymocyte (TMG) globulin preparations to address their mechanism of action. We focused our attention on the role of CTLA-4-specific Abs in the immunosuppressive effect of ATG/TMG, because anti-CTLA-4 agonistic Abs may suppress T-cell proliferation and nonagonistic Abs may lead to T-cell depletion through an Ab-dependent cell cytotoxicity mechanism. ATG/TMG and patients' sera were tested for binding to recombinant human costimulatory molecules by ELISA techniques. CTLA-4 specificity was also analyzed by cytoplasmic immunofluorescence staining of a CTLA-4 transfectant by competitive inhibition immunofluorescence and by cell proliferation assay in allogeneic mixed lymphocyte reaction (MLR). Either ATG or TMG predominantly contained anti-CTLA-4 Abs, with higher reactivity in ATG followed by anti-CD86 and -CD28 Abs, whereas anti-CD80 Abs were found only in ATG. Anti-CTLA-4 Abs present in ATG/TMG recognized the native form of CTLA-4 molecule, and their removal reduced the effect of ATG in an allogeneic MLR. Kinetic studies indicated that such Abs were present in the sera of 12 ATG-treated leukemic patients up to 21 days after ATG administration. These data suggest that the novel anti-CTLA-4 Abs found in ATG may greatly contribute to its immunosuppressive effect, thus accounting for the absence of rejection and exceptionally low incidence of graft-versus-host disease in the group of patients analyzed.

  15. Are BiTEs the "missing link" in cancer therapy?

    Science.gov (United States)

    Suryadevara, Carter M; Gedeon, Patrick C; Sanchez-Perez, Luis; Verla, Terence; Alvarez-Breckenridge, Christopher; Choi, Bryan D; Fecci, Peter E; Sampson, John H

    2015-06-01

    Conventional treatment for cancer routinely includes surgical resection and some combination of chemotherapy and radiation. These approaches are frequently accompanied by unintended and highly toxic collateral damage to healthy tissues, which are offset by only marginal prognostic improvements in patients with advanced cancers. This unfortunate balance has driven the development of novel therapies that aim to target tumors both safely and efficiently. Over the past decade, mounting evidence has supported the therapeutic utility of T-cell-centered cancer immunotherapy, which, in its various iterations, has been shown capable of eliciting highly precise and robust antitumor responses both in animal models and human trials. The identification of tumor-specific targets has further fueled a growing interest in T-cell therapies given their potential to circumvent the non-specific nature of traditional treatments. Of the several strategies geared toward achieving T-cell recognition of tumor, bispecific antibodies (bsAbs) represent a novel class of biologics that have garnered enthusiasm in recent years due to their versatility, specificity, safety, cost, and ease of production. Bispecific T-cell Engagers (BiTEs) are a subclass of bsAbs that are specific for CD3 on one arm and a tumor antigen on the second. As such, BiTEs function by recruiting and activating polyclonal populations of T-cells at tumor sites, and do so without the need for co-stimulation or conventional MHC recognition. Blinatumomab, a well-characterized BiTE, has emerged as a promising recombinant bscCD19×CD3 construct that has demonstrated remarkable antitumor activity in patients with B-cell malignancies. This clinical success has resulted in the rapid extension of BiTE technology against a greater repertoire of tumor antigens and the recent US Food and Drug Administration's (FDA) accelerated approval of blinatumomab for the treatment of a rare form of acute lymphoblastic leukemia (ALL). In this review

  16. Tumor markers in the diagnosis of primary bladder cancer. A systematic review

    NARCIS (Netherlands)

    Glas, Afina S.; Roos, Daphne; Deutekom, Marije; Zwinderman, Aeilko H.; Bossuyt, Patrick M.; Kurth, Karl H.

    2003-01-01

    Purpose: We systematically reviewed the available evidence, and obtained and compared summary estimates of the sensitivity and specificity of cytology and the urine based markers bladder tumor antigen, BTA stat (Polymedco, Redmond, Washington), BTA TRAK (Polymedco), NMP22 (Matritech, Cambridge,

  17. How specific is specific self-efficacy?

    DEFF Research Database (Denmark)

    Nielsen, Tine; Makransky, Guido; Vang, Maria Louison

    2017-01-01

    academic learning self-efficacy (SAL-SE) and specific academic exam self-efficacy (SAE-SE), each scale being measurement invariant relative to age, Gender, admission method and specific course targeted. Furthermore, significant and relevant differences between the SAL-SE and SAE-SE scores dependent......Self-efficacy is an important and much used construct in psychology and social science studies. The validity of the measurements used is not always sufficiently evaluated. The aim was to evaluate the psychometric properties of the Danish translation of the self-efficacy subscale of The Motivated...... Strategies for Learning Questionnaire (MSLQ-SE) within a higher education context. Rasch measurement models were employed focusing on measurement invariance and dimensionality. Results with one students sample showed the MSLQ-SE to be not one, but two separate unidimensional subscales, measuring specific...

  18. Urine specific gravity test

    Science.gov (United States)

    ... medlineplus.gov/ency/article/003587.htm Urine specific gravity test To use the sharing features on this page, please enable JavaScript. Urine specific gravity is a laboratory test that shows the concentration ...

  19. Effects of dendritic cell vaccine activated with protein components of toxoplasma gondii on tumor specific CD8+ T-cells

    Directory of Open Access Journals (Sweden)

    Amari A

    2009-12-01

    Full Text Available "n Normal 0 false false false EN-US X-NONE AR-SA MicrosoftInternetExplorer4 /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-qformat:yes; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"Times New Roman"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:Arial; mso-bidi-theme-font:minor-bidi;} Background: Dendritic Cell (DC is an important antigen-presenting cell that present tumor antigen to CD8+ and CD4+ T- Lymphocytes and induce specific anti-tumor immunity. In order to induce effective anti-tumor response, an option is increasing the efficiency of antigen presentation of dendritic cells and T cell activation capacity. The aim of the present study was to investigate the effect of dendritic cell maturation with protein components of toxoplasma gondii on cytotoxic T lymphocyte activity and their infiltration in to the tumor."n"nMethods: For DC generation, bone marrow cells were cultured in the presence of GM-CSF and IL-4 for five days. After that, LPS, protein components and whole extract of toxoplasma gondii were added to the culture media and incubated for another two days for DC maturation. To generate tumor, mices were injected subcutaneously with WEHI-164 cell line. For immunotherapy 106 DCs matured with different compounds were injected around the tumor site. Infiltration of CD8+ T cells were determined by flow cytometry and cytotoxic activity was measured by LDH detection kit."n"nResults: Immunotherapy with DCs treated with protein components of toxoplasma gondii led to a significant increase in the

  20. Real-time specifications

    DEFF Research Database (Denmark)

    David, A.; Larsen, K.G.; Legay, A.

    2015-01-01

    A specification theory combines notions of specifications and implementations with a satisfaction relation, a refinement relation, and a set of operators supporting stepwise design. We develop a specification framework for real-time systems using Timed I/O Automata as the specification formalism......, with the semantics expressed in terms of Timed I/O Transition Systems. We provide constructs for refinement, consistency checking, logical and structural composition, and quotient of specifications-all indispensable ingredients of a compositional design methodology. The theory is implemented in the new tool Ecdar...

  1. Experiences with effects specifications

    DEFF Research Database (Denmark)

    Simonsen, Jesper; Hertzum, Morten; Barlach, Anders

    2011-01-01

    We describe the effects-specification process from a project that was conducted during the fall 2010 and spring of 2011 in this chapter. The project configured and implemented an electronic patient record system at a maternity ward at a hospital located in a European region. The process comprised...... workshops with effects specification with management and end-users and an agile development process including prototypes configured from the effects specifications. We describe the project and the effects-specification process through which effects were related to the system design and instruments...... for measuring effects were designed. The project is analyzed and lessons learned are discussed....

  2. Review of technical specifications

    International Nuclear Information System (INIS)

    Bedrich, M.; Scholz, D.

    1980-01-01

    The present paper deals with position and function of technical specifications before and during the manufacturing of reactor components, their structure and reasons for specific regulations due to safety philosophy and explains the cooperation of supplier, manufacturer, utilities and supervisory organizations. (RW)

  3. Point specificity in acupuncture

    Directory of Open Access Journals (Sweden)

    Choi Emma M

    2012-02-01

    Full Text Available Abstract The existence of point specificity in acupuncture is controversial, because many acupuncture studies using this principle to select control points have found that sham acupoints have similar effects to those of verum acupoints. Furthermore, the results of pain-related studies based on visual analogue scales have not supported the concept of point specificity. In contrast, hemodynamic, functional magnetic resonance imaging and neurophysiological studies evaluating the responses to stimulation of multiple points on the body surface have shown that point-specific actions are present. This review article focuses on clinical and laboratory studies supporting the existence of point specificity in acupuncture and also addresses studies that do not support this concept. Further research is needed to elucidate the point-specific actions of acupuncture.

  4. Non-covalent association of protein and capsular polysaccharide on bacteria-sized latex beads as a model for polysaccharide-specific humoral immunity to intact Gram-positive extracellular bacteria1

    Science.gov (United States)

    Colino, Jesus; Duke, Leah; Snapper, Clifford M.

    2013-01-01

    Intact Streptococcus pneumoniae, expressing type 14 capsular polysaccharide (PPS14) and type III Streptococcus agalactiae containing a PPS14 core capsule identical to PPS14, exhibit non-covalent associations of PPS14 and bacterial protein, in contrast to soluble covalent conjugates of these respective antigens. Both bacteria and conjugates induce murine PPS14-specific IgG responses dependent on CD4+ T cells. Further, secondary immunization with conjugate and S. agalactiae, although not S. pneumoniae, results in a boosted response. However, in contrast to conjugate, PPS14-specific IgG responses to bacteria lack affinity maturation, utilize the 44.1-idiotype and are dependent on marginal zone B cells. To better understand the mechanism underlying this dichotomy we developed a minimal model of intact bacteria in which PPS14 and pneumococcal surface protein A (PspA) were stably attached to 1 μm (bacteria-sized) latex beads, but not directly linked to each other, in contrast to PPS14-PspA conjugate. PPS14+[PspA] beads, similar to conjugate, induced in mice boosted PPS14-specific IgG secondary responses, dependent on T cells and ICOS-dependent costimulation, and in which priming could be achieved with PspA alone. In contrast to conjugate, but similar to intact bacteria, the primary PPS14-specific IgG response to PPS14+[PspA] beads peaked rapidly, with the secondary response highly enriched for the 44.1-idiotype and lacking affinity maturation. These results demonstrate that non-covalent association in a particle, of polysaccharide and protein, recapitulates essential immunologic characteristics of intact bacteria that are distinct from soluble covalent conjugates of these respective antigens. PMID:23926322

  5. FOXP3-specific immunity

    DEFF Research Database (Denmark)

    Andersen, Mads Hald

    2013-01-01

    Forkhead box P3 (FOXP3)-specific cytotoxic CD8(+) T cells are present among human peripheral blood mononuclear cells (PBMCs), especially in cancer patients. Such T lymphocytes are able not only to specifically recognize dendritic cells (DCs) that have been exposed to recombinant FOXP3 and regulat...... and regulatory T cells, but also to kill FOXP3(+) malignant T cells. The natural occurrence of FOXP3-specific cytotoxic T lymphocytes among human PBMCs suggests a general role for these cells in the complex network of immune regulation....

  6. How Does Ionizing Irradiation Contribute to the Induction of Anti-Tumor Immunity?

    International Nuclear Information System (INIS)

    Rubner, Yvonne; Wunderlich, Roland; Rühle, Paul-Friedrich; Kulzer, Lorenz; Werthmöller, Nina; Frey, Benjamin; Weiss, Eva-Maria; Keilholz, Ludwig; Fietkau, Rainer; Gaipl, Udo S.

    2012-01-01

    Radiotherapy (RT) with ionizing irradiation is commonly used to locally attack tumors. It induces a stop of cancer cell proliferation and finally leads to tumor cell death. During the last years it has become more and more evident that besides a timely and locally restricted radiation-induced immune suppression, a specific immune activation against the tumor and its metastases is achievable by rendering the tumor cells visible for immune attack. The immune system is involved in tumor control and we here outline how RT induces anti-inflammation when applied in low doses and contributes in higher doses to the induction of anti-tumor immunity. We especially focus on how local irradiation induces abscopal effects. The latter are partly mediated by a systemic activation of the immune system against the individual tumor cells. Dendritic cells are the key players in the initiation and regulation of adaptive anti-tumor immune responses. They have to take up tumor antigens and consecutively present tumor peptides in the presence of appropriate co-stimulation. We review how combinations of RT with further immune stimulators such as AnnexinA5 and hyperthermia foster the dendritic cell-mediated induction of anti-tumor immune responses and present reasonable combination schemes of standard tumor therapies with immune therapies. It can be concluded that RT leads to targeted killing of the tumor cells and additionally induces non-targeted systemic immune effects. Multimodal tumor treatments should therefore tend to induce immunogenic tumor cell death forms within a tumor microenvironment that stimulates immune cells.

  7. How does ionizing irradiation contribute to the induction of anti-tumor immunity?

    Directory of Open Access Journals (Sweden)

    Yvonne eRubner

    2012-07-01

    Full Text Available Radiotherapy (RT with ionizing irradiation is commonly used to locally attack tumors. It induces a stop of cancer cell proliferation and finally leads to tumor cell death. During the last years it has become more and more evident that besides a timely and locally restricted radiation-induced immune suppression, a specific immune activation against the tumor and its metastases is achievable by rendering the tumor cells visible for immune attack. The immune system is involved in tumor control and we here outline how RT induces anti-inflammation when applied in low doses and contributes in higher doses to the induction of anti-tumor immunity. We especially focus on how local irradiation induces abscopal effects. The latter are partly mediated by a systemic activation of the immune system against the individual tumor cells. Dendritic cells are the key players in the initiation and regulation of adaptive anti-tumor immune responses. They have to take up tumor antigens and consecutively present tumor peptides in the presence of appropriate co-stimulation. We review how combinations of RT with further immune stimulators such as AnnexinA5 and hyperthermia foster the dendritic cell-mediated induction of anti-tumor immune responses and present reasonable combination schemes of standard tumor therapies with immune therapies. It can be concluded that RT leads to targeted killing of the tumor cells and additionally induces non-targeted systemic immune effects. Multimodal tumor treatments should therefore tend to induce immunogenic tumor cell death forms within a tumor microenvironment that stimulates immune cells.

  8. Place-Specific Computing

    DEFF Research Database (Denmark)

    Messeter, Jörn; Johansson, Michael

    project place- specific computing is explored through design oriented research. This article reports six pilot studies where design students have designed concepts for place-specific computing in Berlin (Germany), Cape Town (South Africa), Rome (Italy) and Malmö (Sweden). Background and arguments...... for place-specific computing as a genre of interaction design are described. A total number of 36 design concepts designed for 16 designated zones in the four cities are presented. An analysis of the design concepts is presented indicating potentials, possibilities and problems as directions for future......An increased interest in the notion of place has evolved in interaction design. Proliferation of wireless infrastructure, developments in digital media, and a ‘spatial turn’ in computing provides the base for place-specific computing as a suggested new genre of interaction design. In the REcult...

  9. TWRSview system requirements specification

    International Nuclear Information System (INIS)

    Caldwell, J.A.; Lee, A.K.

    1995-12-01

    This document provides the system requirements specification for the TWRSview software system. The TWRSview software system is being developed to integrate electronic data supporting the development of the TWRS technical baseline

  10. specific low back pain

    African Journals Online (AJOL)

    2015-09-01

    Sep 1, 2015 ... SPECIFIC LOW BACK PAIN: IMPLICATION FOR DIRECT HEALTH. CARE COST ... abundant evidence suggesting the benefits of therapeu- tic exercise on pain and ... Exercise and behavioural therapies in chronic pain. 174.

  11. Site Specific Vendor's License

    Data.gov (United States)

    Montgomery County of Maryland — This dataset contains information of a site-specific vendor's license which is required if an individual sells or offers to sell goods or services from a stationary...

  12. Construction and material specification

    Science.gov (United States)

    2002-01-01

    These Construction and Material Specifications are written to the Bidder before award of the : Contract and to the Contractor after award of the Contract. The sentences that direct the Contractor to perform Work are written as commands. For example, ...

  13. Specific radiography technique

    International Nuclear Information System (INIS)

    Abdul Nassir Ibrahim; Azali Muhammad; Ab. Razak Hamzah; Abd. Aziz Mohamed; Mohamad Pauzi Ismail

    2008-01-01

    Beside radiography testing using x-ray machine and gamma source, there are several technique that developed specifically to complete the testing that cannot be done with the two earlier. This technique was specific based on several factor, for the example, the advantages of neutron and electron using to show the image was unique compare to x-ray and gamma. Besides that, these special radiography techniques maybe differ in how to detect the radiation get through the object. These technique can used to inspect thin or specimen that contained radioactive material. There are several technique will discussed in this chapter such as neutron radiography, electron radiography, fluoroscopy and also autoradiography.

  14. Comparative Test Case Specification

    DEFF Research Database (Denmark)

    Kalyanova, Olena; Heiselberg, Per

     This document includes a definition of the comparative test cases DSF200_3 and DSF200_4, which previously described in the comparative test case specification for the test cases DSF100_3 and DSF200_3 [Ref.1]....... This document includes a definition of the comparative test cases DSF200_3 and DSF200_4, which previously described in the comparative test case specification for the test cases DSF100_3 and DSF200_3 [Ref.1]....

  15. IDC System Specification Document.

    Energy Technology Data Exchange (ETDEWEB)

    Clifford, David J.

    2014-12-01

    This document contains the system specifications derived to satisfy the system requirements found in the IDC System Requirements Document for the IDC Reengineering Phase 2 project. Revisions Version Date Author/Team Revision Description Authorized by V1.0 12/2014 IDC Reengineering Project Team Initial delivery M. Harris

  16. Specification of Concurrent Objects

    DEFF Research Database (Denmark)

    Sørensen, Morten U.

    relation over two objects and an event. In the model, objects can be composed by parallel composition, encapsulation, and hiding of operations. Refinement between objects is defined as fair trace inclusion.A specification language is presented where objects can be specified operationally by abstract...

  17. Place-Specific Computing

    DEFF Research Database (Denmark)

    Messeter, Jörn

    2009-01-01

    An increased interest in the notion of place has evolved in interaction design based on the proliferation of wireless infrastructures, developments in digital media, and a ‘spatial turn’ in computing. In this article, place-specific computing is suggested as a genre of interaction design that add......An increased interest in the notion of place has evolved in interaction design based on the proliferation of wireless infrastructures, developments in digital media, and a ‘spatial turn’ in computing. In this article, place-specific computing is suggested as a genre of interaction design...... that addresses the shaping of interactions among people, place-specific resources and global socio-technical networks, mediated by digital technology, and influenced by the structuring conditions of place. The theoretical grounding for place-specific computing is located in the meeting between conceptions...... of place in human geography and recent research in interaction design focusing on embodied interaction. Central themes in this grounding revolve around place and its relation to embodiment and practice, as well as the social, cultural and material aspects conditioning the enactment of place. Selected...

  18. Sports-specific injuries.

    Science.gov (United States)

    Plancher, K D; Minnich, J M

    1996-04-01

    Injuries to the upper extremities can happen in any sport. Injury patterns are common to specific sports. Understanding which injuries occur with these sports allows the examiner to diagnose and treat the athlete easily. This article reviews some of the injuries common in sports such as bicycling, golf, gymnastics, martial arts, racquet sports, and weightlifting.

  19. Site-Specific Innovation

    DEFF Research Database (Denmark)

    Reeh, Henrik; Hemmersam, Peter

    2015-01-01

    Currently, cities across the Northern European region are actively redeveloping their former industrial harbours. Indeed, harbours areas are essential in the long-term transition from industrial to information and experience societies; harbours are becoming sites for new businesses and residences...... question is how innovation may contribute to urban life and site-specific qualities....

  20. Specification of Nonmonotonic Reasoning.

    NARCIS (Netherlands)

    Engelfriet, J.; Treur, J.

    2000-01-01

    Two levels of description of nonmonotonic reasoning are distinguished. For these levels semantical formalizations are given. The first Level is defined semantically by the notion of belief state frame, the second Level by the notion of reasoning frame. We introduce two specification languages to

  1. Specification of Nonmonotonic Reasoning

    NARCIS (Netherlands)

    Engelfriet, J.; Treur, J.

    1996-01-01

    Two levels of description of nonmonotonic reasoning are distinguished. For these levels semantical formalizations are given. The first level is defined semantically by the notion of belief state frame, the second level by the notion of reasoning frame. We introduce two specification languages to

  2. Domain-Specific Multimodeling

    DEFF Research Database (Denmark)

    Hessellund, Anders

    the overall level of abstraction. It does, however, also introduce a new problem of coordinating multiple different languages in a single system. We call this problem the coordination problem. In this thesis, we present the coordination method for domain-specific multimodeling that explicitly targets...

  3. Specific Language Impairment

    Science.gov (United States)

    ... Some of the tests use interactions between the child and puppets and other toys to focus on specific rules of grammar, especially ... is not treated early, it can affect a child’s performance in school. ... language development. This kind of classroom program might enlist normally ...

  4. Specifications in software prototyping

    OpenAIRE

    Luqi; Chang, Carl K.; Zhu, Hong

    1998-01-01

    We explore the use of software speci®cations for software prototyping. This paper describes a process model for software prototyping, and shows how specifications can be used to support such a process via a cellular mobile phone switch example.

  5. New usable technical specifications

    International Nuclear Information System (INIS)

    Webster, S.A.; Tomasi, L.T.; Bernier, R.A.

    1989-01-01

    After 2 yr of preparation, 1988 finally saw the nuclear industry writing operator-oriented technical specifications. This effort is a continuation of previous efforts to develop improved and usable standard technical specifications (STSs), and is being conducted by the four nuclear steam supply system vendor owners' groups under the auspices of the Nuclear Management Resources Council. Each participant is currently preparing a set of improved STSs based on a writer's guide that was developed through a combined industry effort. In May of 1987, a Human Factors Improvements to Technical Specifications (HFITS) task group was formed to prepare a writer's guide for improved, industrywide STSs. This task group was composed of two representatives from each owners' group, one with a human factors background and one with some operations background. Two documents were prepared in 6 months, a human factors report laying the groundwork for the considerations to go into technical specifications and a writer's guide for their preparation. This paper reports on the application of this writer's guide to the writing of improved STS

  6. Sport-specific balance.

    Science.gov (United States)

    Zemková, Erika

    2014-05-01

    This review includes the latest findings based on experimental studies addressing sport-specific balance, an area of research that has grown dramatically in recent years. The main objectives of this work were to investigate the postural sway response to different forms of exercise under laboratory and sport-specific conditions, to examine how this effect can vary with expertise, and to provide examples of the association of impaired balance with sport performance and/or increasing risk of injury. In doing so, sports where body balance is one of the limiting factors of performance were analyzed. While there are no significant differences in postural stability between athletes of different specializations and physically active individuals during standing in a standard upright position (e.g., bipedal stance), they have a better ability to maintain balance in specific conditions (e.g., while standing on a narrow area of support). Differences in magnitude of balance impairment after specific exercises (rebound jumps, repeated rotations, etc.) and mainly in speed of its readjustment to baseline are also observed. Besides some evidence on an association of greater postural sway with the increasing risk of injuries, there are many myths related to the negative influence of impaired balance on sport performance. Though this may be true for shooting or archery, findings have shown that in many other sports, highly skilled athletes are able to perform successfully in spite of increased postural sway. These findings may contribute to better understanding of the postural control system under various performance requirements. It may provide useful knowledge for designing training programs for specific sports.

  7. ENVIRONMENTAL SPECIFICATION REQUIREMENTS

    International Nuclear Information System (INIS)

    TIFFT, S.R.

    2003-01-01

    Through regulations, permitting or binding negotiations, Regulators establish requirements, limits, permit conditions and Notice of Construction (NOC) conditions with which the Office of River Protection (ORP) and the Tank Farm Contractor (TFC) must comply. Operating Specifications are technical limits which are set on a process to prevent injury to personnel, or damage to the facility or environment. The main purpose of this document is to provide specification limits and recovery actions for the TFC Environmental Surveillance Program at the Hanford Site. Specification limits are given for monitoring frequencies and permissible variation of readings from an established baseline or previous reading. The requirements in this document are driven by environmental considerations and data analysis issues, rather than facility design or personnel safety issues. This document is applicable to all single-shell tank (SST) and double-shell tank (DST) waste tanks, and the associated catch tanks and receiver tanks, and transfer systems. This Tank Farm Environmental Specifications Document (ESD) implements environmental-regulatory limits on the configuration and operation of the Hanford Tank Farms facility that have been established by Regulators. This ESD contains specific field operational limits and recovery actions for compliance with airborne effluent regulations and agreements, liquid effluents regulations and agreements, and environmental tank system requirements. The scope of this ESD is limited to conditions that have direct impact on Operations Projects or that Operations/Projects have direct impact upon. This document does not supercede or replace any DOE Orders, regulatory permits, notices of construction, or Regulatory agency agreements binding on the ORP or the TFC. Refer to the appropriate regulation, permit, or NOC for an inclusive listing of requirements

  8. Comparative Test Case Specification

    DEFF Research Database (Denmark)

    Kalyanova, Olena; Heiselberg, Per

    This document includes the specification on the IEA task of evaluation building energy simulation computer programs for the Double Skin Facades (DSF) constructions. There are two approaches involved into this procedure, one is the comparative approach and another is the empirical one. In the comp....... In the comparative approach the outcomes of different software tools are compared, while in the empirical approach the modelling results are compared with the results of experimental test cases. The comparative test cases include: ventilation, shading and geometry....

  9. Empirical Test Case Specification

    DEFF Research Database (Denmark)

    Kalyanova, Olena; Heiselberg, Per

    This document includes the empirical specification on the IEA task of evaluation building energy simulation computer programs for the Double Skin Facades (DSF) constructions. There are two approaches involved into this procedure, one is the comparative approach and another is the empirical one. I....... In the comparative approach the outcomes of different software tools are compared, while in the empirical approach the modelling results are compared with the results of experimental test cases....

  10. ENVIRONMENTAL SPECIFICATION REQUIREMENTS

    International Nuclear Information System (INIS)

    TIFFT, S.R.

    2003-01-01

    Through regulations, permitting or binding negotiations, Regulators establish requirements, limits, permit conditions and Notice of Construction (NOC) conditions with which the Office of River Protection (ORP) and the Tank Farm Contractor (TFC) must comply. Operating Specifications are technical limits which are set on a process to prevent injury to personnel, or damage to the facility or environment. The main purpose of this document is to provide specification limits and recovery actions for the TFC Environmental Surveillance Program at the Hanford Site. Specification limits are given for monitoring frequencies and permissible variation of readings from an established baseline or previous reading. The requirements in this document are driven by environmental considerations and data analysis issues, rather than facility design or personnel safety issues. This document is applicable to all SST and DST waste tanks, and the associated catch tanks and receiver tanks, and transfer systems. This Tank Farm ESD implements environmental-regulatory limits on the configuration and operation of the Hanford Tank Farms facility that have been established by Regulators. This ESD contains specific field operational limits and recovery actions for compliance with airborne effluent regulations and agreements, liquid effluents regulations and agreements, and environmental tank system requirements. The scope of this ESD is limited to conditions that have direct impact on Operations/Projects or that Operations/Projects have direct impact upon. This document does not supercede or replace any DOE Orders, regulatory permits, notices of construction, or Regulatory agency agreements binding on the ORP or the TFC. Refer to the appropriate regulation, permit, or NOC for an inclusive listing of requirements

  11. Allergen-specific immunotherapy

    Directory of Open Access Journals (Sweden)

    Moote William

    2011-11-01

    Full Text Available Abstract Allergen-specific immunotherapy is a potentially disease-modifying therapy that is effective for the treatment of allergic rhinitis/conjunctivitis, allergic asthma and stinging insect hypersensitivity. However, despite its proven efficacy in these conditions, it is frequently underutilized in Canada. The decision to proceed with allergen-specific immunotherapy should be made on a case-by-case basis, taking into account individual patient factors such as the degree to which symptoms can be reduced by avoidance measures and pharmacological therapy, the amount and type of medication required to control symptoms, the adverse effects of pharmacological treatment, and patient preferences. Since this form of therapy carries the risk of anaphylactic reactions, it should only be prescribed by physicians who are adequately trained in the treatment of allergy. Furthermore, injections must be given under medical supervision in clinics that are equipped to manage anaphylaxis. In this article, the authors review the indications and contraindications, patient selection criteria, and the administration, safety and efficacy of allergen-specific immunotherapy.

  12. Co-introduced functional CCR2 potentiates in vivo anti-lung cancer functionality mediated by T cells double gene-modified to express WT1-specific T-cell receptor.

    Directory of Open Access Journals (Sweden)

    Hiroaki Asai

    Full Text Available BACKGROUND AND PURPOSE: Although gene-modification of T cells to express tumor-related antigen-specific T-cell receptor (TCR or chimeric antigen receptor (CAR has clinically proved promise, there still remains room to improve the clinical efficacy of re-directed T-cell based antitumor adoptive therapy. In order to achieve more objective clinical responses using ex vivo-expanded tumor-responsive T cells, the infused T cells need to show adequate localized infiltration into the tumor. METHODOLOGY/PRINCIPAL FINDINGS: Human lung cancer cells variously express a tumor antigen, Wilms' Tumor gene product 1 (WT1, and an inflammatory chemokine, CCL2. However, CCR2, the relevant receptor for CCL2, is rarely expressed on activated T-lymphocytes. A HLA-A2402(+ human lung cancer cell line, LK79, which expresses high amounts of both CCL2 and WT1 mRNA, was employed as a target. Normal CD8(+ T cells were retrovirally gene-modified to express both CCR2 and HLA-A*2402-restricted and WT1(235-243 nonapeptide-specific TCR as an effector. Anti-tumor functionality mediated by these effector cells against LK79 cells was assessed both in vitro and in vivo. Finally the impact of CCL2 on WT1 epitope-responsive TCR signaling mediated by the effector cells was studied. Introduced CCR2 was functionally validated using gene-modified Jurkat cells and human CD3(+ T cells both in vitro and in vivo. Double gene-modified CD3(+ T cells successfully demonstrated both CCL2-tropic tumor trafficking and cytocidal reactivity against LK79 cells in vitro and in vivo. CCL2 augmented the WT1 epitope-responsive TCR signaling shown by relevant luciferase production in double gene-modified Jurkat/MA cells to express luciferase and WT1-specific TCR, and CCL2 also dose-dependently augmented WT1 epitope-responsive IFN-γ production and CD107a expression mediated by these double gene-modified CD3(+ T cells. CONCLUSION/SIGNIFICANCE: Introduction of the CCL2/CCR2 axis successfully potentiated in

  13. Co-Introduced Functional CCR2 Potentiates In Vivo Anti-Lung Cancer Functionality Mediated by T Cells Double Gene-Modified to Express WT1-Specific T-Cell Receptor

    Science.gov (United States)

    Asai, Hiroaki; Fujiwara, Hiroshi; An, Jun; Ochi, Toshiki; Miyazaki, Yukihiro; Nagai, Kozo; Okamoto, Sachiko; Mineno, Junichi; Kuzushima, Kiyotaka; Shiku, Hiroshi; Inoue, Hirofumi; Yasukawa, Masaki

    2013-01-01

    Background and Purpose Although gene-modification of T cells to express tumor-related antigen-specific T-cell receptor (TCR) or chimeric antigen receptor (CAR) has clinically proved promise, there still remains room to improve the clinical efficacy of re-directed T-cell based antitumor adoptive therapy. In order to achieve more objective clinical responses using ex vivo-expanded tumor-responsive T cells, the infused T cells need to show adequate localized infiltration into the tumor. Methodology/Principal Findings Human lung cancer cells variously express a tumor antigen, Wilms' Tumor gene product 1 (WT1), and an inflammatory chemokine, CCL2. However, CCR2, the relevant receptor for CCL2, is rarely expressed on activated T-lymphocytes. A HLA-A2402+ human lung cancer cell line, LK79, which expresses high amounts of both CCL2 and WT1 mRNA, was employed as a target. Normal CD8+ T cells were retrovirally gene-modified to express both CCR2 and HLA-A*2402-restricted and WT1235–243 nonapeptide-specific TCR as an effector. Anti-tumor functionality mediated by these effector cells against LK79 cells was assessed both in vitro and in vivo. Finally the impact of CCL2 on WT1 epitope-responsive TCR signaling mediated by the effector cells was studied. Introduced CCR2 was functionally validated using gene-modified Jurkat cells and human CD3+ T cells both in vitro and in vivo. Double gene-modified CD3+ T cells successfully demonstrated both CCL2-tropic tumor trafficking and cytocidal reactivity against LK79 cells in vitro and in vivo. CCL2 augmented the WT1 epitope-responsive TCR signaling shown by relevant luciferase production in double gene-modified Jurkat/MA cells to express luciferase and WT1-specific TCR, and CCL2 also dose-dependently augmented WT1 epitope-responsive IFN-γ production and CD107a expression mediated by these double gene-modifiedCD3+ T cells. Conclusion/Significance Introduction of the CCL2/CCR2 axis successfully potentiated in vivo anti-lung cancer

  14. Potential contribution of a novel Tax epitope-specific CD4+ T cells to graft-versus-Tax effect in adult T cell leukemia patients after allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

    Tamai, Yotaro; Hasegawa, Atsuhiko; Takamori, Ayako; Sasada, Amane; Tanosaki, Ryuji; Choi, Ilseung; Utsunomiya, Atae; Maeda, Yasuhiro; Yamano, Yoshihisa; Eto, Tetsuya; Koh, Ki-Ryang; Nakamae, Hirohisa; Suehiro, Youko; Kato, Koji; Takemoto, Shigeki; Okamura, Jun; Uike, Naokuni; Kannagi, Mari

    2013-04-15

    Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment for adult T cell leukemia/lymphoma (ATL) caused by human T cell leukemia virus type 1 (HTLV-1). We previously reported that Tax-specific CD8(+) cytotoxic T lymphocyte (CTL) contributed to graft-versus-ATL effects in ATL patients after allo-HSCT. However, the role of HTLV-1-specific CD4(+) T cells in the effects remains unclear. In this study, we showed that Tax-specific CD4(+) as well as CD8(+) T cell responses were induced in some ATL patients following allo-HSCT. To further analyze HTLV-1-specific CD4(+) T cell responses, we identified a novel HLA-DRB1*0101-restricted epitope, Tax155-167, recognized by HTLV-1-specific CD4(+) Th1-like cells, a major population of HTLV-1-specific CD4(+) T cell line, which was established from an ATL patient at 180 d after allo-HSCT from an unrelated seronegative donor by in vitro stimulation with HTLV-1-infected cells from the same patient. Costimulation of PBMCs with both the identified epitope (Tax155-167) and known CTL epitope peptides markedly enhanced the expansion of Tax-specific CD8(+) T cells in PBMCs compared with stimulation with CTL epitope peptide alone in all three HLA-DRB1*0101(+) patients post-allo-HSCT tested. In addition, direct detection using newly generated HLA-DRB1*0101/Tax155-167 tetramers revealed that Tax155-167-specific CD4(+) T cells were present in all HTLV-1-infected individuals tested, regardless of HSCT. These results suggest that Tax155-167 may be the dominant epitope recognized by HTLV-1-specific CD4(+) T cells in HLA-DRB1*0101(+)-infected individuals and that Tax-specific CD4(+) T cells may augment the graft-versus-Tax effects via efficient induction of Tax-specific CD8(+) T cell responses.

  15. Data specifications for INSPIRE

    Science.gov (United States)

    Portele, Clemens; Woolf, Andrew; Cox, Simon

    2010-05-01

    In Europe a major recent development has been the entering in force of the INSPIRE Directive in May 2007, establishing an infrastructure for spatial information in Europe to support Community environmental policies, and policies or activities which may have an impact on the environment. INSPIRE is based on the infrastructures for spatial information established and operated by the 27 Member States of the European Union. The Directive addresses 34 spatial data themes needed for environmental applications, with key components specified through technical implementing rules. This makes INSPIRE a unique example of a legislative "regional" approach. One of the requirements of the INSPIRE Directive is to make existing spatial data sets with relevance for one of the spatial data themes available in an interoperable way, i.e. where the spatial data from different sources in Europe can be combined to a coherent result. Since INSPIRE covers a wide range of spatial data themes, the first step has been the development of a modelling framework that provides a common foundation for all themes. This framework is largely based on the ISO 19100 series of standards. The use of common generic spatial modelling concepts across all themes is an important enabler for interoperability. As a second step, data specifications for the first set of themes has been developed based on the modelling framework. The themes include addresses, transport networks, protected sites, hydrography, administrative areas and others. The data specifications were developed by selected experts nominated by stakeholders from all over Europe. For each theme a working group was established in early 2008 working on their specific theme and collaborating with the other working groups on cross-theme issues. After a public review of the draft specifications starting in December 2008, an open testing process and thorough comment resolution process, the draft technical implementing rules for these themes have been

  16. Substructural Logical Specifications

    Science.gov (United States)

    2012-11-14

    and independently in the context of CLF by Schack-Nielsen [SN07] and by Cruz and Hou [CH12]; Schack-Nielsen proves the equivalence of the two specifi...cations, whereas Cruz and Hou used the connection informally. The contribution of this section is to describe a general transformation (of which...Functional Programming (LFP’86), pages 13–27. ACM, 1986. 5.1 [CDE+11] Manuel Clavel, Francisco Durán, Steven Eker, Patrick Lincoln, Narciso Martı́- 290 Oliet

  17. Tendering specification and contracting

    International Nuclear Information System (INIS)

    Koch, E. von

    1975-01-01

    The lecture tendering, specification and contracting is prepared in two parts: This first part deals with technical aspects while part two features the commercial and legal situation in the partnership of two: the supplier of the fuel bundles and the utility. In this lecture a look is given on the way how a supplier can offer its fuel and some certain points are mentioned which are important to compare the bid of one competitor to the other. The major points are summarized which are or at least should be in an offer so as to find out which offer is the best. (orig./FW) [de

  18. Disease specific protein corona

    Science.gov (United States)

    Rahman, M.; Mahmoudi, M.

    2015-03-01

    It is now well accepted that upon their entrance into the biological environments, the surface of nanomaterials would be covered by various biomacromolecules (e.g., proteins and lipids). The absorption of these biomolecules, so called `protein corona', onto the surface of (nano)biomaterials confers them a new `biological identity'. Although the formation of protein coronas on the surface of nanoparticles has been widely investigated, there are few reports on the effect of various diseases on the biological identity of nanoparticles. As the type of diseases may tremendously changes the composition of the protein source (e.g., human plasma/serum), one can expect that amount and composition of associated proteins in the corona composition may be varied, in disease type manner. Here, we show that corona coated silica and polystyrene nanoparticles (after interaction with in the plasma of the healthy individuals) could induce unfolding of fibrinogen, which promotes release of the inflammatory cytokines. However, no considerable releases of inflammatory cytokines were observed for corona coated graphene sheets. In contrast, the obtained corona coated silica and polystyrene nanoparticles from the hypofibrinogenemia patients could not induce inflammatory cytokine release where graphene sheets do. Therefore, one can expect that disease-specific protein coronas can provide a novel approach for applying nanomedicine to personalized medicine, improving diagnosis and treatment of different diseases tailored to the specific conditions and circumstances.

  19. Code, standard and specifications

    International Nuclear Information System (INIS)

    Abdul Nassir Ibrahim; Azali Muhammad; Ab. Razak Hamzah; Abd. Aziz Mohamed; Mohamad Pauzi Ismail

    2008-01-01

    Radiography also same as the other technique, it need standard. This standard was used widely and method of used it also regular. With that, radiography testing only practical based on regulations as mentioned and documented. These regulation or guideline documented in code, standard and specifications. In Malaysia, level one and basic radiographer can do radiography work based on instruction give by level two or three radiographer. This instruction was produced based on guideline that mention in document. Level two must follow the specifications mentioned in standard when write the instruction. From this scenario, it makes clearly that this radiography work is a type of work that everything must follow the rule. For the code, the radiography follow the code of American Society for Mechanical Engineer (ASME) and the only code that have in Malaysia for this time is rule that published by Atomic Energy Licensing Board (AELB) known as Practical code for radiation Protection in Industrial radiography. With the existence of this code, all the radiography must follow the rule or standard regulated automatically.

  20. Specification of brachytherapy sources

    Energy Technology Data Exchange (ETDEWEB)

    1984-10-01

    BCRU recommends that the following specification of gamma-ray brachytherapy sources be adopted. Unless otherwise stated, the output of a cylindrical source should be specified in air kerma rate at a point in free space at a distance of 1 m from the source on the radial plane of symmetry, i.e. the plane bisecting the active length and perpendicular to the cylindrical axis of the source. For a wire source the output should be specified for a 1 cm length. For any other construction of source, the point at which the output is specified should be stated. It is also recommended that the units in which the air kerma rate is expressed should be micrograys per hour (..mu..Gy/h).

  1. A Novel Tumor Antigen and Foxp3 Dual Targeting Tumor Cell Vaccine Enhances the Immunotherapy in a Murine Model of Renal Cell Carcinoma

    Science.gov (United States)

    2015-12-01

    MDSCs facilitate tumor progression by impairing T-cell and natural killer (NK)–cell activation (9) and by modulating angiogenesis. Preclinical data...tasquinimod. Left, tumor growth curves by serial calipermeasurements. Right, tumor weights at the endpoint. B, mice were inoculated s.c. with B16...25 mg/kg) was given as daily i.v. injections on days 3 to 6. Left, tumor growth curves by serial caliper measurements. Right, end-of-treatment tumor

  2. Site specific plan

    International Nuclear Information System (INIS)

    Hutchison, J.; Jernigan, G.

    1989-12-01

    The Environmental Restoration and Waste Management Five-Year Plan (FYP) covers the period for FY 1989 through FY 1995. The plan establishes a Department of Energy -- Headquarters (DOE-HQ) agenda for cleanup and compliance against which overall progress can be measured. The FYP covers three areas: Corrective Activities, Environmental Restoration, and Waste Management Operations. Corrective Activities are those activities necessary to bring active or standby facilities into compliance with local, state, and federal environmental regulations. Environmental restoration activities include the assessment and cleanup of surplus facilities and inactive waste sites. Waste management operations includes the treatment, storage, and disposal of wastes which are generated as a result of ongoing operations. This Site Specific Plan (SSP) has been prepared by the Savannah River Site (SRS) in order to show how environmental restoration and waste management activities that were identified during the preparation of the FYP will be implemented, tracked, and reported. The SSP describes DOE Savannah River (DOE-SR) and operating contractor, Westinghouse Savannah River Company (WSRC), organizations that are responsible, for undertaking the activities identified in this plan. The SSP has been prepared in accordance with guidance received from DOE-HQ. DOE-SR is accountable to DOE-HQ for the implementation of this plan. 8 refs., 46 figs., 23 tabs

  3. ADANS database specification

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1997-01-16

    The purpose of the Air Mobility Command (AMC) Deployment Analysis System (ADANS) Database Specification (DS) is to describe the database organization and storage allocation and to provide the detailed data model of the physical design and information necessary for the construction of the parts of the database (e.g., tables, indexes, rules, defaults). The DS includes entity relationship diagrams, table and field definitions, reports on other database objects, and a description of the ADANS data dictionary. ADANS is the automated system used by Headquarters AMC and the Tanker Airlift Control Center (TACC) for airlift planning and scheduling of peacetime and contingency operations as well as for deliberate planning. ADANS also supports planning and scheduling of Air Refueling Events by the TACC and the unit-level tanker schedulers. ADANS receives input in the form of movement requirements and air refueling requests. It provides a suite of tools for planners to manipulate these requirements/requests against mobility assets and to develop, analyze, and distribute schedules. Analysis tools are provided for assessing the products of the scheduling subsystems, and editing capabilities support the refinement of schedules. A reporting capability provides formatted screen, print, and/or file outputs of various standard reports. An interface subsystem handles message traffic to and from external systems. The database is an integral part of the functionality summarized above.

  4. Immune response to a mammary adenocarcinoma. V. Sera from tumor-bearing rats contain multiple factors blocking cell-mediated cytotoxicity.

    Science.gov (United States)

    Huber, S A; Lucas, Z J

    1978-12-01

    Sera from Fischer rats 3 to 13 days after i.p. injection of syngeneic 13762A mammary adenocarcinoma contain three factors specifically blocking cell-mediated cytotoxicity (CMC). The major blocking factor is a 160,000-dalton IgG that combines specifically to cytolytic lymphocytes but not to tumor cells or tumor antigen, and that is not dissociated after treatment with 8 M urea. The other factors have been putatively identified as tumor antigen (less than 70,000 daltons) and as soluble antigen-antibody complexes (greater than 200,000 daltons). Injecting the tumor antigen into tumor-free rats induced spleen cells specifically cytotoxic to the 13762A tumor and provided partial protection to challenge with live tumor cells. Treating soluble antigen-antibody complexes with 8 M urea decreased the size of the blocking activity from greater than 200,000 to less than 70,000 daltons. Although the IgG fraction dissociated from the complex did not block CMC, it did recombine with the tumor antigen fraction to transfer activity to the greater than 200,000-dalton fraction. In contrast, mixing tumor antigen with the IgG fraction that did block CMC did not alter the size of the blocking activities.

  5. Imaging small human prostate cancer xenografts after pretargeting with bispecific bombesin-antibody complexes and targeting with high specific radioactivity labeled polymer-drug conjugates

    International Nuclear Information System (INIS)

    Patil, Vishwesh; Gada, Keyur; Panwar, Rajiv; Ferris, Craig; Khaw, Ban-An; Varvarigou, Alexandra; Majewski, Stan; Weisenberger, Andrew; Tekabe, Yared

    2012-01-01

    Pretargeting with bispecific monoclonal antibodies (bsMAb) for tumor imaging was developed to enhance target to background activity ratios. Visualization of tumors was achieved by the delivery of mono- and divalent radiolabeled haptens. To improve the ability to image tumors with bsMAb, we have combined the pretargeting approach with targeting of high specific activity radiotracer labeled negatively charged polymers. The tumor antigen-specific antibody was replaced with bombesin (Bom), a ligand that binds specifically to the growth receptors that are overexpressed by many tumors including prostate cancer. Bom-anti-diethylenetriaminepentaacetic acid (DTPA) bispecific antibody complexes were used to demonstrate pretargeting and imaging of very small human prostate cancer xenografts targeted with high specific activity 111 In- or 99m Tc-labeled negatively charged polymers. Bispecific antibody complexes consisting of intact anti-DTPA antibody or Fab' linked to Bom via thioether bonds (Bom-bsCx or Bom-bsFCx, respectively) were used to pretarget PC-3 human prostate cancer xenografts in SCID mice. Negative control mice were pretargeted with Bom or anti-DTPA Ab. 111 In-Labeled DTPA-succinyl polylysine (DSPL) was injected intravenously at 24 h (7.03 ± 1.74 or 6.88 ± 1.89 MBq 111 In-DSPL) after Bom-bsCx or 50 ± 5.34 MBq of 99m Tc-DSPL after Bom-bsFCx pretargeting, respectively. Planar or single photon emission computed tomography (SPECT)/CT gamma images were obtained for up to 3 h and only planar images at 24 h. After imaging, all mice were killed and biodistribution of 111 In or 99m Tc activities were determined by scintillation counting. Both planar and SPECT/CT imaging enabled detection of PC-3 prostate cancer lesions less than 1-2 mm in diameter in 1-3 h post 111 In-DSPL injection. No lesions were visualized in Bom or anti-DTPA Ab pretargeted controls. 111 In-DSPL activity in Bom-bsCx pretargeted tumors (1.21 ± 0.36%ID/g) was 5.4 times that in tumors pretargeted with

  6. Adequate procedures for specific exams

    International Nuclear Information System (INIS)

    Staevie, G.L.G.; Gattringer, D.K.; Dal Mas, C.R.; Tessman, M.

    1996-01-01

    Some ideal procedures for specific radiographic exams are briefly presented. The aim is to improve the quality standard, establishing a specific method for each exam in order to decrease films waste and reduce the patient dose exposure

  7. Teaching English for Specific Purposes

    Directory of Open Access Journals (Sweden)

    Nijolė Netikšienė

    2011-04-01

    Full Text Available Teaching English for Specific Purposes and General English is analysed in the article. The scientific approach of a scientist M. Rosenberg is presented. The experience of teaching English for Specific Purposesat VGTU is alsopresented. The ideas and teaching methods from the classes of general English can be transferred to the classes of English for Specific Purposes.

  8. Technical specification use and application

    International Nuclear Information System (INIS)

    Williamson, D.; Hoffman, D.R.

    1991-01-01

    Since early 1988 intensive efforts have been under way to produce a new and improved Standard Technical Specification. The program involves a coordinated effort between utility personnel representing each of the four nuclear steam supply system (NSSS) product lines, the NSSS vendors, and the US Nuclear Regulatory Commission (NRC). This intensive work period is actually the culmination of a decade of rhetoric about shortcomings of the existing technical specifications. Work on the improved technical specifications provided a unique forum for intense philosophical discussions between the users and enforcers of technical specifications, the outcome of which could have an impact on all licensees. Some of the more intriguing difficulties in the use and application of existing technical specifications, as well as discussions of the resolutions being applied in the improved technical specifications and the dilemmas remaining to be resolved are discussed in the paper

  9. [Multilingualism and specific language impairment].

    Science.gov (United States)

    Arkkila, Eva; Smolander, Sini; Laasonen, Marja

    2013-01-01

    Specific language impairment is one of the most common developmental disturbances in childhood. With the increase of the foreign language population group an increasing number of children assimilating several languages and causing concern in language development attend clinical examinations. Knowledge of factors underlying the specific language impairment and the specific impairment in general, special features of language development of those learning several languages, as well as the assessment and support of the linguistic skills of a multilingual child is essential. The risk of long-term problems and marginalization is high for children having specific language impairment.

  10. Trojan technical specification verification project

    International Nuclear Information System (INIS)

    Bates, L.; Rickenback, M.

    1991-01-01

    The Trojan Technical Specification Verification (TTSV) project at the Trojan plant of Portland General Electric Company was motivated by the recognition that many numbers in the Trojan technical specifications (TTS) potentially lacked the consideration of instrument- and/or process-related errors. The plant setpoints were known to consider such errors, but many of the values associated with the limiting conditions for operation (LCO) did not. In addition, the existing plant instrument error analyses were based on industry values that do not reflect the Trojan plant-specific experience. The purpose of this project is to ensure that the Trojan plant setpoint and LCO values include plant-specific instrument error

  11. Migration inhibition of immune mouse spleen cells by serum from x-irradiated tumor-bearing mice

    International Nuclear Information System (INIS)

    Moroson, H.

    1978-01-01

    Tumor-specific antigens of the chemically induced MC 429 mouse fibrosarcoma were detected in a 3 M KCl extract of tumor by the inhibition of migration of specifically immune spleen cells. Using this assay with serum from tumor-bearing mice no tumor antigen was detected in serum of mice bearing small tumors, unless the tumor was exposed to local x irradiation (3000 R) 1 day prior to collection of serum. It was concluded that local x irradiation of tumor caused increased concentration of tumor antigen in the serum. When the tumor was allowed to grow extremely large, with necrosis, then host serum did cause migration inhibition of both nonimmune and immune spleen cells. This migration-inhibition effect was not associated with tumor antigen, but with a nonspecific serum factor

  12. Hanford Site environmental management specification

    International Nuclear Information System (INIS)

    Grygiel, M.L.

    1998-01-01

    The US Department of Energy, Richland Operations Office (RL) uses this Hanford Site Environmental Management Specification (Specification) to document top-level mission requirements and planning assumptions for the prime contractors involved in Hanford Site cleanup and infrastructure activities under the responsibility of the US Department of Energy, Office of Environmental Management. This Specification describes at a top level the activities, facilities, and infrastructure necessary to accomplish the cleanup of the Hanford Site and assigns this scope to Site contractors and their respective projects. This Specification also references the key National Environmental Policy Act of 1969 (NEPA), Comprehensive Environmental Response, Compensation, and Liability Act of 1980 (CERCLA), and safety documentation necessary to accurately describe the cleanup at a summary level. The information contained in this document reflects RL's application of values, priorities, and critical success factors expressed by those involved with and affected by the Hanford Site project. The prime contractors and their projects develop complete baselines and work plans to implement this Specification. These lower-level documents and the data that support them, together with this Specification, represent the full set of requirements applicable to the contractors and their projects. Figure 1-1 shows the relationship of this Specification to the other basic Site documents. Similarly, the documents, orders, and laws referenced in this specification represent only the most salient sources of requirements. Current and contractual reference data contain a complete set of source documents

  13. Hanford Site environmental management specification

    Energy Technology Data Exchange (ETDEWEB)

    Grygiel, M.L.

    1998-06-10

    The US Department of Energy, Richland Operations Office (RL) uses this Hanford Site Environmental Management Specification (Specification) to document top-level mission requirements and planning assumptions for the prime contractors involved in Hanford Site cleanup and infrastructure activities under the responsibility of the US Department of Energy, Office of Environmental Management. This Specification describes at a top level the activities, facilities, and infrastructure necessary to accomplish the cleanup of the Hanford Site and assigns this scope to Site contractors and their respective projects. This Specification also references the key National Environmental Policy Act of 1969 (NEPA), Comprehensive Environmental Response, Compensation, and Liability Act of 1980 (CERCLA), and safety documentation necessary to accurately describe the cleanup at a summary level. The information contained in this document reflects RL`s application of values, priorities, and critical success factors expressed by those involved with and affected by the Hanford Site project. The prime contractors and their projects develop complete baselines and work plans to implement this Specification. These lower-level documents and the data that support them, together with this Specification, represent the full set of requirements applicable to the contractors and their projects. Figure 1-1 shows the relationship of this Specification to the other basic Site documents. Similarly, the documents, orders, and laws referenced in this specification represent only the most salient sources of requirements. Current and contractual reference data contain a complete set of source documents.

  14. Measuring wood specific gravity, correctly

    Science.gov (United States)

    G. Bruce Williamson; Michael C. Wiemann

    2010-01-01

    The specific gravity (SG) of wood is a measure of the amount of structural material a tree species allocates to support and strength. In recent years, wood specific gravity, traditionally a forester’s variable, has become the domain of ecologists exploring the universality of plant functional traits and conservationists estimating global carbon stocks. While these...

  15. SPECIFIC RESISTANCE AND SPECIFIC INTENSITY OF BELT SANDING OF WOOD

    Directory of Open Access Journals (Sweden)

    Boleslaw Porankiewicz

    2010-06-01

    Full Text Available This paper examines and discusses the specific belt sanding resistance K (N·cm-2 and specific belt sanding intensity SI (g·cm-2·min-1, for wood of Pinus sylvestris L., Picea abies L., Quercus robra L., Acer pseudoplatanus L., Alnus glutinosa Gaertn., and Populus Nigra L., by different sanding pressure pS, different sanding grit NG number, and different wood grain angles Phi(v.

  16. Specificity of immunoassays. Pt. 2

    International Nuclear Information System (INIS)

    Pratt, J.J.; Woldring, M.G.; Boonman, R.; Kittikool, J.

    1979-01-01

    Practical aspects of the measurement of the specificity of immunoassay are reviewed. Antibody heterogeneity in an antiserum makes a pragmatic rather than a theoretical approach necessary. A new method for the measurement of immunoassay specificity is described. This method is based on the errors caused by the cross-reacting antigens and is directly relevant to the validity of results obtained by immunoassay methods. The effect of selectively blocking the least specific antibodies in antisera raised against steroid haptens is tested. The practical consequences of these considerations are tested using steroid radioimmunoassay and enzyme-immunoassay. (orig.) [de

  17. Patient-Specific Computational Modeling

    CERN Document Server

    Peña, Estefanía

    2012-01-01

    This book addresses patient-specific modeling. It integrates computational modeling, experimental procedures, imagine clinical segmentation and mesh generation with the finite element method (FEM) to solve problems in computational biomedicine and bioengineering. Specific areas of interest include cardiovascular problems, ocular and muscular systems and soft tissue modeling. Patient-specific modeling has been the subject of serious research over the last seven years and interest in the area is continually growing and this area is expected to further develop in the near future.

  18. Bid specifications and bid evaluations

    International Nuclear Information System (INIS)

    Zijl, N.A. van

    1977-01-01

    Bid specifications are in view of the size of these projects important and comprehensive documents. The basic content and set up of the specifications are discussed such as: 1) Bid invitation letter, 2) instruction to bidders, 3) draft contract (terms and conditions), 4) technical specifications, 5) side data and information. - The evaluations of bids for nuclear power stations is due to the complexity of such bids a difficult undertaking. Evaluation methods and approaches which can be applied for such bid evaluations are discussed as well as the preparations which are required for carrying out such evaluations. (orig.) [de

  19. Synergy of Technical Specification, functional specifications and scenarios in requirements specifications

    NARCIS (Netherlands)

    Miedema, J.; van der Voort, Mascha C.; Lutters, Diederick; van Houten, Frederikus J.A.M.; Krause, Frank-Lothar

    2007-01-01

    In the (mechanical) design process, the requirements specification is a formal registration of the conditions that are imposed on a new or altered product design, both preceding as well as during the corresponding product development cycle. For a long time, the use of technical specifications has

  20. Youth job market specific features

    Directory of Open Access Journals (Sweden)

    Evgeniya Yu. Zhuravleva

    2011-05-01

    Full Text Available The article considers youth job market peculiarities, its specific features and regulation means, determines theoretical and application tasks of qualitative and quantitative comparison of vocations, which are highly in demand at the job market.

  1. GPS Civil Monitoring Performance Specification

    Science.gov (United States)

    2009-02-10

    This Civil Monitoring Performance Specification (CMPS) is published and maintained at : the direction of the Program Manager for Civil Applications, Global Positioning Systems : Wing (GPSW). The purpose of this document is to provide a comprehensive ...

  2. The role of formal specifications

    International Nuclear Information System (INIS)

    McHugh, J.

    1994-01-01

    The role of formal requirements specification is discussed under the premise that the primary purpose of such specifications is to facilitate clear and unambiguous communications among the communities of interest for a given project. An example is presented in which the failure to reach such an understanding resulted in an accident at a chemical plant. Following the example, specification languages based on logical formalisms and notations are considered. These are rejected as failing to serve the communications needs of diverse communities. The notion of a specification as a surrogate for a program is also considered and rejected. The paper ends with a discussion of the type of formal notation that will serve the communications role and several encouraging developments are noted

  3. CCL22-specific T Cells

    DEFF Research Database (Denmark)

    Martinenaite, Evelina; Munir Ahmad, Shamaila; Hansen, Morten

    2016-01-01

    Tumor cells and tumor-infiltrating macrophages produce the chemokine CCL22, which attracts regulatory T cells (Tregs) into the tumor microenvironment, decreasing anticancer immunity. Here, we investigated the possibility of targeting CCL22-expressing cells by activating specific T cells. We...... analyzed the CCL22 protein signal sequence, identifying a human leukocyte antigen A2- (HLA-A2-) restricted peptide epitope, which we then used to stimulate peripheral blood mononuclear cells (PMBCs) to expand populations of CCL22-specific T cells in vitro. T cells recognizing an epitope derived from...... the signal-peptide of CCL22 will recognize CCL22-expressing cells even though CCL22 is secreted out of the cell. CCL22-specific T cells recognized and killed CCL22-expressing cancer cells. Furthermore, CCL22-specific T cells lysed acute monocytic leukemia cells in a CCL22 expression-dependent manner. Using...

  4. Eternity Variables to Simulate Specifications

    NARCIS (Netherlands)

    Hesselink, WH; Boiten, EA; Moller, B

    2002-01-01

    Simulation of specifications is introduced as a unification and generalization of refinement mappings, history variables, forward simulations, prophecy variables, and backward simulations. Eternity variables are introduced as a more powerful alternative for prophecy variables and backward

  5. Autonomic Fuselet Specification and Composition

    National Research Council Canada - National Science Library

    Mills, Peter H

    2006-01-01

    ... model for its business logic, and to perform workflow composition from a goal and specifications to executable model in a manner that enables feedback mechanisms that can assess and adapt the process...

  6. ATR Technical Specification Upgrade Program

    International Nuclear Information System (INIS)

    McCracken, R.T.; Durney, J.L.; Freund, G.A.

    1990-01-01

    The Advanced Test Reactor (ATR) is a 250 MW, uranium-aluminum fueled test reactor which began full power operation in 1969. The initial operation was controlled by an Operating Limits document based on the original Safety Analysis Report. Additional safety bases were later developed to support Technical Specifications which were approved and implemented in 1977. The Technical Specifications which were initially developed with content and format specified in ANSI/ANS--15.1, ''The Development of Technical Specifications for Research Reactors.'' The safety basis documentation and the Technical Specifications have been updated as required to maintain them current with the ATR facility configuration. All revisions have been made with a content, format and style consistent with the original. A major, two-phase program to upgrade the content, format and style is in progress. This paper describes the first phase of this program

  7. Specific immunotherapy ameliorates ulcerative colitis.

    Science.gov (United States)

    Cai, Min; Zeng, Lu; Li, Lin-Jing; Mo, Li-Hua; Xie, Rui-Di; Feng, Bai-Sui; Zheng, Peng-Yuan; Liu, Zhi-Gang; Liu, Zhan-Ju; Yang, Ping-Chang

    2016-01-01

    Hypersensitivity reaction to certain allergens plays a role in the pathogenesis of inflammatory bowel disease (IBD). This study aims to observe the effect of specific immunotherapy in a group of IBD patients. Patients with both ulcerative colitis (UC) and food allergy were recruited into this study. Food allergy was diagnosed by skin prick test and serum specific IgE. The patients were treated with specific immunotherapy (SIT) and Clostridium butyricum (CB) capsules. After treating with SIT and CB, the clinical symptoms of UC were markedly suppressed as shown by reduced truncated Mayo scores and medication scores. The serum levels of specific IgE, interleukin (IL)-4 and tumor necrosis factor (TNF)-α were also suppressed. Treating with SIT alone or CB alone did not show appreciable improvement of the clinical symptoms of UC. UC with food allergy can be ameliorated by administration with SIT and butyrate-production probiotics.

  8. SPECIFIC EMISSIONS FROM BIOMASS COMBUSTION

    Directory of Open Access Journals (Sweden)

    Pavel Skopec

    2014-02-01

    Full Text Available This paper deals with determining the specific emissions from the combustion of two kinds of biomass fuels in a small-scale boiler. The tested fuels were pellets made of wood and pellets made of rape plant straw. In order to evaluate the specific emissions, several combustion experiments were carried out using a commercial 25 kW pellet-fired boiler. The specific emissions of CO, SO2 and NOx were evaluated in relation to a unit of burned fuel, a unit of calorific value and a unit of produced heat. The specific emissions were compared with some data acquired from the reference literature, with relatively different results. The differences depend mainly on the procedure used for determining the values, and references provide no information about this. Although some of our experimental results may fit with one of the reference sources, they do not fit with the other. The reliability of the references is therefore disputable.

  9. Grade 6 Science Curriculum Specifications.

    Science.gov (United States)

    Alberta Dept. of Education, Edmonton. Curriculum Branch.

    This material describes curriculum specifications for grade 6 science in Alberta. Emphases recommended are: (1) process skills (50%); (2) psychomotor skills (10%); (3) attitudes (10%); and (4) subject matter (30%). Priorities within each category are identified. (YP)

  10. Patient-specific surgical simulation.

    Science.gov (United States)

    Soler, Luc; Marescaux, Jacques

    2008-02-01

    Technological innovations of the twentieth century have provided medicine and surgery with new tools for education and therapy definition. Thus, by combining Medical Imaging and Virtual Reality, patient-specific applications providing preoperative surgical simulation have become possible.

  11. Base compaction specification feasibility analysis.

    Science.gov (United States)

    2012-12-01

    The objective of this research is to establish the technical engineering and cost : analysis concepts that will enable WisDOT management to objectively evaluate the : feasibility of switching construction specification philosophies for aggregate base...

  12. [Tissue-specific nucleoprotein complexes].

    Science.gov (United States)

    Riadnova, I Iu; Shataeva, L K; Khavinson, V Kh

    2000-01-01

    A method of isolation of native nucleorprotein complexes from cattle cerebral cortex, thymus, and liver was developed. Compositions of these complexes were studied by means of gel-chromatography and ion-exchange chromatography. These preparations were shown to consist of several fractions of proteins and their complexes differ by molecular mass and electro-chemical properties. Native nucleoprotein complexes revealed high tissue specific activity, which was not species-specific.

  13. XML specifications DanRIS

    DEFF Research Database (Denmark)

    2009-01-01

    XML specifications for DanRIS (Danish Registration- og InformationsSystem), where the the aim is: Improved exchange of data Improved data processing Ensuring future access to all gathered data from the year 1999 until now......XML specifications for DanRIS (Danish Registration- og InformationsSystem), where the the aim is: Improved exchange of data Improved data processing Ensuring future access to all gathered data from the year 1999 until now...

  14. Niche-specific cognitive strategies

    DEFF Research Database (Denmark)

    Hulgard, K.; Ratcliffe, J. M.

    2014-01-01

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

  15. MUC1-specific immune therapy generates a strong anti-tumor response in a MUC1-tolerant colon cancer model.

    Science.gov (United States)

    Mukherjee, P; Pathangey, L B; Bradley, J B; Tinder, T L; Basu, G D; Akporiaye, E T; Gendler, S J

    2007-02-19

    A MUC1-based vaccine was used in a preclinical model of colon cancer. The trial was conducted in a MUC1-tolerant immune competent host injected with MC38 colon cancer cells expressing MUC1. The vaccine included: MHC class I-restricted MUC1 peptides, MHC class II-restricted pan-helper-peptide, unmethylated CpG oligodeoxynucleotide, and granulocyte macrophage-colony stimulating factor. Immunization was successful in breaking MUC1 self-tolerance, and in eliciting a robust anti-tumor response. The vaccine stimulated IFN-gamma-producing CD4(+) helper and CD8(+) cytotoxic T cells against MUC1 and other undefined MC38 tumor antigens. In the prophylactic setting, immunization caused complete rejection of tumor cells, while in the therapeutic regimen, tumor burden was significantly reduced.

  16. NIF optical specifications - the importance of the RMS gradient specification

    International Nuclear Information System (INIS)

    Auerbach, J. M.; Cotton, C. T.; English, R. E.; Henesian, M. A.; Hunt, J. T.; Kelly, J. H.; Lawson, J. K.; Sacks, J. B.; Shoup, M. J.; Trenholme, W. H.

    1998-01-01

    The performance of the National Ignition Facility (NIF), especially in terms of laser focusability, will be determined by several key factors. One of these key factors is the optical specification for the thousands of large aperture optics that will comprise the 192 beamlines. We have previously reported on the importance of the specification of the power spectral density (PSD) on NIF performance. Recently, we have been studying the importance of long spatial wavelength (>33 mm) phase errors on focusability. We have concluded that the preferred metric for determining the impact of these long spatial wavelength phase errors is the rms phase gradient. In this paper, we outline the overall approach to NIF optical specifications, detail the impact of the rms phase gradient on NIF focusability, discuss its trade-off with the PSD in determining the spot size and review measurements of optics similar to those to be manufactured for NIF

  17. CASL, the Common Algebraic Specification Language

    DEFF Research Database (Denmark)

    Mossakowski, Till; Haxthausen, Anne Elisabeth; Sannella, Donald

    2008-01-01

    CASL is an expressive specification language that has been designed to supersede many existing algebraic specification languages and provide a standard. CASL consists of several layers, including basic (unstructured) specifications, structured specifications and architectural specifications...

  18. Standard Technical Specifications, Westinghouse plants

    International Nuclear Information System (INIS)

    1992-09-01

    This NUREG contains improved Standard Technical Specifications (STS) for Westinghouse Plants and documents the positions of the Nuclear Regulatory Commission based on the Westinghouse Owners Group's proposed STS. This document is the result of extensive technical meetings and discussions among the NRC staff, the Nuclear Steam Supply System (NSSS) Owners Groups, the NSSS vendors, and the Nuclear Management and Resources Council (NUMARC). The improved STS were developed based on the criteria in the interim Commission Policy Statement on Technical Specification Improvements for Nuclear Power Reactors, dated February 6, 1987. The improved STS will be used as the basis for individual nuclear power plant licensees to develop improved plant-specific technical specifications. This report contains three volumes. Volume 1 contains the Specifications for all chapters and sections of the improved STS. Volume 2 contains the Bases for Chapters 2.0 and 3.0, and Sections 3.1--3.3 of the improved STS. This document, Volume 3, contains the Bases for Sections 3.4--3.9 of the improved STS

  19. Standard Technical Specifications, Westinghouse Plants

    International Nuclear Information System (INIS)

    1992-09-01

    This NUREG contains improved Standard Technical Specifications (STS) for Westinghouse Plants and documents the positions of the Nuclear Regulatory Commission based on the Westinghouse Owners Group's proposed STS. This document is the result of extensive technical meetings and discussions among the NRC staff, the Nuclear Steam Supply System (NSSS) Owners Groups, the NSSS vendors, and the Nuclear Management and Resources Council (NUMARC). The improved STS were developed based on the criteria in the interim Commission Policy Statement on Technical Specification Improvements for Nuclear Power Reactors, dated February 6, 1987. The improved STS will be used as the basis for individual nuclear power plant licensees to develop improved plant-specific technical specifications. This report contains three volumes. Volume 1 contains the Specifications for all chapters and sections of the improved STS. Volume 2 contains the Bases for Chapters 2.0 and 3.0, and Sections 3.1--3.3 of the unproved STS. Volume 3 contains the Bases for Sections 3.4--3.9 of the improved STS which contain information on safety limits, reactivity control systems, power distribution limits, and instrumentation

  20. Industry specific financial distress modeling

    Directory of Open Access Journals (Sweden)

    Naz Sayari

    2017-01-01

    Full Text Available This study investigates uncertainty levels of various industries and tries to determine financial ratios having the greatest information content in determining the set of industry characteristics. It then uses these ratios to develop industry specific financial distress models. First, we employ factor analysis to determine the set of ratios that are most informative in specified industries. Second, we use a method based on the concept of entropy to measure the level of uncertainty in industries and also to single out the ratios that best reflect the uncertainty levels in specific industries. Finally, we conduct a logistic regression analysis and derive industry specific financial distress models which can be used to judge the predictive ability of selected financial ratios for each industry. The results show that financial ratios do indeed echo industry characteristics and that information content of specific ratios varies among different industries. Our findings show diverging impact of industry characteristics on companies; and thus the necessity of constructing industry specific financial distress models.

  1. Technical specification for vacuum systems

    International Nuclear Information System (INIS)

    Khaw, J.

    1987-01-01

    The vacuum systems at the Stanford Linear Accelerator Center (SLAC) are primarily of all-metal construction and operate at pressures from 10 -5 to 10 -11 Torr. The primary gas loads during operation result from thermal desorption and beam-induced desorption from the vacuum chamber walls. These desorption rates can be extremely high in the case of hydrocarbons and other contaminants. These specifications place a major emphasis on eliminating contamination sources. The specifications and procedures have been written to insure the cleanliness and vacuum integrity of all SLAC vacuum systems, and to assist personnel involved with SLAC vacuum systems in choosing and designing components that are compatible with existing systems and meet the quality and reliability of SLAC vacuum standards. The specification includes requirements on design, procurement, fabrication, chemical cleaning, clean room practices, welding and brazing, helium leak testing, residual gas analyzer testing, bakeout, venting, and pumpdown. Also appended are specifications regarding acceptable vendors, isopropyl alcohol, bakeable valve cleaning procedure, mechanical engineering safety inspection, notes on synchrotron radiation, and specifications of numerous individual components

  2. Standard Technical Specifications, Westinghouse plants

    International Nuclear Information System (INIS)

    1992-09-01

    This NUREG contains improved Standard Technical Specifications (STS) for Westinghouse Plants and documents the positions of the Nuclear Regulatory Commission based on the Westinghouse Owners Group's proposed STS. This document is the result of extensive technical meetings and discussions among the NRC staff, the Nuclear Steam Supply System (NSSS) Owners Groups, the NSSS vendors, and the Nuclear Management and Resources Council (NUMARC). The improved STS were developed based on the criteria in the interim Commission Policy Statement on Technical Specification Improvements for Nuclear Power Reactors, dated February 6, 1987. The improved STS will be used as the basis for individual nuclear power plant licensees to develop improved plant-specific technical specifications. This report contains three volumes. This document, Volume 1, contains the Specifications for all chapters and sections of the improved STS. Volume 2 contains the Bases for Chapters 2.0 and 3.0, and Sections 3.1--3.3 of the improved STS. Volume 3 contains the Bases for Sections 3.4--3.9 of the improved STS

  3. Age‑specific Serum Prostate Specific Antigen Ranges Among ...

    African Journals Online (AJOL)

    ethnic differences.[16] Although similar studies have been presented for a number of different groups of men and few studies have looked at the pattern of serum PSA among Nigerians[17‑20] but no such studies on normal serum PSA ranges and the age‑specific pattern have been carried out among healthy Nigerian men.

  4. ROS signalling - specificity is required

    DEFF Research Database (Denmark)

    Møller, Ian M; Sweetlove, Lee J

    2010-01-01

    Reactive oxygen species (ROS) production increases in plants under stress. ROS can damage cellular components, but they can also act in signal transduction to help the cell counteract the oxidative damage in the stressed compartment. H2O2 might induce a general stress response, but it does not have...... the required specificity to selectively regulate nuclear genes required for dealing with localized stress, e.g. in chloroplasts or mitochondria. Here we argue that peptides deriving from proteolytic breakdown of oxidatively damaged proteins have the requisite specificity to act as secondary ROS messengers...... and regulate source-specific genes and in this way contribute to retrograde ROS signalling during oxidative stress. Likewise, unmodified peptides deriving from the breakdown of redundant proteins could help coordinate organellar and nuclear gene expression...

  5. Methylation-Specific PCR Unraveled

    Directory of Open Access Journals (Sweden)

    Sarah Derks

    2004-01-01

    Full Text Available Methylation‐specific PCR (MSP is a simple, quick and cost‐effective method to analyze the DNA methylation status of virtually any group of CpG sites within a CpG island. The technique comprises two parts: (1 sodium bisulfite conversion of unmethylated cytosine's to uracil under conditions whereby methylated cytosines remains unchanged and (2 detection of the bisulfite induced sequence differences by PCR using specific primer sets for both unmethylated and methylated DNA. This review discusses the critical parameters of MSP and presents an overview of the available MSP variants and the (clinical applications.

  6. Portable File Format (PFF) specifications

    Energy Technology Data Exchange (ETDEWEB)

    Dolan, Daniel H. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)

    2015-02-01

    Created at Sandia National Laboratories, the Portable File Format (PFF) allows binary data transfer across computer platforms. Although this capability is supported by many other formats, PFF files are still in use at Sandia, particularly in pulsed power research. This report provides detailed PFF specifications for accessing data without relying on legacy code.

  7. Human-Specific Endogenous Retroviruses

    Directory of Open Access Journals (Sweden)

    Anton Buzdin

    2007-01-01

    Full Text Available This review focuses on a small family of human-specific genomic repetitive elements, presented by 134 members that shaped ~330 kb of the human DNA. Although modest in terms of its copy number, this group appeared to modify the human genome activity by endogenizing ~50 functional copies of viral genes that may have important implications in the immune response, cancer progression, and antiretroviral host defense. A total of 134 potential promoters and enhancers have been added to the human DNA, about 50% of them in the close gene vicinity and 22% in gene introns. For 60 such human-specific promoters, their activity was confirmed by in vivo assays, with the transcriptional level varying ~1000-fold from hardly detectable to as high as ~3% of β-actin transcript level. New polyadenylation signals have been provided to four human RNAs, and a number of potential antisense regulators of known human genes appeared due to human-specific retroviral insertional activity. This information is given here in the context of other major genomic changes underlining differences between human and chimpanzee DNAs. Finally, a comprehensive database, is available for download, of human-specific and polymorphic endogenous retroviruses is presented, which encompasses the data on their genomic localization, primary structure, encoded viral genes, human gene neighborhood, transcriptional activity, and methylation status.

  8. Manufacturer Usage Description Specification Implementation

    OpenAIRE

    Srinivasan, Kaushik

    2017-01-01

    Manufacturer Usage Description Specification (MUDS) is aframework under RFC development that aims to automate Internet access control rules for IoT devices . These access controls prevent malicious IoT devices from attacking other devices and also protect the IoT devices from being attacked by other devices.We are implementing this framework and trying to improve its security.

  9. Competitive Procurement and Asset Specificity

    NARCIS (Netherlands)

    Sorana, V.

    2003-01-01

    This paper studies the effects of asset specificity on the performance of procurement auctions with subcontracting and asset sales.The analysis highlights the role of several asset features like transfer costs, type of alternative uses and maintenance requirements.It is argued that, if bargaining

  10. Final Empirical Test Case Specification

    DEFF Research Database (Denmark)

    Kalyanova, Olena; Heiselberg, Per

    This document includes the empirical specification on the IEA task of evaluation building energy simulation computer programs for the Double Skin Facades (DSF) constructions. There are two approaches involved into this procedure, one is the comparative approach and another is the empirical one....

  11. LOTOS specification style for OSI

    NARCIS (Netherlands)

    Turner, K.J.; van Sinderen, Marten J.; Bolognesi, T.; van de Lagemaat, J.; Vissers, C.A.

    1995-01-01

    The architecture of OSI is used to derive guidelines for writing LOTOS specifications of distributed systems. In particular, the architectural concepts that underlie service and protocol designs are examined in detail. For each of these concepts a representation in LOTOS is given. Examples are

  12. LOTOS specification style for OSI

    NARCIS (Netherlands)

    Brinksma, Hendrik; Turner, K.J.; Bolognesi, T.; van Sinderen, Marten J.; Vissers, C.A.

    1992-01-01

    The architecture of OSI is used to derive guidelines for writing LOTOS specifications of distributed systems. In particular, the architectural concepts that underlie service and protocol designs are examined in detail. For each of these concepts a representation in LOTOS is given. Examples are

  13. THE SPECIFICITY OF INTRACOMMUNITY TRANSACTIONS

    Directory of Open Access Journals (Sweden)

    PALIU-POPA LUCIA

    2011-09-01

    Full Text Available Considered from the perspective of Romania's accession to the European Union, we can say that starting with 1 January 2007, foreign trade transactions were delimited in relation to the customs borders in intra-Community transactions and international transactions. In this context, the way of conducting these operations is influenced by both the economic and financial features specific to both categories of transactions, that relate to the economic character of the activity, the diversity and specificity of the foreign trade activity, transport of goods, the complexity and regulation of intra-Community and international commercial transactions, and by the specific features of each category of transaction. Starting from the consideration that the economic and financial characteristics of foreign trade activity, specific to intra-Community commercial transactions, have a significant influence in the organization and management of accounting of the entities involved in such transactions, determining in a greater or lesser extent, the way of capitalization of the financial and accounting information in the processes of analysis, decision and control, in this paper we proposed to address the features of intra-Community trade.

  14. Microbeams, microdosimetry and specific dose

    International Nuclear Information System (INIS)

    Randers-Pehrson, H.

    2002-01-01

    Dose and its usefulness as a single parameter to describe the amount of radiation absorbed are well established for most situations. The conditions where the concept of dose starts to break down are well known, mostly from the study of microdosimetry. For low doses of high LET radiation it is noted that the process of taking the limiting value of the energy absorbed within a test volume divided by the mass within that volume yields either zero or a relatively large value. The problem is further exacerbated with microbeam irradiations where the uniformity of the energy deposition is experimentally manipulated on the spatial scale of cells being irradiated. Booz introduced a quantity to deal with these problems: the unfortunately named 'mean specific energy in affected volumes'. This quantity multiplied by the probability that a test volume has received an energy deposit is equal to dose (in situations where dose can be defined). I propose that Booz's quantity be renamed 'specific dose', that is the mean energy deposited divided by the mass within a specified volume. If we believe for instance that the nucleus of a cell is the critical volume for biological effects, we can refer to the nuclear specific dose. A microbeam experiment wherein 10 per cent of the cell nuclei were targeted with 10 alpha particles would be described as delivering a nuclear specific dose of 1.6 Gy to 10 per cent of the population. (author)

  15. [Specificities in children wound healing].

    Science.gov (United States)

    Sanchez, J; Antonicelli, F; Tuton, D; Mazouz Dorval, S; François, C

    2016-10-01

    Children have specific characteristics of wound healing. The aim of this study was to describe the specific clinical characteristics of wounds healing in children and to present the current knowledge on the specific mechanisms with regard to infant age. The tissue insult or injury in fetus can heal without scar, mainly due to reduced granulation tissue associated to diminished or even no inflammatory phase, modified extracellular matrix such as the concentration of hyaluronic acid in amniotic liquid, expression and arrangement of collagen and tenascin. Thickness of children skin is a serious negative factor in case of trauma, whereas poor co-morbidities and efficient growth tissue mechanisms are beneficial to good evolution, even in cases of extensive damage and loss of tissue. The subsequent tissue mechanical forces, wound healing during childhood, spanning from the age of 2 until the end of puberty, is associated with more hypertrophic scars, both in duration and in intensity. Consequently, unnecessary surgery has to be avoided during this period when possible, and children with abnormal or pathologic wound healing should benefit from complementary treatments (hydration, massage, brace, silicone, hydrotherapy…), which represent efficient factors to minimize tissue scarring. After wound healing, the growth body rate can be responsible for specific complications, such as contractures, alopecia, and scar intussusceptions. Its evolutionary character implies the need of an attentive follow-up until adult age. Psychologic repercussions, as a consequence of pathologic scars, must be prevented and investigated by the surgeon. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  16. Specific and non-specific match effects in negative priming.

    Science.gov (United States)

    Labossière, Danielle I; Leboe-McGowan, Jason P

    2018-01-01

    The negative priming effect occurs when withholding a response to a stimulus impairs generation of subsequent responding to a same or a related stimulus. Our goal was to use the negative priming procedure to obtain insights about the memory representations generated by ignoring vs. attending/responding to a prime stimulus. Across three experiments we observed that ignoring a prime stimulus tends to generate higher identity-independent, non-specific repetition effects, owing to an overlap in the coarse perceptual form of a prime distractor and a probe target. By contrast, attended repetition effects generate predominantly identity-specific sources of facilitation. We use these findings to advocate for using laboratory phenomena to illustrate general principles that can be of practical use to non-specialists. In the case of the negative priming procedure, we propose that the procedure provides a useful means for investigating attention/memory interactions, even if the specific cause (or causes) of negative priming effects remain unresolved. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. [Specific immunotherapy with depigmented allergoids].

    Science.gov (United States)

    Klimek, L; Thorn, C; Pfaar, O

    2010-01-01

    Specific immunotherapy is the only available causative treatment for IgE-mediated allergic conditions. The state of the art is treatment via the subcutaneous route with crude extracts in a water solution, with physically linked (semidepot) extracts or chemically modified semidepot extracts (allergoids). A relatively new purification method combines depigmentation followed by polymerization with glutaraldehyde. This modification results in increased tolerance with a reduction in both local and systemic adverse effects. As controlled clinical trials have shown, the effectiveness is comparable to that of specific immunotherapy with crude allergen extracts. Recent data suggest that the modified polymerized allergoids allow a safe rush titration in a few days or even in 1 day (ultra-rush titration).

  18. UNBIASED ESTIMATORS OF SPECIFIC CONNECTIVITY

    Directory of Open Access Journals (Sweden)

    Jean-Paul Jernot

    2011-05-01

    Full Text Available This paper deals with the estimation of the specific connectivity of a stationary random set in IRd. It turns out that the "natural" estimator is only asymptotically unbiased. The example of a boolean model of hypercubes illustrates the amplitude of the bias produced when the measurement field is relatively small with respect to the range of the random set. For that reason unbiased estimators are desired. Such an estimator can be found in the literature in the case where the measurement field is a right parallelotope. In this paper, this estimator is extended to apply to measurement fields of various shapes, and to possess a smaller variance. Finally an example from quantitative metallography (specific connectivity of a population of sintered bronze particles is given.

  19. Vibrio chromosome-specific families

    DEFF Research Database (Denmark)

    Lukjancenko, Oksana; Ussery, David

    2014-01-01

    We have compared chromosome-specific genes in a set of 18 finished Vibrio genomes, and, in addition, also calculated the pan- and core-genomes from a data set of more than 250 draft Vibrio genome sequences. These genomes come from 9 known species and 2 unknown species. Within the finished...... chromosomes, we find a core set of 1269 encoded protein families for chromosome 1, and a core of 252 encoded protein families for chromosome 2. Many of these core proteins are also found in the draft genomes (although which chromosome they are located on is unknown.) Of the chromosome specific core protein...... families, 1169 and 153 are uniquely found in chromosomes 1 and 2, respectively. Gene ontology (GO) terms for each of the protein families were determined, and the different sets for each chromosome were compared. A total of 363 different "Molecular Function" GO categories were found for chromosome 1...

  20. Specific bibliography on Anastrepha fraterculus

    International Nuclear Information System (INIS)

    Salles, L.A.; Jaldo, H.

    1999-01-01

    Most publications on Anastrepha fraterculus are in the literature sources from South America, and papers were published in Spanish or Portuguese. Many literature sources mentioned in this list are not indexed in entomological abstracts and, consequently, are not easily available outside their home state or country. Due to this fact, the inclusion of a list of specific bibliography on A. fraterculus could be a help for researchers and students interested in fruit flies. In this list are included only references directly dealing with Anastrepha fraterculus. Obviously, many more references exist that consider this species, but general or non-specific work or data concerning A. fraterculus were not included in the present list. (author)

  1. Multilingualism and Specific Language Impairment

    OpenAIRE

    Engel de Abreu, Pascale

    2014-01-01

    Is a multilingual education beneficial for children? What are the optimal conditions under which a child can become perfectly multilingual? When should we be concerned about a multilingual child's language skills? What are the signs of Specific Language Impairment in a child who speaks more than one language? Developmental psychologist and Associate Professor in multilingual cognitive development at the University of Luxembourg Pascale Engel de Abreu will address these questions based on what...

  2. Nanobody Based Dual Specific CARs

    Directory of Open Access Journals (Sweden)

    Stijn De Munter

    2018-01-01

    Full Text Available Recent clinical trials have shown that adoptive chimeric antigen receptor (CAR T cell therapy is a very potent and possibly curative option in the treatment of B cell leukemias and lymphomas. However, targeting a single antigen may not be sufficient, and relapse due to the emergence of antigen negative leukemic cells may occur. A potential strategy to counter the outgrowth of antigen escape variants is to broaden the specificity of the CAR by incorporation of multiple antigen recognition domains in tandem. As a proof of concept, we here describe a bispecific CAR in which the single chain variable fragment (scFv is replaced by a tandem of two single-antibody domains or nanobodies (nanoCAR. High membrane nanoCAR expression levels are observed in retrovirally transduced T cells. NanoCARs specific for CD20 and HER2 induce T cell activation, cytokine production and tumor lysis upon incubation with transgenic Jurkat cells expressing either antigen or both antigens simultaneously. The use of nanobody technology allows for the production of compact CARs with dual specificity and predefined affinity.

  3. Nanobody Based Dual Specific CARs.

    Science.gov (United States)

    De Munter, Stijn; Ingels, Joline; Goetgeluk, Glenn; Bonte, Sarah; Pille, Melissa; Weening, Karin; Kerre, Tessa; Abken, Hinrich; Vandekerckhove, Bart

    2018-01-30

    Recent clinical trials have shown that adoptive chimeric antigen receptor (CAR) T cell therapy is a very potent and possibly curative option in the treatment of B cell leukemias and lymphomas. However, targeting a single antigen may not be sufficient, and relapse due to the emergence of antigen negative leukemic cells may occur. A potential strategy to counter the outgrowth of antigen escape variants is to broaden the specificity of the CAR by incorporation of multiple antigen recognition domains in tandem. As a proof of concept, we here describe a bispecific CAR in which the single chain variable fragment (scFv) is replaced by a tandem of two single-antibody domains or nanobodies (nanoCAR). High membrane nanoCAR expression levels are observed in retrovirally transduced T cells. NanoCARs specific for CD20 and HER2 induce T cell activation, cytokine production and tumor lysis upon incubation with transgenic Jurkat cells expressing either antigen or both antigens simultaneously. The use of nanobody technology allows for the production of compact CARs with dual specificity and predefined affinity.

  4. Mutational specificity of SOS mutagenesis

    International Nuclear Information System (INIS)

    Kato, Takeshi

    1986-01-01

    In an approach to the isolation of mutants of E. coli unable to produce mutations by ultraviolet light, the author has found new umuC-mutants. Their properties could be explained by ''SOS hypothesis of Radman and Witkin'', which has now been justified by many investigators. Analysis of the umuC region of E. coli chromosome cloned in pSK 100 has led to the conclusion that two genes, umuD and umuC, having the capacity of mutation induction express in the same mechanism as that of SOS genes, which is known to be inhibited by LexA protein bonding to ''SOS box'' found at promotor region. Suppressor analysis for mutational specificity has revealed: (i) umuDC-independent mutagens, such as EMS and (oh) 4 Cy, induce selected base substitution alone; and (ii) umuDC-dependent mutagens, such as X-rays and gamma-rays, induce various types of base substitution simultaneously, although they have mutational specificity. In the umuDC-dependent processes of basechange mutagenesis, the spectra of base substitution were a mixture of base substitution reflecting the specific base damages induced by individual mutagens and nonspecific base substitution. In conclusion, base substitution plays the most important role in umuDC-dependent mutagenesis, although mutagenesis of umuDC proteins remains uncertain. (Namekawa, K.)

  5. Conversion of NEK standard technical specifications into improved technical specifications

    International Nuclear Information System (INIS)

    Glaser, B.

    2003-01-01

    Neck is currently using a standard format of operation's Technical Specifications - STS (based on NUREG-0452), which are planned to be converted into Improved Technical Specifications - ITS (based on NUREG-1431). To facilitate the development of individual ITS, each reactor vendor owners group (OG) and the NRC staff developed improved standard TS (ISTS). For Westinghouse plants, the ISTS are published as NUREG-1431, and this document is going to be the basis for the new NEK ITS. It has been recognized that nuclear safety in all plants would benefit from improvement and standardization of ITS, so this was also addressed and recognized by the NRC. There are several plants around Europe and US, which have replaced the format into ITS which brings a lot of improvements and practical value in operations. The main objective of conversion is to completely rewrite, reformat, and streamline the existing STS. Emphasis is placed on human factors principles to improve clarity and understanding. The Bases section will be significantly expanded to clarify and better explain the purpose and foundation of each specification. There might be some proposed changes to the existing STS that deviated from the ITS in NUREG-1431 and constitute a relaxation of the existing STS. Each of these additional proposed changes will be described and evaluated in amendment application and justified on a case-by-case basis. Since the NEK is going to operate for more than 20 year without considering life extension, such conversion will be beneficial for operation personnel as well as regulation, surveillance and focus on operation's safety. At the present, only preliminary plan of STS conversion exists, showing the time frame of approximately 2 years of conversion process and numerous tasks that need to be performed. The plan is to begin with process in year 2004 and finish project in 2006, which means use of new ITS in main control room in year 2007. Beside the main process of conversion, there are

  6. JBK-75 microstructure specification recommendation

    International Nuclear Information System (INIS)

    Brewer, A.W.

    1977-01-01

    Since the ASTM-E-45 standard for microcleanliness is not applicable to superalloys like JBK-75 stainless steel (Modified A-286), Rocky Flats should adopt the Ladish microcleanliness standard (APML Cleanliness Classification of High Temperature Alloys Chart, 1971), as a guide for setting material acceptance specifications for JBK-75. Inclusion ratings of S-2, N-2, C-2, and M-2 should be acceptable. The microstructure should have a grain size of 5 or finer, but not smaller than 9, and microsegregation (banding) should be kept to a minimum

  7. Gender specific determinants of goitre

    International Nuclear Information System (INIS)

    Jamshid, F.; Kerstin, C.; Elena, G.; Wilhelm, O.; Karl, W.; Hwe, M.

    2004-01-01

    Despite the strong implications of differences between females and males in the risk of goitre, gender-specific issues have not been extensively addressed in investigations of goitre prevalence. The Objective of our analysis was to investigate the gender-specific determinants of goitre. Methods: A total of 853 healthy employees from 4 institutions in western part of Germany aged between 18 and 68 years were examined by ultrasound of the neck to determine the thyroid volume between April 2001 and April 2002. Information on sex, age, daily use of iodised salt, the history of goitre in the first degree relatives, type and amount of' smoking, oral contraceptives and number of pregnancies were assessed by standardised questionnaires. Gender-specific predictors of goitre prevalence were assessed by multivariate logistic regression. Results: The overall prevalence of goitre among study subjects was (204/853) 23.9%. Goitre was present in 80 out of 370 females (21.6%) vs. 124/483 (25.7%) in males.In general smoking (<0.0001), increasing age (p<0.0001) and lack of daily intake of iodised salt (p=0.004) associated with goitre prevalence, but not sex (0.4) and family history of goitre (p=0.2). In 370 females, parity (p=0.004) and lack of daily intake of iodised salt (p=0.01) were the major determinants for goitre, whereas, age (p=0.2), oral contraceptives (p=0.8), family history of goitre (p=0.3), and smoking (p=0.1) did not affect the goitre prevalence. In 483 males, smoking (p<0.0001) and age (p<0.001) affected the goitre prevalence, but not family history of goitre (p=0.4) and the iodine status failed just to reach the significant level (p=0.08) in this analysis. Conclusions: Gender specific determinants of goitre are parity and iodine status in females and smoking and increasing age in males. (authors)

  8. Specification for personal photographic dosemeters

    International Nuclear Information System (INIS)

    1981-01-01

    The 1981 British/International Standard Specification, prepared under the direction of the Nuclear Engineering Standards Committee and TC85 of the International Organization for Standardization, is described for personal photographic dosemeters. The Standard specifies classification, characteristics and test procedures to determine absorbed doses due to X or gamma radiations (energy less than 3 MeV) and absorbed doses due to beta radiation (max. energy 0.6 to 3 MeV), whether or not accompanied by X, gamma or bremsstrahlung photon radiation. The Standard is particularly applicable to dosemeters intended to be carried on the chest or wrist. (U.K.)

  9. Domain specific MT in use

    DEFF Research Database (Denmark)

    Offersgaard, Lene; Povlsen, Claus; Almsten, Lisbeth Kjeldgaard

    2008-01-01

    point scale evaluate the sentence from the point of view of the post-editor. The post-editor profile defined by the LSP is based on the experiences of introducing MT in the LSP workflow. The relation between the Translation Edit Rate (TER) scores and “Usability” scores is tested. We find TER a candidate......The paper focuses on domain specific use of MT with a special focus on SMT in the workflow of a Language Service Provider (LSP). We report on the feedback of post-editors using fluency/adequacy evaluation and the evaluation metric ’Usability’, understood in this context as where users on a three...

  10. Central Solenoid Insert Technical Specification

    Energy Technology Data Exchange (ETDEWEB)

    Martovetsky, Nicolai N [ORNL; Smirnov, Alexandre [ORNL

    2011-09-01

    The US ITER Project Office (USIPO) is responsible for the ITER central solenoid (CS) contribution to the ITER project. The Central Solenoid Insert (CSI) project will allow ITER validation the appropriate lengths of the conductors to be used in the full-scale CS coils under relevant conditions. The ITER Program plans to build and test a CSI to verify the performance of the CS conductor. The CSI is a one-layer solenoid with an inner diameter of 1.48 m and a height of 4.45 m between electric terminal ends. The coil weight with the terminals is approximately 820 kg without insulation. The major goal of the CSI is to measure the temperature margin of the CS under the ITER direct current (DC) operating conditions, including determining sensitivity to load cycles. Performance of the joints, ramp rate sensitivity, and stability against thermal or electromagnetic disturbances, electrical insulation, losses, and instrumentation are addressed separately and therefore are not major goals in this project. However, losses and joint performance will be tested during the CSI testing campaign. The USIPO will build the CSI that will be tested at the Central Solenoid Model Coil (CSMC) Test Facility at the Japan Atomic Energy Agency (JAEA), Naka, Japan. The industrial vendors (the Suppliers) will report to the USIPO (the Company). All approvals to proceed will be issued by the Company, which in some cases, as specified in this document, will also require the approval of the ITER Organization. Responsibilities and obligations will be covered by respective contracts between the USIPO, called Company interchangeably, and the industrial Prime Contractors, called Suppliers. Different stages of work may be performed by more than one Prime Contractor, as described in this specification. Technical requirements of the contract between the Company and the Prime Contractor will be covered by the Fabrication Specifications developed by the Prime Contractor based on this document and approved by

  11. The Specificity of Human Aesthetics

    DEFF Research Database (Denmark)

    Bouchet, Dominique

    2015-01-01

    Today, humankind is being reintroduced within nature. Humankind is no longer presented as supernatural to nature. There is no longer a clear divide between animal and human. What makes us human is neither culture, nor language nor labor, nor art, but the degree of complexity those products and ca...... creativity. Art is fundamentally about shaping visions and very closely related to this specific human ability to make projects. Especially in times of crisis, when the old sources of meaning hardly can make sense in a new context, imagination must be used in order to survive....

  12. Advances in bacterial specific imaging

    International Nuclear Information System (INIS)

    Wareham, David; Das, Satya; London Univ.

    2005-01-01

    Nuclear medicine is a powerful diagnostic technique able to detect inflammatory foci in human disease. A wide range of agents have been evaluated for their ability to distinguish lesions due to microbial infection from those due to sterile inflammation. Advances continue to be made on the use of radiolabelled antibiotics which as well as being highly specific in the diagnosis of infection may be useful in monitoring the treatment and course of disease. Here we provide an update on in-vitro and clinical studies with a number of established and novel radiopharmaceuticals. (author)

  13. Logic programming and metadata specifications

    Science.gov (United States)

    Lopez, Antonio M., Jr.; Saacks, Marguerite E.

    1992-01-01

    Artificial intelligence (AI) ideas and techniques are critical to the development of intelligent information systems that will be used to collect, manipulate, and retrieve the vast amounts of space data produced by 'Missions to Planet Earth.' Natural language processing, inference, and expert systems are at the core of this space application of AI. This paper presents logic programming as an AI tool that can support inference (the ability to draw conclusions from a set of complicated and interrelated facts). It reports on the use of logic programming in the study of metadata specifications for a small problem domain of airborne sensors, and the dataset characteristics and pointers that are needed for data access.

  14. Food Odours Direct Specific Appetite

    Directory of Open Access Journals (Sweden)

    Harriët F. A. Zoon

    2016-02-01

    Full Text Available Olfactory food cues were found to increase appetite for products similar in taste. We aimed to replicate this phenomenon for taste (sweet/savoury, determine whether it extends to energy density (high/low as well, and uncover whether this effect is modulated by hunger state. Twenty-nine healthy-weight females smelled four odours differing in the energy density and taste they signalled, one non-food odour, and one odourless solution (control, in random order, for three minutes each. Appetite for 15 food products was rated in the following two minutes. Mixed model analyses revealed that exposure to an odour signalling a specific taste (respectively sweet, savoury led to a greater appetite for congruent food products (sweet/savoury compared to incongruent food products (savoury p < 0.001; sweet p < 0.001 or neutral food products (p = 0.02; p = 0.003. A similar pattern was present for the energy-density category (respectively high-energy dense, low-energy dense signalled by the odours (low-energy products p < 0.001; high-energy products p = 0.008. Hunger state did not have a significant impact on sensory-specific appetite. These results suggest that exposure to food odours increases appetite for congruent products, in terms of both taste and energy density, irrespective of hunger state. We speculate that food odours steer towards intake of products with a congruent macronutrient composition.

  15. Hanford Site Environmental Management Specification

    International Nuclear Information System (INIS)

    DAILY, J.L.

    2001-01-01

    The US Department of Energy, Richland Operations Office (RL) has established a document hierarchy as part of its integrated management system. The Strategic Plan defines the vision, values, missions, strategic goals, high-level outcomes, and the basic strategies in achieving those outcomes. As shown in Figure 1-1, the Site Specification derives requirements from the Strategic Plan and documents the top-level mission technical requirements for the work involved in the RL Hanford Site cleanup and infrastructure activities under the responsibility of the U.S. Department of Energy, Office of Environmental Management (EM). It also provides the basis for all contract technical requirements. Since this is limited to the EM work, neither the Fast Flux Test Facility (FFTF) nor the Pacific Northwest National Laboratory (PNNL) non-EM science activities are included. Figure 1-1 also shows the relationship between this Site Specification and the other Site management and planning documents. Similarly, the documents, orders, and laws referenced in this document represent only the most salient sources of requirements. Current and contractual reference data contain a complete set of source documents

  16. [Specific immunotherapy. Hyposensitization with allergens].

    Science.gov (United States)

    Wedi, B; Kapp, A

    2004-04-01

    Successful allergen-specific immunotherapy (SIT) induces complex immunologic chan-ges resulting in reduced allergic inflammatory reactions. SIT has long-term effects in mild forms of inhalant allergies and is effective even when standard pharmacotherapy fails. Moreover, the risk to develop additional allergic sensitizations and the development of asthma is significantly reduced in children with allergic rhinitis. SIT is the treatment of choice in patients with systemic reactions to hymenoptera venoms. Although the exact effector mechanisms of SIT still have to be clarified, the most probable effect is a modulation of regulatory T cells associated with a switch of allergen-specific B-cells towards IgG4 production. The critical point to insure efficacy and safety is the selection of patients and allergens, task best performed by a specialist trained in allergology. Further details are available in the position papers of the German allergy societies - DGAI(Deutsche Gesellschaft fiir Allergologie und Klinische Immunologie) and ADA (Arzte-verband Deutscher Allergologen) - which can be found at www.dgaki.de.

  17. Is sexual victimization gender specific?

    DEFF Research Database (Denmark)

    Sundaram, Vanita; Laursen, Bjarne; Helweg-Larsen, Karin

    2008-01-01

    The present study investigates the prevalence of sexual victimization and correlations between sexual victimization and indicators of poor health in two representative samples of men and women in Denmark. Specifically, the authors explore the prevalence of self-reported victimization among...... adolescents (N = 5,829) and adults (N = 3,932) and analyze differences in self-reported health outcomes between male and female victims and corresponding controls. Gender differences are found in the reported prevalence of sexual victimization. Significantly more females than males reported forced sexual...... experiences in both samples. Associations between sexual victimization and poor health outcomes are found for both genders. Comparable patterns of association for men and women are found on a number of variables, particularly those pertaining to risk behavior....

  18. Compositional specification of commercial contracts

    DEFF Research Database (Denmark)

    Andersen, Jesper; Elsborg, Ebbe; Henglein, Fritz

    2006-01-01

    -definable analysis of their state before, during and after execution. We provide several realistic examples of commercial contracts and their analyses. A variety of (real) contracts can be expressed in such a fashion as to support their integration, management and analysis in an operational environment......We present a declarative language for compositional specification of contracts governing the exchange of resources. It extends Eber and Peyton Jones’s declarative language for specifying financial contracts (Jones et al. in The Fun of Programming. 2003) to the exchange of money, goods and services...... amongst multiple parties and complements McCarthy’s Resources, Events and Agents (REA) accounting model (McCarthy in Account Rev. LVII(3), 554–578, 1982) with a view- independent formal contract model that supports definition of user-defined contracts, automatic monitoring under execution and user...

  19. Specificity of discoveries in radiochemistry

    International Nuclear Information System (INIS)

    Krivomazov, A.N.

    1977-01-01

    The development of radiochemistry as a science is elucidated. On the basis of original papers and archives materials which have become available only recently, specific features of opening the law of radioactive displacements and isotopy of radioactive elements are presented in detail. A contribution of Hevesy, Russel, Fajans, and Soddy into the solution of this problem is considered; an important role of Rutherford in putting down the priority conflict is shown. Two stages of scientific generalization are singled out in the history of opening the law of radioactive displacements: the stage of the rules and the stage of the laws. On this basis the solutions of the priority problems have been reconsidered. It is shown that the history of radiochemistry is rich in discoveries which have undergone a relatively long evolution

  20. Genetic specificity of face recognition.

    Science.gov (United States)

    Shakeshaft, Nicholas G; Plomin, Robert

    2015-10-13

    Specific cognitive abilities in diverse domains are typically found to be highly heritable and substantially correlated with general cognitive ability (g), both phenotypically and genetically. Recent twin studies have found the ability to memorize and recognize faces to be an exception, being similarly heritable but phenotypically substantially uncorrelated both with g and with general object recognition. However, the genetic relationships between face recognition and other abilities (the extent to which they share a common genetic etiology) cannot be determined from phenotypic associations. In this, to our knowledge, first study of the genetic associations between face recognition and other domains, 2,000 18- and 19-year-old United Kingdom twins completed tests assessing their face recognition, object recognition, and general cognitive abilities. Results confirmed the substantial heritability of face recognition (61%), and multivariate genetic analyses found that most of this genetic influence is unique and not shared with other cognitive abilities.

  1. Testing of badminton specific endurance

    DEFF Research Database (Denmark)

    Madsen, Christian Møller; Højlyng, Mads; Nybo, Lars

    2016-01-01

    In the present study, a novel intermittent badminton endurance test (B-ENDURANCE) was developed and tested in elite (n=17) and skilled (n=9) badminton players as well as in age-matched physically active men (non-badminton players; n=8). In addition, B-ENDURANCE test-retest reproducibility...... was evaluated in nine badminton players.B-ENDURANCE is an incremental test where each level consists of repeated sequences of badminton specific actions towards the four corners on the court. The subject starts in the center of the court in front of a computer screen and within each sequence he must...... decreases until the subjects cannot follow the dictated tempo.B-ENDURANCE performance for elite players was better (Pbadminton players. In addition, B-ENDURANCE performance correlated (r=0.8; P

  2. FY97 ICCS prototype specification

    International Nuclear Information System (INIS)

    Woodruff, J.

    1997-01-01

    The ICCS software team will implement and test two iterations of their software product during FY97. This document specifies the products to be delivered in that first prototype and projects the direction that the second prototype will take. Detailed specification of the later iteration will be written when the results of the first iteration are complete. The selection of frameworks to be implemented early is made on a basis of risk analysis from the point of view of future development in the ICCS project. The prototype will address risks in integration of object- oriented components, in refining our development process, and in emulation testing for FEP devices. This document is a specification that identifies products and processes to undertake for resolving these risks. The goals of this activity are to exercise our development process at a modest scale and to probe our architecture plan for fundamental limits and failure modes. The product of the iterations will be the framework software which will be useful in future ICCS code. Thus the FY97 products are intended for internal usage by the ICCS team and for demonstration to the FEP software developers of the strategy for integrating supervisory software with FEP computers. This will be the first of several expected iterations of the software development process and the performance measurements that ICCS will demonstrate, intended to support confidence in our ability to meet project RAM goals. The design of the application software is being carried out in a separate WBS 1.5.2 activity. The design activity has as its FY97 product a series of Software Design Documents that will specify the functionality of the controls software of ICCS. During the testing of this year''s prototypes, the application functionality needed for test will be provided by sample maintenance controls. These are early precursors of controls that can be used for low level device control. Since the devices under test will be represented by

  3. Eternity Variables to Prove Simulation of Specifications

    NARCIS (Netherlands)

    Hesselink, Wim H.

    2005-01-01

    Simulations of specifications are introduced as a unification and generalization of refinement mappings, history variables, forward simulations, prophecy variables, and backward simulations. A specification implements another specification if and only if there is a simulation from the first one to

  4. According to Hepatitis C Virus (HCV) Infection Stage, Interleukin-7 Plus 4-1BB Triggering Alone or Combined with PD-1 Blockade Increases TRAF1low HCV-Specific CD8+ Cell Reactivity.

    Science.gov (United States)

    Moreno-Cubero, Elia; Subirá, Dolores; Sanz-de-Villalobos, Eduardo; Parra-Cid, Trinidad; Madejón, Antonio; Miquel, Joaquín; Olveira, Antonio; González-Praetorius, Alejandro; García-Samaniego, Javier; Larrubia, Juan-Ramón

    2018-01-15

    , restorable by IL-7 plus 4-1BBL treatment, characterizes short/midduration PI. In long-lasting disease, HCV-specific CD8 + T cells are rarely detectable ex vivo , but treatment with IL-7, 4-1BBL, and anti-PD-L1 recovers their reactivity in vitro in slow fibrosers. IMPORTANCE Hepatitis C virus (HCV) infects 71 million people worldwide. Two-thirds develop a chronic disease that can lead to cirrhosis and hepatocellular carcinoma. Direct-acting antivirals clear the infection, but there are still patients who relapse. In these cases, additional immunotherapy could play a vital role. A successful anti-HCV immune response depends on virus-specific CD8 + T cells. During chronic infection, these cells are functionally impaired, which could be due to the failure of costimulation. This study describes exhausted specific T cells, characterized by low levels of expression of the signal transducer TRAF1 of the positive costimulatory pathway 4-1BB/4-1BBL. IL-7 upregulated TRAF1 expression and improved T cell reactivity in patients with short/midduration disease, while in patients with long-lasting infection, it was also necessary to block the negative PD-1/PD-L1 checkpoint. When the results are taken together, this work supports novel ways of restoring the specific CD8 + T cell response, shedding light on the importance of TRAF1 signaling. This could be a promising target for future immunotherapy. Copyright © 2018 American Society for Microbiology.

  5. Are specific emotions narrated differently?

    Science.gov (United States)

    Habermas, Tilmann; Meier, Michaela; Mukhtar, Barbara

    2009-12-01

    Two studies test the assertion that anger, sadness, fear, pride, and happiness are typically narrated in different ways. Everyday events eliciting these 5 emotions were narrated by young women (Study 1) and 5- and 8-year-old girls (Study 2). Negative narratives were expected to engender more effort to process the event, be longer, more grammatically complex, more often have a complication section, and use more specific emotion labels than global evaluations. Narratives of Hogan's (2003) juncture emotions anger and fear were expected to focus more on action and to contain more core narrative sections of orientation, complication, and resolution than narratives of the outcome emotions sadness and happiness. Hypotheses were confirmed for adults except for syntactic complexity, whereas children showed only some of these differences. Hogan's theory that juncture emotions are restricted to the complication section was not confirmed. Finally, in adults, indirect speech was more frequent in anger narratives and internal monologue in fear narratives. It is concluded that different emotions should be studied in how they are narrated, and that narratives should be analyzed according to qualitatively different emotions.

  6. [Amusia and its topic specification].

    Science.gov (United States)

    Buklina, S B; Skvortsova, V B

    2007-01-01

    A historical development of views on amusia and its clinical phenomenology is reviewed. The authors present a case of atypical amusia in a patient aged 32 years with glioma of the right temporal lobe including the upper temporal gyrus. Amusia was combined with euphoria and disturbances of evaluation of speech intonation. It has been assumed that different mechanisms implicated with different regions of both brain hemispheres may underlie amusia. Sometimes these mechanisms appear to be universal, e.g. disorders of symbolic gnosis in posterior hemisphere lesions, being comorbid with amusia as disturbances in reading music and letter agnosia. In our case, the right temporal lobe lesion, especially with involvement of the upper temporal gyrus, caused specific music agnosia with disturbances of perception of some notes and duration of their phonation or a musical contour of the whole melody. Motor amusia is developed due to additional disturbances of motor and premotor brain functions, with significant contribution of the Broca's speech area. Music may be a model for investigation into processes of multimodal integration and hemisphere interaction.

  7. Advances in bacterial specific imaging

    Directory of Open Access Journals (Sweden)

    David Wareham

    2005-10-01

    Full Text Available Nuclear medicine is a powerful diagnostic technique able to detect inflammatory foci in human disease. A wide range of agents have been evaluated for their ability to distinguish lesions due to microbial infection from those due to sterile inflammation. Advances continue to be made on the use of radiolabelled antibiotics which as well as being highly specific in the diagnosis of infection may be useful in monitoring the treatment and course of disease. Here we provide an update on in-vitro and clinical studies with a number of established and novel radiopharmaceuticalsA medicina nuclear é uma técnica poderosa de diagnóstico capaz de detectar focos inflamatórios em doenças humanas. Uma ampla gama de agentes tem sido avaliada em sua capacidade de distinguir lesões, devidas a infecções microbianas daquelas causadas por inflamações estéreis. Avanços continuam sendo realizados no uso de antibióticos radiomarcados que, da mesma forma que têm sido usados no diagnóstico altamente específico de infecções, podem ser úteis na monitoração do tratamento e do curso da doença. Neste estudo, nós apresentamos uma atualização sobre estudos in vitro e clínicos, com alguns novos radiofármacos e outros já consagrados.

  8. Specificities of sustainable tourism planning

    Directory of Open Access Journals (Sweden)

    Jegdić Vaso

    2013-01-01

    Full Text Available In the past two decades, companies have been mentioning achievement of sustainability in their activities as a target of companies, governments and non-profit organizations, although measuring the degree to which an organization conducts its activities in a sustainable manner, can be very difficult. Sustainable tourism development requires a process of planning and management that will unite the interests of various stakeholders in a sustainable and strategic way. It requires an understanding of the meaning of sustainable development and guiding values for promoting sustainable tourism. The paper points to the importance of cross-sector partnerships and the roles of different stakeholders in the planning of sustainable tourism projects. Special importance is given to the community of which a willingness to understand the impacts of tourism industry is expected, as well as various procedures of engagement in participatory planning, consensus building and conflict resolution among all stakeholders. The aim of this research is to find an optimal model of planning of sustainable tourism projects that would take into consideration the interests of all stakeholders and reflect the specificities imposed by the acceptance of the concept of sustainable development by all participants in the project.

  9. 31 CFR 596.309 - Specific license.

    Science.gov (United States)

    2010-07-01

    ... FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY TERRORISM LIST GOVERNMENTS SANCTIONS REGULATIONS General Definitions § 596.309 Specific license. The term specific license means any license or...

  10. The Specificity Principle in Acculturation Science

    Science.gov (United States)

    Bornstein, Marc H.

    2016-01-01

    The Specificity Principle in Acculturation Science asserts that specific setting conditions of specific people at specific times moderate specific domains in acculturation by specific processes. Our understanding of acculturation depends critically on what is studied where, in whom, how, and when. This article defines, explains, and illustrates the Specificity Principle in Acculturation Science. Research hypotheses about acculturation can be more adequately tested, inconsistencies and discrepancies in the acculturation literature can be satisfactorily resolved, acculturation interventions can be tailored to be more successful, and acculturation policies can be brought to new levels of effectiveness if the specificity principle that governs acculturation science is more widely recognized. PMID:28073331

  11. Specific CT findings of eclampsia

    International Nuclear Information System (INIS)

    Takahashi, Hiroshi; Nakazawa, Shozo; Imaya, Hisatoshi

    1985-01-01

    Two cases of specific computed tomographic (CT) findings of eclampsia were reported. Case 1 was a 25-year-old primipara in the 10th month of pregnancy, and Case 2 was a 36-year-old primipara in the 9th month of pregnancy. Both were brought to our hospital because of attacks of preeclampsia and eclampsia. On admission, they were in a comatose state. Computed tomography (CT) on admission showed low- and high-density areas in the basal ganglia regions in Case 1 and low-density areas in the same regions in Case 2. In Case 1, cerebral angiograms obtained two days after the attack showed diffuse cerebral vasospasms in the anterior and middle cerebral arteries of both sides and the basilar artery. In Case 2, however, cerebral angiograms obtained three days after the attack showed no abnormal findings. The patients were saved by crisis-overcoming emergency treatment and care. The neurological condition gradually improved. Repeated CT three weeks after the onset showed only a slight low-density area and a small high-density area in the left basal ganglia region in Case 1, while the low-density areas in the bilateral basal ganglia regions disappeared in Case 2. Seven weeks after the attack, cerebral angiography was again performed, but the diffuse vasospasms had disappeared. The clinical courses were good, and the patients were discharged about eight weeks after the onset, by which time their consciousness had become clear and the neurological deficits had been well overcome. Cerebrovascular disorders caused by toxemia of pregnancy is rare; when they do occur, the main lesions of the brain are edema, focal ischemia, thrombosis, and hemorrhage. They may be related to cerebral vasospasm, and subsequent ischemic changes are observed at times with eclampsia. (author)

  12. Gender-Specific Health Challenges Facing Women

    Science.gov (United States)

    ... with facebook share with twitter share with linkedin Gender-Specific Health Challenges Facing Women Global Research Global ... adverse reactions to the drugs. Women also suffer gender-specific consequences of HIV, including recurrent vaginal yeast ...

  13. Model Commissioning Plan and Guide Specifications

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1997-03-01

    The objectives of Model Commissioning Plan and Guide Specifications are to ensure that the design team applies commissioning concepts to the design and prepares commissioning specifications and a commission plan for inclusion in the bid construction documents.

  14. Technical specification improvement through safety margin considerations

    International Nuclear Information System (INIS)

    Howard, R.C.; Jansen, R.L.

    1986-01-01

    Westinghouse has developed an approach for utilizing safety analysis margin considerations to improve plant operability through technical specification revision. This approach relies on the identification and use of parameter interrelations and sensitivities to identify acceptable operating envelopes. This paper summarizes technical specification activities to date and presents the use of safety margin considerations as another viable method to obtain technical specification improvement

  15. Genre-Specific Semantic Video Indexing

    NARCIS (Netherlands)

    Wu, J.; Worring, M.

    2010-01-01

    In many applications, we find large video collections from different genres where the user is often only interested in one or two specific video genres. So, when users are querying the system with a specific semantic concept, they are likely aiming a genre specific instantiation of this concept.

  16. 42 CFR 37.203 - Autopsy specifications.

    Science.gov (United States)

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Autopsy specifications. 37.203 Section 37.203... EXAMINATIONS SPECIFICATIONS FOR MEDICAL EXAMINATIONS OF UNDERGROUND COAL MINERS Autopsies § 37.203 Autopsy specifications. (a) Every autopsy for which a claim for payment is submitted pursuant to this part: (1) Shall be...

  17. Specific cooling capacity of liquid nitrogen

    Science.gov (United States)

    Kilgore, R. A.; Adcock, J. B.

    1977-01-01

    The assumed cooling process and the method used to calculate the specific cooling capacity of liquid nitrogen are described, and the simple equation fitted to the calculated specific cooling capacity data, together with the graphical form calculated values of the specific cooling capacity of nitrogen for stagnation temperatures from saturation to 350 K and stagnation pressures from 1 to 10 atmospheres, are given.

  18. Isothermal Gravitational Segregation: Algorithms and Specifications

    DEFF Research Database (Denmark)

    Halldórsson, Snorri; Stenby, Erling Halfdan

    2000-01-01

    New algorithms for calculating the isothermal equilibrium state of reservoir fluids under the influence of gravity are presented. Two types of specifications are considered: the specification of pressure and composition at a reference depth; and the specification of the total overall content of t...

  19. Information Concerning Preparation of Specifications for Carpeting.

    Science.gov (United States)

    Gilliland, John W.

    This paper argues for detailed, written carpeting specifications to assure that schools obtain quality products at competitive prices. The advantages of and specifications for school carpeting are given. A sample written specification contains items on: scope, general features, materials, acoustic characteristics, identification and acoustic…

  20. 14 CFR 91.1015 - Management specifications.

    Science.gov (United States)

    2010-01-01

    ... complete and separate set of its management specifications at its principal base of operations, or at a... 14 Aeronautics and Space 2 2010-01-01 2010-01-01 false Management specifications. 91.1015 Section... Operations Program Management § 91.1015 Management specifications. (a) Each person conducting operations...

  1. Towards a theory of product design specifications

    DEFF Research Database (Denmark)

    Hansen, Claus Thorp; Andreasen, Mogens Myrup

    2004-01-01

    , which express the customers¿ need and perception of value. In this paper we will scrutinize this assumption. We outline the roles and tasks of the product design specification in order to identify the requirements on a theory of product design specifications and we identify existing theory elements....... In the design methodology literature we find guidelines and methods to compile a product design specification. The contributions are based on the common underlying assumption that it is meaningful and the only feasible approach to interpret the result of a need analysis into a set of technical specifications...... to build such a theory of product design specifications upon....

  2. Standard technical specifications combustion engineering plants

    International Nuclear Information System (INIS)

    1992-09-01

    This report documents the results of the combined effort of the NRC and the industry to produce improved Standard Technical Specifications (STS) for Combustion Engineering Plants. The improved STS wee developed based on the criteria in the interim Commission Policy Statement on Technical Specification Improvements for Nuclear Power Reactors, dated February 6, 1987. The improved STS will be used as the basis for individual nuclear power plant licensees to develop improved plant-specific technical specifications. This report contains three volumes. This document, Volume 1, contains the Specifications for all chapters and sections of the improved STS. Volume 2 contains the Bases for Sections 3.4--3.9 of the improved STS

  3. Allelic variation of the inducible costimulator (ICOS) gene: detection of polymorphisms, analysis of the promoter region, and extended haplotype estimation

    DEFF Research Database (Denmark)

    Andersen, A.D.H.; Lange, Marianne; Lillevang, S.T.

    2003-01-01

    The human chromosome region 2q33 including the three costimulatory molecules CD28, CTLA-4 and ICOS, has been subject to much attention due to its linkage to a number of autoimmune diseases. The search for the causal relationship of this linkage has revealed several polymorphisms, but no variations...... in the amino acid sequences except for one polymorphism in, the leader sequence of CTLA-4. In the present study, we examined the ICOS gene of an unrelated group of healthy donors from the Danish population. We were able to report 16 intronic SNP, one intronic G-insert and two repeat regions in intron 4......, consistent with the [T](n) and the [GT](n) regions reported in a Japanese study. Putative haplotypes for the established SNP and repeat polymorphisms have been estimated by computational analysis. Sequencing of similar to3500 by of the upstream region of ICOS revealed an additional eight SNP of which two...

  4. CD154 costimulated ovine primary B cells, a cell culture system that supports productive infection by bovine leukemia virus.

    Science.gov (United States)

    Van den Broeke, A; Cleuter, Y; Beskorwayne, T; Kerkhofs, P; Szynal, M; Bagnis, C; Burny, A; Griebel, P

    2001-02-01

    Bovine leukemia virus (BLV) is closely associated with the development of B-cell leukemia and lymphoma in cattle. BLV infection has also been studied extensively in an in vivo ovine model that provides a unique system for studying B-cell leukemogenesis. There is no evidence that BLV can directly infect ovine B cells in vitro, and there are no direct data regarding the oncogenic potential of the viral Tax transactivator in B cells. Therefore, we developed ovine B-cell culture systems to study the interaction between BLV and its natural target, the B cell. In this study, we used murine CD154 (CD40 ligand) and gamma-chain-common cytokines to support the growth of B cells isolated from ovine lymphoid tissues. Integrated provirus, extrachromosomal forms, and viral transcripts were detected in BLV-exposed populations of immature, rapidly dividing surface immunoglobulin M-positive B cells from sheep ileal Peyer's patches and also in activated mature B cells isolated from blood. Conclusive evidence of direct B-cell infection by BLV was obtained through the use of cloned B cells derived from sheep jejunal Peyer's patches. Finally, inoculation of sheep with BLV-infected cultures proved that infectious virus was shed from in vitro-infected B cells. Collectively, these data confirm that a variety of ovine B-cell populations can support productive infection by BLV. The development of ovine B-cell cultures permissive for BLV infection provides a controlled system for investigating B-cell leukemogenic processes and the pathogenesis of BLV infection.

  5. Enhancing the potency and specificity of engineered T cells for cancer treatment.

    Science.gov (United States)

    Sukumaran, Sujita; Watanabe, Norihiro; Bajgain, Pradip; Raja, Kanchana; Mohammed, Somala; Fisher, William E; Brenner, Malcolm K; Leen, Ann M; Vera, Juan F

    2018-06-07

    The adoptive transfer of chimeric antigen receptor (CAR)-modified T cells has produced tumor responses even in patients with refractory diseases. However, the paucity of antigens that are tumor selective has resulted, on occasion, in "on-target, off-tumor" toxicities. To address this issue, we developed an approach to render T cells responsive to an expression pattern present exclusively at the tumor by using a trio of novel chimeric receptors. Using pancreatic cancer as a model, we demonstrate how T cells engineered with receptors that recognize PSCA, TGFβ, and IL4, and whose endodomains recapitulate physiologic T cell signaling by providing signals for activation, co-stimulation and cytokine support, produce potent anti-tumor effects selectively at the tumor site. In addition, this strategy has the benefit of rendering our cells resistant to otherwise immunosuppressive cytokines (TGFβ and IL4) and can be readily extended to other inhibitory molecules present at the tumor site (e.g. PD-L1, IL10, IL13). Copyright ©2018, American Association for Cancer Research.

  6. Technical specifications and performance of CANDU fuel

    International Nuclear Information System (INIS)

    Sejnoha, R.

    1997-01-01

    The relations between Technical Specifications and fuel performance are discussed in terms of design limits and margins. The excellent performance record of CANDU reactor fuel demonstrates that the fuel design defined in the Technical Specifications (and with it other components of the procurement cycle, such as fuel manufacturing), satisfy the requirements. New requirements, changing conditions of fuel application and accumulating experience make periodic updates of the Technical Specifications necessary. Under the CANDU Owners Group (COG) Working Party 9, a Work Package has been conducted to support the review of the Specifications and the documentation of the rationales for their requirements. So far, the review has been completed for 4 Specifications: 1 for Zircaloy tubing, and 3 for uranium dioxide powder. It is planned to complete the review of all 11 currently used specifications by 1999. The paper summarizes the results achieved to mid 1997. (author)

  7. An Algebraic Specification of the Semantic Web

    OpenAIRE

    Ksystra, Katerina; Triantafyllou, Nikolaos; Stefaneas, Petros; Frangos, Panayiotis

    2011-01-01

    We present a formal specification of the Semantic Web, as an extension of the World Wide Web using the well known algebraic specification language CafeOBJ. Our approach allows the description of the key elements of the Semantic Web technologies, in order to give a better understanding of the system, without getting involved with their implementation details that might not yet be standardized. This specification is part of our work in progress concerning the modeling the Social Semantic Web.

  8. Map Specifications and Exchange of Geographical Information

    DEFF Research Database (Denmark)

    Frederiksen, Poul

    1999-01-01

    Specifications for Technical Maps 1993 – 99 are described giving an overview of the specification structure including the object description of the latest version: TK99.The technical map specifications are related to the standards for topographical maps - especially the TOP10DK standard. Common...... object definitions are essential for the standards. Technical as well as topographical map information is exchangeable through the Danish developed “Standard for Exchange of Digital Map Information”, known as the DSFL-format....

  9. Cervical cancer: intracavitary dose specification and prescription

    International Nuclear Information System (INIS)

    Potish, R.A.; Gerbi, B.J.

    1987-01-01

    Dose and volume specifications for reporting intracavitary therapy were analyzed according to criteria recommended by the International Commission on Radiation Units and Measurements (ICRU). Ninety Fletcher-Suit radium applications were studied to examine the validity of the assumptions of the ICRU and the merit of their routine reporting. It was demonstrated that the reporting recommendations were inconsistent with clinical prescription systems and added little to dose specification. The distinction between dose specification and dose prescription was stressed

  10. Product specifications for the end use

    International Nuclear Information System (INIS)

    Navaretta, G.

    1992-01-01

    This paper reports on the concept of total quality which provides a foundation upon which NGL specifications could be built. Total quality has been embraced by a large constituency within the Refining and Petrochemical business, so, the NGL industry can not afford to discount it. As a concept, total quality certainly includes a specific management approach, but the roots of the quality movement lie with traditional product quality values. Naturally, the subject of product quality leads directly to product specifications, thus proving the intimate relationship between the total quality concept and NGL specifications

  11. Steps in Modular Specifications for Concurrent Modules

    DEFF Research Database (Denmark)

    Da Rocha Pinto, Pedro; Dinsdale-Young, Thomas; Gardner, Philippa

    2015-01-01

    The specification of a concurrent program module is a difficult problem. The specifications must be strong enough to enable reasoning about the intended clients without reference to the underlying module implementation. We survey a range of verification techniques for specifying concurrent module......, in particular highlighting four key concepts: auxiliary state, interference abstraction, resource ownership and atomicity. We show how these concepts combine to provide powerful approaches to specifying concurrent modules.......The specification of a concurrent program module is a difficult problem. The specifications must be strong enough to enable reasoning about the intended clients without reference to the underlying module implementation. We survey a range of verification techniques for specifying concurrent modules...

  12. Technical specifications for the Bulk Shielding Reactor

    International Nuclear Information System (INIS)

    1982-04-01

    Technical specifications are presented concerning the safety limits and limiting safety system settings; limiting conditions for operation; surveillance requirements; design features; and administrative controls

  13. AOV Facility Tool/Facility Safety Specifications -

    Data.gov (United States)

    Department of Transportation — Develop and maintain authorizing documents that are standards that facilities must follow. These standards are references of FAA regulations and are specific to the...

  14. User Interface Technology for Formal Specification Development

    Science.gov (United States)

    Lowry, Michael; Philpot, Andrew; Pressburger, Thomas; Underwood, Ian; Lum, Henry, Jr. (Technical Monitor)

    1994-01-01

    Formal specification development and modification are an essential component of the knowledge-based software life cycle. User interface technology is needed to empower end-users to create their own formal specifications. This paper describes the advanced user interface for AMPHION1 a knowledge-based software engineering system that targets scientific subroutine libraries. AMPHION is a generic, domain-independent architecture that is specialized to an application domain through a declarative domain theory. Formal specification development and reuse is made accessible to end-users through an intuitive graphical interface that provides semantic guidance in creating diagrams denoting formal specifications in an application domain. The diagrams also serve to document the specifications. Automatic deductive program synthesis ensures that end-user specifications are correctly implemented. The tables that drive AMPHION's user interface are automatically compiled from a domain theory; portions of the interface can be customized by the end-user. The user interface facilitates formal specification development by hiding syntactic details, such as logical notation. It also turns some of the barriers for end-user specification development associated with strongly typed formal languages into active sources of guidance, without restricting advanced users. The interface is especially suited for specification modification. AMPHION has been applied to the domain of solar system kinematics through the development of a declarative domain theory. Testing over six months with planetary scientists indicates that AMPHION's interactive specification acquisition paradigm enables users to develop, modify, and reuse specifications at least an order of magnitude more rapidly than manual program development.

  15. Motorcycle Education Curriculum Specifications. Final Report.

    Science.gov (United States)

    McKnight, A. James; And Others

    This report contains specifications for a motorcycle safety education curriculum designed to reduce the incidence and severity of motorcycle accidents. The specifications prescribe objectives, prerequisites, methods, materials, equipment, facilities, and proficiency measures for six units of instruction: (1) basic riding skills, (2) street riding…

  16. Domain-specific languages in perspective

    NARCIS (Netherlands)

    J. Heering (Jan); M. Mernik (Marjan)

    2007-01-01

    textabstractDomain-specific languages (DSLs) are languages tailored to a specific application domain. They offer substantial gains in expressiveness and ease of use compared with general-purpose languages in their domain of application. Although the use of DSLs is by no means new, it is receiving

  17. The Logic of the RAISE Specification Language

    DEFF Research Database (Denmark)

    George, Chris; Haxthausen, Anne Elisabeth

    2003-01-01

    This paper describes the logic of the RAISE Specification Language, RSL. It explains the particular logic chosen for RAISE, and motivates this choice as suitable for a wide spectrum language to be used for designs as well as initial specifications, and supporting imperative and concurrent...

  18. Specific and social phobias in ICD-11

    NARCIS (Netherlands)

    Emmelkamp, P.M.G.

    2012-01-01

    The purpose of this article is to discuss the current status of research with respect to specific phobias and social phobia as defined in the ICD-10 and DSM-IV, and to provide op- tions for their classification in the ICD-11. Both ICD-10 and DSM-IV identify three main classes of phobias: specific

  19. Technical specifications: Health Physics Research Reactor

    International Nuclear Information System (INIS)

    1979-02-01

    The technical specifications define the key limitations that must be observed for safe operation of the Health Physics Research Reactor (HPRR) and an envelope of operation within which there is assurance that these limits will not be exceeded. The specifications were written to satisfy the requirements of the Department of Energy (DOE) Manual Chapter 0540, September 1, 1972

  20. Guidelines for writing user friendly technical specifications

    International Nuclear Information System (INIS)

    Webster, S.A.; Braun, J.C.; Pearce, R.T.

    1986-01-01

    This study investigates some of the ergonomic considerations of writer's guides for the preparation of instructions. It is a precedent for the preparation of such a writer's guide for technical specifications for nuclear power plants. This writer's guide will be part of a revision to the industry's standard ANSI/ANS 58.4, Criteria for Technical Specifications for Nuclear Power Stations

  1. Specific skills and social competence in schizophrenia

    NARCIS (Netherlands)

    Appelo, M.T.; van Nieuwenhuizen, C.J.; Emmelkamp, P.M.G.; Slooff, C.J.; Louwerens, J.W.

    1992-01-01

    Generalization of skills is a major problem in social skills training for schizophrenic patients. Assessment of skills is mostly not based on objective indices of specific skill deficits. The results of this study show that global competence of schizophrenics can be differentiated from specific

  2. The Logic of the RAISE Specification Language

    DEFF Research Database (Denmark)

    George, Chris; Haxthausen, Anne Elisabeth

    2008-01-01

    This chapter describes the logic of the RAISE Specification Language, RSL. It explains the particular logic chosen for RAISE, and motivates this choice as suitable for a wide spectrum language to be used for designs as well as initial specifications, and supporting imperative and concurrent...

  3. Specific heats of degenerate ideal gases

    OpenAIRE

    Caruso, Francisco; Oguri, Vitor; Silveira, Felipe

    2017-01-01

    From arguments based on Heisenberg's uncertainty principle and Pauli's exclusion principle, the molar specific heats of degenerate ideal gases at low temperatures are estimated, giving rise to values consistent with the Nerst-Planck Principle (third law of Thermodynamics). The Bose-Einstein condensation phenomenon based on the behavior of specific heat of massive and non-relativistic boson gases is also presented.

  4. Shape configuration and category-specificity

    DEFF Research Database (Denmark)

    Gerlach, Christian; Law, Ian; Paulson, Olaf B.

    2006-01-01

    a recent account of category-specificity and lends support to the notion that category-specific impairments can occur for both natural objects and artefacts following damage to pre-semantic stages in visual object recognition. The implications of the present findings are discussed in relation to theories...

  5. Fundamental Characteristics of Industrial Variant Specification Systems

    DEFF Research Database (Denmark)

    Hansen, Benjamin Loer; Hvam, Lars

    2004-01-01

    fundamental concepts related to this task, which are relevant to understand for academia and practitioners working with the subject. This is done through a description of variant specification tasks and typical aspects of system solutions. To support the description of variant specification tasks and systems...

  6. SPECIFIC SKILLS AND SOCIAL COMPETENCE IN SCHIZOPHRENIA

    NARCIS (Netherlands)

    APPELO, MT; WOONINGS, FMJ; VANNIEUWENHUIZEN, CJ; EMMELKAMP, PMG; SLOOFF, CJ; LOUWERENS, JW

    Generalization of skills is a major problem in social skills training for schizophrenic patients. Assessment of skills is mostly not based on objective indices of specific skill deficits. The results of this study show that global competence of schizophrenics can be differentiated from specific

  7. Building finite automata from DI specifications

    NARCIS (Netherlands)

    Udding, J.T

    1998-01-01

    Numerous formalisms exist to specify delay-insensitive computations and their implementations. It is not always straightforward to compare specifications in the different formalisms. One way of comparing specifications is transforming them to automata in which nodes are annotated with progress

  8. The Specificity of Creativity: Figurative and Scientific

    Science.gov (United States)

    Bernal, Ana; Esparza, Javier; Ruiz, María-José; Ferrando, Mercedes; Sainz, Marta

    2017-01-01

    Introduction: This work tackles the question about the nature of creativity as a general vs. domain-specific ability. First we deal with the concept of creativity and then, the main approaches to the debate of generality vs. specificity are exposed. Method: A total of 133 students attending 3rd grade of secondary education in Murcia Region took…

  9. Efficient genre-specific semantic video indexing

    NARCIS (Netherlands)

    Wu, J.; Worring, M.

    2012-01-01

    Large video collections such as YouTube contain many different video genres, while in many applications the user might be interested in one or two specific video genres only. Thus, when users are querying the system with a specific semantic concept like AnchorPerson, and MovieStars, they are likely

  10. Autonomy Level Specification for Intelligent Autonomous Vehicles

    Science.gov (United States)

    2003-09-01

    Autonomy Level Specification for Intelligent Autonomous Vehicles : Interim Progress Report Hui-Min Huang, Elena Messina, James Albus...Level Specification for Intelligent Autonomous Vehicles : Interim Progress Report 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6

  11. 324 and 327 Facilities Environmental Effluent Specifications

    International Nuclear Information System (INIS)

    JOHNSON, D.L.

    1999-01-01

    These effluent specifications address requirements for the 324/321 Facilities, which are undergoing stabilization activities. Effluent specifications are imposed to protect personnel, the environment and the public, by ensuring adequate implementation and compliance with federal and state regulatory requirements and Hanford programs

  12. PCR specific for Actinobacillus pleuropneumoniae serotype 3

    DEFF Research Database (Denmark)

    Zhou, L.; Jones, S.C.P.; Angen, Øystein

    2008-01-01

    , but the method has liminations, for example, cross-reactions between serotypes 3, 6, and 8. This study describes the development of a serotype 3-specific PCR, based on the capsule locus, which can be used in a multiplex format with the organism's specific gene apxIV. The PCR test was evaluated on 266 strains...

  13. ITER ISS system alternative specification study

    International Nuclear Information System (INIS)

    Kveton, O.K.

    1990-08-01

    Recent comments suggested that the fuel systems, in particular the ISS, could be simplified if the ITER specifications were relaxed from the data specified for ITER. This interim report addresses the first part of the analysis, which considers the impact of design specifications on fuel systems design

  14. Plutonium Immobilization Can Loading Preliminary Specifications

    Energy Technology Data Exchange (ETDEWEB)

    Kriikku, E.

    1998-11-25

    This report discusses the Plutonium Immobilization can loading preliminary equipment specifications and includes a process block diagram, process description, equipment list, preliminary equipment specifications, plan and elevation sketches, and some commercial catalogs. This report identifies loading pucks into cans and backfilling cans with helium as the top priority can loading development areas.

  15. Technical specifications: Tower Shielding Reactor II

    International Nuclear Information System (INIS)

    1979-02-01

    The technical specifications define the key limitations that must be observed for safe operation of the Tower Shielding Reactor II (TSR-II) and an envelope of operation within which there is reasonable assurance that these limits cannot be exceeded. The specifications were written to satisfy the requirements of the Department of Energy (DOE) Manual Chapter 0540, September 1, 1972

  16. Development of technical specifications for research reactors

    International Nuclear Information System (INIS)

    Anon.

    1983-01-01

    This standard identifies and establishes the content of technical specifications for research reactors. Areas addressed are: definitions, safety limits, limiting safety system settings, limiting conditions for operation, surveillance requirements, design features and administrative controls. Sufficient detail is incorporated so that applicable specifications can be derived or extracted

  17. 11 CFR 1.14 - Specific exemptions.

    Science.gov (United States)

    2010-01-01

    ... to refer apparent violations of the Act to the Attorney General or other law enforcement authorities... 11 Federal Elections 1 2010-01-01 2010-01-01 false Specific exemptions. 1.14 Section 1.14 Federal Elections FEDERAL ELECTION COMMISSION PRIVACY ACT § 1.14 Specific exemptions. (a) No individual, under the...

  18. Determining the specific electric resistance of rock

    Energy Technology Data Exchange (ETDEWEB)

    Persad' ko, V.Ia.

    1982-01-01

    Data are presented on perfecting the method of laboratory determination of the specific electric resistance of a rock formation. The average error in determining the specific electric resistance of the core at various locations is no more than two percent with low resistance values (2-5 ohms).

  19. Specific phobia predicts psychopathology in young women

    NARCIS (Netherlands)

    Trumpf, J.; Margraf, J.; Vriends, N.; Meyer, A.H.; Becker, E.S.

    2010-01-01

    Although specific phobia is characterized by an early age at onset and by high rates of comorbidity, few studies have examined comorbid relationships prospectively. The present study investigated the association between specific phobia and the risk of a broad range of psychopathology among young

  20. Screening specifications for Gulf Coast salt domes

    International Nuclear Information System (INIS)

    Brunton, G.D.; Laughon, R.B.; McClain, W.C.

    1978-01-01

    A reconnaissance survey of the salt domes of Mississippi, Louisiana, and east Texas is being planned to identify study areas for potential sites for radioactive waste disposal. Preliminary screening specifications were derived for each of the geological evaluation criteria by application of the significant factors that will have an impact on the reconnaissance survey. The procedure for the derivation of each screening specification is discussed. The screening specifications are the official OWI values to be used for the first-cut acceptance for salt dome study areas along the Gulf Coast. The derivation of the screening specifications is illustrated by (1) a statement of the geological evaluation criterion, (2) a discussion of the pertinent factors affecting the criterion, and (3) the evaluation of the value of the specification

  1. Tissue Specific Promoters in Colorectal Cancer

    Directory of Open Access Journals (Sweden)

    A. R. Rama

    2015-01-01

    Full Text Available Colorectal carcinoma is the third most prevalent cancer in the world. In the most advanced stages, the use of chemotherapy induces a poor response and is usually accompanied by other tissue damage. Significant progress based on suicide gene therapy has demonstrated that it may potentiate the classical cytotoxic effects in colorectal cancer. The inconvenience still rests with the targeting and the specificity efficiency. The main target of gene therapy is to achieve an effective vehicle to hand over therapeutic genes safely into specific cells. One possibility is the use of tumor-specific promoters overexpressed in cancers. They could induce a specific expression of therapeutic genes in a given tumor, increasing their localized activity. Several promoters have been assayed into direct suicide genes to cancer cells. This review discusses the current status of specific tumor-promoters and their great potential in colorectal carcinoma treatment.

  2. Specifications in early conceptual design work

    DEFF Research Database (Denmark)

    Hansen, Claus Thorp; Andreasen, Mogens Myrup

    2007-01-01

    In early conceptual design the design team is working in an uncertain situation, where the understanding of a need is limited and not much is known about the solution space. In this situation the design team has to both analyse need and explore solution space. Thus, the team has to formulate design...... specifications, which express attractive product goals, and has to synthesise the product idea. The authors of this paper see a challenge to enhance and improve our understanding of the nature of design specifications as a means to support the synthesis of a product idea. In this empirical study we analyse...... the structure and content of design specifications during early ideation activities, where initial design specifications are formulated and a product idea is synthesised. We have analysed specification documents of 19 teams of novice designers. Our analysis indicates that a productive product design...

  3. Improvements to Technical Specifications surveillance requirements

    International Nuclear Information System (INIS)

    Lobel, R.; Tjader, T.R.

    1992-12-01

    In August 1983 an NRC task group was formed to investigate problems with surveillance testing required by Technical Specifications, and to recommend approaches to effect improvements. NUREG-1024 (''Technical Specifications-Enhancing Safety Impact'') resulted, and it contained recommendations to review the basis for test frequencies; to ensure that the tests promote safety and do not degrade equipment; and to review surveillance tests so that they do not unnecessarily burden personnel. The Technical Specifications Improvement Program (TSIP) was established in December 1984 to provide the framework for rewriting and improving the Technical Specifications. As an element of the TSIP, all Technical Specifications surveillance requirements were comprehensively examined as recommended in NUREG-1024. The results of that effort are presented in this report. The study found that while some testing at power is essential to verify equipment and system operability, safety can be improved, equipment degradation decreased, and unnecessary personnel burden relaxed by reducing the amount of testing at power

  4. Standard Technical Specifications, Babcock and Wilcox plants

    International Nuclear Information System (INIS)

    1992-09-01

    This NUREG contains improved Standard Technical Specifications (STS) for Babcock and Wilcox (B ampersand W) Plants and documents the positions of the Nuclear Regulatory Commission based on the B ampersand W Owners Group's proposed STS. This document is the result of extensive technical meetings and discussions among the NRC staff, the Nuclear Steam Supply System (NSSS) Owners Groups, the NSSS vendors, and the Nuclear Management and Resources Council (NUMARC). The unproved STS were developed based on the, criteria in the interim Commission Policy Statement on Technical Specification Improvements for Nuclear Power Reactors, dated February 6, 1987. The improved STS will be used as the basis for individual nuclear power plant licensees to develop proved plant-specific technical specifications. This report contains three volumes. This document, Volume 1 contains the Specifications for all chapters and sections of the improved STS

  5. Rf system specifications for a linear accelerator

    International Nuclear Information System (INIS)

    Young, A.; Eaton, L.E.

    1992-01-01

    A linear accelerator contains many systems; however, the most complex and costly is the RF system. The goal of an RF system is usually simply stated as maintaining the phase and amplitude of the RF signal within a given tolerance to accelerate the charged particle beam. An RF system that drives a linear accelerator needs a complete system specification, which should contain specifications for all the subsystems (i.e., high-power RF, low-level RF, RF generation/distribution, and automation control). This paper defines a format for the specifications of these subsystems and discusses each RF subsystem independently to provide a comprehensive understanding of the function of each subsystem. This paper concludes with an example of a specification spreadsheet allowing one to input the specifications of a subsystem. Thus, some fundamental parameters (i.e., the cost and size) of the RF system can be determined

  6. Specificity of transmembrane protein palmitoylation in yeast.

    Directory of Open Access Journals (Sweden)

    Ayelén González Montoro

    Full Text Available Many proteins are modified after their synthesis, by the addition of a lipid molecule to one or more cysteine residues, through a thioester bond. This modification is called S-acylation, and more commonly palmitoylation. This reaction is carried out by a family of enzymes, called palmitoyltransferases (PATs, characterized by the presence of a conserved 50- aminoacids domain called "Asp-His-His-Cys- Cysteine Rich Domain" (DHHC-CRD. There are 7 members of this family in the yeast Saccharomyces cerevisiae, and each of these proteins is thought to be responsible for the palmitoylation of a subset of substrates. Substrate specificity of PATs, however, is not yet fully understood. Several yeast PATs seem to have overlapping specificity, and it has been proposed that the machinery responsible for palmitoylating peripheral membrane proteins in mammalian cells, lacks specificity altogether.Here we investigate the specificity of transmembrane protein palmitoylation in S. cerevisiae, which is carried out predominantly by two PATs, Swf1 and Pfa4. We show that palmitoylation of transmembrane substrates requires dedicated PATs, since other yeast PATs are mostly unable to perform Swf1 or Pfa4 functions, even when overexpressed. Furthermore, we find that Swf1 is highly specific for its substrates, as it is unable to substitute for other PATs. To identify where Swf1 specificity lies, we carried out a bioinformatics survey to identify amino acids responsible for the determination of specificity or Specificity Determination Positions (SDPs and showed experimentally, that mutation of the two best SDP candidates, A145 and K148, results in complete and partial loss of function, respectively. These residues are located within the conserved catalytic DHHC domain suggesting that it could also be involved in the determination of specificity. Finally, we show that modifying the position of the cysteines in Tlg1, a Swf1 substrate, results in lack of palmitoylation, as

  7. Validating Avionics Conceptual Architectures with Executable Specifications

    Directory of Open Access Journals (Sweden)

    Nils Fischer

    2012-08-01

    Full Text Available Current avionics systems specifications, developed after conceptual design, have a high degree of uncertainty. Since specifications are not sufficiently validated in the early development process and no executable specification exists at aircraft level, system designers cannot evaluate the impact of their design decisions at aircraft or aircraft application level. At the end of the development process of complex systems, e. g. aircraft, an average of about 65 per cent of all specifications have to be changed because they are incorrect, incomplete or too vaguely described. In this paper, a model-based design methodology together with a virtual test environment is described that makes complex high level system specifications executable and testable during the very early levels of system design. An aircraft communication system and its system context is developed to demonstrate the proposed early validation methodology. Executable specifications for early conceptual system architectures enable system designers to couple functions, architecture elements, resources and performance parameters, often called non-functional parameters. An integrated executable specification at Early Conceptual Architecture Level is developed and used to determine the impact of different system architecture decisions on system behavior and overall performance.

  8. Position paper: the science of deep specification.

    Science.gov (United States)

    Appel, Andrew W; Beringer, Lennart; Chlipala, Adam; Pierce, Benjamin C; Shao, Zhong; Weirich, Stephanie; Zdancewic, Steve

    2017-10-13

    We introduce our efforts within the project 'The science of deep specification' to work out the key formal underpinnings of industrial-scale formal specifications of software and hardware components, anticipating a world where large verified systems are routinely built out of smaller verified components that are also used by many other projects. We identify an important class of specification that has already been used in a few experiments that connect strong component-correctness theorems across the work of different teams. To help popularize the unique advantages of that style, we dub it deep specification , and we say that it encompasses specifications that are rich , two-sided , formal and live (terms that we define in the article). Our core team is developing a proof-of-concept system (based on the Coq proof assistant) whose specification and verification work is divided across largely decoupled subteams at our four institutions, encompassing hardware microarchitecture, compilers, operating systems and applications, along with cross-cutting principles and tools for effective specification. We also aim to catalyse interest in the approach, not just by basic researchers but also by users in industry.This article is part of the themed issue 'Verified trustworthy software systems'. © 2017 The Author(s).

  9. Cell-cycle phase specificity of chloroethylnitrosoureas

    International Nuclear Information System (INIS)

    Linfoot, P.A.

    1986-01-01

    Although the cancer chemotherapeutic agent 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) is considered a non-cell cycle phase specific drug, it has been shown to produce differential cell killing in G 1 , S, and G 2 /M phase cells, with S phase cells appearing relatively resistant. Studies of cell cycle phase specific cell killing produced by nitrosoureas with different chemical reactivities, clearly indicated that the ability of compounds to cross-link DNA was important in determining their phase specificity. Cells that lacked guanine O 6 -alkytransferase activity showed similar patterns of BCNU phase specificity regardless of their intrinsic sensitivity to BCNU. DNA inter-strand cross-linking, as measured by alkaline elution, was similar in cells exposed to BCNU in G 1 or S phase. 3 H [1-chloroethyl-1nitrosourea] binding to DNA was the same in G 1 , S and G 2 /M phase cells indicating that phase-specific differences in drug uptake and intracellular drug dose were not responsible for phase specific cell kill. These studies suggest that cross-link lesions, other than DNA inter-strand cross-links, and/or effects on DNA repair, other than guanine O 6 -alkyltransferase, are additional important determinants of BCNU phase specific cell killing

  10. Formal specifications for safety grade systems

    International Nuclear Information System (INIS)

    Chisholm, G.H.; Smith, B.T.; Wojcik, A.S.

    1992-01-01

    The authors describe the findings of a study into the application of formal methods to the specification of a safety system for an operating nuclear reactor. They developed a formal specification that is used to verify and validate that no unsafe condition will result from action or inaction of the system. For this reason, the specification must facilitate thinking about, talking about, and implementing the system. In fact, the specification must provide a bridge between people (designers, engineers, policy makers) and diverse implementations (hardware, software, sensors, power supplies) at all levels. For a specification to serve as an effective linkage, it must have the following properties: (1) completeness, (2) conciseness, (3) unambiguity, and (4) communicativeness. In this paper they describe the development of a specification that has three properties. This development is based on the use of formal methods, i.e., methods that add mathematical rigor to the development, analysis and operation of computer systems and to applications based thereon (Neumann). They demonstrate that a specification derived from a formal basis facilitates development of the design and its subsequent verification

  11. Non-specific immunization against babesiosis

    International Nuclear Information System (INIS)

    Cox, F.E.G.

    1980-01-01

    The rodent babesias, Babesia rodhaini and the less virulent B. microti, are useful models with which to study immunity to and immunization against babesiosis. In contrast with the difficulty in inducing specific immunity to these parasites it is comparatively easy to induce non-specific immunity by prior exposure to related and unrelated intra-erythrocytic protozoa, micro-organisms such as Mycobacterium bovis (BCG) and Corynebacterium parvum, microbial extracts and muramyl dipeptide. This non-specific immunity is long lasting and extremely effective. It is characterized by the facts that (a) it occurs early in the infection at the height of the first peak of parasitaemia, and (b) it involves the intra-erythrocytic death of the parasites. After the primary parasitaemia has resolved, some parasites continue to persist at a low level and when introduced into clean mice produce only low-level 'attenuated' infections in these. Non-specific immunity is not equally effective in all strains of mice. It is suggested that immunity to babesiosis, and infections caused by other intra-erythrocytic protozoa, involves two mechanisms, the first non-specific and the second specific. The actual balance between these two mechanisms varies from parasite to parasite and from host to host. An effective vaccine would have to be based on an understanding of the roles of non-specific immunity in the actual disease under consideration, and would ideally combine an adjuvant that would also stimulate non-specific immunity and an attenuated strain of parasite that would induce a specific response. (author)

  12. Assessment of the specificity of norethisterone radioimmunoassays

    Energy Technology Data Exchange (ETDEWEB)

    Bedolla-Tovar, N; Rahman, S A; Cekan, S Z; Diczfalusy, E [Swedish Medical Research Council, Karolinska Hospital, Stockholm

    1978-06-01

    It is concluded that (1) the significance of cross- reaction studies as well as that of the parallelism test for the assessment of the over-all specificity of the assay is limited, (2) a single chromatography prior to the radioimmunoassay proper improves the assay specificity, but may not be sufficient to remove all interfering compounds, (3) a comparison of the direct and chromatographic assay procedures using several antisera is useful for the selection of the relatively most specific radioimmunoassay procedure. In the present study, this is the technique employing either antiserum C or antiserum D, the latter, however, only after chromatography.

  13. PD-L1-specific T cells

    DEFF Research Database (Denmark)

    Ahmad, Shamaila Munir; Borch, Troels Holz; Hansen, Morten

    2016-01-01

    -specific T cells that recognize both PD-L1-expressing immune cells and malignant cells. Thus, PD-L1-specific T cells have the ability to modulate adaptive immune reactions by reacting to regulatory cells. Thus, utilization of PD-L1-derived T cell epitopes may represent an attractive vaccination strategy...... for targeting the tumor microenvironment and for boosting the clinical effects of additional anticancer immunotherapy. This review summarizes present information about PD-L1 as a T cell antigen, depicts the initial findings about the function of PD-L1-specific T cells in the adjustment of immune responses...

  14. Quality Assurance for Iraqi Bottled Water Specifications

    Directory of Open Access Journals (Sweden)

    May George Kassir

    2015-10-01

    Full Text Available In this research the specifications of Iraqi drinking bottled water brands are investigated throughout the comparison between local brands, Saudi Arabia and the World Health Organization (WHO for bottled water standard specifications. These specifications were also compared to that of Iraqi Tap Water standards. To reveal variations in the specifications for Iraqi bottled water, and above mentioned standards some quality control tools are conducted for more than 33% of different bottled water brands (of different origins such as spring, purified,..etc in Iraq by investigating the selected quality parameters registered on their marketing labels. Results employing Minitab software (ver. 16 to generate X bar, and Pareto chart. It was found from X bar charts that the quality parameters of some drinking bottled water brands are not within Iraqi standards set by the “Central Agency for Standardization and Quality Control” such as pH values, Fe, Na, and Mg concentrations. While the comparison of previously mentioned standard specifications through radar chart many important issues are detected such as the absence of lower limits the whole bottled water quality parameters such as for Na and Mg also the radar chart shows that Iraqi bottled and tap water specifications are almost equal in their quality values. Also the same chart pictured the limited range of Iraqi specifications compared to that of Saudi Arabia, and WHO and the need to introduce other water specifications such as K, Na, etc. This confirms the need to improve Iraqi bottled water specifications since it was introduced on 2000. These results also highlighted the weakness of quality assurance activities since only 33 % of the investigated companies registered the whole water quality specifications as shown in Pareto chart. Other companies do not register any quality characteristics. Also certain companies should be stopped due to non-conforming specifications, yet these companies are

  15. Technical specification optimization program - engineered safety features

    International Nuclear Information System (INIS)

    Andre, G.R.; Jansen, R.L.

    1986-01-01

    The Westinghouse Technical Specification Program (TOP) was designed to evaluate on a quantitative basis revisions to Nuclear Power Plant Technical Specifications. The revisions are directed at simplifying plant operation, and reducing unnecessary transients, shutdowns, and manpower requirements. In conjunction with the Westinghouse Owners Group, Westinghouse initiated a program to develop a methodology to justify Technical Specification revisions; particularly revisions related to testing and maintenance requirements on plant operation for instrumentation systems. The methodology was originally developed and applied to the reactor trip features of the reactor protection system (RPS). The current study further refined the methodology and applied it to the engineered safety features of the RPS

  16. Table of specific activities of selected isotopes

    International Nuclear Information System (INIS)

    Shipley, G.

    The bulk of this publication consists of a table of the half-lives, decay modes, and specific activities of isotopes selected for their particular interest to the Environmental Health and Safety Department, LBL. The specific activities were calculated with a PDP 9/15 computer. Also included in the report is a table of stable isotopes, the Th and U decay chains, a chart of the nuclides for elements 101 through 106, the heavy element region of the periodic table, and a specific activity monograph. 5 figures, 2 tables

  17. Mining software specifications methodologies and applications

    CERN Document Server

    Lo, David

    2011-01-01

    An emerging topic in software engineering and data mining, specification mining tackles software maintenance and reliability issues that cost economies billions of dollars each year. The first unified reference on the subject, Mining Software Specifications: Methodologies and Applications describes recent approaches for mining specifications of software systems. Experts in the field illustrate how to apply state-of-the-art data mining and machine learning techniques to address software engineering concerns. In the first set of chapters, the book introduces a number of studies on mining finite

  18. Breckinridge Project, initial effort. Report III, Volume 2. Specifications

    Energy Technology Data Exchange (ETDEWEB)

    None

    1982-01-01

    Report III, Volume 2 contains those specifications numbered K through Y, as follows: Specifications for Compressors (K); Specifications for Piping (L); Specifications for Structures (M); Specifications for Insulation (N); Specifications for Electrical (P); Specifications for Concrete (Q); Specifications for Civil (S); Specifications for Welding (W); Specifications for Painting (X); and Specifications for Special (Y). The standard specifications of Bechtel Petroleum Incorporated have been amended as necessary to reflect the specific requirements of the Breckinridge Project and the more stringent specifications of Ashland Synthetic Fuels, Inc. These standard specifications are available for the Initial Effort (Phase Zero) work performed by all contractors and subcontractors.

  19. Interior Design's Role in Educational Specifications.

    Science.gov (United States)

    Keller, Mary Ann

    1986-01-01

    An experienced interior designer, equipped with a well-written educational specification, will specify the best materials and coordinate colors, materials, and furnishings in line with the district's budget. (MLF)

  20. Cockpit management and Specific Behavioral Objectives (SBOs)

    Science.gov (United States)

    Mudge, R. W.

    1987-01-01

    One of the primary tools used to accomplish the task of effective training is the specific behavioral objective (SBO). An SBO is simply a statement which specifically identifies a small segment of the final behavior sought, and a little more. The key word is specific. The company pinpoints exactly what it is it wants the pilot to do after completing training, and what it should evaluate from the point of view of both the program and the pilot. It tells the junior crewmember exactly, specifically, what he should monitor and support insofar as the management function is concerned. It gives greater meaning to the term second in command. And finally, it tells the supervisory pilot exactly what he should observe, evaluate, and instruct, insofar as the management function is concerned.

  1. 14 CFR 211.10 - Filing specifications.

    Science.gov (United States)

    2010-01-01

    ...) ECONOMIC REGULATIONS APPLICATIONS FOR PERMITS TO FOREIGN AIR CARRIERS General Requirements § 211.10 Filing... in § 302.3 of this chapter as to execution, number of copies, and formal specifications of papers. (b...

  2. Non-specific immunization against parasites

    International Nuclear Information System (INIS)

    Cox, F.E.G.

    1981-01-01

    Non-specific resistance to tumours can be induced by pretreating animals with micro-organisms, microbial extracts or various synthetic substances. Mycobacterium bovis, Corynebacterium parvum and a number of other micro-organisms also protect mice against rodent piroplasms and there is evidence that they are also protective against other parasites including Schistosoma mansoni. The actual mechanisms of non-specific immunity are still unclear but it is influenced by both the genetic make-up of the host and the nature of the parasite. Non-specific immunization may be a possible alternative to specific immunization and may avoid many of the potential immunopathological changes induced during parasite infections. Irradiated vaccines (Dictyocaulus viviparus, schistomiasis) are mentioned marginally only

  3. Standard specification for silvered flat glass mirror

    CERN Document Server

    American Society for Testing and Materials. Philadelphia

    2008-01-01

    1.1 This specification covers the requirements for silvered flat glass mirrors of rectangular shape supplied as cut sizes, stock sheets or as lehr ends and to which no further processing (such as edgework or other fabrication) has been done. 1.2 This specification covers the quality requirements of silvered annealed monolithic clear and tinted flat glass mirrors up to 6 mm (¼ in.) thick. The mirrors are intended to be used indoors for mirror glazing, for components of decorative accessories or for similar uses. 1.3 This specification does not address safety glazing materials nor requirements for mirror applications. Consult model building codes and other applicable standards for safety glazing applications. 1.4 Mirrors covered in this specification are not intended for use in environments where high humidity or airborne corrosion promoters, or both, are consistently present (such as swimming pool areas, ocean-going vessels, chemical laboratories and other corrosive environments). 1.5 The dimensional val...

  4. Chemical cleaning specification: few tube test model

    International Nuclear Information System (INIS)

    Hampton, L.V.; Simpson, J.L.

    1979-09-01

    The specification is for the waterside chemical cleaning of the 2 1/4 Cr - 1 Mo steel steam generator tubes. It describes the reagents and conditions for post-chemical cleaning passivation of the evaporator tubes

  5. Performance evaluation and specification of trackless tack.

    Science.gov (United States)

    2016-09-01

    Several trackless tack products have come to market in Texas; however, there are currently no specifications to : ensure the products have trackless properties and adequate bond strength. The objectives of this project were to : (1) evaluate the trac...

  6. ROS signalling – Specificity is required

    DEFF Research Database (Denmark)

    Møller, Ian Max; Sweetlove, Lee J

    2011-01-01

    The production of reactive oxygen species (ROS) increases in plants under stress. ROS can damage cellular components, but they can also act in signal transduction to help the cell counteract the oxidative damage in the stressed compartment. H2O2 may induce a general stress response, but it does...... messengers and regulate source-specific genes and in this way contribute to retrograde ROS signalling during oxidative stress. (This is a new project funded by FNU) References: Møller, I.M. & Sweetlove, L.J. 2010. ROS signalling – Specificity is required. Trends Plant Sci. 15: 370-374...... not have the required specificity to selectively regulate nuclear genes required for dealing with localized stress, e.g., in chloroplasts or mitochondria. We here argue that peptides deriving from proteolytic breakdown of oxidatively damaged proteins have the requisite specificity to act as secondary ROS...

  7. Technical specifications: Health Physics Research Reactor

    International Nuclear Information System (INIS)

    1986-03-01

    These technical specifications define the key limitations that must be observed for safe operation of the Health Physics Research Reactor (HPRR) and an envelope of operation within which there is assurance that these limits will not be exceeded

  8. Iteration and Prototyping in Creating Technical Specifications.

    Science.gov (United States)

    Flynt, John P.

    1994-01-01

    Claims that the development process for computer software can be greatly aided by the writers of specifications if they employ basic iteration and prototyping techniques. Asserts that computer software configuration management practices provide ready models for iteration and prototyping. (HB)

  9. Computational network design from functional specifications

    KAUST Repository

    Peng, Chi Han; Yang, Yong Liang; Bao, Fan; Fink, Daniel; Yan, Dongming; Wonka, Peter; Mitra, Niloy J.

    2016-01-01

    of people in a workspace. Designing such networks from scratch is challenging as even local network changes can have large global effects. We investigate how to computationally create networks starting from only high-level functional specifications

  10. Double-Shell Tank (DST) Utilities Specification

    International Nuclear Information System (INIS)

    SUSIENE, W.T.

    2000-01-01

    This specification establishes the performance requirements and provides the references to the requisite codes and standards to he applied during the design of the Double-Shell Tank (DST) Utilities Subsystems that support the first phase of waste feed delivery (WFD). The DST Utilities Subsystems provide electrical power, raw/potable water, and service/instrument air to the equipment and structures used to transfer low-activity waste (LAW) and high-level waste (HLW) to designated DST staging tanks. The DST Utilities Subsystems also support the equipment and structures used to deliver blended LAW and HLW feed from these staging tanks to the River Protection Project (RPP) Privatization Contractor facility where the waste will be immobilized. This specification is intended to be the basis for new projects/installations. This specification is not intended to retroactively affect previously established project design criteria without specific direction by the program

  11. Specific energy released in power reactors

    International Nuclear Information System (INIS)

    Zaritskaya, T.S.; Kiselev, G.V.; Rudik, A.P.; Tsenter, Eh.M.

    1986-01-01

    Technique of determination are described and analysis of specific energy for different methods of critically maintance of RBMK and WWER-440 reactors are conducted. Characteristics of the optimal mode of critically maintanance are determined

  12. Finding Specification Pages from the Web

    Science.gov (United States)

    Yoshinaga, Naoki; Torisawa, Kentaro

    This paper presents a method of finding a specification page on the Web for a given object (e.g., ``Ch. d'Yquem'') and its class label (e.g., ``wine''). A specification page for an object is a Web page which gives concise attribute-value information about the object (e.g., ``county''-``Sauternes'') in well formatted structures. A simple unsupervised method using layout and symbolic decoration cues was applied to a large number of the Web pages to acquire candidate attributes for each class (e.g., ``county'' for a class ``wine''). We then filter out irrelevant words from the putative attributes through an author-aware scoring function that we called site frequency. We used the acquired attributes to select a representative specification page for a given object from the Web pages retrieved by a normal search engine. Experimental results revealed that our system greatly outperformed the normal search engine in terms of this specification retrieval.

  13. High Flux Isotope Reactor technical specifications

    International Nuclear Information System (INIS)

    1985-11-01

    This report gives technical specifications for the High Flux Isotope Reactor (HFIR) on the following: safety limits and limiting safety system settings; limiting conditions for operation; surveillance requirements; design features; and administrative controls

  14. Cdc42-mediated tubulogenesis controls cell specification

    DEFF Research Database (Denmark)

    Kesavan, Gokul; Sand, Fredrik Wolfhagen; Greiner, Thomas Uwe

    2009-01-01

    Understanding how cells polarize and coordinate tubulogenesis during organ formation is a central question in biology. Tubulogenesis often coincides with cell-lineage specification during organ development. Hence, an elementary question is whether these two processes are independently controlled......, or whether proper cell specification depends on formation of tubes. To address these fundamental questions, we have studied the functional role of Cdc42 in pancreatic tubulogenesis. We present evidence that Cdc42 is essential for tube formation, specifically for initiating microlumen formation and later...... for maintaining apical cell polarity. Finally, we show that Cdc42 controls cell specification non-cell-autonomously by providing the correct microenvironment for proper control of cell-fate choices of multipotent progenitors. For a video summary of this article, see the PaperFlick file with the Supplemental Data...

  15. Site-specific weed control technologies

    DEFF Research Database (Denmark)

    Christensen, Svend; Søgaard, Henning Tangen; Kudsk, Per

    2009-01-01

    Site-specific weed control technologies are defined as machinery or equipment embedded with technologies that detect weeds growing in a crop and, taking into account predefined factors such as economics, takes action to maximise the chances of successfully controlling them. In the article, we...... describe the basic parts of site specific weed control technologies, comprising of weed sensing systems, weed management models and precision weed control implements. A review of state-of-the-art technologies shows that several weed sensing systems and precision implements have been developed over the last...... of knowledge about the economic and environmental potential for increasing the resolution of weed control. The integration of site-specific information on weed distribution, weed species composition and density, and the effect on crop yield, is decisive for successful site-specific weed management.   Keywords...

  16. Cancer Chemotherapy Specific to Acidic Nests.

    Science.gov (United States)

    Kobayashi, Hiroshi

    2017-04-20

    The realization of cancer therapeutics specific to cancer cells with less of an effect on normal tissues is our goal. Many trials have been carried out for this purpose, but this goal is still far from being realized. It was found more than 80 years ago that solid cancer nests are acidified, but in vitro studies under acidic conditions have not been extensively studied. Recently, in vitro experiments under acidic conditions were started and anti-cancer drugs specific to acidic areas have been identified. Many genes have been reported to be expressed at a high level under acidic conditions, and such genes may be potent targets for anti-cancer drugs specific to acidic nests. In this review article, recent in vitro, in vivo, and clinical achievements in anti-cancer drugs with marked efficacy under acidic conditions are summarized, and the clinical use of anti-cancer drugs specific to acidic nests is discussed.

  17. Specification for symbol for ionizing radiation

    International Nuclear Information System (INIS)

    1974-01-01

    This Malaysia Standard specification specifies a symbol recommended for use only to signify the actual or potential presence of ionizing radiation (#betta#, α, #betta# only) and to identify objects, devices, materials or combinations of materials which emit such radiation. (author)

  18. Standard Technical Specifications, Babcock and Wilcox Plants

    International Nuclear Information System (INIS)

    1992-09-01

    This NUREG contains improved Standard Technical Specifications (STS) for Babcock and Wilcox (B ampersand W) plants and documents the positions of the Nuclear Regulatory Commission (NRC) based on the B ampersand W Owners Group's proposed STS. This document is the result of extensive technical meetings and discussions among the NRC staff, the Nuclear Steam Supply System (NSSS) Owners Groups, the NSSS vendors, and the Nuclear Management and Resources Council. The improved STS were developed based on the criteria in the interim Commission Policy Statement on Technical Specification Improvements for Nuclear Power Reactors, dated February 6, 1987. The improved STS will be used as the basis for developing improved plant-specific technical specifications by individual nuclear power plant licensees. This volume contains sections 3.4--3.9 which cover: Reactor coolant systems, emergency core cooling systems, containment systems, plant systems, electrical power systems, refueling operations

  19. Factors influencing women's decisions to purchase specific ...

    African Journals Online (AJOL)

    aimed at identifying the factors that influence women's decisions to purchase specific .... influence of all the factors influencing their decision to purchase a selected .... one free” promotions seemed to have had the greatest influence on this ...

  20. Disease specific therapies in leukodystrophies and leukoencephalopathies

    NARCIS (Netherlands)

    Helman, Guy; van Haren, Keith; Bonkowsky, Joshua L.; Bernard, Genevieve; Pizzino, Amy; Braverman, Nancy; Suhr, Dean; Patterson, Marc C.; Ali Fatemi, S.; Leonard, Jeff; van der Knaap, Marjo S.; Back, Stephen A.; Damiani, Stephen; Goldman, Steven A.; Takanohashi, Asako; Petryniak, Magdalena; Rowitch, David; Messing, Albee; Wrabetz, Lawrence; Schiffmann, Raphael; Eichler, Florian; Escolar, Maria L.; Vanderver, Adeline

    2015-01-01

    Leukodystrophies are a heterogeneous, often progressive group of disorders manifesting a wide range of symptoms and complications. Most of these disorders have historically had no etiologic or disease specific therapeutic approaches. Recently, a greater understanding of the pathologic mechanisms

  1. Peptide binding specificity of the chaperone calreticulin

    DEFF Research Database (Denmark)

    Sandhu, N.; Duus, K.; Jorgensen, C.S.

    2007-01-01

    Calreticulin is a molecular chaperone with specificity for polypeptides and N-linked monoglucosylated glycans. In order to determine the specificity of polypeptide binding, the interaction of calreticulin with polypeptides was investigated using synthetic peptides of different length and composit......Calreticulin is a molecular chaperone with specificity for polypeptides and N-linked monoglucosylated glycans. In order to determine the specificity of polypeptide binding, the interaction of calreticulin with polypeptides was investigated using synthetic peptides of different length...... than 5 amino acids showed binding and a clear correlation with hydrophobicity was demonstrated for oligomers of different hydrophobic amino acids. Insertion of hydrophilic amino acids in a hydrophobic sequence diminished or abolished binding. In conclusion our results show that calreticulin has...

  2. Prostate-Specific Antigen (PSA) Test

    Science.gov (United States)

    ... Cancer Prostate Cancer Screening Research Prostate-Specific Antigen (PSA) Test On This Page What is the PSA ... parts of the body before being detected. The PSA test may give false-positive or false-negative ...

  3. Bottomland Hardwood Planting: Example Contract Specifications

    National Research Council Canada - National Science Library

    Humprey, Monica

    2002-01-01

    This technical note provides an example of contract specifications that can be used as a template by USACE biologists, engineers, or contracting officers for contracting the planting of bottomland hardwood (BLH) seedlings...

  4. Specific detection of proteins using Nanomechanical resonators

    DEFF Research Database (Denmark)

    Fischer, Lee MacKenzie; Wright, V.A.; Guthy, C.

    2008-01-01

    of probes onto their surfaces in order to enable the specificity of the detection. Such nanoresonator-based specific detection of proteins is here reported using streptavidin as target system, and immobilized biotin as probe. Nanomechanical resonators resistant to stiction were first realized from silicon...... carbonitride using a novel fabrication method. Vapor-phase deposition of mercaptopropyl trimethoxysilane was performed, and an added mass of 2.22 +/- 0.07 fg/mu m(2) was measured. This linker molecule was used to attach biotin onto the devices, enabling the specific detection of streptavidin. A mass of 3.6 fg....../mu m(2) was attributed to the added streptavidin, corresponding to one molecule per 27 nm(2). The specificity of this recognition was confirmed by exposing the devices to a solution of streptavidin that was already saturated with biotin. An additional negative control was also performed by also...

  5. Analyzing Security-Enhanced Linux Policy Specifications

    National Research Council Canada - National Science Library

    Archer, Myla

    2003-01-01

    NSA's Security-Enhanced (SE) Linux enhances Linux by providing a specification language for security policies and a Flask-like architecture with a security server for enforcing policies defined in the language...

  6. Technical specifications for the bulk shielding reactor

    International Nuclear Information System (INIS)

    1986-05-01

    This report provides information concerning the technical specifications for the Bulk Shielding Reactor. Areas covered include: safety limits and limiting safety settings; limiting conditions for operation; surveillance requirements; design features; administrative controls; and monitoring of airborne effluents. 10 refs

  7. Technical specifications for the pool critical assembly

    International Nuclear Information System (INIS)

    1978-07-01

    Technical specifications for the ORNL-PCA Reactor are presented concerning safety limits and limiting safety system settings, limiting conditions for operation, surveillance requirements, design features, and administrative controls

  8. Index to Drug-Specific Information

    Science.gov (United States)

    ... Postmarket Drug Safety Information for Patients and Providers Index to Drug-Specific Information Share Tweet Linkedin Pin ... options Linkedin Pin it Email Print Note: This Index does not include all FDA approved drugs. It ...

  9. Project NEO Specific Impulse Testing Solutions

    Science.gov (United States)

    Baffa, Bill

    2018-01-01

    The Neo test stand is currently configured to fire a horizontally mounted rocket motor with up to 6500 lbf thrust. Currently, the Neo test stand can measure flow of liquid propellant and oxidizer, pressures residing in the closed system up to the combustion chamber. The current configuration does not have the ability to provide all data needed to compute specific impulse. This presents three methods to outfit the NEO test fixture with instrumentation allowing for calculation of specific impulse.

  10. Affect and person specificity in mood regulation

    OpenAIRE

    Corby, Emma Kate

    2007-01-01

    489 university students in three countries completed questionnaires in a study investigating affect and person specificity in the use of mood regulation strategies. The major aims of the study were to (1) describe the relationship between specific affective states and the strategies utilised, (2) explore the role that individual differences variables played in the tendency to use particular strategies, and (3) measure the impact that the use of different strategies had upon subjective well-b...

  11. Production of Monoclonal Antibodies specific for Progesterone

    OpenAIRE

    YÜCEL, Fatıma

    2014-01-01

    Progesterone levels in milk and serum are indicators of pregnancy in cattle. The progesterone level reaches a peak on the 21 st and 22 nd days of pregnancy. Monoclonal antibodies specific to progesterone could be used for the immunodetection of milk and serum progesterone levels. We report here the development of hybrid cells prdoducing monoclonal antibodies specific for progesterone using hybridoma technology. Hybridoma cells secreting monoclonal antibodies against progesterone (MAM 2H1...

  12. Chemical and radiochemical specifications - PWR power plants

    International Nuclear Information System (INIS)

    Stutzmann, A.

    1997-01-01

    Published by EDF this document gives the chemical specifications of the PWR (Pressurized Water Reactor) nuclear power plants. Among the chemical parameters, some have to be respected for the safety. These parameters are listed in the STE (Technical Specifications of Exploitation). The values to respect, the analysis frequencies and the time states of possible drops are noticed in this document with the motion STE under the concerned parameter. (A.L.B.)

  13. [Psychological specificities of living donor kidney transplantation].

    Science.gov (United States)

    Papeloux-Heitzmann, Élodie

    2016-12-01

    For people with end-stage kidney disease, a transplant is the promise of a future without dialysis. Living donor kidney transplantation comprises many specificities and is distinct from cadaveric donor transplantation. Some psychological aspects explain these specificities. They may be subconscious and difficult to access, but it is essential to decipher them in order to adapt the support provided to these people. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  14. Patient-Specific Modeling in Tomorrow's Medicine

    CERN Document Server

    2012-01-01

    This book reviews the frontier of research and clinical applications of Patient Specific Modeling, and provides a state-of-the-art update as well as perspectives on future directions in this exciting field. The book is useful for medical physicists, biomedical engineers and other engineers who are interested in the science and technology aspects of Patient Specific Modeling, as well as for radiologists and other medical specialists who wish to be updated about the state of implementation.

  15. Task-Specific Training and Job Design

    OpenAIRE

    Felipe Balmaceda

    2006-01-01

    This paper provides a simple theoretical framework based on a new type of human capital introduced by Gibbons and Waldman (2004), called task-specific training, to understand job design. Mainly, in the presence of task-specific training, promotions might result ex-post in the underutilization of human capital and thus firms at the time of designing jobs should attempt to diversify this risk.

  16. Specific phobia predicts psychopathology in young women

    OpenAIRE

    Trumpf, Julia; Margraf, Jürgen; Vriends, Noortje; Meyer, Andrea Hans; Becker, Eni S.

    2010-01-01

    Background Although specific phobia is characterized by an early age at onset and by high rates of comorbidity, few studies have examined comorbid relationships prospectively. Objectives The present study investigated the association between specific phobia and the risk of a broad range of psychopathology among young women in the community. Method Data came from the Dresden Predictor Study in which 1,538 German women (18?25?years) completed a diagnostic interview at two time points. Results W...

  17. Enzyme specific activity in functionalized nanoporous supports

    International Nuclear Information System (INIS)

    Lei Chenghong; Soares, Thereza A; Shin, Yongsoon; Liu Jun; Ackerman, Eric J

    2008-01-01

    Here we reveal that enzyme specific activity can be increased substantially by changing the protein loading density (P LD ) in functionalized nanoporous supports so that the enzyme immobilization efficiency (I e , defined as the ratio of the specific activity of the immobilized enzyme to the specific activity of the free enzyme in solution) can be much higher than 100%. A net negatively charged glucose oxidase (GOX) and a net positively charged organophosphorus hydrolase (OPH) were entrapped spontaneously in NH 2 - and HOOC-functionalized mesoporous silica (300 A, FMS) respectively. The specific activity of GOX entrapped in FMS increased with decreasing P LD . With decreasing P LD , I e of GOX in FMS increased from 150%. Unlike GOX, OPH in HOOC-FMS showed increased specific activity with increasing P LD . With increasing P LD , the corresponding I e of OPH in FMS increased from 100% to>200%. A protein structure-based analysis of the protein surface charges directing the electrostatic interaction-based orientation of the protein molecules in FMS demonstrates that substrate access to GOX molecules in FMS is limited at high P LD , consequently lowering the GOX specific activity. In contrast, substrate access to OPH molecules in FMS remains open at high P LD and may promote a more favorable confinement environment that enhances the OPH activity

  18. Autobiographical memory specificity in dissociative identity disorder.

    Science.gov (United States)

    Huntjens, Rafaële J C; Wessel, Ineke; Hermans, Dirk; van Minnen, Agnes

    2014-05-01

    A lack of adequate access to autobiographical knowledge has been related to psychopathology. More specifically, patients suffering from depression or a history of trauma have been found to be characterized by overgeneral memory, in other words, they show a relative difficulty in retrieving a specific event from memory located in time and place. Previous studies of overgeneral memory have not included patients with dissociative disorders. These patients are interesting to consider, as they are hypothesized to have the ability to selectively compartmentalize information linked to negative emotions. This study examined avoidance and overgeneral memory in patients with dissociative identity disorder (DID; n = 12). The patients completed the autobiographical memory test (AMT). Their performance was compared with control groups of posttraumatic stress disorder (PTSD) patients (n = 26), healthy controls (n = 29), and DID simulators (n = 26). Specifically, we compared the performance of separate identity states in DID hypothesized to diverge in the use of avoidance as a coping strategy to deal with negative affect. No significant differences in memory specificity were found between the separate identities in DID. Irrespective of identity state, DID patients were characterized by a lack of memory specificity, which was similar to the lack of memory specificity found in PTSD patients. The converging results for DID and PTSD patients add empirical evidence for the role of overgeneral memory involved in the maintenance of posttraumatic psychopathology.

  19. Standardized Technical Specifications for Westinghouse PWRs

    International Nuclear Information System (INIS)

    1978-01-01

    This Standard Technical Specification (STS) has been structured for the broadest possible use on Westinghouse plants currently being reviewed for an Operating License. Accordingly, the document contains specifications applicable to plants (1) with either 3 or 4 loops and (2) with and without loop stop valves. In addition, four separate and discrete containment specification sections are provided for each of the following containment types: Atmospheric, Ice Condenser, Sub-Atmospheric, and Dual. Optional specifications are provided for those features and systems which may be included in individual plant designs but are not generic in their scope of application. Alternate specifications are provided in a limited number of cases to cover situations where alternate specification requirements are necessary on a generic basis because of design differences. The format of the STS addresses the categories required by 10 CFR 50 and consists of six sections covering the areas of: Definitions, Safety Limits and Limiting Safety System Settings, Limiting Conditions for Operation, Surveillance Requirements, Design Features, and Administrative Controls

  20. Age-specific reference ranges of serum prostate-specific antigen in Iranian men

    Directory of Open Access Journals (Sweden)

    Gholamreza Pourmand

    2015-08-01

    Conclusion: Findings of the present study showed that PSA levels are correlated with age. It was also revealed that the PSA age-specific reference range obtained in this study is different from other races and is specific to Iranian men. Therefore, age-specific reference ranges of PSA obtained in the present study can increase PSA test sensitivity and specificity by reducing unnecessary diagnostic procedures and early detection of prostate cancer in Iranian men.

  1. Domain Specific Language Support for Exascale

    Energy Technology Data Exchange (ETDEWEB)

    Mellor-Crummey, John [Rice Univ., Houston, TX (United States)

    2017-10-20

    A multi-institutional project known as D-TEC (short for “Domain- specific Technology for Exascale Computing”) set out to explore technologies to support the construction of Domain Specific Languages (DSLs) to map application programs to exascale architectures. DSLs employ automated code transformation to shift the burden of delivering portable performance from application programmers to compilers. Two chief properties contribute: DSLs permit expression at a high level of abstraction so that a programmer’s intent is clear to a compiler and DSL implementations encapsulate human domain-specific optimization knowledge so that a compiler can be smart enough to achieve good results on specific hardware. Domain specificity is what makes these properties possible in a programming language. If leveraging domain specificity is the key to keep exascale software tractable, a corollary is that many different DSLs will be needed to encompass the full range of exascale computing applications; moreover, a single application may well need to use several different DSLs in conjunction. As a result, developing a general toolkit for building domain-specific languages was a key goal for the D-TEC project. Different aspects of the D-TEC research portfolio were the focus of work at each of the partner institutions in the multi-institutional project. D-TEC research and development work at Rice University focused on on three principal topics: understanding how to automate the tuning of code for complex architectures, research and development of the Rosebud DSL engine, and compiler technology to support complex execution platforms. This report provides a summary of the research and development work on the D-TEC project at Rice University.

  2. Formal specification level concepts, methods, and algorithms

    CERN Document Server

    Soeken, Mathias

    2015-01-01

    This book introduces a new level of abstraction that closes the gap between the textual specification of embedded systems and the executable model at the Electronic System Level (ESL). Readers will be enabled to operate at this new, Formal Specification Level (FSL), using models which not only allow significant verification tasks in this early stage of the design flow, but also can be extracted semi-automatically from the textual specification in an interactive manner.  The authors explain how to use these verification tasks to check conceptual properties, e.g. whether requirements are in conflict, as well as dynamic behavior, in terms of execution traces. • Serves as a single-source reference to a new level of abstraction for embedded systems, known as the Formal Specification Level (FSL); • Provides a variety of use cases which can be adapted to readers’ specific design flows; • Includes a comprehensive illustration of Natural Language Processing (NLP) techniques, along with examples of how to i...

  3. Standard Technical Specifications, Babcock and Wilcox plants

    International Nuclear Information System (INIS)

    1992-09-01

    This NUREG contains improved Standard Technical Specifications (STS) for Babcock and Wilcox (B ampersand W) Plants and documents the positions of the Nuclear Regulatory Commission based on the B ampersand W Owners Group's proposed STS. This document is the result of extensive technical meetings and discussions among the NRC staff, the Nuclear Steam Supply System (NSSS) Owners Groups, the NSSS vendors, and the Nuclear Management and Resources Council (NUMARC). The improved STS were developed based on the criteria in the interim Commission Policy Statement on Technical Specification Improvements for Nuclear Power Reactors, dated February 6, 1987. The improved STS will be used as the basis for individual nuclear power plant licensees to develop improved plant-specific technical specifications. This report contains three volumes. Volume 1 contains the Specifications for all chapters and sections of the improved STS. This document Volume 2, contains the Bases for Chapters 2.0 and 3.0, and Sections 3.1--3.3 of the improved STS. Volume 3 contains the Bases for Sections 3.4--3.10 of the improved STS

  4. Standard Technical Specifications, Combustion Engineering plants

    International Nuclear Information System (INIS)

    1992-09-01

    This NUREG contains improved Standard Technical Specifications (M) for Combustion Engineering (CE) Plants and documents the positions of the Nuclear Regulatory Commission based on the CE Owners Group's proposed STS. This document is the result of extensive technical meetings and discussions among the NRC staff, the Nuclear Steam Supply System (NSSS) Owners Groups, the NSSS vendors, and the Nuclear Management and Resources Council (NUMARC). The improved STS were developed based on the criteria in the interim Commission Policy Statement on Technical Specification Improvements for Nuclear Power Reactors, dated February 6, 1987. The improved STS will be used as the basis for individual nuclear power plant licensees to develop improved plant-specific technical specifications. This report contains three volumes. Volume 1 contains the Specifications for all chapters and sections of the improved STS. This document Volume 2 contains the Bases for Chapters 2.0 and 3.0, and Sections 3.1--3.3 of the improved STS. Volume 3 contains the Bases for Sections 3.4--3.9 of the improved STS

  5. Chromosome-specific DNA Repeat Probes

    Energy Technology Data Exchange (ETDEWEB)

    Baumgartner, Adolf; Weier, Jingly Fung; Weier, Heinz-Ulrich G.

    2006-03-16

    In research as well as in clinical applications, fluorescence in situ hybridization (FISH) has gained increasing popularity as a highly sensitive technique to study cytogenetic changes. Today, hundreds of commercially available DNA probes serve the basic needs of the biomedical research community. Widespread applications, however, are often limited by the lack of appropriately labeled, specific nucleic acid probes. We describe two approaches for an expeditious preparation of chromosome-specific DNAs and the subsequent probe labeling with reporter molecules of choice. The described techniques allow the preparation of highly specific DNA repeat probes suitable for enumeration of chromosomes in interphase cell nuclei or tissue sections. In addition, there is no need for chromosome enrichment by flow cytometry and sorting or molecular cloning. Our PCR-based method uses either bacterial artificial chromosomes or human genomic DNA as templates with {alpha}-satellite-specific primers. Here we demonstrate the production of fluorochrome-labeled DNA repeat probes specific for human chromosomes 17 and 18 in just a few days without the need for highly specialized equipment and without the limitation to only a few fluorochrome labels.

  6. Standard Technical Specifications, Combustion Engineering plants

    International Nuclear Information System (INIS)

    1992-09-01

    This NUREG contains improved Standard Technical Specifications (STS) for Combustion Engineering (CE) Plants and documents the positions of the Nuclear Regulatory Commission based on the CE Owners Group's proposed STS. This document is the result of extensive technical meetings and discussions among the NRC staff, the Nuclear Steam Supply System (NSSS) Owners Groups, the NSSS vendors, and the Nuclear Management and Resources Council (NUMARC). The improved STS were developed based on the criteria in the interim Commission Policy Statement on Technical Specification Improvements for Nuclear Power Reactors, dated February 6, 1987. The improved STS will be used as the basis for individual nuclear power plant licensees to develop improved plant-specific technical specifications. This report contains three volumes. Volume 1 contains the Specifications for all chapters and sections of the improved SM. Volume 2 contains the Bases for Chapters 2.0 and 3.0, and Sections 3.1--3.3 of the improved STS. This document Volume 3 contains the Bases for Sections 3.4--3.9 of the improved M

  7. The specificity and organisation of autobiographical memories.

    Science.gov (United States)

    Schulkind, Matthew D; Rahhal, Tamara A; Klein, Megan R; Lacher, Samantha R

    2012-01-01

    Previous research suggests that autobiographical memories are over-general and are organised according to life periods. One experiment assessed the specificity and organisation of autobiographical memory by manipulating two variables. The retrieval cues were either a set of three words (a theme, a time period, and an emotional valence) or a short narrative that included a specific theme, time period, and emotional valence. The instructions either encouraged the participants to respond as though they were conversing with a friend (social instructions) or did not specify a target audience (standard instructions). Narrative cues and standard instructions elicited more specific responses than word cues and social instructions, respectively. Whereas word cues elicited memories that were most likely to match the cues in terms of time period, narrative cues elicited memories that were most likely to match the cues in terms of theme. These data suggest that previous research underestimated the specificity of the autobiographical knowledge base and overestimated the importance of temporally defined life periods for organising autobiographical memory. Previous conclusions regarding the specificity and organisation of autobiographical memory may reflect the structure of autobiographical narratives and the methodologies used to collect such narratives rather than the content of autobiographical memory itself.

  8. The Role of Non-specific and Specific Immune Systems in Poultry against Newcastle Disease

    Directory of Open Access Journals (Sweden)

    Dyah Ayu Hewajuli

    2015-09-01

    Full Text Available Newcastle disease (ND is caused by avian paramyxovirus-1 which belong to Avulavirus genus and Paramyxoviridae family. The birds have abnormalities in humoral (bursa fabricius and cellular (thymus and spleen lymphoid organs. Lesions decrease the immune system. Immune system consists of non-specific and specific immune systems. The main components of non-specific immunity are physical and chemical barrier (feather and skin or mucosa, phagocytic cells (macrophages and natural killer, protein complement and the mediator of inflammation and cytokines. Interferons (IFNs belong to a group of cytokines that play a major role in the nonspecific or innate (natural immunity. The virulent ND virus encodes protein of V gene can be suppressed IFN type I. This leads to non-specific immune system fail to respond to the virulent strains resulting in severe pathogenicity. The defense mechanism of the host is replaced by specific immunity (adaptive immunity when natural immunity fails to overcome the infection. The specific immune system consists of humoral mediated immunity (HMI and cell-mediated immunity (CMI. The cells of immune system that react specifically with the antigen are B lymphocytes producing the antibodies, T lymphocytes that regulate the synthesis of antibodies and T cells as effector or the direct cytotoxic cells. Both non-specific and specific immunities are complementary against the invasion of ND virus in the birds. The objective of this article is to discuss the role of non specific and specific immune system in ND.

  9. NetH2pan: A Computational Tool to Guide MHC peptide prediction on Murine Tumors

    DEFF Research Database (Denmark)

    DeVette, Christa I; Andreatta, Massimo; Bardet, Wilfried

    2018-01-01

    With the advancement of personalized cancer immunotherapies, new tools are needed to identify tumor antigens and evaluate T-cell responses in model systems, specifically those that exhibit clinically relevant tumor progression. Key transgenic mouse models of breast cancer are generated and mainta......With the advancement of personalized cancer immunotherapies, new tools are needed to identify tumor antigens and evaluate T-cell responses in model systems, specifically those that exhibit clinically relevant tumor progression. Key transgenic mouse models of breast cancer are generated...... for evaluating antigen specificity in the murine FVB strain. Our study provides the first detailed molecular and immunoproteomic characterization of the FVB H-2q MHC Class I alleles, including >8500 unique peptide ligands, a multi-allele murine MHC peptide prediction tool, and in vivo validation of these data...

  10. Forum on specification and Design Languages

    CERN Document Server

    Maehne, Torsten

    2015-01-01

    This book brings together a selection of the best papers from the sixteenth edition of the Forum on specification and Design Languages Conference (FDL), which was held in September 2013 in Paris, France. FDL is a well-established international forum devoted to dissemination of research results, practical experiences and new ideas in the application of specification, design and verification languages to the design, modeling and verification of integrated circuits, complex hardware/software embedded systems, and mixed-technology systems. • Covers applications of formal methods for specification, verification and debug; • Includes embedded analog and mixed-signal system design; • Enables model-driven engineering for embedded systems design and development.

  11. Safety of MR liver specific contrast media

    Energy Technology Data Exchange (ETDEWEB)

    Bellin, Marie-France [Hopital Paul Brousse, Universite Paris 11, Villejuif Cedex (France); Webb, Judith A.W. [St. Bartholomew' s Hospital, Department of Diagnostic Imaging, London (United Kingdom); Molen, Aart J. van der [Leiden University Medical Centre, Department of Radiology, Leiden (Netherlands); Thomsen, Henrik S. [Copenhagen University Hospital at Herlev, Department of Diagnostic Radiology 54E2, Herlev (Denmark); Morcos, Sameh K. [Northern General Hospital, Sheffield Teaching Hospitals NHS Trust, Department of Diagnostic Imaging, Sheffield (United Kingdom)

    2005-08-01

    Over the past few years a number of magnetic resonance (MR) liver specific contrast agents have been introduced. In this report the safety issues of these agents are addressed. A literature search was carried out. Based on the available information, simple guidelines on the safety issue of liver specific contrast agents have been produced by the Contrast Media Safety Committee of the European Society of Urogenital Radiology. The report and guidelines were discussed at the 11th European Symposium on Urogenital Radiology in Santiago de Compostela. Liver specific contrast agents appear in general to be safe and well tolerated. However, the incidence of adverse reactions with iron oxides and the intravenous manganese based agent seems to be slightly higher than with gadolinium based agents. However, no safety information from comparative clinical trials has been published. Guidelines on the safety aspects are presented. (orig.)

  12. Safety of MR liver specific contrast media

    International Nuclear Information System (INIS)

    Bellin, Marie-France; Webb, Judith A.W.; Molen, Aart J. van der; Thomsen, Henrik S.; Morcos, Sameh K.

    2005-01-01

    Over the past few years a number of magnetic resonance (MR) liver specific contrast agents have been introduced. In this report the safety issues of these agents are addressed. A literature search was carried out. Based on the available information, simple guidelines on the safety issue of liver specific contrast agents have been produced by the Contrast Media Safety Committee of the European Society of Urogenital Radiology. The report and guidelines were discussed at the 11th European Symposium on Urogenital Radiology in Santiago de Compostela. Liver specific contrast agents appear in general to be safe and well tolerated. However, the incidence of adverse reactions with iron oxides and the intravenous manganese based agent seems to be slightly higher than with gadolinium based agents. However, no safety information from comparative clinical trials has been published. Guidelines on the safety aspects are presented. (orig.)

  13. Procedures for evaluating technical specifications (PETS)

    International Nuclear Information System (INIS)

    Samanta, P.K.; Boccio, J.L.; Vesely, W.E.

    1987-01-01

    In this paper, aspects of technical specifications relating to Generic Issues B-56 and B-61 are discussed from a risk-standpoint. These primarily deal with the risk issues associated with (1) adaptive diesel test requirements/surveillance test intervals, and (2) the effectiveness of cumulative outage time requirements for controlling downtime risk. Risk and reliability approaches are presented which (1) allow risk-acceptable test intervals to be determined for any diesel and (2) show the potential risk-control capability of prescribed allowed cumulative outage times. This work was conducted through NRC's Procedures for Evaluating Technical Specifications (PETS) Program. The overall objective of this program is to develop and demonstrate methodologies that utilize risk insights and reliability techniques for evaluating the scope, detailed requirements, and safety impact of plant technical specifications

  14. Technical specifications requirements: Automated reasoning applications

    International Nuclear Information System (INIS)

    Lidsky, L.M.; Dobrzeniecki, A.B.

    1990-03-01

    Several software systems were developed and tested to determine what advantages could be gained from explicitly translating complicated regulatory requirements into computerized relationships. The Technical Specifications for US nuclear power plants were chosen as the test-bed application domain, and two analysis systems were developed to monitor plant compliance with operational limits, and track and schedule equipment test and maintenance activities mandated by Technical Specifications. Choosing PROLOG as the computer language to represent these regulatory requirements resulted in a natural match between the semantic structure of the written specifications and the corollary coded rules. Additional research results affirmed the utility of declarative programming styles, explicit management of problem complexity, and attention to the robustness and flexibility of the overall software systems. 5 refs., 2 figs

  15. Specifications for human factors guiding documents

    Energy Technology Data Exchange (ETDEWEB)

    Rhodes, W; Szlapetis, I; MacGregor, C [Rhodes and Associates Inc., Toronto, ON (Canada)

    1995-04-01

    This report specifies the content, function and appearance of three proposed human factors guiding documents to be used by the Atomic Energy Control board and its licensees. These three guiding documents, to be developed at a later date, are: (a) Human Factors Process Guide; (b) Human Factors Activities Guide; and (c) Human Factors Design Integration Guide. The specifications were developed by examining the best documents as identified in a previous contract with the AECB (Review of Human Factors Guidelines and Methods by W. Rhodes, I. Szlapetis et al. 1992), and a brief literature review. The best features and content were selected from existing documents and used to develop specifications for the guiding documents. The developer of the actual guides would use these specifications to produce comprehensive and consolidated documents at a later date. (author). 128 ref., 7 figs.

  16. Specifications for human factors guiding documents

    International Nuclear Information System (INIS)

    Rhodes, W.; Szlapetis, I.; MacGregor, C.

    1995-04-01

    This report specifies the content, function and appearance of three proposed human factors guiding documents to be used by the Atomic Energy Control board and its licensees. These three guiding documents, to be developed at a later date, are: (a) Human Factors Process Guide; (b) Human Factors Activities Guide; and (c) Human Factors Design Integration Guide. The specifications were developed by examining the best documents as identified in a previous contract with the AECB (Review of Human Factors Guidelines and Methods by W. Rhodes, I. Szlapetis et al. 1992), and a brief literature review. The best features and content were selected from existing documents and used to develop specifications for the guiding documents. The developer of the actual guides would use these specifications to produce comprehensive and consolidated documents at a later date. (author). 128 ref., 7 figs

  17. Property Specification Patterns for intelligence building software

    Science.gov (United States)

    Chun, Seungsu

    2018-03-01

    In this paper, through the property specification pattern research for Modal MU(μ) logical aspects present a single framework based on the pattern of intelligence building software. In this study, broken down by state property specification pattern classification of Dwyer (S) and action (A) and was subdivided into it again strong (A) and weaknesses (E). Through these means based on a hierarchical pattern classification of the property specification pattern analysis of logical aspects Mu(μ) was applied to the pattern classification of the examples used in the actual model checker. As a result, not only can a more accurate classification than the existing classification systems were easy to create and understand the attributes specified.

  18. Emergency Medicine Gender-specific Education.

    Science.gov (United States)

    Ashurst, John V; McGregor, Alyson J; Safdar, Basmah; Weaver, Kevin R; Quinn, Shawn M; Rosenau, Alex M; Goyke, Terrence E; Roth, Kevin R; Greenberg, Marna R

    2014-12-01

    The 2014 Academic Emergency Medicine consensus conference has taken the first step in identifying gender-specific care as an area of importance to both emergency medicine (EM) and research. To improve patient care, we need to address educational gaps in this area concurrent with research gaps. In this article, the authors highlight the need for sex- and gender-specific education in EM and propose guidelines for medical student, resident, and faculty education. Specific examples of incorporating this content into grand rounds, simulation, bedside teaching, and journal club sessions are reviewed. Future challenges and strategies to fill the gaps in the current education model are also described. © 2014 by the Society for Academic Emergency Medicine.

  19. Computational network design from functional specifications

    KAUST Repository

    Peng, Chi Han

    2016-07-11

    Connectivity and layout of underlying networks largely determine agent behavior and usage in many environments. For example, transportation networks determine the flow of traffic in a neighborhood, whereas building floorplans determine the flow of people in a workspace. Designing such networks from scratch is challenging as even local network changes can have large global effects. We investigate how to computationally create networks starting from only high-level functional specifications. Such specifications can be in the form of network density, travel time versus network length, traffic type, destination location, etc. We propose an integer programming-based approach that guarantees that the resultant networks are valid by fulfilling all the specified hard constraints and that they score favorably in terms of the objective function. We evaluate our algorithm in two different design settings, street layout and floorplans to demonstrate that diverse networks can emerge purely from high-level functional specifications.

  20. Transactions in domain-specific information systems

    Science.gov (United States)

    Zacek, Jaroslav

    2017-07-01

    Substantial number of the current information system (IS) implementations is based on transaction approach. In addition, most of the implementations are domain-specific (e.g. accounting IS, resource planning IS). Therefore, we have to have a generic transaction model to build and verify domain-specific IS. The paper proposes a new transaction model for domain-specific ontologies. This model is based on value oriented business process modelling technique. The transaction model is formalized by the Petri Net theory. First part of the paper presents common business processes and analyses related to business process modeling. Second part defines the transactional model delimited by REA enterprise ontology paradigm and introduces states of the generic transaction model. The generic model proposal is defined and visualized by the Petri Net modelling tool. Third part shows application of the generic transaction model. Last part of the paper concludes results and discusses a practical usability of the generic transaction model.

  1. Spent nuclear fuel project product specification

    International Nuclear Information System (INIS)

    Pajunen, A.L.

    1998-01-01

    Product specifications are limits and controls established for each significant parameter that potentially affects safety and/or quality of the Spent Nuclear Fuel (SNF) packaged for transport to dry storage. The product specifications in this document cover the spent fuel packaged in MultiCanister Overpacks (MCOs) to be transported throughout the SNF Project. The SNF includes N Reactor fuel and single-pass reactor fuel. The FRS removes the SNF from the storage canisters, cleans it, and places it into baskets. The MCO loading system places the baskets into MCO/Cask assembly packages. These packages are then transferred to the Cold Vacuum Drying (CVD) Facility. After drying at the CVD Facility, the MCO cask packages are transferred to the Canister Storage Building (CSB), where the MCOs are removed from the casks, staged, inspected, sealed (by welding), and stored until a suitable permanent disposal option is implemented. The key criteria necessary to achieve these goals are documented in this specification

  2. Naturally occurring, tumor-specific, therapeutic proteins.

    Science.gov (United States)

    Argiris, Konstantinos; Panethymitaki, Chrysoula; Tavassoli, Mahvash

    2011-05-01

    The emerging approach to cancer treatment known as targeted therapies offers hope in improving the treatment of therapy-resistant cancers. Recent understanding of the molecular pathogenesis of cancer has led to the development of targeted novel drugs such as monoclonal antibodies, small molecule inhibitors, mimetics, antisense and small interference RNA-based strategies, among others. These compounds act on specific targets that are believed to contribute to the development and progression of cancers and resistance of tumors to conventional therapies. Delivered individually or combined with chemo- and/or radiotherapy, such novel drugs have produced significant responses in certain types of cancer. Among the most successful novel compounds are those which target tyrosine kinases (imatinib, trastuzumab, sinutinib, cetuximab). However, these compounds can cause severe side-effects as they inhibit pathways such as epidermal growth factor receptor (EGFR) or platelet-derived growth factor receptor, which are also important for normal functions in non-transformed cells. Recently, a number of proteins have been identified which show a remarkable tumor-specific cytotoxic activity. This toxicity is independent of tumor type or specific genetic changes such as p53, pRB or EGFR aberrations. These tumor-specific killer proteins are either derived from common human and animal viruses such as E1A, E4ORF4 and VP3 (apoptin) or of cellular origin, such as TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) and MDA-7 (melanoma differentiation associated-7). This review aims to present a current overview of a selection of these proteins with preferential toxicity among cancer cells and will provide an insight into the possible mechanism of action, tumor specificity and their potential as novel tumor-specific cancer therapeutics.

  3. Engineered waste-package-system design specification

    International Nuclear Information System (INIS)

    1983-05-01

    This report documents the waste package performance requirements and geologic and waste form data bases used in developing the conceptual designs for waste packages for salt, tuff, and basalt geologies. The data base reflects the latest geotechnical information on the geologic media of interest. The parameters or characteristics specified primarily cover spent fuel, defense high-level waste, and commercial high-level waste forms. The specification documents the direction taken during the conceptual design activity. A separate design specification will be developed prior to the start of the preliminary design activity

  4. Automated effect-specific mammographic pattern measures

    DEFF Research Database (Denmark)

    Raundahl, Jakob; Loog, Marco; Pettersen, Paola

    2008-01-01

    We investigate the possibility to develop methodologies for assessing effect specific structural changes of the breast tissue using a general statistical machine learning framework. We present an approach of obtaining objective mammographic pattern measures quantifying a specific biological effect......, such as hormone replacement therapy (HRT). We compare results using this approach to using standard density measures. We show that the proposed method can quantify both age related effects and effects caused by HRT. Age effects are significantly detected by our method where standard methodologies fail...

  5. System specifications for the NDS EXFOR System

    International Nuclear Information System (INIS)

    Attree, P.M.; Smith, P.M.

    1979-07-01

    EXFOR is the agreed exchange format for the magnetic-tape exchange of nuclear reaction data between national and international nuclear data centres for the benefit of nuclear data users in all countries. The NDS EXFOR System is a computerized system for the storage and retrieval of EXFOR information compiled or received by the IAEA. This document is an internal manual for the system specifications of the NDS EXFOR System. It includes flow charts, system and program summaries, input and output specifications and file and record descriptions. The manual is updated from time to time when system modifications are made

  6. Technical specifications for PWR secondary water chemistry

    International Nuclear Information System (INIS)

    Weeks, J.R.; van Rooyen, D.

    1977-08-01

    The bases for establishing Technical Specifications for PWR secondary water chemistry are reviewed. Whereas extremely stringent control of secondary water needs to be maintained to prevent denting in some units, sound bases for establishing limits that will prevent stress corrosion, wastage, and denting do not exist at the present time. This area is being examined very thoroughly by industry-sponsored research programs. Based on the evidence available to date, short term control limits are suggested; establishment of these or other limits as Technical Specifications is not recommended until the results of the research programs have been obtained and evaluated

  7. Asian product specifications to tighten by 2000

    International Nuclear Information System (INIS)

    Anon.

    1995-01-01

    The Asia/Pacific region is characterized by much diversity in environmental standards for petroleum products. Specifications in Japan, for example, are quite stringent, while, in India, kerosene--even that used for cooking or lighting--may contain as much as 0.2% sulfur. Widhyawan Prawiraatmadja and Fereidun Fesharaki of the East-West Center in Honolulu outlined regional product quality in a report titled, ''Trends in Petroleum Product Specifications in the Asia-Pacific Region: A Supply/Demand Analysis and Government Policy Responses.'' This paper summarizes the findings of this report with emphasis on gasoline, diesel fuels, and fuel oil demand, fuel consumption, and quality

  8. Site-Specific Infrared Probes of Proteins

    Science.gov (United States)

    Ma, Jianqiang; Pazos, Ileana M.; Zhang, Wenkai; Culik, Robert M.; Gai, Feng

    2015-01-01

    Infrared spectroscopy has played an instrumental role in studying a wide variety of biological questions. However, in many cases it is impossible or difficult to rely on the intrinsic vibrational modes of biological molecules of interest, such as proteins, to reveal structural and/or environmental information in a site-specific manner. To overcome this limitation, many recent efforts have been dedicated to the development and application of various extrinsic vibrational probes that can be incorporated into biological molecules and used to site-specifically interrogate their structural and/or environmental properties. In this Review, we highlight some recent advancements of this rapidly growing research area. PMID:25580624

  9. Clojure for domain-specific languages

    CERN Document Server

    Kelker, Ryan D

    2013-01-01

    An example-oriented approach to develop custom domain-specific languages.If you've already developed a few Clojure applications and wish to expand your knowledge on Clojure or domain-specific languages in general, then this book is for you. If you're an absolute Clojure beginner, then you may only find the detailed examples of the core Clojure components of value. If you've developed DSLs in other languages, this Lisp and Java-based book might surprise you with the power of Clojure.

  10. Photomask specifications for high energy physics detectors

    CERN Document Server

    Pindo, M

    2002-01-01

    Planar technologies used for radiation detector fabrication imply an extensive use of photomasks whose characteristics are critical in determining final detector performance. Compatibly with their manufacturing process, photomasks must satisfy the application-specific requirements dictated both by wafer manufacturers and detector final users. The design and realization of microstrip and pixel detectors, widely used in high energy physics experiments, ask for intensive scientific effort, advanced technology and important economical investments. Photomask specification definition is one of the fundamental steps to optimize detector fabrication processes and fulfill experimental requirements at the most appropriate cost.

  11. System specifications for the NDS EXFOR System

    Energy Technology Data Exchange (ETDEWEB)

    Attree, P M; Smith, P M

    1982-06-01

    EXFOR is the agreed exchange format for the magnetic-tape exchange of nuclear reaction data between national and international nuclear data centers for the benefit of nuclear data users in all countries. The NDS EXFOR System is a computerized system for the storage and retrieval of EXFOR information compiled or received of the IAEA. This document is an internal manual for the system specifications of the NDS EXFOR System. It includes flow charts, system and program summaries, input and output specifications and file and record descriptions. The manual is updated from time to time when system modifications are made; the first version was issued in July 1979. (author)

  12. Immunotherapy with GD2 specific monoclonal antibodies

    International Nuclear Information System (INIS)

    Cheung, N.K.V.; Medof, E.M.; Munn, D.

    1988-01-01

    Targeted immunotherapy focuses anti-tumor activity of antibodies and effector cells, which are actively developed by the host or adoptively transferred, onto tumor cells and into tumor sites. Such tumor selective therapy can be more specific and efficient. The value of such an approach is evident in the classical interaction of antibodies. This paper reports that the ganglioside G D2 is an ideal antigen for specific tumor targeting because of its relative lack of heterogeneity among human neuroblastoma, its high density on tumor cells, its lack of antigen modulation upon binding to antibody, and its restricted distribution in normal tissues

  13. A Class-Specific Optimizing Compiler

    Directory of Open Access Journals (Sweden)

    Michael D. Sharp

    1993-01-01

    Full Text Available Class-specific optimizations are compiler optimizations specified by the class implementor to the compiler. They allow the compiler to take advantage of the semantics of the particular class so as to produce better code. Optimizations of interest include the strength reduction of class:: array address calculations, elimination of large temporaries, and the placement of asynchronous send/recv calls so as to achieve computation/communication overlap. We will outline our progress towards the implementation of a C++ compiler capable of incorporating class-specific optimizations.

  14. DOE site-specific threat assessment

    International Nuclear Information System (INIS)

    West, D.J.; Al-Ayat, R.A.; Judd, B.R.

    1985-01-01

    A facility manager faced with the challenges of protecting a nuclear facility against potential threats must consider the likelihood and consequences of such threats, know the capabilities of the facility safeguards and security systems, and make informed decisions about the cost-effectivness of safeguards and security upgrades. To help meet these challenges, the San Francisco Operations Office of the Department of Energy, in conjunction with the Lawrence Livermore Laboratory, has developed a site-specific threat assessment approach and a quantitative model to improve the quality and consistency of site-specific threat assessment and resultant security upgrade decisions at sensitive Department of Energy facilities. 5 figs

  15. Software engineering with application-specific languages

    Science.gov (United States)

    Campbell, David J.; Barker, Linda; Mitchell, Deborah; Pollack, Robert H.

    1993-01-01

    Application-Specific Languages (ASL's) are small, special-purpose languages that are targeted to solve a specific class of problems. Using ASL's on software development projects can provide considerable cost savings, reduce risk, and enhance quality and reliability. ASL's provide a platform for reuse within a project or across many projects and enable less-experienced programmers to tap into the expertise of application-area experts. ASL's have been used on several software development projects for the Space Shuttle Program. On these projects, the use of ASL's resulted in considerable cost savings over conventional development techniques. Two of these projects are described.

  16. System specifications for the NDS Dictionary System

    International Nuclear Information System (INIS)

    Attree, P.M.; Smith, P.M.

    1979-09-01

    The NDS Dictionary System is a computerized system for maintaining and distributing the EXFOR dictionaries and for preparing internal versions of these dictionaries for use in the NDS EXFOR System and other NDS systems. This document is an internal manual for the system specifications of the NDS Dictionary System. It includes flow charts, system and program summaries, input and output specifications and file and record descriptions. This manual is updated from time to time when system modifications are made; this is the version of January 1979

  17. [Development of domain specific search engines].

    Science.gov (United States)

    Takai, T; Tokunaga, M; Maeda, K; Kaminuma, T

    2000-01-01

    As cyber space exploding in a pace that nobody has ever imagined, it becomes very important to search cyber space efficiently and effectively. One solution to this problem is search engines. Already a lot of commercial search engines have been put on the market. However these search engines respond with such cumbersome results that domain specific experts can not tolerate. Using a dedicate hardware and a commercial software called OpenText, we have tried to develop several domain specific search engines. These engines are for our institute's Web contents, drugs, chemical safety, endocrine disruptors, and emergent response for chemical hazard. These engines have been on our Web site for testing.

  18. Specifications from a biotechnology industry perspective.

    Science.gov (United States)

    Garnick, R L

    1997-01-01

    The emergence of new analytical technology and the production of pharmaceuticals for a global market in a cost-effective manner necessitate the establishment of worldwide specifications that are appropriate for the product and the manufacturing process. This requires a thorough knowledge of the protein and control of the systems that produce it as well as an understanding of the accuracy and precision of the assays used for testing. Harmonization of specifications among the worldwide regulatory authorities is critical for the future development of new pharmaceuticals. A continuing dialogue between industry and regulators to achieve this goal needs to be encouraged and supported.

  19. From UML Specification into FPGA Implementation

    Directory of Open Access Journals (Sweden)

    Grzegorz Bazydlo

    2014-01-01

    Full Text Available In the paper a method of using the Unified Modeling Language for specification of digital systems, especially logic controllers, is presented. The proposed method is based mainly on the UML state machine diagrams and uses Hierarchical Concurrent Finite State Machines (HCFSMs as a temporary model. The paper shows a way to transform the UML diagrams, expressed in XML language, to the form that is acceptable by reconfigurable FPGAs (Field Programmable Gate Arrays. The UML specification is used to generate an effective program in Hardware Description Languages (HDLs, especially Verilog.

  20. Domain Specific Language Support for Exascale

    Energy Technology Data Exchange (ETDEWEB)

    Sadayappan, Ponnuswamy [The Ohio State Univ., Columbus, OH (United States)

    2017-02-24

    Domain-Specific Languages (DSLs) offer an attractive path to Exascale software since they provide expressive power through appropriate abstractions and enable domain-specific optimizations. But the advantages of a DSL compete with the difficulties of implementing a DSL, even for a narrowly defined domain. The DTEC project addresses how a variety of DSLs can be easily implemented to leverage existing compiler analysis and transformation capabilities within the ROSE open source compiler as part of a research program focusing on Exascale challenges. The OSU contributions to the DTEC project are in the area of code generation from high-level DSL descriptions, as well as verification of the automatically-generated code.

  1. NEEDS ANALYSIS IN ENGLISH FOR SPECIFIC PURPOSES

    Directory of Open Access Journals (Sweden)

    SIMION MINODORA OTILIA

    2015-03-01

    Full Text Available Needs analysis is considered to be the cornerstone of English for Specific Purposes(ESP. The concept of Needs analysis has been different along the decades. At the initial stages of ESP( the 1960s and early 1970s, needs analysis consisted in assessing the communicative needs of the learners and the techniques of achieving specific teaching objectives. Nowadays, the tasks of needs analysis is much more complex: it aims at collecting information about the learners and at defining the target situation and environment of studying ESP.

  2. Spent Nuclear Fuel (SNF) Project Product Specification

    International Nuclear Information System (INIS)

    PAJUNEN, A.L.

    2000-01-01

    The process for removal of Spent Nuclear Fuel (SNF) from the K Basins has been divided into major sub-systems. The Fuel Retrieval System (FRS) removes fuel from the existing storage canisters, cleans it, and places it into baskets. The multi-canister overpack (MCO) loading system places the baskets into an MCO that has been pre-loaded in a cask. The cask, containing a loaded MCO, is then transferred to the Cold Vacuum Drying (CVD) Facility. After drying at the CVD Facility, the cask, and MCO, are transferred to the Canister Storage Building (CSB), where the MCO is removed from the cask, staged, inspected, sealed (by welding), and stored until a suitable permanent disposal option is implemented. The purpose of this document is to specify the process related characteristics of an MCO at the interface between major process systems. The characteristics are derived from the primary technical documents that form the basis for safety analysis and design calculations. This document translates the calculation assumptions into implementation requirements and describes the method of verifying that the requirement is achieved. These requirements are used to define validation test requirements and describe requirements that influence multiple sub-project safety analysis reports. This product specification establishes limits and controls for each significant process parameter at interfaces between major sub-systems that potentially affect the overall safety and/or quality of the SNF packaged for processing, transport, and interim dry storage. The product specifications in this document cover the SNF packaged in MCOs to be transported throughout the SNF Project. The description of the product specifications are organized in the document as follows: Section 2.0--Summary listing of product specifications at each major sub-system interface. Section 3.0--Summary description providing guidance as to how specifications are complied with by equipment design or processing within a major

  3. Spent Nuclear Fuel (SNF) Project Product Specification

    Energy Technology Data Exchange (ETDEWEB)

    PAJUNEN, A.L.

    2000-12-07

    The process for removal of Spent Nuclear Fuel (SNF) from the K Basins has been divided into major sub-systems. The Fuel Retrieval System (FRS) removes fuel from the existing storage canisters, cleans it, and places it into baskets. The multi-canister overpack (MCO) loading system places the baskets into an MCO that has been pre-loaded in a cask. The cask, containing a loaded MCO, is then transferred to the Cold Vacuum Drying (CVD) Facility. After drying at the CVD Facility, the cask, and MCO, are transferred to the Canister Storage Building (CSB), where the MCO is removed from the cask, staged, inspected, sealed (by welding), and stored until a suitable permanent disposal option is implemented. The purpose of this document is to specify the process related characteristics of an MCO at the interface between major process systems. The characteristics are derived from the primary technical documents that form the basis for safety analysis and design calculations. This document translates the calculation assumptions into implementation requirements and describes the method of verifying that the requirement is achieved. These requirements are used to define validation test requirements and describe requirements that influence multiple sub-project safety analysis reports. This product specification establishes limits and controls for each significant process parameter at interfaces between major sub-systems that potentially affect the overall safety and/or quality of the SNF packaged for processing, transport, and interim dry storage. The product specifications in this document cover the SNF packaged in MCOs to be transported throughout the SNF Project. The description of the product specifications are organized in the document as follows: Section 2.0--Summary listing of product specifications at each major sub-system interface. Section 3.0--Summary description providing guidance as to how specifications are complied with by equipment design or processing within a major

  4. Ultrahigh Specific Impulse Nuclear Thermal Propulsion

    Energy Technology Data Exchange (ETDEWEB)

    Anne Charmeau; Brandon Cunningham; Samim Anghaie

    2009-02-09

    Research on nuclear thermal propulsion systems (NTP) have been in forefront of the space nuclear power and propulsion due to their design simplicity and their promise for providing very high thrust at reasonably high specific impulse. During NERVA-ROVER program in late 1950's till early 1970's, the United States developed and ground tested about 18 NTP systems without ever deploying them into space. The NERVA-ROVER program included development and testing of NTP systems with very high thrust (~250,000 lbf) and relatively high specific impulse (~850 s). High thrust to weight ratio in NTP systems is an indicator of high acceleration that could be achieved with these systems. The specific impulse in the lowest mass propellant, hydrogen, is a function of square root of absolute temperature in the NTP thrust chamber. Therefor optimizing design performance of NTP systems would require achieving the highest possible hydrogen temperature at reasonably high thrust to weight ratio. High hydrogen exit temperature produces high specific impulse that is a diret measure of propellant usage efficiency.

  5. Language specific bootstraps for UG categories

    NARCIS (Netherlands)

    van Kampen, N.J.

    2005-01-01

    This paper argues that the universal categories N/V are not applied to content words before the grammatical markings for reference D(eterminers) and predication I(nflection) have been acquired (van Kampen, 1997, contra Pinker, 1984). Child grammar starts as proto-grammar with language-specific

  6. DETERMINATION OF THE SPECIFIC GROWTH RATE ON ...

    African Journals Online (AJOL)

    Sewage generation is one of the dense problems Nigerians encounter on daily bases, mostly at the urbanized area where factories and industries are located. This paper is aimed at determining the specific growth rate “K” of biological activities on cassava wastewater during degradation using Michaelis-Menten Equation.

  7. Side-Specific Reward Memories in Honeybees

    Science.gov (United States)

    Gil, Mariana; Menzel, Randolf; De Marco, Rodrigo J.

    2009-01-01

    We report a hitherto unknown form of side-specific learning in honeybees. We trained bees individually by coupling gustatory and mechanical stimulation of each antenna with either increasing or decreasing volumes of sucrose solution offered to the animal's proboscis along successive learning trials. Next, we examined their proboscis extension…

  8. Autobiographical Memory Specificity in Dissociative Identity Disorder

    NARCIS (Netherlands)

    Huntjens, R.J.C.; Wessel, I.; Hermans, D.; Minnen, A. van

    2014-01-01

    A lack of adequate access to autobiographical knowledge has been related to psychopathology. More specifically, patients suffering from depression or a history of trauma have been found to be characterized by overgeneral memory, in other words, they show a relative difficulty in retrieving a

  9. Autobiographical memory specificity in dissociative identity disorder

    NARCIS (Netherlands)

    Huntjens, Rafaële J. C.; Wessel, Ineke; Hermans, Dirk; van Minnen, Agnes

    A lack of adequate access to autobiographical knowledge has been related to psychopathology. More specifically, patients suffering from depression or a history of trauma have been found to be characterized by overgeneral memory, in other words, they show a relative difficulty in retrieving a

  10. Patient-specific models of cardiac biomechanics

    Science.gov (United States)

    Krishnamurthy, Adarsh; Villongco, Christopher T.; Chuang, Joyce; Frank, Lawrence R.; Nigam, Vishal; Belezzuoli, Ernest; Stark, Paul; Krummen, David E.; Narayan, Sanjiv; Omens, Jeffrey H.; McCulloch, Andrew D.; Kerckhoffs, Roy C. P.

    2013-07-01

    Patient-specific models of cardiac function have the potential to improve diagnosis and management of heart disease by integrating medical images with heterogeneous clinical measurements subject to constraints imposed by physical first principles and prior experimental knowledge. We describe new methods for creating three-dimensional patient-specific models of ventricular biomechanics in the failing heart. Three-dimensional bi-ventricular geometry is segmented from cardiac CT images at end-diastole from patients with heart failure. Human myofiber and sheet architecture is modeled using eigenvectors computed from diffusion tensor MR images from an isolated, fixed human organ-donor heart and transformed to the patient-specific geometric model using large deformation diffeomorphic mapping. Semi-automated methods were developed for optimizing the passive material properties while simultaneously computing the unloaded reference geometry of the ventricles for stress analysis. Material properties of active cardiac muscle contraction were optimized to match ventricular pressures measured by cardiac catheterization, and parameters of a lumped-parameter closed-loop model of the circulation were estimated with a circulatory adaptation algorithm making use of information derived from echocardiography. These components were then integrated to create a multi-scale model of the patient-specific heart. These methods were tested in five heart failure patients from the San Diego Veteran's Affairs Medical Center who gave informed consent. The simulation results showed good agreement with measured echocardiographic and global functional parameters such as ejection fraction and peak cavity pressures.

  11. Community-Specific Strategies of Intergenerational Language ...

    African Journals Online (AJOL)

    This study concerns minority language maintenance, specifically it explores local practices that make it possible for a community to sustain its traditional language. Two variables were the focus of the research; speakers' attitudes and language use patterns. These were examined to determine their influence in facilitating ...

  12. SPECIFICITY IN DEVELOPMENT OF CONSTRUCTION INDUSTRY

    Directory of Open Access Journals (Sweden)

    O. S. Golubova

    2012-01-01

    Full Text Available Specificity in development of construction industry of the Republic of Belarus determines  character of competition on the construction market, forms a pricing, marketing and product policy of building companies. Construction represents itself as a highly developed complex where interaction of business entities is of rather complicated multilateral character.

  13. Essential Specification Elements for Heat Exchanger Replacement

    Energy Technology Data Exchange (ETDEWEB)

    Bower, L.

    2015-07-01

    Performance upgrade and equipment degradation are the primary impetuses for a nuclear power plant to engage in the large capital cost project of heat exchanger replacement. Along with attention to these issues, consideration of heat exchanger Codes and Standards, material improvements, thermal redesign, and configuration are essential for developing User’s Design Specifications for successful replacement projects. The User’s Design Specification is the central document in procuring ASME heat exchangers. Properly stated objectives for the heat exchanger replacement are essential for obtaining the materials, configurations and thermal designs best suited for the nuclear power plant. Additionally, the code of construction required and the applied manufacturing standard (TEMA or HEI) affects how the heat exchanger may be designed or configured to meet the replacement goals. Knowledge of how Codes and Standards affect design and configuration details will aid in writing the User’s Design Specification. Joseph Oat Corporation has designed and fabricated many replacement heat exchangers for the nuclear power industry. These heat exchangers have been constructed per ASME Section III to various Code-Years or ASME Section VIII-1 to the current Code-Year also in accordance with TEMA and HEI. These heat exchangers have been a range of like-for-like replacement to complete thermal, material and configuration redesigns. Several examples of these heat exchangers with their Code, Standard and specification implications are presented. (Author.

  14. Research overview : design specifications for hybrid vehicles

    NARCIS (Netherlands)

    Hofman, T.; Druten, van R.M.

    2004-01-01

    In this paper a method is proposed for determination of the design specifications regarding the energy exchange systems for different chargesustaining hybrid vehicles of different vehicle classes. Hybrid drivetrains for vehicles combine multiple power sources in order to increase the driving

  15. Isotope specific arbitrary material flow meter

    Science.gov (United States)

    Barty, Christopher P. J.; Post, John C.; Jones, Edwin

    2016-10-25

    A laser-based mono-energetic gamma-ray source is used to provide non-destructive and non-intrusive, quantitative determination of the absolute amount of a specific isotope contained within pipe as part of a moving fluid or quasi-fluid material stream.

  16. Composing a Tumor Specific Bacterial Promoter.

    Directory of Open Access Journals (Sweden)

    Igor V Deyneko

    Full Text Available Systemically applied Salmonella enterica spp. have been shown to invade and colonize neoplastic tissues where it retards the growth of many tumors. This offers the possibility to use the bacteria as a vehicle for the tumor specific delivery of therapeutic molecules. Specificity of such delivery is solely depending on promoter sequences that control the production of a target molecule. We have established the functional structure of bacterial promoters that are transcriptionally active exclusively in tumor tissues after systemic application. We observed that the specific transcriptional activation is accomplished by a combination of a weak basal promoter and a strong FNR binding site. This represents a minimal set of control elements required for such activation. In natural promoters, additional DNA remodeling elements are found that alter the level of transcription quantitatively. Inefficiency of the basal promoter ensures the absence of transcription outside tumors. As a proof of concept, we compiled an artificial promoter sequence from individual motifs representing FNR and basal promoter and showed specific activation in a tumor microenvironment. Our results open possibilities for the generation of promoters with an adjusted level of expression of target proteins in particular for applications in bacterial tumor therapy.

  17. Specific Ion Effects in Cholesterol Monolayers

    Directory of Open Access Journals (Sweden)

    Teresa Del Castillo-Santaella

    2016-05-01

    Full Text Available The interaction of ions with interfaces and, in particular, the high specificity of these interactions to the particular ions considered, are central questions in the field of surface forces. Here we study the effect of different salts (NaI, NaCl, CaCl2 and MgCl2 on monolayers made of cholesterol molecules, both experimentally (surface area vs. lateral pressure isotherms measured by a Langmuir Film Balance and theoretically (molecular dynamics (MD all-atomic simulations. We found that surface isotherms depend, both quantitatively and qualitatively, on the nature of the ions by altering the shape and features of the isotherm. In line with the experiments, MD simulations show clear evidences of specific ionic effects and also provide molecular level details on ion specific interactions with cholesterol. More importantly, MD simulations show that the interaction of a particular ion with the surface depends strongly on its counterion, a feature ignored so far in most theories of specific ionic effects in surface forces.

  18. Measurement of low-temperature specific heat

    International Nuclear Information System (INIS)

    Stewart, G.R.

    1983-01-01

    The measurement of low-temperature specific heat (LTSH) (0.1 K< T<60 K) has seen a number of breakthroughs both in design concepts and instrumentation in the last 15 years: particularly in small sample calorimetry. This review attempts to provide an overview of both large and small sample calorimetry techniques at temperatures below 60 K, with sufficient references to enable more detailed study. A comprehensive review is made of the most reliable measurements of the LTSH of 84 of the elements to illustrate briefly some of the problems of measurements and analysis, as well as to provide additional references. More detail is devoted to three special areas of low-temperature calorimetry that have seen rapid development recently: (1) measurement of the specific heat of highly radioactive samples, (2) measurement of the specific heat of materials in high magnetic fields (18 T), and (3) measurement of the specific heat of very small (100 μg) samples. The review ends with a brief discussion of the frontier research currently underway on microcalorimetry for nanogram sample weights

  19. Specificity, Transfer, and the Development of Expertise

    Science.gov (United States)

    Brookes, David T.; Ross, Brian H.; Mestre, Jose P.

    2011-01-01

    In this paper we present the results of two experiments designed to understand how physics students' learning of the concept of refraction is influenced by the cognitive phenomenon of "specificity." In both experiments participants learned why light bends as it travels from one optical medium to another with an analogy made to a car…

  20. 21 CFR 107.100 - Nutrient specifications.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 2 2010-04-01 2010-04-01 false Nutrient specifications. 107.100 Section 107.100 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD... Maximum level Protein Grams 1.8 4.5 Fat do 3.3 6.0 Percent calories 30 54 Linoleic acid Milligrams 300...

  1. Population specific analysis of Yakut exomes

    NARCIS (Netherlands)

    Zlobin, A. S.; Sharapov, S. Sh.; Guryev, V. P.; Bevova, M. R.; Tsepilov, Y. A.; Sivtseva, T. M.; Boyarskih, U. A.; Sokolova, E. A.; Aulchenko, Y. S.; Filipenko, M. L.; Osakovsky, V. L.

    We studied the genetic diversity of the Yakut population using exome sequencing. We performed comparative analysis of the Yakut population and the populations that are included in the "1000 Genomes" project and we identified the alleles specific to the Yakut population. We showed, that the Yakuts

  2. Brayton Isotope Power System (BIPS) facility specification

    International Nuclear Information System (INIS)

    1976-01-01

    General requirements for the Brayton Isotope Power System (BIPS)/Ground Demonstration System (GDS) assembly and test facility are defined. The facility will include provisions for a complete test laboratory for GDS checkout, performance, and endurance testing, and a contamination-controlled area for assembly, fabrication, storage, and storage preparation of GDS components. Specifications, schedules, and drawings are included

  3. Prospects for site specific weed management

    DEFF Research Database (Denmark)

    Christensen, Svend; Rasmussen, Jesper; Pedersen, Søren Marcus

    2014-01-01

    Research on Site Specific Weed Management (SSWM) started in the late 80's. Since that moment, considerable research has been conducted on different aspects of SSWM, from fundamental studies on the spatial ecology of weeds to the applied development and testing of new technologies for weed detection...

  4. Social-psychological specific of individual adaptation

    OpenAIRE

    Ovsyanik, Olga

    2012-01-01

    There is analyzing of specific of social-psychological adaptation person by model of adaptation. Structure model of adaptation of women of our age group, which was named “adaptation complex” was made by theoretic analyzes of problem of adaptation adult.

  5. Structural similarity and category-specificity

    DEFF Research Database (Denmark)

    Gerlach, Christian; Law, Ian; Paulson, Olaf B

    2004-01-01

    It has been suggested that category-specific recognition disorders for natural objects may reflect that natural objects are more structurally (visually) similar than artefacts and therefore more difficult to recognize following brain damage. On this account one might expect a positive relationshi...

  6. Methodes for identification of specific language impairment

    Directory of Open Access Journals (Sweden)

    Toktam Maleki Shahmahmood

    2014-06-01

    Full Text Available Background and Aim: Specific language impiarment (SLI is one of the most prevalent developmental language disorders its diagnosis is a problematic issue among researchers and clinicians because of the heterogeneity of language profiles in the affected population and overlapping with other developmental language disorders. The aim of this study was to review the suggested diagnostic criteria for this disorder, controversies about these criteria and identify the most accurate diagnostic methods.Methods: Published article from 1980 to 2012 in bibliographic and publisher databases including Pubmed, Google scholar, Cochran library, Web of Science, ProQuest, Springer, Oxford, Science direct, Ovid, Iran Medex and Magiran about the diagnostic methods for discriminating preschoool children with specific language impiarment from normal developing children were reviewd in this article. These keywords were used for research: “specific language impairment”, “SLI”, “diagnosis or identification”, “standardized tests”, and “tests for language development”.Conclusion: The results of this study show inspite of agreement of researchers and clinicians about exclusionary criteria as one basic part of the diagnosis of specific language impiarment , there is no consensus about the other part, inclusionary criteria. Different studies used different inclusionary criteria which can be divided to categories of clincal judgment, discrepancy-based criteria, standardized testing, clinical markers and markers from spontaneous speech samples. Advantages, disadvantages, and clinical applicability of each diagnostic method are discussed in this article.

  7. IPv6-specific misconfigurations in the DNS

    NARCIS (Netherlands)

    Hendriks, Luuk; de Boer, Pieter-Tjerk; Pras, Aiko

    2017-01-01

    With the Internet transitioning from IPv4 to IPv6, the number of IPv6-specific DNS records (AAAA) increases. Misconfigurations in these records often go unnoticed, as most systems are provided with connectivity over both IPv4 and IPv6, and automatically fall back to IPv4 in case of connection

  8. 31 CFR 595.312 - Specific license.

    Science.gov (United States)

    2010-07-01

    ... 31 Money and Finance: Treasury 3 2010-07-01 2010-07-01 false Specific license. 595.312 Section 595.312 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY TERRORISM SANCTIONS REGULATIONS General Definitions...

  9. Ultrasonic hydrometer. [Specific gravity of electrolyte

    Science.gov (United States)

    Swoboda, C.A.

    1982-03-09

    The disclosed ultrasonic hydrometer determines the specific gravity (density) of the electrolyte of a wet battery, such as a lead-acid battery. The hydrometer utilizes a transducer that when excited emits an ultrasonic impulse that traverses through the electrolyte back and forth between spaced sonic surfaces. The transducer detects the returning impulse, and means measures the time t between the initial and returning impulses. Considering the distance d between the spaced sonic surfaces and the measured time t, the sonic velocity V is calculated with the equation V = 2d/t. The hydrometer also utilizes a thermocouple to measure the electrolyte temperature. A hydrometer database correlates three variable parameters including sonic velocity in and temperature and specific gravity of the electrolyte, for temperature values between 0 and 40/sup 0/C and for specific gravity values between 1.05 and 1.30. Upon knowing two parameters (the calculated sonic velocity and the measured temperature), the third parameter (specific gravity) can be uniquely found in the database. The hydrometer utilizes a microprocessor for data storage and manipulation.

  10. COMPARATIVE STUDY ON SPECIFIC AND EARLY DETECTION ...

    African Journals Online (AJOL)

    The objective of this study was to compare the sensitivity and specificity of smear and culture methods with rapid serological EIA myco kits manufactured by Omega diagnostics, for the early detection of Mycobacterium tuberculosis (MTB) complex. Sera from various categories of smear and culture results were compared ...

  11. 32 CFR 292.4 - Specific policy.

    Science.gov (United States)

    2010-07-01

    ... INFORMATION ACT PROGRAM DEFENSE INTELLIGENCE AGENCY (DIA) FREEDOM OF INFORMATION ACT § 292.4 Specific policy... of source and object codes, regardless of medium are not agency records. (This does not include the... existing computer program or printout for retrieval of the requested information. (c) The prior application...

  12. Radioimmunoassay for a human prostate specific antigen

    International Nuclear Information System (INIS)

    Machida, T.; Miki, M.; Ohishi, Y.; Kido, A.; Morikawa, J.; Ogawa, Y.

    1983-01-01

    As a marker for prostatic cancer, a prostate-specific antigen was purified from human prostatic tissues. Double antibody radioimmunoassay utilizing immune reaction was developed on the basis of the purified prostatic antigen (PA). Measurement results have revealed that PA radioimmunoassay is much better than prostatic acid phosphatase (PAP) radioimmunoassay in the diagnosis of prostatic cancer

  13. Justifying group-specific common morality.

    Science.gov (United States)

    Strong, Carson

    2008-01-01

    Some defenders of the view that there is a common morality have conceived such morality as being universal, in the sense of extending across all cultures and times. Those who deny the existence of such a common morality often argue that the universality claim is implausible. Defense of common morality must take account of the distinction between descriptive and normative claims that there is a common morality. This essay considers these claims separately and identifies the nature of the arguments for each claim. It argues that the claim that there is a universal common morality in the descriptive sense has not been successfully defended to date. It maintains that the claim that there is a common morality in the normative sense need not be understood as universalist. This paper advocates the concept of group specific common morality, including country-specific versions. It suggests that both the descriptive and the normative claims that there are country-specific common moralities are plausible, and that a country-specific normative common morality could provide the basis for a country's bioethics.

  14. Modular specification of real-time systems

    DEFF Research Database (Denmark)

    Inal, Recep

    1994-01-01

    Duration Calculus, a real-time interval logic, has been embedded in the Z specification language to provide a notation for real-time systems that combines the modularisation and abstraction facilities of Z with a logic suitable for reasoning about real-time properties. In this article the notation...

  15. Canine specific ELISA for coagulation factor VII

    DEFF Research Database (Denmark)

    Knudsen, Tom; Kjelgaard-Hansen, Mads; Tranholm, Mikael

    2011-01-01

    available to date. In this study, a canine specific ELISA for measurement of FVII:Ag in plasma was developed and validated. The FVII:Ag ELISA correctly diagnosed homozygous and heterozygous hereditary FVII deficiency. Together with activity based assays, such as FVII:C, the FVII:Ag ELISA should be valuable...

  16. Specificity of Structural Assessment of Knowledge

    Science.gov (United States)

    Trumpower, David L.; Sharara, Harold; Goldsmith, Timothy E.

    2010-01-01

    This study examines the specificity of information provided by structural assessment of knowledge (SAK). SAK is a technique which uses the Pathfinder scaling algorithm to transform ratings of concept relatedness into network representations (PFnets) of individuals' knowledge. Inferences about individuals' overall domain knowledge based on the…

  17. Parallel object-oriented specification language

    NARCIS (Netherlands)

    Florescu, O.; Voeten, J.P.M.; Theelen, B.D.; Geilen, M.C.W.; Corporaal, H.; Burns, Alan

    2008-01-01

    The Parallel Object-Oriented Specification Language (POOSL) is an expressive modelling language for hardware/software systems [10]. It was originally defined in [7] as an object-oriented extension of process algebra CCS [6], supporting (conditional) synchronous message passing between

  18. Primary Auditory Cortex Regulates Threat Memory Specificity

    Science.gov (United States)

    Wigestrand, Mattis B.; Schiff, Hillary C.; Fyhn, Marianne; LeDoux, Joseph E.; Sears, Robert M.

    2017-01-01

    Distinguishing threatening from nonthreatening stimuli is essential for survival and stimulus generalization is a hallmark of anxiety disorders. While auditory threat learning produces long-lasting plasticity in primary auditory cortex (Au1), it is not clear whether such Au1 plasticity regulates memory specificity or generalization. We used…

  19. 48 CFR 836.202 - Specifications.

    Science.gov (United States)

    2010-10-01

    ... specifications. (b) During the design stage, contract architect-engineers must not use “brand name or equal” or... phase, prior to award of a contract for design. (c) If VA has determined that only one product will meet.... This clause places bidders on notice that the “brand name or equal” provisions of the clause found at...

  20. Specificity in liquid metal induced embrittlement

    CSIR Research Space (South Africa)

    Fernandes, PJL

    1996-12-01

    Full Text Available One of the most intriguing features of liquid metal induced embrittlement (LMIE) is the observation that some liquid metal-solid metal couples are susceptible to embrittlement, while others appear to be immune. This is referred to as the specificity...

  1. Age-Specific Correlates of Child Growth

    NARCIS (Netherlands)

    M. Rieger (Matthias); S.K. Trommlerová (Sofia Karina)

    2016-01-01

    textabstractGrowth faltering describes a widespread phenomenon that height- and weight-for-age of children in developing countries collapse rapidly in the first two years of life. We study age-specific correlates of child nutrition using Demographic and Health Surveys from 56 developing countries to

  2. Brayton Isotope Power System (BIPS) facility specification

    Energy Technology Data Exchange (ETDEWEB)

    1976-05-31

    General requirements for the Brayton Isotope Power System (BIPS)/Ground Demonstration System (GDS) assembly and test facility are defined. The facility will include provisions for a complete test laboratory for GDS checkout, performance, and endurance testing, and a contamination-controlled area for assembly, fabrication, storage, and storage preparation of GDS components. Specifications, schedules, and drawings are included.

  3. 12 CFR 347.119 - Specific consent.

    Science.gov (United States)

    2010-01-01

    ... processing procedure. (d) Specific consent. Direct or indirect investments in or activities of foreign... control such organization as a result of a foreign investment; or (ii) A bank would be establishing a... foreign country. (1) Applicable law or practice in the foreign country where the foreign organization or...

  4. TAL effectors specificity stems from negative discrimination.

    Directory of Open Access Journals (Sweden)

    Basile I M Wicky

    Full Text Available Transcription Activator-Like (TAL effectors are DNA-binding proteins secreted by phytopathogenic bacteria that interfere with native cellular functions by binding to plant DNA promoters. The key element of their architecture is a domain of tandem-repeats with almost identical sequences. Most of the polymorphism is located at two consecutive amino acids termed Repeat Variable Diresidue (RVD. The discovery of a direct link between the RVD composition and the targeted nucleotide allowed the design of TAL-derived DNA-binding tools with programmable specificities that revolutionized the field of genome engineering. Despite structural data, the molecular origins of this specificity as well as the recognition mechanism have remained unclear. Molecular simulations of the recent crystal structures suggest that most of the protein-DNA binding energy originates from non-specific interactions between the DNA backbone and non-variable residues, while RVDs contributions are negligible. Based on dynamical and energetic considerations we postulate that, while the first RVD residue promotes helix breaks--allowing folding of TAL as a DNA-wrapping super-helix--the second provides specificity through a negative discrimination of matches. Furthermore, we propose a simple pharmacophore-like model for the rationalization of RVD-DNA interactions and the interpretation of experimental findings concerning shared affinities and binding efficiencies. The explanatory paradigm presented herein provides a better comprehension of this elegant architecture and we hope will allow for improved designs of TAL-derived biotechnological tools.

  5. Accounting valuation development of specific assets

    Directory of Open Access Journals (Sweden)

    I.V. Zhigley

    2017-12-01

    Full Text Available The current issues of accounting estimate development are considered. The necessity of the development of accounting estimate in the context of the non-institutional theory principles based on the selection of a number of reasons is grounded. The reasons for deterioration of accounting reputation as a separate socio-economic institute in the context of developing the methodology for specific assets accounting are discovered. The system of normative regulation of accounting estimate of enterprise non-current assets in the case of diminishing their usefulness is analyzed. The procedure for determining and accounting for the depreciation of assets in accordance with IFRS 36 «Depreciation of Assets» is developed. The features of the joint use of the concept of «value in use» and «fair value» in the accounting system are disclosed. The procedure for determining the value of compensation depending on the degree of specificity of assets is developed. The necessity to clarify the features that indicate the possibility of diminishing the usefulness of specific assets (termination or pre-term termination of the contract for the use of a specific asset is grounded.

  6. Iron addition to soil specifically stabilized lignin

    Science.gov (United States)

    Steven J. Hall; Whendee L. Silver; Vitaliy I. Timokhin; Kenneth E. Hammel

    2016-01-01

    The importance of lignin as a recalcitrant constituent of soil organic matter (SOM) remains contested. Associations with iron (Fe) oxides have been proposed to specifically protect lignin from decomposition, but impacts of Fe-lignin interactions on mineralization rates remain unclear. Oxygen (O2) fluctuations characteristic of humid tropical...

  7. Chapter 9: Questions from CNEN specific exams

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2018-04-01

    The following are real questions from CNEN specific exams for obtaining the certification of RSO for gamma irradiators. These are questions that require essay answers, that are interpretative ones and therefore that may accept more than one interpretation, therefore more than one answer. For this reason, suggestions of answers will be presented in the second part of this chapter.

  8. 14 CFR 29.1397 - Color specifications.

    Science.gov (United States)

    2010-01-01

    ... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Color specifications. 29.1397 Section 29.1397 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT...) Aviation green— x is not greater than 0.440−0.320y; x is not greater than y−0.170; and y is not less than 0...

  9. 14 CFR 23.1397 - Color specifications.

    Science.gov (United States)

    2010-01-01

    ... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Color specifications. 23.1397 Section 23.1397 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT... greater than 0.002. (b) Aviation green— x is not greater than 0.440−0.320y; x is not greater than y−0.170...

  10. 14 CFR 25.1397 - Color specifications.

    Science.gov (United States)

    2010-01-01

    ... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Color specifications. 25.1397 Section 25.1397 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT...) Aviation green— x is not greater than 0.440−0.320y ; x is not greater than y−0.170; and y is not less than...

  11. 14 CFR 27.1397 - Color specifications.

    Science.gov (United States)

    2010-01-01

    ... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Color specifications. 27.1397 Section 27.1397 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT...) Aviation green— x is not greater than 0.440−0.320y; x is not greater than y−0.170; and y is not less than 0...

  12. MODEL OF TEACHING PROFESSION SPECIFIC BILATERAL TRANSLATION

    Directory of Open Access Journals (Sweden)

    Yana Fabrychna

    2017-03-01

    Full Text Available The article deals with the author’s interpretation of the process of teaching profession specific bilateral translation to student teacher of English in the Master’s program. The goal of the model of teaching profession specific bilateral translation development is to determine the logical sequence of educational activities of the teacher as the organizer of the educational process and students as its members. English and Ukrainian texts on methods of foreign languages and cultures teaching are defined as the object of study. Learning activities aimed at the development of student teachers of English profession specific competence in bilateral translation and Translation Proficiency Language Portfolio for Student Teachers of English are suggested as teaching tools. The realization of the model of teaching profession specific bilateral translation to student teachers of English in the Master’s program is suggested within the module topics of the academic discipline «Practice of English as the first foreign language»: Globalization; Localization; Education; Work; The role of new communication technologies in personal and professional development. We believe that the amount of time needed for efficient functioning of the model is 48 academic hours, which was determined by calculating the total number of academic hours allotted for the academic discipline «Practice of English as the first foreign language» in Ukrainian universities. Peculiarities of the model realization as well as learning goals and content of class activities and home self-study work of students are outlined.

  13. Slicing AADL specifications for model checking

    NARCIS (Netherlands)

    Odenbrett, M.R.; Nguyen, V.Y.; Noll, T.

    2010-01-01

    To combat the state-space explosion problem in model checking larger systems, abstraction techniques can be employed. Here, methods that operate on the system specification before constructing its state space are preferable to those that try to minimize the resulting transition system as they

  14. [The "specific" liability regime for blood products].

    Science.gov (United States)

    Byk, Christian

    2017-10-13

    Based on the system of liability for defective products as organized by the European Directive of 25 July 1985, responsibility for blood products does not therefore constitute a genuine specific regime. However, European law leaves States a margin of discretion in the implementation of the Directive with regard to health products. This is the case in particular with the exemption for development risk.

  15. Digital PET compliance to EARL accreditation specifications

    NARCIS (Netherlands)

    Koopman, Daniëlle; Groot Koerkamp, Maureen; Jager, Pieter L.; Arkies, Hester; Knollema, Siert; Slump, Cornelis H.; Sanches, Pedro G.; van Dalen, Jorn A.

    2017-01-01

    Background: Our aim was to evaluate if a recently introduced TOF PET system with digital photon counting technology (Philips Healthcare), potentially providing an improved image quality over analogue systems, can fulfil EANM research Ltd (EARL) accreditation specifications for tumour imaging with

  16. Chapter 9: Questions from CNEN specific exams

    International Nuclear Information System (INIS)

    2018-01-01

    The following are real questions from CNEN specific exams for obtaining the certification of RSO for gamma irradiators. These are questions that require essay answers, that are interpretative ones and therefore that may accept more than one interpretation, therefore more than one answer. For this reason, suggestions of answers will be presented in the second part of this chapter

  17. Standard specification for agencies performing nondestructive testing

    CERN Document Server

    American Society for Testing and Materials. Philadelphia

    2009-01-01

    1.1 This specification covers minimum requirements for agencies performing nondestructive testing (NDT). 1.2 When using this specification to assess the capability of, or to accredit NDT agencies, Guide E 1359 shall be used as a basis for the survey. It can be supplemented as necessary with more detail in order to meet the auditor's specific needs. 1.3 This specification can be used as a basis to evaluate testing or inspection agencies, or both, and is intended for use for the qualifying or accrediting, or both, of testing or inspection agencies, public or private. 1.4 The use of SI or inch-pound units, or combination thereof, will be the responsibility of the technical committee whose standards are referred to in this standard. 1.5 This standard does not purport to address all of the safety concerns, if any, associated with its use. It is the responsibility of the user of this standard to establish appropriate safety and health practices and determine the applicability of regulatory limitations prior to...

  18. NIF small optics laser damage test specifications

    International Nuclear Information System (INIS)

    Sheehan, L

    1999-01-01

    The Laser Damage Group is currently conducting tests on small optics samples supplied for initial evaluation of potential NIF suppliers. This document is meant to define the specification of laser-induced damage for small optics and the test methods used to collect the data. A rating system which will be applied for vendor selection is presented

  19. Spent nuclear fuel project product specification

    International Nuclear Information System (INIS)

    PAJUNEN, A.L.

    1999-01-01

    This document establishes the limits and controls for the significant parameters that could potentially affect the safety and/or quality of the Spent Nuclear Fuel (SNF) packaged for processing, transport, and storage. The product specifications in this document cover the SNF packaged in Multi-Canister Overpacks to be transported throughout the SNF Project

  20. A camera specification for tendering purposes

    International Nuclear Information System (INIS)

    Lunt, M.J.; Davies, M.D.; Kenyon, N.G.

    1985-01-01

    A standardized document is described which is suitable for sending to companies which are being invited to tender for the supply of a gamma camera. The document refers to various features of the camera, the performance specification of the camera, maintenance details, price quotations for various options and delivery, installation and warranty details. (U.K.)