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Sample records for intratumoral foxp3-positive regulatory

  1. Increased intratumoral FOXP3-positive regulatory immune cells during interleukin-2 treatment in metastatic renal cell carcinoma

    DEFF Research Database (Denmark)

    Jensen, Hanne Krogh; Donskov, Frede; Nordsmark, Marianne

    2009-01-01

    PURPOSE: The administration of interleukin-2 (IL-2) may increase the frequency of peripherally circulating FOXP3-positive regulatory immune cells, thus potentially compromising this treatment option for patients with metastatic renal cell carcinoma. The impact of IL-2-based therapy...... on the accumulation of FOXP3-positive immune cells in the tumor microenvironment in metastatic renal cell carcinoma is unknown. EXPERIMENTAL DESIGN: Baseline (n = 58) and on-treatment (n = 42) tumor core biopsies were prospectively obtained from patients with clear cell metastatic renal cell carcinoma before...... and during IL-2-based immunotherapy. Immunohistochemical expression of FOXP3 was estimated by stereological counting technique and correlated with other immune cell subsets and overall survival. RESULTS: A significant increase in absolute intratumoral FOXP3-positive immune cells was observed comparing...

  2. Role of Foxp3-positive regulatory T cells during infection

    Science.gov (United States)

    Belkaid, Yasmine

    2012-01-01

    Surviving an infection requires the generation of an immune response that controls the invading pathogen while limiting collateral damage to self tissues that may result from an exuberant immune response. Various populations of regulatory cells, including Foxp3+ Treg, have been shown to play a central role in the establishment of these controlled immune responses. In this review, I discuss current hypotheses and points of polemic associated with the origin, mode of action and antigen specificity of Foxp3+ Treg during infection. PMID:18395860

  3. Increased numbers of Foxp3-positive regulatory T cells in gastritis, peptic ulcer and gastric adenocarcinoma

    Science.gov (United States)

    Cheng, Hsin-Hung; Tseng, Guan-Ying; Yang, Hsiao-Bai; Wang, Hung-Jung; Lin, Hwai-Jeng; Wang, Wen-Ching

    2012-01-01

    AIM: To determine the number of regulatory T cells (Tregs) in gastric mucosa of patients with gastritis, peptic ulcers and gastric cancer. METHODS: This study was a retrospective analysis of gastric antrum biopsy specimens from healthy controls (n = 22) and patients with gastritis (n = 30), peptic ulcer (n = 83), or gastric cancer (n = 32). Expression of CD4, CD25 and Foxp3 was determined by immunohistochemistry in three consecutive sections per sample. RESULTS: Compared with healthy controls, there was an increased number of CD25+ and Foxp3+ cells in patients with gastritis (P = 0.004 and P = 0.008), peptic ulcer (P cancer (P gastritis (P gastritis and peptic ulcer groups. PMID:22228968

  4. The number of Foxp3-positive regulatory T cells is increased in Helicobacter pylori gastritis and gastric cancer.

    Science.gov (United States)

    Jang, Tae Jung

    2010-01-15

    Helicobacter pylori (H. pylori) colonization induces vigorous innate and specific immune responses; however, the infection is not removed, a state of chronic active gastritis persists for life if untreated. Recent studies have shown that CD4(+) CD25(+) Foxp3-positive regulatory T cells (Tregs) suppress the immune response to H. pylori. Persistent H. pylori-associated gastritis is closely associated with gastric carcinogenesis. We investigated the number of Tregs in the context of H. pylori colonization in chronic gastritis, examined the relationship between it and histopathological findings and compared it with that of gastric dysplasia and adenocarcinoma. This study was based on the analysis of gastric biopsy specimens from 126 cases of H. pylori-associated gastritis, 16 cases of H. pylori-negative gastritis, 17 cases of gastric dysplasia, and 25 cases of gastric adenocarcinoma. The number of Tregs was elevated in H. pylori-associated gastritis, where it was positively correlated with the grade of chronic inflammation and the number of lymphoid follicles. It was significantly elevated in adenocarcinomas compared to chronic gastritis and gastric dysplasia. In summary, the number of Tregs is increased in H. pylori-associated gastritis and gastric cancer. Copyright 2009 Elsevier GmbH. All rights reserved.

  5. Identification of a subset of perpheral T-cell lymphoma, not otherwise specified, characterized by FOXP3-positive regulatory T-cell phenotype, HTLV-1 negativity and poor outcome

    DEFF Research Database (Denmark)

    Pedersen, Martin Bjerregård; Hamilton-Dutoit, Stephen Jacques; Bendix, Knud

    2014-01-01

    Identification of a subset of perpheral T-cell lymphoma, not otherwise specified, characterized by FOXP3-positive regulatory T-cell phenotype, HTLV-1 negativity and poor outcome.......Identification of a subset of perpheral T-cell lymphoma, not otherwise specified, characterized by FOXP3-positive regulatory T-cell phenotype, HTLV-1 negativity and poor outcome....

  6. FOXP3 positive regulatory T-cells in cutaneous and systemic CD30 positive T-cell lymphoproliferations

    DEFF Research Database (Denmark)

    Gjerdrum, Lise Mette; Woetmann, Anders; Ødum, Niels

    2008-01-01

    for FOXP3 expression in tumour cells and tumour infiltrating Tregs. Labelling of a majority of the neoplastic cells was seen in one case of C-ALCL. Another three cases (one LyP and two C-ALCL) displayed weak labelling of very occasional atypical T-cells. In the remaining 38 cases the atypical lymphoid...... infiltrate was FOXP3 negative. By contrast, all biopsies contained tumour infiltrating FOXP3-positive Tregs. Significant higher numbers were recorded in ALK negative S-ALCL and LyP than in C-ALCL and S-ALCL positive for ALK. In conclusion, it is shown that FOXP3 expression in cutaneous and systemic CD30...

  7. Low numbers of FOXP3 positive regulatory T cells are present in all developmental stages of human atherosclerotic lesions

    NARCIS (Netherlands)

    de Boer, Onno J.; van der Meer, Jelger J.; Teeling, Peter; van der Loos, Chris M.; van der Wal, Allard C.

    2007-01-01

    BACKGROUND: T cell mediated inflammation contributes to atherogenesis and the onset of acute cardiovascular disease. Effector T cell functions are under a tight control of a specialized T cell subset, regulatory T cells (Treg). At present, nothing is known about the in situ presence of Treg in human

  8. Detection of Tax-specific CTLs in lymph nodes of adult T-cell leukemia/lymphoma patients and its association with Foxp3 positivity of regulatory T-cell function.

    Science.gov (United States)

    Ichikawa, Ayako; Miyoshi, Hiroaki; Arakawa, Fumiko; Kiyasu, Junichi; Sato, Kensaku; Niino, Daisuke; Kimura, Yoshizo; Yoshida, Maki; Kawano, Riko; Muta, Hiroko; Sugita, Yasuo; Ohshima, Koichi

    2017-06-01

    Human T-cell lymphotropic virus type (HTLV)-1 Tax is a viral protein that has been reported to be important in the proliferation of adult T-cell leukemia/lymphoma (ATLL) cells and to be a target of HTLV-1-specific cytotoxic T lymphocytes (CTLs). However, it is not clear how Tax-specific CTLs behave in lymph nodes of ATLL patients. The present study analyzed the immunostaining of Tax-specific CTLs. Furthermore, ATLL tumor cells are known to be positive for forkhead box P3 (Foxp3)and to have a regulatory T (Treg)-cell-like function. The association between T-reg function and number and activity of Tax-specific CTLs was also investigated. A total of 15 ATLL lymphoma cases with human leukocyte antigen (HLA)-A24, for which Tax has a high affinity, were selected from the files of the Department of Pathology, School of Medicine, Kurume University (Kurume, Japan) using a polymerase chain reaction (PCR) method. Immunostaining was performed for cluster of differentiation (CD) 20, CD3, CD4, CD8, T-cell intracellular antigen-1 and Foxp3 in paraffin sections, and for Tax, interferon γ and HLA-A24 in frozen sections. In addition, the staining of Tax-specific CTLs (HLA-A24-restricted) was analyzed by MHC Dextramer ® assay in frozen sections. In addition, the messenger RNA expression of Tax and HTLV-1 basic leucine zipper factor were also evaluated by reverse transcription-PCR. Immunohistochemical staining of Tax protein in lymphoma tissue revealed the presence of positive lymphoma cells ranging from 5 to 80%, and immunohistochemical staining of HLA-A24 revealed the presence of positive lymphoma cells ranging from 1 to 95%. The expression of Tax and HLA-A24 was downregulated by viral function. Foxp3, a marker for Treg cells, was expressed in 0-90% of cells. Several cases exhibited Tax-specific CTL (HLA-A24-restricted)-positive cells, and there was an inverse correlation between Tax-specific CTLs and Foxp3. However, neither Tax nor HLA-A24 expression was associated with CTL or

  9. Comparison of circulating and intratumoral regulatory T cells in patients with renal cell carcinoma.

    Science.gov (United States)

    Asma, Gati; Amal, Gorrab; Raja, Marrakchi; Amine, Derouiche; Mohammed, Chebil; Amel, Ben Ammar Elgaaied

    2015-05-01

    The clear evidence that tumor-infiltrating lymphocytes (TIL) exists in the tumor microenvironment raises the question why renal cell carcinoma (RCC) progresses. Numerous studies support the implication of CD4(+)CD25(high) regulatory T (Treg) cells in RCC development. We aimed in this study to characterize the phenotype and function of circulating and intratumoral Treg cells of RCC patient in order to evaluate their implication in the inhibition of the local antitumor immune response. Our results demonstrate that the proportion of Treg in TIL was, in average, similar to that found in circulating CD4(+) T cells of patients or healthy donors. However, intratumoral Treg exhibit a marked different phenotype when compared with the autologous circulating Treg. A higher CD25 mean level, HLA-DR, Fas, and GITR, and a lower CD45RA expression were observed in intratumoral Treg, suggesting therefore that these cells are effector in the tumor microenvironment. Additionally, intratumoral Treg showed a higher inhibitory function on autologous CD4(+)CD25(-) T cells when compared with circulating Treg that may be explained by an overexpression of FoxP3 transcription factor. These findings suggest that intratumoral Treg could be major actors in the impairment of local antitumor immune response for RCC patients.

  10. Expansion of peripheral and intratumoral regulatory T-cells in hepatocellular carcinoma: A case-control study

    Directory of Open Access Journals (Sweden)

    Sapna Thakur

    2011-01-01

    Full Text Available Background: Hepatocellular carcinoma (HCC is notorious for poor prognosis with limited therapeutic options. A better understanding of the role of regulatory T-cells (Tregs in HCC is important for design of immunotherapy based clinical protocol. The objective of the present study was to evaluate the presence of Tregs in tumor microenvironment in patients with HCC compared to chronic hepatitis (CH. Materials and Methods: The frequency of CD4 + CD25 + Treg cells was evaluated from peripheral blood (PB of 28 patients of HCC and 30 controls including CH cases and healthy donors using flowcytometry. Intratumoral Treg were also analyzed in tissue samples from 17 HCC cases and 15 CH cases. In addition the expression of FOXP3 and CTLA-4 was also studied by RT-PCR. Results: Frequency of CD4 + CD25 + cells in the PBMCs of HCC cases was significantly higher than in HC (10.8 ± 7.64 vs 3.05 ± 1.30, P < 0.005 and CH patients (2.88 ± 1.92, P < 0.005. Also Treg population was significantly higher in HCC tumor microenvironment compared to CH biopsies (15.8 ± 5.32 vs 5.51 ± 3.40, P < 0.05. Expression of FOXP3 and CTLA-4 was also significantly higher in HCC patients ( P < 0.05 compared to CH group. Conclusions: We provide evidence of an increased population of Treg not only in the PB but also in tumor microenvironment of HCC patients, suggesting association of enhanced Treg activity with poor immune responses to tumor antigens. These findings may in future play a significant role in designing immunotherapeutic approaches in HCC.

  11. Intratumoral Approaches for the Treatment of Melanoma.

    Science.gov (United States)

    Bommareddy, Praveen K; Silk, Ann W; Kaufman, Howard L

    There have been significant advances in the immunotherapy of melanoma over the last decade. The tumor microenvironment is now known to promote an immune-suppressive milieu that can block effective immune-mediated tumor rejection. Several novel strategies designed to overcome local immunosuppression hold promise for treatment of melanoma and other cancers. These approaches include oncolytic viruses, plasmid DNA delivery, Toll-like receptor agonists, inflammatory dyes, cytokines, checkpoint inhibitors, immunomodulatory agents, and host and pathogenic cell-based vectors. In addition, there are several novel methods for local drug delivery, including direct injection, image-guided, electroporation, and nanodelivery techniques under study. The approval of talimogene laherparepvec (Imlygic), an attenuated, recombinant oncolytic herpesvirus, for melanoma treatment is the first intratumoral agent to receive regulatory approval for the treatment of patients with melanoma. This review will focus on the rationale for intratumoral treatment in melanoma, describe the clinical and safety data for some of the agents in clinical development, and provide a perspective for future clinical investigation with intratumoral approaches. Melanoma has been a paradigm tumor for progress in targeted therapy and immunotherapy and will likely also be the tumor to establish the therapeutic role of intratumoral treatment for cancer.

  12. Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing

    DEFF Research Database (Denmark)

    Gerlinger, Marco; Rowan, Andrew J.; Horswell, Stuart

    2012-01-01

    BACKGROUND: Intratumor heterogeneity may foster tumor evolution and adaptation and hinder personalized-medicine strategies that depend on results from single tumor-biopsy samples.METHODSTo examine intratumor heterogeneity, we performed exome sequencing, chromosome aberration analysis, and ploidy ...

  13. Heme oxygenase-1 prevents smoke induced B-cell infiltrates: a role for regulatory T cells?

    Directory of Open Access Journals (Sweden)

    Luinge Marjan A

    2008-02-01

    Full Text Available Abstract Background Smoking is the most important cause for the development of COPD. Since not all smokers develop COPD, it is obvious that other factors must be involved in disease development. We hypothesize that heme oxygenase-1 (HO-1, a protective enzyme against oxidative stress and inflammation, is insufficiently upregulated in COPD. The effects of HO-1 modulation on cigarette smoke induced inflammation and emphysema were tested in a smoking mouse model. Methods Mice were either exposed or sham exposed to cigarette smoke exposure for 20 weeks. Cobalt protoporphyrin or tin protoporphyrin was injected during this period to induce or inhibit HO-1 activity, respectively. Afterwards, emphysema development, levels of inflammatory cells and cytokines, and the presence of B-cell infiltrates in lung tissue were analyzed. Results Smoke exposure induced emphysema and increased the numbers of inflammatory cells and numbers of B-cell infiltrates, as well as the levels of inflammatory cytokines in lung tissue. HO-1 modulation had no effects on smoke induced emphysema development, or the increases in neutrophils and macrophages and inflammatory cytokines. Interestingly, HO-1 induction prevented the development of smoke induced B-cell infiltrates and increased the levels of CD4+CD25+ T cells and Foxp3 positive cells in the lungs. Additionally, the CD4+CD25+ T cells correlated positively with the number of Foxp3 positive cells in lung tissue, indicating that these cells were regulatory T cells. Conclusion These results support the concept that HO-1 expression influences regulatory T cells and indicates that this mechanism is involved in the suppression of smoke induced B-cell infiltrates. The translation of this interaction to human COPD should now be pursued.

  14. Structure of Intratumor Heterogeneity: Is Cancer Hedging Its Bets?

    OpenAIRE

    Brutovsky, B.; Horvath, D.

    2013-01-01

    Development of resistance limits transferability of most anticancer therapies into curative treatment and understanding mechanisms beyond it remains a big challenge. Many high resolution experimental observations show enormous intratumor heterogeneity at molecular, genetic and cellular levels which is made responsible for emerging resistance to therapy. Therefore, researchers search techniques to influence development of intratumor heterogeneity, which requires understanding its role within t...

  15. Phenotypically non-suppressive cells predominate among FoxP3-positive cells in oral lichen planus.

    Science.gov (United States)

    Schreurs, Olav; Karatsaidis, Andreas; Schenck, Karl

    2016-11-01

    Oral lichen planus (OLP) is a common T-cell-dominated oral chronic inflammatory disease occurring in periods of remission, quiescence, activity with pronounced inflammation, and acute ulceration. Cell infiltrates in OLP contain varying numbers of CD4 + T cells expressing the transcription factor FoxP3. FoxP3 + CD4 + T cells are, however, a heterogeneous cell population containing suppressive and non-suppressive cells, and their distribution in infiltrates from OLP is unknown. Biopsies were taken from normal oral mucosa (n = 8) and OLP lesions (n = 19), and a set of in situ methods for the determination of the functional phenotype of FoxP3 + CD4 + T cells was applied. Numbers of FoxP3 + CD4 + T cells were highest in the atrophic form of the disease, yet low in the ulcerative form. The main FoxP3 + CD4 + T-cell population observed was FoxP3 + CD45RA - CD25 + CD45RO + and CD15s - , a phenotype delineating a non-suppressive subset. Numbers of cells with an actively suppressing phenotype (FoxP3 + CD45RA - CD25 + CD45RO + and CD15s + ) were, however, about twice as high in reticular lesions as compared with the atrophic form. Many FoxP3 + CD4 + T cells expressed T-bet, the hallmark transcription factor for IFN-γ-producing T cells, indicating that they may enhance immune and inflammatory responses rather than suppress them. The absence of actively suppressing FoxP3 + CD4 + T cells may in part explain why OLP is a remarkably persisting condition, in spite of the presence of substantially high numbers of FoxP3 + CD4 + T cells. The findings emphasize that it is crucial to examine not only numbers but also functional phenotype of FoxP3 + CD4 + T cells in human tissues. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  16. Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing

    DEFF Research Database (Denmark)

    Gerlinger, Marco; Rowan, Andrew J.; Horswell, Stuart

    2012-01-01

    BACKGROUND: Intratumor heterogeneity may foster tumor evolution and adaptation and hinder personalized-medicine strategies that depend on results from single tumor-biopsy samples.METHODSTo examine intratumor heterogeneity, we performed exome sequencing, chromosome aberration analysis, and ploidy...... and 4EBP phosphorylation in vivo and constitutive activation of mTOR kinase activity in vitro. Mutational intratumor heterogeneity was seen for multiple tumor-suppressor genes converging on loss of function; SETD2, PTEN, and KDM5C underwent multiple distinct and spatially separated inactivating...... mutations within a single tumor, suggesting convergent phenotypic evolution. Gene-expression signatures of good and poor prognosis were detected in different regions of the same tumor. Allelic composition and ploidy profiling analysis revealed extensive intratumor heterogeneity, with 26 of 30 tumor samples...

  17. Direct intratumoral infusion of liposome encapsulated rhenium radionuclides for cancer therapy: Effects of nonuniform intratumoral dose distribution

    International Nuclear Information System (INIS)

    Hrycushko, Brian A.; Li Shihong; Goins, Beth; Otto, Randal A.; Bao, Ande

    2011-01-01

    Purpose: Focused radiation therapy by direct intratumoral infusion of lipid nanoparticle (liposome)-carried beta-emitting radionuclides has shown promising results in animal model studies; however, little is known about the impact the intratumoral liposomal radionuclide distribution may have on tumor control. The primary objective of this work was to investigate the effects the intratumoral absorbed dose distributions from this cancer therapy modality have on tumor control and treatment planning by combining dosimetric and radiobiological modeling with in vivo imaging data. Methods: 99m Tc-encapsulated liposomes were intratumorally infused with a single injection location to human head and neck squamous cell carcinoma xenografts in nude rats. High resolution in vivo planar imaging was performed at various time points for quantifying intratumoral retention following infusion. The intratumoral liposomal radioactivity distribution was obtained from 1 mm resolution pinhole collimator SPECT imaging coregistered with CT imaging of excised tumors at 20 h postinfusion. Coregistered images were used for intratumoral dosimetric and radiobiological modeling at a voxel level following extrapolation to the therapeutic analogs, 186 Re/ 188 Re liposomes. Effective uniform dose (EUD) and tumor control probability (TCP) were used to assess therapy effectiveness and possible methods of improving upon tumor control with this radiation therapy modality. Results: Dosimetric analysis showed that average tumor absorbed doses of 8.6 Gy/MBq (318.2 Gy/mCi) and 5.7 Gy/MBq (209.1 Gy/mCi) could be delivered with this protocol of radiation delivery for 186 Re/ 188 Re liposomes, respectively, and 37-92 MBq (1-2.5 mCi)/g tumor administered activity; however, large intratumoral absorbed dose heterogeneity, as seen in dose-volume histograms, resulted in insignificant values of EUD and TCP for achieving tumor control. It is indicated that the use of liposomes encapsulating radionuclides with higher

  18. Magnetic nanoparticle biodistribution following intratumoral administration

    Energy Technology Data Exchange (ETDEWEB)

    Giustini, A J; Hoopes, P J [Dartmouth Medical School and the Thayer School of Engineering, 8000 Cummings Hall, Dartmouth College, Hanover, NH 03755 (United States); Ivkov, R, E-mail: andrew.j.giustini@dartmouth.edu [Triton BioSystems, Inc. , Chelmsford, MA 01824 (United States)

    2011-08-26

    Recently, heat generated by iron oxide nanoparticles (IONPs) stimulated by an alternating magnetic field (AMF) has shown promise in the treatment of cancer. To determine the mechanism of nanoparticle-induced cytotoxicity, the physical association of the cancer cells and the nanoparticles must be determined. We have used transmission electron microscopy (TEM) to define the time dependent cellular uptake of intratumorally administered dextran-coated, core-shell configuration IONP having a mean hydrodynamic diameter of 100-130 nm in a murine breast adenocarcinoma cell line (MTG-B) in vivo. Tumors averaging volumes of 115 mm{sup 3} were injected with iron oxide nanoparticles. The tumors were then excised and fixed for TEM at time 0.1-120 h post-IONP injection. Intracellular uptake of IONPs was 5.0, 48.8 and 91.1% uptake at one, 2 and 4 h post-injection of IONPs, respectively. This information is essential for the effective use of IONP hyperthermia in cancer treatment.

  19. Towards inverse modeling of intratumor heterogeneity

    Science.gov (United States)

    Brutovsky, Branislav; Horvath, Denis

    2015-08-01

    Development of resistance limits efficiency of present anticancer therapies and preventing it remains a big challenge in cancer research. It is accepted, at the intuitive level, that resistance emerges as a consequence of the heterogeneity of cancer cells at the molecular, genetic and cellular levels. Produced by many sources, tumor heterogeneity is extremely complex time dependent statistical characteristics which may be quantified by measures defined in many different ways, most of them coming from statistical mechanics. In this paper, we apply the Markovian framework to relate population heterogeneity to the statistics of the environment. As, from an evolutionary viewpoint, therapy corresponds to a purposeful modi- fication of the cells' fitness landscape, we assume that understanding general relationship between the spatiotemporal statistics of a tumor microenvironment and intratumor heterogeneity will allow to conceive the therapy as an inverse problem and to solve it by optimization techniques. To account for the inherent stochasticity of biological processes at cellular scale, the generalized distancebased concept was applied to express distances between probabilistically described cell states and environmental conditions, respectively.

  20. Imaging-documented repeated intratumoral hemorrhage in vestibular schwannoma: a case report

    NARCIS (Netherlands)

    Mandl, E. S.; Vandertop, W. P.; Meijer, O. W. M.; Peerdeman, S. M.

    2009-01-01

    Intratumoral hemorrhage in vestibular schwannomas is rare. Symptoms often have an acute onset and include headache, nausea, vomiting, vertigo, and depressed consciousness. Intratumoral hemorrhage is probably caused by vascular fragility associated with tumor characteristics and growth. With

  1. Inter- and intratumoral heterogeneity of BCL2 correlates with IgH expression and prognosis in follicular lymphoma

    International Nuclear Information System (INIS)

    Barreca, A; Martinengo, C; Annaratone, L; Righi, L; Chiappella, A; Ladetto, M; Demurtas, A; Chiusa, L; Stacchini, A; Crosetto, N; Oudenaarden, A van; Chiarle, R

    2014-01-01

    Most follicular lymphomas (FLs) are genetically defined by the t(14;18)(q32;q21) translocation that juxtaposes the BCL2 gene to the immunoglobulin heavy chain (IgH) 3' regulatory regions (IgH-3'RRs). Despite this recurrent translocation, FL cases are heterogeneous in terms of intratumoral clonal diversity for acquired mutations and variations in the tumor microenvironment. Here we describe an additional mechanism that contributes to inter- and intratumoral heterogeneity in FLs. By applying a novel single-molecule RNA fluorescence-based in situ hybridization (FISH) technique to detect mRNA molecules of BCL2 and IgH in single cells, we found marked heterogeneity in the number of BCL2 mRNA transcripts within individual lymphoma cells. Moreover, BCL2 mRNA molecules correlated with IgH mRNA molecules in individual cells both in t(14;18) lymphoma cell lines and in patient samples. Consistently, a strong correlation between BCL2 and IgH protein levels was found in a series of 205 primary FL cases by flow cytometry and immunohistochemistry. Inter- and intratumoral heterogeneity of BCL2 expression determined resistance to drugs commonly used in FL treatment and affected overall survival of FL patients. These data demonstrate that BCL2 and IgH expressions are heterogeneous and coregulated in t(14;18)-translocated cells, and determine the response to therapy in FL patients

  2. Primary central nervous system lymphoma: is absence of intratumoral hemorrhage a characteristic finding on MRI?

    Science.gov (United States)

    Sakata, Akihiko; Okada, Tomohisa; Yamamoto, Akira; Kanagaki, Mitsunori; Fushimi, Yasutaka; Dodo, Toshiki; Arakawa, Yoshiki; Takahashi, Jun C; Miyamoto, Susumu; Togashi, Kaori

    2015-06-01

    Previous studies have shown that intratumoral hemorrhage is a common finding in glioblastoma multi-forme, but is rarely observed in primary central nervous system lymphoma. Our aim was to reevaluate whether intratumoral hemorrhage observed on T2-weighted imaging (T2WI) as gross intratumoral hemorrhage and on susceptibility-weighted imaging as intratumoral susceptibility signal can differentiate primary central nervous system lymphoma from glioblastoma multiforme. A retrospective cohort of brain tumors from August 2008 to March 2013 was searched, and 58 patients (19 with primary central nervous system lymphoma, 39 with glioblastoma multiforme) satisfied the inclusion criteria. Absence of gross intratumoral hemorrhage was examined on T2WI, and an intratumoral susceptibility signal was graded using a 3-point scale on susceptibility-weighted imaging. Results were compared between primary central nervous system lymphoma and glioblastoma multiforme, and values of P central nervous system lymphoma and 23 patients (59%) with glioblastoma multiforme. Absence of gross intratumoral hemorrhage could not differentiate between the two disorders (P = 0.20). However, intratumoral susceptibility signal grade 1 or 2 was diagnostic of primary central nervous system lymphoma with 78.9% sensitivity and 66.7% specificity (P central nervous system lymphoma from glioblastoma multiforme. However, specificity in this study was relatively low, and primary central nervous system lymphoma cannot be excluded based solely on the presence of an intratumoral susceptibility signal.

  3. Parasellar dermoid tumor with intra-tumoral hemorrhage

    Energy Technology Data Exchange (ETDEWEB)

    Mamata, H.; Yanagimachi, N.; Matsuyama, S. [Department of Radiology I, Tokai University School of Medicine, Kanagawa (Japan); Matsumae, M.; Takamiya, Y.; Tsugane, R. [Department of Neurosurgery, Tokai University School of Medicine, Kanagawa (Japan)

    1998-12-01

    We report a case of parasellar dermoid tumor with intra-tumoral hemorrhage. It is rare for a dermoid tumor that hemorrhage was detected as high attenuation on the initial CT. In the present case, the tumor content included a little fat component and mostly cholesterin-rich fluid which resulted in extremely low signal intensity on T2-weighted and high signal on T1-weighted MR images. In addition to this, hemosiderin accumulation in the tumor could be the reason for low signal intensity on T2-weighted images. (orig.) With 3 figs., 19 refs.

  4. Intratumoral heterogeneity of Ki67 expression in early breast cancers exceeds variability between individual tumours

    NARCIS (Netherlands)

    Focke, Cornelia M.; Decker, Thomas; van Diest, Paul J.

    2016-01-01

    Aims: Regional differences in proliferative activity are commonly seen within breast cancers, but little is known on the extent of intratumoral heterogeneity of Ki67 expression. Our aim was to study the intratumoral heterogeneity of Ki67 expression in early breast cancers and its association with

  5. Erratum: PDGF-BB induces intratumoral lymphangiogenesis and promotes lymphatic metastasis

    DEFF Research Database (Denmark)

    Cao, R.H.; Bjorndahl, M.A.; Religa, P.

    2006-01-01

    This corrects the article "PDGF-BB induces intratumoral lymphangiogenesis and promotes lymphatic metastasis", Cancer Cell, 2004, vol. 6(4), pg 333-45.......This corrects the article "PDGF-BB induces intratumoral lymphangiogenesis and promotes lymphatic metastasis", Cancer Cell, 2004, vol. 6(4), pg 333-45....

  6. Intratumoral genome diversity parallels progression and predicts outcome in pediatric cancer

    NARCIS (Netherlands)

    Mengelbier, Linda Holmquist; Karlsson, Jenny; Lindgren, David; Valind, Anders; Lilljebjörn, Henrik; Jansson, Caroline; Bexell, Daniel; Braekeveldt, Noémie; Ameur, Adam; Jonson, Tord; Kultima, Hanna Göransson; Isaksson, Anders; Asmundsson, Jurate; Versteeg, Rogier; Rissler, Marianne; Fioretos, Thoas; Sandstedt, Bengt; Börjesson, Anna; Backman, Torbjörn; Pal, Niklas; Øra, Ingrid; Mayrhofer, Markus; Gisselsson, David

    2015-01-01

    Genetic differences among neoplastic cells within the same tumour have been proposed to drive cancer progression and treatment failure. Whether data on intratumoral diversity can be used to predict clinical outcome remains unclear. We here address this issue by quantifying genetic intratumoral

  7. Regulatory T cells are strong promoters of acute ischemic stroke in mice by inducing dysfunction of the cerebral microvasculature.

    Science.gov (United States)

    Kleinschnitz, Christoph; Kraft, Peter; Dreykluft, Angela; Hagedorn, Ina; Göbel, Kerstin; Schuhmann, Michael K; Langhauser, Friederike; Helluy, Xavier; Schwarz, Tobias; Bittner, Stefan; Mayer, Christian T; Brede, Marc; Varallyay, Csanad; Pham, Mirko; Bendszus, Martin; Jakob, Peter; Magnus, Tim; Meuth, Sven G; Iwakura, Yoichiro; Zernecke, Alma; Sparwasser, Tim; Nieswandt, Bernhard; Stoll, Guido; Wiendl, Heinz

    2013-01-24

    We have recently identified T cells as important mediators of ischemic brain damage, but the contribution of the different T-cell subsets is unclear. Forkhead box P3 (FoxP3)-positive regulatory T cells (Tregs) are generally regarded as prototypic anti-inflammatory cells that maintain immune tolerance and counteract tissue damage in a variety of immune-mediated disorders. In the present study, we examined the role of Tregs after experimental brain ischemia/reperfusion injury. Selective depletion of Tregs in the DEREG mouse model dramatically reduced infarct size and improved neurologic function 24 hours after stroke and this protective effect was preserved at later stages of infarct development. The specificity of this detrimental Treg effect was confirmed by adoptive transfer experiments in wild-type mice and in Rag1(-/-) mice lacking lymphocytes. Mechanistically, Tregs induced microvascular dysfunction in vivo by increased interaction with the ischemic brain endothelium via the LFA-1/ICAM-1 pathway and platelets and these findings were confirmed in vitro. Ablation of Tregs reduced microvascular thrombus formation and improved cerebral reperfusion on stroke, as revealed by ultra-high-field magnetic resonance imaging at 17.6 Tesla. In contrast, established immunoregulatory characteristics of Tregs had no functional relevance. We define herein a novel and unexpected role of Tregs in a primary nonimmunologic disease state.

  8. Immunological profiling of haemodialysis patients and young healthy individuals with implications for clinical regulatory T cell sorting.

    Science.gov (United States)

    Bergström, M; Joly, A-L; Seiron, P; Isringhausen, S; Modig, E; Fellström, B; Andersson, J; Berglund, D

    2015-05-01

    With the increasing interest in clinical trials with regulatory T cells (Tregs), immunological profiling of prospective target groups and standardized procedures for Treg isolation are needed. In this study, flow cytometry was used to assess peripheral blood lymphocyte profiles of young healthy individuals and patients undergoing haemodialysis treatment. Tregs obtained from the former may be used in haematopoietic stem cell transplantation and Tregs from the latter in the prevention of kidney transplant rejection. FOXP3 mRNA expression with accompanying isoform distribution was also assessed by the quantitative reverse transcriptase polymerase chain reaction. Flow-cytometric gating strategies were systematically analysed to optimize the isolation of Tregs. Our findings showed an overall similar immunological profile of both cohorts in spite of great differences in both age and health. Analysis of flow-cytometric gating techniques highlighted the importance of gating for both CD25high and CD127low expression in the isolation of FOXP3-positive cells. This study provides additional insight into the immunological profile of young healthy individuals and uraemic patients as well as in-depth analysis of flow-cytometric gating strategies for Treg isolation, supporting the development of Treg therapy using cells from healthy donors and uraemic patients. © 2015 John Wiley & Sons Ltd.

  9. Modeling Breast Cancer Intertumor and Intratumor Heterogeneity Using Xenografts.

    Science.gov (United States)

    Bruna, Alejandra; Rueda, Oscar M; Caldas, Carlos

    2016-01-01

    Breast cancer is a heterogeneous disease that can be stratified in at least 10 different subtypes. We present here a platform for derivation of preclinical models based on patient-derived tumor xenografts (PDTXs) that represent these subgroups. These models preserve the transcriptome, methylome, copy-number, and mutational landscape features of the tumor of origin through different passaging. Furthermore, the intratumoral composition of these models is formed by communities of clones very similar to the ones present in the originating tumor. Finally, we show that short-term cultures of cells from these models (PDTX-derived tumor cells, PDTCs) also preserve the molecular features of the tumor and can be used for high-throughput drug testing of single compounds or combinations, with high reproducibility and clinical predictive power. © 2016 Bruna et al; Published by Cold Spring Harbor Laboratory Press.

  10. Prognostic and predictive role of FOXP3 positive tumor infiltrating lymphocytes (TILs in curatively resected non small cell lung cancer other than stage IA

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    Fatih Kose

    2017-12-01

    Full Text Available Lung cancer is the leading cause of cancer-related mortality and responsible for 1.6 million deaths per year through world-wide. Surgical resection with negative margin combined with the adjuvant therapy [except for stage IA and IB (<4 cm] is the Standard treatment for early-stage Non-small cell lung cancer (NSCLC. Early-stage NSCLC, however, has relapse rate over 40% mostly at distant sites. Therefore, high relapse rate necessitates urgent novel biomarker for these patients. In this study, we aim to evaluate the predictive and prognostic role of FOXP3+ Treg cells along with well defined Clinicohistopathological factors in early-stage non-small cell lung cancer (NSCLC. FOXP3 expression in tumor infiltrating lymphocytes (TIL was examined by immunohistochemical staining from resected early-stage 48 NSCLC patients. Data of patients and FOXP3 expression status along with common clinicohistopathological prognostic factors were evaluated retrospectively. Median age of patients was 62 years-old (range 43–78. Mean follow-up, median overall survival (OS, and disease-free survival (DFS were 49, 49 and 30 months, respectively. FOXP3 expression was positive in 23 (47.9% patients. Adjuvant chemotherapy (4 cycles of cisplatin-vinorelbine was given to 16 patients (33.3% at physician discretion. Patients with a FOXP3 expression of 25% or higher significantly lower OS and DFS when compared with patients with a FOXP3 staining lower than 25% with p-value of 0.016 and 0.032, respectively. In the patients with high FOXP3 expression, platin-based adjuvant chemotherapy had showed a detrimental effect on DFS and OS. These results suggest that FOXP3 expression may be used as useful prognostic biomarker in resected NSCLC. Our findings also suggest that resected NSCLC patients with FOXP3 expression of 25% or higher staining intensity may not get any benefit even disfavor from adjuvant platin chemotherapy.

  11. Quantitative Clinical Imaging Methods for Monitoring Intratumoral Evolution.

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    Kim, Joo Yeun; Gatenby, Robert A

    2017-01-01

    Solid tumors are multiscale, open, complex, dynamic systems: complex because they have many interacting components, dynamic because both the components and their interactions can change with time, and open because the tumor freely communicates with surrounding and even distant host tissue. Thus, it is not surprising that striking intratumoral variations are commonly observed in clinical imaging such as MRI and CT and that several recent studies found striking regional variations in the molecular properties of cancer cells from the same tumor. Interestingly, this spatial heterogeneity in molecular properties of tumor cells is typically ascribed to branching clonal evolution due to accumulating mutations while macroscopic variations observed in, for example, clinical MRI scans are usually viewed as functions of blood flow. The clinical significance of spatial heterogeneity has not been fully determined but there is a general consensus that the varying intratumoral landscape along with patient factors such as age, morbidity and lifestyle, contributes significantly to the often unpredictable response of individual patients within a disease cohort treated with the same standard-of-care therapy.Here we investigate the potential link between macroscopic tumor heterogeneity observed by clinical imaging and spatial variations in the observed molecular properties of cancer cells. We build on techniques developed in landscape ecology to link regional variations in the distribution of species with local environmental conditions that define their habitat. That is, we view each region of the tumor as a local ecosystem consisting of environmental conditions such as access to nutrients, oxygen, and means of waste clearance related to blood flow and the local population of tumor cells that both adapt to these conditions and, to some extent, change them through, for example, production of angiogenic factors. Furthermore, interactions among neighboring habitats can produce broader

  12. Radiosensitizing effect of intratumoral interleukin-12 gene electrotransfer in murine sarcoma

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    Sedlar Ales

    2013-01-01

    Full Text Available Abstract Background Interleukin-12 (IL-12 based radiosensitization is an effective way of tumor treatment. Local cytokine production, without systemic shedding, might provide clinical benefit in radiation treatment of sarcomas. Therefore, the aim was to stimulate intratumoral IL-12 production by gene electrotransfer of plasmid coding for mouse IL-12 (mIL-12 into the tumors, in order to explore its radiosensitizing effect after single or multiple intratumoral gene electrotransfer. Methods Solid SA-1 fibrosarcoma tumors, on the back of A/J mice, were treated intratumorally by mIL-12 gene electrotransfer and 24 h later irradiated with a single dose. Treatment effectiveness was measured by tumor growth delay and local tumor control assay (TCD50 assay. With respect to therapeutic index, skin reaction in the radiation field was scored. The tumor and serum concentrations of cytokines mIL-12 and mouse interferon γ (mIFNγ were measured. Besides single, also multiple intratumoral mIL-12 gene electrotransfer before and after tumor irradiation was evaluated. Results Single intratumoral mIL-12 gene electrotransfer resulted in increased intratumoral but not serum mIL-12 and mIFNγ concentrations, and had good antitumor (7.1% tumor cures and radiosensitizing effect (21.4% tumor cures. Combined treatment resulted in the radiation dose-modifying factor of 2.16. Multiple mIL-12 gene electrotransfer had an even more pronounced antitumor (50% tumor cures and radiosensitizing (86.7% tumor cures effect. Conclusions Single or multiple intratumoral mIL-12 gene electrotransfer resulted in increased intratumoral mIL-12 and mIFNγ cytokine level, and may provide an efficient treatment modality for soft tissue sarcoma as single or adjuvant therapy to tumor irradiation.

  13. Pilot study of intratumoral injection of recombinant heat shock protein 70 in the treatment of malignant brain tumors in children

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    Shevtsov MA

    2014-06-01

    Full Text Available Maxim A Shevtsov,1,2 Alexander V Kim,2 Konstantin A Samochernych,2 Irina V Romanova,3 Boris A Margulis,1 Irina V Guzhova,1 Igor V Yakovenko,2 Alexander M Ischenko,4 William A Khachatryan2 1Institute of Cytology of the Russian Academy of Sciences, 2AL Polenov Russian Research Scientific Institute of Neurosurgery, 3IM Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, 4Research Institute of Highly Pure Biopreparations, St Petersburg, Russian Federation Abstract: Intratumoral injections of recombinant heat shock protein (Hsp70 were explored for feasibility in patients with brain tumors. Patients aged 4.5–14 years with untreated newly diagnosed tumors (n=12 were enrolled. After tumor resection, five injections of recombinant Hsp70 (total 2.5 mg were administered into the resection cavity through a catheter. Before administration of Hsp70 and after the last injection, specific immune responses to the autologous tumor lysate were evaluated using the delayed-type hypersensitivity test. Further, peripheral blood was monitored to identify possible changes in lymphocyte subpopulations, cytokine levels, and the cytolytic activity of natural killer cells. The follow-up period in this trial was 12 months. Intratumoral injections of Hsp70 were well tolerated by patients. One patient had a complete clinical response documented by radiologic findings and one patient had a partial response. A positive delayed-type hypersensitivity test was observed in three patients. In peripheral blood, there was a shift from cytokines provided by Th2 cells toward cytokines of a Th1-cell-mediated response. These data corresponded to changes in lymphocyte subpopulations. Immunosuppressive T-regulatory cell levels were also reduced after injection of Hsp70, as well as production of interleukin-10. The cytolytic activity of natural killer cells was unchanged. The present study demonstrates the feasibility of intratumoral delivery

  14. Intratumoral Heterogeneous F 18 Fluorodeoxyglucose Uptake Corresponds with Glucose Transporter 1 and Ki-67 Expression in a Case of Krukenberg Tumor: Localization of Intratumoral Hypermetabolic Focus by Fused PET/MR

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    Im, Hyung Jun; Kim, Youg il; Kim, Woo Ho; Kim, Seung Hyup; Kang, Keon Wook [Seoul National Univ. College of Medicine, Seoul (Korea, Republic of)

    2011-06-15

    The expression of glucose transporters (Glut 1, Glut 3), Hexokinase II, and Ki-67 has been proposed to explain intratumoral heterogeneous F-18 fluorodeoxyglucose (FDG) uptake. We report a case of Krukenberg tumor with intratumoral heterogeneous FDG uptake which corresponded well with the expression tomography (PET)/magnetic resonance (MR) imaging was helpful for localizing the metabolically active area in the tumor specimen. This report elucidates the relationship between the intratumoral heterogeneous FDG uptake and biologic heterogeneity, and shows the usefulness of PET/MR in research on intratumoral heterogeneity.

  15. Tertiary Intratumor Lymphoid Tissue in Colo-Rectal Cancer

    International Nuclear Information System (INIS)

    Bergomas, Francesca; Grizzi, Fabio; Doni, Andrea; Pesce, Samantha; Laghi, Luigi; Allavena, Paola; Mantovani, Alberto; Marchesi, Federica

    2011-01-01

    Ectopic (or tertiary) lymphoid tissue develops at sites of inflammation or infection in non lymphoid organs and is associated with chronic inflammation. In colon mucosa, small lymphoid aggregates are already present in homeostatic conditions, as part of the gut-associated lymphoid tissue and play an essential role in the immune response to perturbations of the mucosal microenvironment. Despite the recognized role of inflammation in tumor progression, the presence and biological function of lymphoid tissue in cancer has been poorly investigated. We identified aggregates of lymphocytes resembling tertiary lymphoid tissue in human colorectal cancer specimens; intratumor accumulations of lymphocytes display a high degree of compartmentalization, with B and T cells, mature dendritic cells and a network of CD21 + follicular dendritic cells (FDC). We analyzed the adaptation of colon lymphoid tissue in a murine model of colitis-associated cancer (AOM/DSS). B cell follicle formation increases in the context of the chronic inflammation associated to intestinal neoplasia, in this model. A network of lymphatic and haematic vessels surrounding B cell follicles is present and includes high endothelial venules (HEV). Future task is to determine whether lymphoid tissue contributes to the persistence of the tumor-associated inflammatory reaction, rather than represent a functional immune compartment, potentially participating to the anti tumor response

  16. Tertiary Intratumor Lymphoid Tissue in Colo-Rectal Cancer

    Directory of Open Access Journals (Sweden)

    Federica Marchesi

    2011-12-01

    Full Text Available Ectopic (or tertiary lymphoid tissue develops at sites of inflammation or infection in non lymphoid organs and is associated with chronic inflammation. In colon mucosa, small lymphoid aggregates are already present in homeostatic conditions, as part of the gut-associated lymphoid tissue and play an essential role in the immune response to perturbations of the mucosal microenvironment. Despite the recognized role of inflammation in tumor progression, the presence and biological function of lymphoid tissue in cancer has been poorly investigated. We identified aggregates of lymphocytes resembling tertiary lymphoid tissue in human colorectal cancer specimens; intratumor accumulations of lymphocytes display a high degree of compartmentalization, with B and T cells, mature dendritic cells and a network of CD21+ follicular dendritic cells (FDC. We analyzed the adaptation of colon lymphoid tissue in a murine model of colitis-associated cancer (AOM/DSS. B cell follicle formation increases in the context of the chronic inflammation associated to intestinal neoplasia, in this model. A network of lymphatic and haematic vessels surrounding B cell follicles is present and includes high endothelial venules (HEV. Future task is to determine whether lymphoid tissue contributes to the persistence of the tumor-associated inflammatory reaction, rather than represent a functional immune compartment, potentially participating to the anti tumor response.

  17. Tertiary Intratumor Lymphoid Tissue in Colo-Rectal Cancer

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    Bergomas, Francesca [Department of Immunology and Inflammation, IRCCS Humanitas Clinical Institute, Via Manzoni 56, 20089 Rozzano, Milan (Italy); Grizzi, Fabio [Laboratory of Molecular Gastroenterology, IRCCS Humanitas Clinical Institute, Via Manzoni 56, 20089 Rozzano, Milan (Italy); Doni, Andrea; Pesce, Samantha [Department of Immunology and Inflammation, IRCCS Humanitas Clinical Institute, Via Manzoni 56, 20089 Rozzano, Milan (Italy); Laghi, Luigi [Laboratory of Molecular Gastroenterology, IRCCS Humanitas Clinical Institute, Via Manzoni 56, 20089 Rozzano, Milan (Italy); Department of Gastroenterology, IRCCS Humanitas Clinical Institute, Via Manzoni 56, 20089 Rozzano, Milan (Italy); Allavena, Paola [Department of Immunology and Inflammation, IRCCS Humanitas Clinical Institute, Via Manzoni 56, 20089 Rozzano, Milan (Italy); Mantovani, Alberto [Department of Immunology and Inflammation, IRCCS Humanitas Clinical Institute, Via Manzoni 56, 20089 Rozzano, Milan (Italy); Department of Translational Medicine, University of Milan, Milan 20089 (Italy); Marchesi, Federica, E-mail: federica.marchesi@humanitasresearch.it [Department of Immunology and Inflammation, IRCCS Humanitas Clinical Institute, Via Manzoni 56, 20089 Rozzano, Milan (Italy)

    2011-12-28

    Ectopic (or tertiary) lymphoid tissue develops at sites of inflammation or infection in non lymphoid organs and is associated with chronic inflammation. In colon mucosa, small lymphoid aggregates are already present in homeostatic conditions, as part of the gut-associated lymphoid tissue and play an essential role in the immune response to perturbations of the mucosal microenvironment. Despite the recognized role of inflammation in tumor progression, the presence and biological function of lymphoid tissue in cancer has been poorly investigated. We identified aggregates of lymphocytes resembling tertiary lymphoid tissue in human colorectal cancer specimens; intratumor accumulations of lymphocytes display a high degree of compartmentalization, with B and T cells, mature dendritic cells and a network of CD21{sup +} follicular dendritic cells (FDC). We analyzed the adaptation of colon lymphoid tissue in a murine model of colitis-associated cancer (AOM/DSS). B cell follicle formation increases in the context of the chronic inflammation associated to intestinal neoplasia, in this model. A network of lymphatic and haematic vessels surrounding B cell follicles is present and includes high endothelial venules (HEV). Future task is to determine whether lymphoid tissue contributes to the persistence of the tumor-associated inflammatory reaction, rather than represent a functional immune compartment, potentially participating to the anti tumor response.

  18. Factors Controlling the Pharmacokinetics, Biodistribution and Intratumoral Penetration of Nanoparticles

    Science.gov (United States)

    Ernsting, Mark J.; Murakami, Mami; Roy, Aniruddha; Li, Shyh-Dar

    2014-01-01

    Nanoparticle drug delivery to the tumor is impacted by multiple factors: nanoparticles must evade clearance by renal filtration and the reticuloendothelial system, extravasate through the enlarged endothelial gaps in tumors, penetrate through dense stroma in the tumor microenvironment to reach the tumor cells, remain in the tumor tissue for a prolonged period of time, and finally release the active agent to induce pharmacological effect. The physicochemical properties of nanoparticles such as size, shape, surface charge, surface chemistry (PEGylation, ligand conjugation) and composition affect the pharmacokinetics, biodistribution, intratumoral penetration and tumor bioavailability. On the other hand, tumor biology (blood flow, perfusion, permeability, interstitial fluid pressure and stroma content) and patient characteristics (age, gender, tumor type, tumor location, body composition and prior treatments) also have impact on drug delivery by nanoparticles. It is now believed that both nanoparticles and the tumor microenvironment have to be optimized or adjusted for optimal delivery. This review provides a comprehensive summary of how these nanoparticle and biological factors impact nanoparticle delivery to tumors, with discussion on how the tumor microenvironment can be adjusted and how patients can be stratified by imaging methods to receive the maximal benefit of nanomedicine. Perspectives and future directions are also provided. PMID:24075927

  19. Intratumor Heterogeneity of ALK-Rearrangements and Homogeneity of EGFR-Mutations in Mixed Lung Adenocarcinoma.

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    Federica Zito Marino

    Full Text Available Non Small Cell Lung Cancer is a highly heterogeneous tumor. Histologic intratumor heterogeneity could be 'major', characterized by a single tumor showing two different histologic types, and 'minor', due to at least 2 different growth patterns in the same tumor. Therefore, a morphological heterogeneity could reflect an intratumor molecular heterogeneity. To date, few data are reported in literature about molecular features of the mixed adenocarcinoma. The aim of our study was to assess EGFR-mutations and ALK-rearrangements in different intratumor subtypes and/or growth patterns in a series of mixed adenocarcinomas and adenosquamous carcinomas.590 Non Small Cell Lung Carcinomas tumor samples were revised in order to select mixed adenocarcinomas with available tumor components. Finally, only 105 mixed adenocarcinomas and 17 adenosquamous carcinomas were included in the study for further analyses. Two TMAs were built selecting the different intratumor histotypes. ALK-rearrangements were detected through FISH and IHC, and EGFR-mutations were detected through IHC and confirmed by RT-PCR.10/122 cases were ALK-rearranged and 7 from those 10 showing an intratumor heterogeneity of the rearrangements. 12/122 cases were EGFR-mutated, uniformly expressing the EGFR-mutated protein in all histologic components.Our data suggests that EGFR-mutations is generally homogeneously expressed. On the contrary, ALK-rearrangement showed an intratumor heterogeneity in both mixed adenocarcinomas and adenosquamous carcinomas. The intratumor heterogeneity of ALK-rearrangements could lead to a possible impact on the therapeutic responses and the disease outcomes.

  20. Combination of External Beam Radiotherapy (EBRT) With Intratumoral Injection of Dendritic Cells as Neo-Adjuvant Treatment of High-Risk Soft Tissue Sarcoma Patients

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    Finkelstein, Steven E., E-mail: steven.finkelstein@moffitt.org [H. Lee Moffitt Cancer Center, Tampa, FL (United States); Iclozan, Cristina; Bui, Marilyn M.; Cotter, Matthew J.; Ramakrishnan, Rupal; Ahmed, Jamil; Noyes, David R.; Cheong, David; Gonzalez, Ricardo J.; Heysek, Randy V.; Berman, Claudia; Lenox, Brianna C.; Janssen, William; Zager, Jonathan S.; Sondak, Vernon K.; Letson, G. Douglas; Antonia, Scott J. [H. Lee Moffitt Cancer Center, Tampa, FL (United States); Gabrilovich, Dmitry I., E-mail: dmitry.gabrilovich@moffitt.org [H. Lee Moffitt Cancer Center, Tampa, FL (United States)

    2012-02-01

    Purpose: The goal of this study was to determine the effect of combination of intratumoral administration of dendritic cells (DC) and fractionated external beam radiation (EBRT) on tumor-specific immune responses in patients with soft-tissue sarcoma (STS). Methods and Material: Seventeen patients with large (>5 cm) high-grade STS were enrolled in the study. They were treated in the neoadjuvant setting with 5,040 cGy of EBRT, split into 28 fractions and delivered 5 days per week, combined with intratumoral injection of 10{sup 7} DCs followed by complete resection. DCs were injected on the second, third, and fourth Friday of the treatment cycle. Clinical evaluation and immunological assessments were performed. Results: The treatment was well tolerated. No patient had tumor-specific immune responses before combined EBRT/DC therapy; 9 patients (52.9%) developed tumor-specific immune responses, which lasted from 11 to 42 weeks. Twelve of 17 patients (70.6%) were progression free after 1 year. Treatment caused a dramatic accumulation of T cells in the tumor. The presence of CD4{sup +} T cells in the tumor positively correlated with tumor-specific immune responses that developed following combined therapy. Accumulation of myeloid-derived suppressor cells but not regulatory T cells negatively correlated with the development of tumor-specific immune responses. Experiments with {sup 111}In labeled DCs demonstrated that these antigen presenting cells need at least 48 h to start migrating from tumor site. Conclusions: Combination of intratumoral DC administration with EBRT was safe and resulted in induction of antitumor immune responses. This suggests that this therapy is promising and needs further testing in clinical trials design to assess clinical efficacy.

  1. Intratumoral hemorrhage in acoustic neurinoma after gamma knife therapy. A case report

    International Nuclear Information System (INIS)

    Misaki, Toshinari; Arai, Hiroshi; Sasaki, Teruo; Kobayashi, Masakazu; Okuguchi, Taku; Ogasawara, Kuniaki; Ogawa, Akira

    2005-01-01

    A patient who developed symptomatic intratumoral hemorrhage six years after gamma knife surgery for acoustic neurinoma is presented. The patient was a 72-year-old woman who was diagnosed with right acoustic neurinoma and underwent gamma knife surgery. Since symptomatic intratumoral hemorrhage was confirmed six years later, tumor resection was performed. Pathological analysis confirmed widespread hyaline thickening of the vascular endothelia. Symptomatic intratumoral hemorrhage is a relatively rare complication of schwannoma. The pathological features of spontaneous hemorrhage include such vascular anomalies as angioma, clusters of telangiectasia-like abnormal vessels, or numerous thin-walled, dilated vessels. In the present patient, hyaline thickening of vascular endothelia was noted. The association between this histological feature and spontaneous bleeding in neurinoma has not been previously reported in the literature. Delayed effects of radiation include hyaline thickening of the vascular endothelia and narrowing of the vascular lumen. These histological changes have been reported to occur in intratumoral hemorrhage in malignant brain tumors. In the present patient, as hyaline thickening of vascular endothelia due to the gamma knife surgery might have been implicated in symptomatic hemorrhage, the relationship between irradiation and symptomatic intratumoral hemorrhage was examined with reference to the relevant literature. (author)

  2. Mathematical modeling analysis of intratumoral disposition of anticancer agents and drug delivery systems.

    Science.gov (United States)

    Popilski, Hen; Stepensky, David

    2015-05-01

    Solid tumors are characterized by complex morphology. Numerous factors relating to the composition of the cells and tumor stroma, vascularization and drainage of fluids affect the local microenvironment within a specific location inside the tumor. As a result, the intratumoral drug/drug delivery system (DDS) disposition following systemic or local administration is non-homogeneous and its complexity reflects the differences in the local microenvironment. Mathematical models can be used to analyze the intratumoral drug/DDS disposition and pharmacological effects and to assist in choice of optimal anticancer treatment strategies. The mathematical models that have been applied by different research groups to describe the intratumoral disposition of anticancer drugs/DDSs are summarized in this article. The properties of these models and of their suitability for prediction of the drug/DDS intratumoral disposition and pharmacological effects are reviewed. Currently available mathematical models appear to neglect some of the major factors that govern the drug/DDS intratumoral disposition, and apparently possess limited prediction capabilities. More sophisticated and detailed mathematical models and their extensive validation are needed for reliable prediction of different treatment scenarios and for optimization of drug treatment in the individual cancer patients.

  3. TRAF6 is essential for maintenance of regulatory T cells that suppress Th2 type autoimmunity.

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    Go Muto

    Full Text Available Regulatory T cells (Tregs maintain immune homeostasis by limiting inflammatory responses. TRAF6 plays a key role in the regulation of innate and adaptive immunity by mediating signals from various receptors including the T-cell receptor (TCR. T cell-specific deletion of TRAF6 has been shown to induce multiorgan inflammatory disease, but the role of TRAF6 in Tregs remains to be investigated. Here, we generated Treg-specific TRAF6-deficient mice using Foxp3-Cre and TRAF6-flox mice. Treg-specific TRAF6-deficient (cKO mice developed allergic skin diseases, arthritis, lymphadenopathy and hyper IgE phenotypes. Although TRAF6-deficient Tregs possess similar in vitro suppression activity compared to wild-type Tregs, TRAF6-deficient Tregs did not suppress colitis in lymphopenic mice very efficiently due to reduced number of Foxp3-positive cells. In addition, the fraction of TRAF6-deficient Tregs was reduced compared with wild-type Tregs in female cKO mice without inflammation. Moreover, adoptive transfer of Foxp3 (+ Tregs into Rag2(-/- mice revealed that TRAF6-deficient Tregs converted into Foxp3(- cells more rapidly than WT Tregs under lymphopenic conditions. Fate-mapping analysis also revealed that conversion of Tregs from Foxp3(+ to Foxp3(- (exFoxp3 cells was accelerated in TRAF6-deficient Tregs. These data indicate that TRAF6 in Tregs plays important roles in the maintenance of Foxp3 in Tregs and in the suppression of pathogenic Th2 type conversion of Tregs.

  4. Intratumoral convergence of the TCR repertoires of effector and Foxp3+ CD4+ T cells.

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    Michal Kuczma

    2010-10-01

    Full Text Available The presence of Foxp3(+ regulatory CD4(+ T cells in tumor lesions is considered one of the major causes of ineffective immune response in cancer. It is not clear whether intratumoral T(reg cells represent T(reg cells pre-existing in healthy mice, or arise from tumor-specific effector CD4(+ T cells and thus representing adaptive T(reg cells. The generation of T(reg population in tumors could be further complicated by recent evidence showing that both in humans and mice the peripheral population of T(reg cells is heterogenous and consists of subsets which may differentially respond to tumor-derived antigens. We have studied T(reg cells in cancer in experimental mice that express naturally selected, polyclonal repertoire of CD4(+ T cells and which preserve the heterogeneity of the T(reg population. The majority of T(reg cells present in healthy mice maintained a stable suppressor phenotype, expressed high level of Foxp3 and an exclusive set of TCRs not used by naive CD4(+ T cells. A small T(reg subset, utilized TCRs shared with effector T cells and expressed a lower level of Foxp3. We show that response to tumor-derived antigens induced efficient clonal recruitment and expansion of antigen-specific effector and T(reg cells. However, the population of T(reg cells in tumors was dominated by cells expressing TCRs shared with effector CD4(+ T cells. In contrast, T(reg cells expressing an exclusive set of TCRs, that dominate in healthy mice, accounted for only a small fraction of all T(reg cells in tumor lesions. Our results suggest that the T(reg repertoire in tumors is generated by conversion of effector CD4(+ T cells or expansion of a minor subset of T(reg cells. In conclusion, successful cancer immunotherapy may depend on the ability to block upregulation of Foxp3 in effector CD4(+ T cells and/or selectively inhibiting the expansion of a minor T(reg subset.

  5. Pathological Bases and Clinical Impact of Intratumor Heterogeneity in Clear Cell Renal Cell Carcinoma.

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    López, José I; Angulo, Javier C

    2018-01-27

    Intratumor heterogeneity is an inherent event in tumor development that is receiving much attention in the last years since it is responsible for most failures of current targeted therapies. The purpose of this review is to offer clinicians an updated insight of the multiple manifestations of a complex event that impacts significantly patient's life. Clear cell renal cell carcinoma is the most common renal tumor and a paradigmatic example of a heterogeneous neoplasm. Next-generation sequencing has demonstrated that intratumor heterogeneity encompasses genetic, epigenetic, and microenvironmental variability. Currently accepted protocols of tumor sampling seem insufficient in unveiling intratumor heterogeneity with reliability and need to be updated. This variability challenges the precise morphological diagnosis, its molecular characterization, and the selection of optimal personalized therapies in clear cell renal cell carcinoma, a neoplasm traditionally considered chemo- and radio-resistant. We review the state of the art of the different approaches to intratumor heterogeneity in clear cell renal cell carcinomas, from the simple morphology to the most sophisticated massive sequencing tools.

  6. Uveal Melanoma with Histopathologic Intratumoral Heterogeneity Associated with Gene Expression Profile Discordance.

    Science.gov (United States)

    Miller, Audra K; Benage, Matthew J; Wilson, David J; Skalet, Alison H

    2017-07-01

    To report a case of intratumoral gene expression profile discordance in a malignant uveal melanoma, associated with intratumoral heterogeneity based upon histopathologic features. The clinical history, fundus findings, imaging and histopathologic features, and DecisionDx-UM gene expression profile results (Castle Biosciences, Inc., Phoenix, AZ, USA) of the tumor were reviewed. A trans-retinal fine-needle aspiration biopsy was performed for a thin, pigmented choroidal tumor in a 33-year-old man. Cells obtained from this biopsy were tested using the DecisionDx-UM gene expression profile test and the tumor was classified as class 1A. Cytology confirmed melanoma. The patient subsequently elected to undergo enucleation. On microscopic examination of the globe, the tumor was composed primarily of spindle B cells, but had a focal area composed of epithelioid cells. This portion of the tumor was subsequently tested and demonstrated a class 1B gene expression profile. Intratumoral discordance in gene expression profile results has been described in uveal melanomas. Here we demonstrate that this discordance may be associated in some cases with intratumoral heterogeneity based upon histopathologic features.

  7. Intra-tumor heterogeneity in breast cancer has limited impact on transcriptomic-based molecular profiling.

    Science.gov (United States)

    Karthik, Govindasamy-Muralidharan; Rantalainen, Mattias; Stålhammar, Gustav; Lövrot, John; Ullah, Ikram; Alkodsi, Amjad; Ma, Ran; Wedlund, Lena; Lindberg, Johan; Frisell, Jan; Bergh, Jonas; Hartman, Johan

    2017-11-29

    Transcriptomic profiling of breast tumors provides opportunity for subtyping and molecular-based patient stratification. In diagnostic applications the specimen profiled should be representative of the expression profile of the whole tumor and ideally capture properties of the most aggressive part of the tumor. However, breast cancers commonly exhibit intra-tumor heterogeneity at molecular, genomic and in phenotypic level, which can arise during tumor evolution. Currently it is not established to what extent a random sampling approach may influence molecular breast cancer diagnostics. In this study we applied RNA-sequencing to quantify gene expression in 43 pieces (2-5 pieces per tumor) from 12 breast tumors (Cohort 1). We determined molecular subtype and transcriptomic grade for all tumor pieces and analysed to what extent pieces originating from the same tumors are concordant or discordant with each other. Additionally, we validated our finding in an independent cohort consisting of 19 pieces (2-6 pieces per tumor) from 6 breast tumors (Cohort 2) profiled using microarray technique. Exome sequencing was also performed on this cohort, to investigate the extent of intra-tumor genomic heterogeneity versus the intra-tumor molecular subtype classifications. Molecular subtyping was consistent in 11 out of 12 tumors and transcriptomic grade assignments were consistent in 11 out of 12 tumors as well. Molecular subtype predictions revealed consistent subtypes in four out of six patients in this cohort 2. Interestingly, we observed extensive intra-tumor genomic heterogeneity in these tumor pieces but not in their molecular subtype classifications. Our results suggest that macroscopic intra-tumoral transcriptomic heterogeneity is limited and unlikely to have an impact on molecular diagnostics for most patients.

  8. Large-scale Isolation of Highly Pure "Untouched" Regulatory T Cells in a GMP Environment for Adoptive Cell Therapy.

    Science.gov (United States)

    Haase, Doreen; Puan, Kia Joo; Starke, Mireille; Lai, Tuck Siong; Soh, Melissa Yan Ling; Karunanithi, Iyswariya; San Luis, Boris; Poh, Tuang Yeow; Yusof, Nurhashikin; Yeap, Chun Hsien; Phang, Chew Yen; Chye, Willis Soon Yuan; Chan, Marieta; Koh, Mickey Boon Chai; Goh, Yeow Tee; Bertin-Maghit, Sebastien; Nardin, Alessandra; Ho, Liam Pock; Rotzschke, Olaf

    2015-01-01

    Adoptive cell therapy is an emerging treatment strategy for a number of serious diseases. Regulatory T (Treg) cells represent 1 cell type of particular interest for therapy of inflammatory conditions, as they are responsible for controlling unwanted immune responses. Initial clinical trials of adoptive transfer of Treg cells in patients with graft-versus-host disease were shown to be safe. However, obtaining sufficient numbers of highly pure and functional Treg cells with minimal contamination remains a challenge. We developed a novel approach to isolate "untouched" human Treg cells from healthy donors on the basis of negative selection using the surface markers CD49d and CD127. This procedure, which uses an antibody cocktail and magnetic beads for separation in an automated system (RoboSep), was scaled up and adapted to be compatible with good manufacturing practice conditions. With this setup we performed 9 Treg isolations from large-scale leukapheresis samples in a good manufacturing practice facility. These runs yielded sufficient numbers of "untouched" Treg cells for immediate use in clinical applications. The cell preparations consisted of viable highly pure FoxP3-positive Treg cells that were functional in suppressing the proliferation of effector T cells. Contamination with CD4 effector T cells was cell types did not exceed 2% in the final product. Remaining isolation reagents were reduced to levels that are considered safe. Treg cells isolated with this procedure will be used in a phase I clinical trial of adoptive transfer into leukemia patients developing graft-versus-host disease after stem cell transplantation.

  9. Cutaneous infiltration of plasmacytoid dendritic cells and T regulatory cells in skin lesions of polymorphic light eruption.

    Science.gov (United States)

    Rossi, M T; Arisi, M; Lonardi, S; Lorenzi, L; Ungari, M; Serana, F; Fusano, M; Moggio, E; Calzavara-Pinton, P G; Venturini, M

    2018-02-11

    Polymorphic light eruption (PLE) is the most common autoimmune photodermatosis. Plasmacytoid dendritic cells (PDCs) are important mediators of innate antimicrobial immunity involved in the pathogenesis of many inflammatory skin diseases. In addition to PDCs, regulatory T cells (Tregs) are involved in controlling inflammation and adaptive immunity in skin by their immunosuppressive capacity. The aim of this study was to investigate the presence of PDCs and Tregs in photoexposed skin from PLE compared to healthy skin. Patients with PLE diagnosis and healthy controls were recruited and underwent a photoprovocative test. A 4-mm punch biopsy was taken from the site of positive photoprovocation test reaction, and immunohistochemistry for BDCA2 as marker for PDCs, CD4 and FOXP3 as markers for Tregs was performed. Double immunostain for FOXP3 and CD4 was performed as well. Absolute counts for CD4, BDCA2 and FOXP3 were performed in at least 5 High Power Fields (HPF). Percentage of CD4-, BDCA2- and CD4FOXP3-positive cells over the total inflammatory infiltrate was assessed for each case. We enrolled 23 patients and controls. BDCA2+ cells were present in 91.3% of PLE skin samples and 100% of healthy volunteer. Both in PLE patients and healthy controls, PDCs distribution was mainly dermic (P PLE patients (P PLE patients and healthy controls, Tregs distribution was mainly dermic (P PLE patients compared to controls (P PLE, and dermal distribution of PDCs in PLE skin biopsies seems to confirm a possible overlap with cutaneous lupus erythematosus (CLE). © 2018 European Academy of Dermatology and Venereology.

  10. Therapy with omeprazole modulates regulatory T cell/T helper 17 immune response in children with duodenal ulcers.

    Science.gov (United States)

    Li, Chuan-Ying; Wu, Cheng

    2018-04-01

    The purpose of this study was to determine the effect of omeprazole on the regulatory T cell (Treg) and T helper 17 (Th17)-mediated response in patients with duodenal ulcers (DUs). DU patients were randomly divided into omeprazole and colloid bismuth subcitrate treatment groups. The ratios of Th17 and Treg in peripheral blood mononuclear cells (PBMCs) were measured. Cytokine production and Foxp3 + - and RORγt-positive cells were detected. The expressions of STAT3, p-STAT3, STAT5 and p-STAT5 were detected by Western blot. The results showed that DU patients had an imbalanced Treg/Th17 response, as reflected by the higher IL-17 level and Th17 ratio and lower IL-10 level and Treg proportion in serum compared with those in the healthy volunteers. The administration of omeprazole to the patients significantly increased Treg and IL-10 levels and reduced Th17 and IL-17 levels. Omeprazole markedly increased the number of Foxp3-positive cells, decreased the number of RORγt-positive cells and restored the balanced ratio of IL-10/IL-17 in the ulcer tissue. Interestingly, we observed a negative correlation between the ratios of Treg/Th17 and the pathological scores in damaged tissues. Of note, H. pylori-infected PBMCs showed decreased Treg and an increased Th17 proportion, which could be reversed by omeprazole. Finally, omeprazole increased the expression of p-STAT5 and reduced the level of p-STAT3 without any effects on the total expression of STAT5 and STAT3. Our data suggest that omeprazole treatment restores the equilibrium of the Treg/Th17-mediated response in DU patients. Moreover, the modulation of p-STAT3 and p-STAT5 expression by omeprazole induced balanced polarisation of Treg/Th17.

  11. Intratumoral Administration of Holmium-166 Acetylacetonate Microspheres : Antitumor Efficacy and Feasibility of Multimodality Imaging in Renal Cancer

    NARCIS (Netherlands)

    Bult, Wouter; Kroeze, Stephanie G. C.; Elschot, Mattijs; Seevinck, Peter R.; Beekman, Freek J.; de Jong, Hugo W. A. M.; Uges, Donald R. A.; Kosterink, Jos G. W.; Luijten, Peter R.; Hennink, Wim E.; Schip, Alfred D. van Het; Bosch, J. L. H. Ruud; Nijsen, J. Frank W.; Jans, Judith J. M.

    2013-01-01

    Purpose: The increasing incidence of small renal tumors in an aging population with comorbidities has stimulated the development of minimally invasive treatments. This study aimed to assess the efficacy and demonstrate feasibility of multimodality imaging of intratumoral administration of

  12. Intratumoral administration of Holmium-166 Acetylacetonate Microspheres : Antitumor efficacy and feasibility of multimodality imaging in renal cancer

    NARCIS (Netherlands)

    Bult, W.; Kroeze, S.G.C.; Elschot, M.; Seevinck, P.R.; Beekman, F.J.; De Jong, H.W.A.M.; Uges, D.R.A.; Kosterink, J.G.W.; Luijten, P.R.; Hennink, W.E.

    2013-01-01

    The increasing incidence of small renal tumors in an aging population with comorbidities has stimulated the development of minimally invasive treatments. This study aimed to assess the efficacy and demonstrate feasibility of multimodality imaging of intratumoral administration of holmium-166

  13. Prognostic value of podoplanin expression in intratumoral stroma and neoplastic cells of uterine cervical carcinomas

    Science.gov (United States)

    Carvalho, Filomena M; Zaganelli, Fabricia L; Almeida, Bernardo G L; Goes, Joao Carlos Sampaio; Baracat, Edmund C; Carvalho, Jesus P

    2010-01-01

    OBJECTIVE: To investigate the clinicopathological significance of podoplanin expression in the intratumoral stroma and neoplastic cells of early stage uterine cervical cancer. MATERIALS AND METHODS: A total of 143 patients with clinical stage I and IIA uterine cervical carcinomas underwent surgery between 2000 and 2007. Clinicopathological data and slides associated with these cases were retrospectively reviewed. Immunodetection of podoplanin expression in histologic sections of tissue microarray blocks was performed using the monoclonal antibody D2‐40. RESULTS: Expression of podoplanin was detected in neoplastic cells in 31/143 (21.6%) cases, with 29/31 (93.5%) of these cases diagnosed as squamous carcinoma. For all of the cases examined, the strongest signal for podoplanin expression was observed at the proliferating edge of the tumor nests. The rate of positive podoplanin expression for node‐positive cases was lower than that of node‐negative (18.9% vs. 22.6%, respectively). Furthermore, the rate of positive podoplanin expression in fatal cases was 10.5% vs. 21.6%, respectively. In 27/143 (18.8%) cases, podoplanin expression was detected in fibroblasts of the intratumoral stroma, and this expression did not correlate with patient age, clinical stage, tumor size, histologic type, depth of infiltration, or vascular involvement. Moreover, expression of podoplanin in intratumoral stroma fibroblasts was only negatively associated with nodal metastasis. A greater number of fatal cases was observed among negative intratumoral stroma fibroblasts (15.5% vs. 3.7%, respectively), although this difference was not significant. CONCLUSIONS: These preliminary results suggest that podoplanin may have a role in host‐tumor interactions and, as a result, may represent a favorable prognostic factor for squamous cervical carcinomas. PMID:21340215

  14. Prognostic value of podoplanin expression in intratumoral stroma and neoplastic cells of uterine cervical carcinomas

    Directory of Open Access Journals (Sweden)

    Filomena M Carvalho

    2010-01-01

    Full Text Available OBJECTIVE: To investigate the clinicopathological significance of podoplanin expression in the intratumoral stroma and neoplastic cells of early stage uterine cervical cancer. MATERIALS AND METHODS: A total of 143 patients with clinical stage I and IIA uterine cervical carcinomas underwent surgery between 2000 and 2007. Clinicopathological data and slides associated with these cases were retrospectively reviewed. Immunodetection of podoplanin expression in histologic sections of tissue microarray blocks was performed using the monoclonal antibody D2-40. RESULTS: Expression of podoplanin was detected in neoplastic cells in 31/143 (21.6% cases, with 29/31 (93.5% of these cases diagnosed as squamous carcinoma. For all of the cases examined, the strongest signal for podoplanin expression was observed at the proliferating edge of the tumor nests. The rate of positive podoplanin expression for node-positive cases was lower than that of node-negative (18.9% vs. 22.6%, respectively. Furthermore, the rate of positive podoplanin expression in fatal cases was 10.5% vs. 21.6%, respectively. In 27/143 (18.8% cases, podoplanin expression was detected in fibroblasts of the intratumoral stroma, and this expression did not correlate with patient age, clinical stage, tumor size, histologic type, depth of infiltration, or vascular involvement. Moreover, expression of podoplanin in intratumoral stroma fibroblasts was only negatively associated with nodal metastasis. A greater number of fatal cases was observed among negative intratumoral stroma fibroblasts (15.5% vs. 3.7%, respectively, although this difference was not significant. CONCLUSIONS: These preliminary results suggest that podoplanin may have a role in host-tumor interactions and, as a result, may represent a favorable prognostic factor for squamous cervical carcinomas.

  15. Reproducibility of Intratumor Distribution of 18F-Fluoromisonidazole in Head and Neck Cancer

    International Nuclear Information System (INIS)

    Nehmeh, Sadek A.; Lee, Nancy Y.; Schroeder, Heiko; Squire, Olivia; Zanzonico, Pat B.; Erdi, Yusuf E.; Greco, Carlo; Mageras, Gig; Pham, Hai S.; Larson, Steve M.; Ling, Clifton C.; Humm, John L.

    2008-01-01

    Purpose: Hypoxia is one of the main causes of the failure to achieve local control using radiotherapy. This is due to the increased radioresistance of hypoxic cells. 18 F-fluoromisonidazole ( 18 F-FMISO) positron emission tomography (PET) is a noninvasive imaging technique that can assist in the identification of intratumor regions of hypoxia. The aim of this study was to evaluate the reproducibility of 18 F-FMISO intratumor distribution using two pretreatment PET scans. Methods and Materials: We enrolled 20 head and neck cancer patients in this study. Of these, 6 were excluded from the analysis for technical reasons. All patients underwent an 18 F-fluorodeoxyglucose study, followed by two 18 F-FMISO studies 3 days apart. The hypoxic volumes were delineated according to a tumor/blood ratio ≥1.2. The 18 F-FMISO tracer distributions from the two 18 F-FMISO studies were co-registered on a voxel-by-voxel basis using the computed tomography images from the PET/computed tomography examinations. A correlation between the 18 F-FMISO intensities of the corresponding spatial voxels was derived. Results: A voxel-by-voxel analysis of the 18 F-FMISO distributions in the entire tumor volume showed a strong correlation in 71% of the patients. Restraining the correlation to putatively hypoxic zones reduced the number of patients exhibiting a strong correlation to 46%. Conclusion: Variability in spatial uptake can occur between repeat 18 F-FMISO PET scans in patients with head and neck cancer. Blood data for one patient was not available. Of 13 patients, 6 had well-correlated intratumor distributions of 18 F-FMISO-suggestive of chronic hypoxia. More work is required to identify the underlying causes of changes in intratumor distribution before single-time-point 18 F-FMISO PET images can be used as the basis of hypoxia-targeting intensity-modulated radiotherapy

  16. Intratumoral heterogeneity of Ki67 expression in early breast cancers exceeds variability between individual tumours.

    Science.gov (United States)

    Focke, Cornelia M; Decker, Thomas; van Diest, Paul J

    2016-11-01

    Regional differences in proliferative activity are commonly seen within breast cancers, but little is known on the extent of intratumoral heterogeneity of Ki67 expression. Our aim was to study the intratumoral heterogeneity of Ki67 expression in early breast cancers and its association with clinicopathological features, such as oestrogen receptor (ER) status, grade and histological subtype. The Ki67-labelling index (Ki67-LI) was assessed in hot, cold and intermediate spots of 233 invasive breast cancers by counting a total of 1020 cells, according to a protocol of the International Ki67 in Breast Cancer Working Group. Differences between the spots per tumour were analysed further for clinicopathological subgroups defined by ER status, grade and histological subtype. All clinicopathological subgroups showed significant differences in Ki67-LI between hot, intermediate and cold spots (P cancers (72.6 versus 49.2%, P cancers. Nested analysis of variance indicated that in both ER-positive and ER-negative cancers, variance in Ki67-LI within tumours contributed more to the total variance (56% for ER-positive, 60% for ER-negative cancers) than the variance between tumours. Intratumoral heterogeneity in Ki67-LI is a ubiquitous phenomenon across various pathological subgroups of breast cancer that may impact assessment of Ki67 levels for clinical decision-making, and sheds new light on recommended cut-offs. © 2016 John Wiley & Sons Ltd.

  17. Intratumoral Photodynamic Therapy With Newly Synthesized Pheophorbide a in Murine Oral Cancer.

    Science.gov (United States)

    Ahn, Mee-Young; Yoon, Hyo-Eun; Moon, Seong-Yong; Kim, Yong-Chul; Yoon, Jung-Hoon

    2017-01-26

    Photodynamic therapy (PDT) is a therapeutic alternative for malignant tumors that uses a photosensitizer. Our group recently synthesized photosensitizer pheophorbide a (Pa) from chlorophyll-a. The present study investigated the therapeutic effect of PDT using intratumoral administration of the synthetic photosensitizer Pa in an in vivo murine oral squamous cell carcinoma (OSCC) animal model. Pa accumulation was measured using the fluorescence spectrum and imaging in living C3H mice. Intratumoral treatment of Pa-PDT (IT Pa-PDT) significantly inhibited the growth of transplanted OSCC cells. Histopathological examination of tumor tissues showed that PCNA expression was significantly decreased, while TUNEL-stained cells were markedly increased in the IT Pa-PDT group compared to controls. IT Pa-PDT-induced apoptosis was confirmed by immunoblot. Reduction of Bcl-2 and cleavage of caspase 3 and PARP were observed in IT Pa-PDT. These data demonstrate that IT Pa-PDT inhibited tumor cell proliferation and induced apoptosis, which is correlated with the anticancer activity of IT Pa-PDT. These potent antitumor activities of IT Pa-PDT were observed in both the immunohistochemistry and Western blot experiments. Our findings suggest the intratumoral therapeutic potential of Pa-PDT on OSCC. Additionally, demonstrated detection of Pa using a fluorescence spectroscopy system or molecular imaging system provides a means for simultaneous diagnosis and treatment of OSCC.

  18. Improved Intratumoral Oxygenation Through Vascular Normalization Increases Glioma Sensitivity to Ionizing Radiation

    International Nuclear Information System (INIS)

    McGee, Mackenzie C.; Hamner, J. Blair; Williams, Regan F.; Rosati, Shannon F.; Sims, Thomas L.; Ng, Catherine Y.; Gaber, M. Waleed; Calabrese, Christopher; Wu Jianrong; Nathwani, Amit C.; Duntsch, Christopher; Merchant, Thomas E.; Davidoff, Andrew M.

    2010-01-01

    Purpose: Ionizing radiation, an important component of glioma therapy, is critically dependent on tumor oxygenation. However, gliomas are notable for areas of necrosis and hypoxia, which foster radioresistance. We hypothesized that pharmacologic manipulation of the typically dysfunctional tumor vasculature would improve intratumoral oxygenation and, thus, the antiglioma efficacy of ionizing radiation. Methods and Materials: Orthotopic U87 xenografts were treated with either continuous interferon-β (IFN-β) or bevacizumab, alone, or combined with cranial irradiation (RT). Tumor growth was assessed by quantitative bioluminescence imaging; the tumor vasculature using immunohistochemical staining, and tumor oxygenation using hypoxyprobe staining. Results: Both IFN-β and bevaziumab profoundly affected the tumor vasculature, albeit with different cellular phenotypes. IFN-β caused a doubling in the percentage of area of perivascular cell staining, and bevacizumab caused a rapid decrease in the percentage of area of endothelial cell staining. However, both agents increased intratumoral oxygenation, although with bevacizumab, the effect was transient, being lost by 5 days. Administration of IFN-β or bevacizumab before RT was significantly more effective than any of the three modalities as monotherapy or when RT was administered concomitantly with IFN-β or bevacizumab or 5 days after bevacizumab. Conclusion: Bevacizumab and continuous delivery of IFN-β each induced significant changes in glioma vascular physiology, improving intratumoral oxygenation and enhancing the antitumor activity of ionizing radiation. Additional investigation into the use and timing of these and other agents that modify the vascular phenotype, combined with RT, is warranted to optimize cytotoxic activity.

  19. Regulatory agencies and regulatory risk

    OpenAIRE

    Knieps, Günter; Weiß, Hans-Jörg

    2008-01-01

    The aim of this paper is to show that regulatory risk is due to the discretionary behaviour of regulatory agencies, caused by a too extensive regulatory mandate provided by the legislator. The normative point of reference and a behavioural model of regulatory agencies based on the positive theory of regulation are presented. Regulatory risk with regard to the future behaviour of regulatory agencies is modelled as the consequence of the ex ante uncertainty about the relative influence of inter...

  20. Intratumoral estrogen production and actions in luminal A type invasive lobular and ductal carcinomas.

    Science.gov (United States)

    Takagi, Mayu; Miki, Yasuhiro; Miyashita, Minoru; Hata, Shuko; Yoda, Tomomi; Hirakawa, Hisashi; Sagara, Yasuaki; Rai, Yoshiaki; Ohi, Yasuyo; Tamaki, Kentaro; Ishida, Takanori; Suzuki, Takashi; Ouchi, Noriaki; Sasano, Hironobu

    2016-02-01

    The great majority of invasive lobular carcinoma (ILC) is estrogen-dependent luminal A type carcinoma but the details of estrogen actions and its intratumoral metabolism have not been well studied compared to invasive ductal carcinoma (IDC). We first immunolocalized estrogen-related enzymes including estrogen sulfotransferase (EST), estrogen sulfatase (STS), 17β-hydroxysteroid dehydrogenase (HSD) 1/2, and aromatase. We then evaluated the tissue concentrations of estrogens in ILC and IDC and subsequently estrogen-responsive gene profiles in these tumors in order to explore the possible differences and/or similarity of intratumoral estrogen environment of these two breast cancer subtypes. The status of STS and 17βHSD1 was significantly lower in ILCs than IDCs (p = 0.022 and p < 0.0001), but that of EST and 17βHSD2 vice versa (p < 0.0001 and p = 0.0106). In ILCs, tissue concentrations of estrone and estradiol were lower than those in IDCs (p = 0.0709 and 0.069). In addition, the great majority of estrogen response genes tended to be lower in ILCs. Among those genes above, FOXP1 was significantly higher in ILCs than in IDCs (p = 0.002). FOXP1 expression was reported to be significantly higher in relapse-free IDC patients treated with tamoxifen. Therefore, tamoxifen may be considered an option of endocrine therapy for luminal A type ILC patients. This is the first study to demonstrate the detailed and comprehensive status of intratumoral production and metabolism of estrogens and the status of estrogen response genes in luminal A-like ILC with comparison to those in luminal A-like IDCs.

  1. CT-guided intratumoral gene therapy in non-small-cell lung cancer

    International Nuclear Information System (INIS)

    Kauczor, H.U.; Heussel, C.P.; Thelen, M.; Schuler, M.; Huber, C.; Weymarn, A. von; Bongartz, G.; Rochlitz, C.

    1999-01-01

    The objective of this study was to prove the principle of CT-guided gene therapy by intratumoral injection of a tumor suppressor gene as an alternative treatment approach of incurable non-small-cell lung cancer. In a prospective clinical phase I trial six patients with non-small-cell lung cancer and a mutation of the tumor suppressor gene p53 were treated by CT-guided intratumoral gene therapy. Ten milliliters of a vector solution (replication-defective adenovirus with complete wild-type p53 cDNA) were injected under CT guidance. In four cases the vector solution was completely applied to the tumor center, whereas in two cases 2 ml aliquots were injected into different tumor areas. For the procedure the scan room had been approved as a biosafety cabinet. Gene transfer was assessed by reverse transcription and polymerase chain reaction in biopsy specimens obtained under CT guidance 24-48 h after therapy. Potential therapeutic efficacy was evaluated on day 28 after treatment using spiral CT. The CT-guided gene therapy was easily performed in all six patients without intervention-related complications. Besides flu-like symptoms, no significant adverse effects of gene therapy were noted. Three of the four patients with central injection exhibited gene transfer in the posttreatment biopsy. Gene transfer could not be proven in the two patients with multiple 2 ml injections. After 28 days, four of the six patients showed stable disease at the treated tumor site, whereas other tumor manifestations progressed. Computed tomography-guided injections are an adequate and easy-to-perform procedure for intratumoral gene therapy. (orig.)

  2. Positron emission tomography studies with 11C-ethanol in intratumoral therapy for cell carcinoma

    International Nuclear Information System (INIS)

    Dimitrakopoulou-Strauss, A.; Gutzler, F.; Strauss, L.G.; Irngartinger, G.; Oberdorfer, F.; Doll, J.; Stremmel, W.; Kaick, G. van

    1996-01-01

    Positron emission tomography (PET) is a noninvasive functional method for the study of solid tumor perfusion, metabolism and interaction with different therapeutic agents. The aim of the study was the investigation of the metabolism of hepatocellular carcinomas (HCC) and the kinetics during a treatment with intratumoral ethanol by PET. The ongoing study includes seven patients with child A cirrhosis and HCC (UICC stage III-IVA; tumor size 3-6 cm). Dynamic PET studies (60 min) with 18 F-fluordeoxyglucose (FDG) were performed prior to therapy to assess tumor viability. The evaluation of the FDG data demonstrated a liver-equivalent uptake in six of the tumors (well and moderately differentiated HCC), which were poorly delinated against the normal liver parenchyma. One moderately differentiated HCC showed an increased FDG metabolism, indicating no correlation between histology and metabolism. A dose of 37-80 MBq 11 C-ethanol was applied together with a nonlabelled therapeutic dose of the drug via a puncture needle positioned under sonography. Five out of seven tumors demonstrated a high 11 C uptake shortly after the end of the ethanol injection followed by constant 11 C-ethanol concentration during the whole study period of 45 min. The PET data demonstrated no significant elimination of the 11 C-ethanol from the tumor and no accumulation in the surrounding liver tissue. One case showed a decrease of the intratumoral 11 C -ethanol concentration due to a punkture of a tumor vein, and in another case the surrounding liver parenchyma demonstrated significant 11 C uptake in the early phase following paratumoral injection of the drug. In conclusion, PET is a useful tool for the study of the mechanism and the kinetics of percutaneous intratumoral ethanol injection of HCC. (orig.) [de

  3. Technique, pharmacokinetics, toxicity, and efficacy of intratumoral etanidazole and radiotherapy for treatment of spontaneous feline oral squamous cell carcinoma

    International Nuclear Information System (INIS)

    Evans, S.M.; LaCreta, F.; Helfand, S.; VanWinkle, T.; Curran, W.J. Jr.; Brown, D.Q.; Hanks, G.

    1991-01-01

    The histologic appearance, locoregional recurrence, and rate/site of metastases of spontaneous feline oral squamous cell carcinoma are similar to head and neck cancer in humans. A feasibility study of intratumoral Etanidazole, a hypoxic cell sensitizer, and radiation therapy were instituted in this model. Eleven cats with feline squamous cell carcinoma were treated with intratumoral Etanidazole and radiation therapy. Total Etanidazole doses were 1.5-24.0 gms/m2 (0.5-6.9 gms). The tumor partial response rate was 100% (11/11); the median volume regression was 70%. All cats have died as a result of tumor recurrence or tumor-related complications. Median survival was 116 days. Ten cats have been autopsied. Non-necrotic and necrotic tumor cells were identified at the treatment site in all cats. Pharmacokinetic studies were performed in six cats. Following intravenous infusion, the plasma elimination of the Etanidazole was biexponential. The systemic availability following intratumoral administration was 61.2 +/- 21.1%. Peak plasma Etanidazole levels were observed 14 minutes following intratumoral injection, after which elimination was biexponential. Thirty minutes following intratumoral Etanidazole administration, tumor Etanidazole levels were 62.8% of plasma levels. Feline squamous cell carcinoma appears to be a useful model of human head and neck cancer. Cats tolerate substantial doses of intratumoral and intravenous Etanidazole. Etanidazole and radiation therapy cause rapid regression, but not cure, of feline squamous cell carcinoma. There is a similarity between the intravenous kinetics of Etanidazole in humans and cats. Further studies in this model are planned

  4. Hemorragia maciça intratumoral em esclerose tuberosa estudo autóptico de um caso

    Directory of Open Access Journals (Sweden)

    Lígia M. Barbosa-Coutinho

    1991-12-01

    Full Text Available O caso de um menino com esclerose tuberosa, apresentando o quadro clínico típico e que morreu com hemorragia intratumoral maciça, é estudado. A autópsia parcial de crânio revelou hemorragia cerebral maciça à esquerda, no interior da qual se identificou um tumor que, à microscopia, mostrou se tratar de astrocitoma subependimário de células gigantes. Este é o segundo caso, na literatura, no qual um paciente com esclerose tuberosa morre de hemorragia maciça intratumoral, com inundação ventricular.

  5. [Non invasive intracranial hyperthermia with Electric Capacitive Transference -ECT- Intratumoral and cerebral thermometry results].

    Science.gov (United States)

    Ley-Valle, A

    2003-02-01

    The aim of this work is to present the results of thermic increase obtained at the brain and intratumoral levels through a non invasive technique -Electric Capacitive Transference- (ECT), developed in 1985 by Indiba. A review of the literature does not provide any reference of cerebral and intratumoral thermometry in real time with a non invasive technique of intracranial hyperthermia. In the 8 studied patients, the increases of temperature in the brain, ranged between 0.7 and 1.5 degrees C in relation to the depth of the thermometric probe and the incidence angle of the external electrode. Between tumoral and perilesional brain tissues, thermic increase was 0.3 to 0.7 degrees C greater at tumoral level. The observation that in no case the surrounding brain tissue registered a temperature over 39.2 degrees C supports the harmlessness of the technique regarding the potential damage to healthy brain tissue and seems to confirm previous data obtained in anatomopathological studies in animal experimentation performed in 1990, which showed an absence of lesions in tissues and organs. The greater and somewhat more prolonged thermic increase observed at tumoral level has been called the "greenhouse effect".

  6. Modulation of the Intratumoral Immune Landscape by Oncolytic Herpes Simplex Virus Virotherapy

    Directory of Open Access Journals (Sweden)

    Jie Yin

    2017-06-01

    Full Text Available Vaccines and immunotherapeutic approaches to cancers with the advent of immune checkpoint inhibitors and chimeric antigen receptor-modified T cells have recently demonstrated preclinical success and entered clinical trials. Despite advances in these approaches and combinatorial therapeutic regimens, depending on the nature of the cancer and the immune and metabolic landscape within the tumor microenvironment, current immunotherapeutic modalities remain inadequate. Recent clinical trials have demonstrated clear evidence of significant, and sometimes dramatic, antitumor activity, and long-term survival effects of a variety of oncolytic viruses (OVs, particularly oncolytic herpes simplex virus (oHSV. Acting as a multifaceted gene therapy vector and potential adjuvant-like regimens, oHSV can carry genes encoding immunostimulatory molecules in its genome. The oncolytic effect of oHSV and the inflammatory response that the virus stimulates provide a one-two punch at attacking tumors. However, mechanisms underlying oHSV-induced restoration of intratumoral immunosuppression demand extensive research in order to further improve its therapeutic efficacy. In this review, we discuss the current OV-based therapy, with a focus on the unique aspects of oHSV-initiated antiviral and antitumor immune responses, arising from virus-mediated immunological cell death to intratumoral innate and adaptive immunity.

  7. High intratumoral accumulation of stealth liposomal doxorubicin in sarcomas--rationale for combination with radiotherapy

    International Nuclear Information System (INIS)

    Koukourakis, M.I.; Koukouraki, S.; Giatromanolaki, A.; Kakolyris, S.; Georgoulias, V.; Velidaki, A.; Archimandritis, S.; Karkavitsas, N.N.

    2000-01-01

    Sarcomas are radioresistant tumors, the only curative therapy being radical surgical resection. Stealth liposomal doxorubicin (Caelyx) is a novel drug formulation that allows prolonged circulation and high intratumoral concentration. This study investigates the concurrent use of radiotherapy with Caelyx in a cohort of 7 patients with locally advanced or recurrent sarcoma. Radiotherapy was given as a standard fractionation regimen to a total dose of 70 Gy. Caelyx was given as a 30-min infusion at a dose of 25 mg/m 2 every 2 weeks. Scintigraphic imaging with Caelyx- 99m Tc-DTPA showed an increased (2.8 +/- 0.9 times higher) intratumoral drug accumulation compared to the surrounding healthy tissue. The regimen was well tolerated without any severe hematological or systemic toxicity. 'In field' radiation toxicity was not increased. Complete response was observed in 4/7 cases. It is concluded that combined chemo-radiotherapy with stealth liposomal doxorubicin for locally advanced sarcomas is feasible and promising, the benefit expected from the unique ability of the stealth liposomes to accumulate selectively in the tumoral tissue

  8. A Biobank of Breast Cancer Explants with Preserved Intra-tumor Heterogeneity to Screen Anticancer Compounds.

    Science.gov (United States)

    Bruna, Alejandra; Rueda, Oscar M; Greenwood, Wendy; Batra, Ankita Sati; Callari, Maurizio; Batra, Rajbir Nath; Pogrebniak, Katherine; Sandoval, Jose; Cassidy, John W; Tufegdzic-Vidakovic, Ana; Sammut, Stephen-John; Jones, Linda; Provenzano, Elena; Baird, Richard; Eirew, Peter; Hadfield, James; Eldridge, Matthew; McLaren-Douglas, Anne; Barthorpe, Andrew; Lightfoot, Howard; O'Connor, Mark J; Gray, Joe; Cortes, Javier; Baselga, Jose; Marangoni, Elisabetta; Welm, Alana L; Aparicio, Samuel; Serra, Violeta; Garnett, Mathew J; Caldas, Carlos

    2016-09-22

    The inter- and intra-tumor heterogeneity of breast cancer needs to be adequately captured in pre-clinical models. We have created a large collection of breast cancer patient-derived tumor xenografts (PDTXs), in which the morphological and molecular characteristics of the originating tumor are preserved through passaging in the mouse. An integrated platform combining in vivo maintenance of these PDTXs along with short-term cultures of PDTX-derived tumor cells (PDTCs) was optimized. Remarkably, the intra-tumor genomic clonal architecture present in the originating breast cancers was mostly preserved upon serial passaging in xenografts and in short-term cultured PDTCs. We assessed drug responses in PDTCs on a high-throughput platform and validated several ex vivo responses in vivo. The biobank represents a powerful resource for pre-clinical breast cancer pharmacogenomic studies (http://caldaslab.cruk.cam.ac.uk/bcape), including identification of biomarkers of response or resistance. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  9. A population genetics perspective on the determinants of intra-tumor heterogeneity.

    Science.gov (United States)

    Hu, Zheng; Sun, Ruping; Curtis, Christina

    2017-04-01

    Cancer results from the acquisition of somatic alterations in a microevolutionary process that typically occurs over many years, much of which is occult. Understanding the evolutionary dynamics that are operative at different stages of progression in individual tumors might inform the earlier detection, diagnosis, and treatment of cancer. Although these processes cannot be directly observed, the resultant spatiotemporal patterns of genetic variation amongst tumor cells encode their evolutionary histories. Such intra-tumor heterogeneity is pervasive not only at the genomic level, but also at the transcriptomic, phenotypic, and cellular levels. Given the implications for precision medicine, the accurate quantification of heterogeneity within and between tumors has become a major focus of current research. In this review, we provide a population genetics perspective on the determinants of intra-tumor heterogeneity and approaches to quantify genetic diversity. We summarize evidence for different modes of evolution based on recent cancer genome sequencing studies and discuss emerging evolutionary strategies to therapeutically exploit tumor heterogeneity. This article is part of a Special Issue entitled: Evolutionary principles - heterogeneity in cancer?, edited by Dr. Robert A. Gatenby. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Presence of intratumoral platelets is associated with tumor vessel structure and metastasis

    International Nuclear Information System (INIS)

    Li, Rong; Zhang, Xu; Zhang, Zhuo; Zhang, Xiao; Ran, Bing; Wu, Jianbo; Ren, Meiping; Chen, Ni; Luo, Mao; Deng, Xin; Xia, Jiyi; Yu, Guang; Liu, Jinbo; He, Bing

    2014-01-01

    Platelets play a fundamental role in maintaining hemostasis and have been shown to participate in hematogenous dissemination of tumor cells. Abundant platelets were detected in the tumor microenvironment outside of the blood vessel, thus, platelet -tumor cell interaction outside of the bloodstream may play a role in regulating primary tumor growth and metastasis initiation. However, it is unclear that platelet depletion affects tumor vessel structure and dynamics. Using thrombocytopenia induction in two different tumor-bearing mouse models, tumor tissues were performed by Westernblotting and immunohistochemical staining. Vascular permeability was evaluated by determination of intratumoral Evans blue and Miles vascular permeability assay. Furthermore, microdialysis was used to examining the intratumoral extracellular angiogenic growth factors (VEGF, TGF-β) by ELISA. Platelet depletion showed no change in tumor growth and reduced lung metastasis. Platelet depletion led to reduced tumor hypoxia and Met receptor activation and was associated with a decreased release of MMP-2, 9, PAI-1, VEGF, and TGF-β. Tumor vessels in platelet-depleted mice showed impaired vessel density and maturation. Our findings demonstrate that platelets within the primary tumor microenvironment play a critical role in the induction of vascular permeability and initiation of tumor metastasis

  11. Ovarian fibromas: MR imaging findings with emphasis on intratumoral cyst formation

    Energy Technology Data Exchange (ETDEWEB)

    Kato, Hiroki, E-mail: hkato@gifu-u.ac.jp [Department of Radiology, Gifu University School of Medicine, 1-1 Yanagido, Gifu 501-1194 (Japan); Kanematsu, Masayuki, E-mail: masa_gif@yahoo.co.jp [Department of Radiology, Gifu University School of Medicine, 1-1 Yanagido, Gifu 501-1194 (Japan); High-level Imaging Diagnosis Center, Gifu University Hospital, 1-1 Yanagido, Gifu 501-1194 (Japan); Ono, Hiromi, E-mail: hiromi11_br@yahoo.co.jp [Department of Radiology, Gifu University School of Medicine, 1-1 Yanagido, Gifu 501-1194 (Japan); Yano, Ryuichiro, E-mail: yanoryu@gifu-u.ac.jp [Department of Obstetrics and Gynecology, Gifu University School of Medicine, Gifu (Japan); Furui, Tatsuro, E-mail: furui@gifu-u.ac.jp [Department of Obstetrics and Gynecology, Gifu University School of Medicine, Gifu (Japan); Morishige, Ken-ichirou, E-mail: mken@gifu-u.ac.jp [Department of Obstetrics and Gynecology, Gifu University School of Medicine, Gifu (Japan); Hatano, Yuichiro, E-mail: yuha@gifu-u.ac.jp [Department of Pathology, Gifu University School of Medicine, Gifu (Japan)

    2013-09-15

    Purpose: The purpose of this study was to assess MR imaging findings of ovarian fibromas with emphasis on intratumoral cyst formation. Materials and methods: MR images with a 1.5-T unit obtained in 17 consecutive patients (age range, 18–87 years; mean age, 58 years) with 17 histologically proven ovarian fibromas were retrospectively reviewed for the size, configuration, signal intensity of solid components, and presence of cystic degeneration and edema within tumor. Size, number, and location of intratumoral cysts were also assessed. Results: The maximum diameter of tumors ranged from 3.3 to 19.1 cm (mean, 10.9 cm). Seven (41%) tumors were multinodular. On T2-weighted images, solid components of tumors were heterogeneously mixed hypo- and hyperintensity in 16 (94%) tumors. Nine (53%) tumors demonstrated cysts and 16 (94%) demonstrated edema within tumor. The maximum diameter of the largest cysts ranged from 1.0 to 13.2 cm (mean, 6.4 cm), and the number of cysts per tumor ranged from 1 to 60 (mean, 15.6). Of the nine tumors with cystic formation, the predominant location of the cysts was peripheral in five (56%), exophytic in two (22%), central (11%) in one, and diffuse in one (11%). Conclusion: Peripheral or exophytic cyst formation may be characteristic MR imaging features with ovarian fibromas.

  12. Regulatory activities

    International Nuclear Information System (INIS)

    2001-01-01

    This publication, compiled in 8 chapters, presents the regulatory system developed by the Nuclear Regulatory Authority (NRA) of the Argentine Republic. The following activities and developed topics in this document describe: the evolution of the nuclear regulatory activity in Argentina; the Argentine regulatory system; the nuclear regulatory laws and standards; the inspection and safeguards of nuclear facilities; the emergency systems; the environmental systems; the environmental monitoring; the analysis laboratories on physical and biological dosimetry, prenatal irradiation, internal irradiation, radiation measurements, detection techniques on nuclear testing, medical program on radiation protection; the institutional relations with national and international organization; the training courses and meeting; the technical information

  13. Vitamin C Fosters the In Vivo Differentiation of Peripheral CD4+ Foxp3- T Cells into CD4+ Foxp3+ Regulatory T Cells but Impairs Their Ability to Prolong Skin Allograft Survival.

    Science.gov (United States)

    Oyarce, Karina; Campos-Mora, Mauricio; Gajardo-Carrasco, Tania; Pino-Lagos, Karina

    2018-01-01

    Regulatory T cells (Tregs) are critical players of immunological tolerance due to their ability to suppress effector T cell function thereby preventing transplant rejection and autoimmune diseases. During allograft transplantation, increases of both Treg expansion and generation, as well as their stable function, are needed to ensure allograft acceptance; thus, efforts have been made to discover new molecules that enhance Treg-mediated tolerance and to uncover their mechanisms. Recently, vitamin C (VitC), known to regulate T cell maturation and dendritic cell-mediated T cell polarization, has gained attention as a relevant epigenetic remodeler able to enhance and stabilize the expression of the Treg master regulator gene Foxp3, positively affecting the generation of induced Tregs (iTregs). In this study, we measured VitC transporter (SVCT2) expression in different immune cell populations, finding Tregs as one of the cell subset with the highest levels of SVCT2 expression. Unexpectedly, we found that VitC treatment reduces the ability of natural Tregs to suppress effector T cell proliferation in vitro , while having an enhancer effect on TGFβ-induced Foxp3 + Tregs. On the other hand, VitC increases iTregs generation in vitro and in vivo , however, no allograft tolerance was achieved in animals orally treated with VitC. Lastly, Tregs isolated from the draining lymph nodes of VitC-treated and transplanted mice also showed impaired suppression capacity ex vivo . Our results indicate that VitC promotes the generation and expansion of Tregs, without exhibiting CD4 + T cell-mediated allograft tolerance. These observations highlight the relevance of the nutritional status of patients when immune regulation is needed.

  14. Transcriptional profiling of dividing tumor cells detects intratumor heterogeneity linked to cell proliferation in a brain tumor model

    Czech Academy of Sciences Publication Activity Database

    Endaya, B.; Lam, P.Y.P.; Meedeniya, A.C.B.; Neužil, Jiří

    2016-01-01

    Roč. 10, č. 1 (2016), s. 126-137 ISSN 1574-7891 R&D Projects: GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:86652036 Keywords : Intratumor heterogeneity * Click chemistry * Proliferation * Gene profiling Subject RIV: FD - Oncology ; Hematology Impact factor: 5.314, year: 2016

  15. Heterogeneous intratumoral distribution of gadolinium nanoparticles within U87 human glioblastoma xenografts unveiled by micro-PIXE imaging.

    Science.gov (United States)

    Carmona, Asuncion; Roudeau, Stéphane; L'Homel, Baptiste; Pouzoulet, Frédéric; Bonnet-Boissinot, Sarah; Prezado, Yolanda; Ortega, Richard

    2017-04-15

    Metallic nanoparticles have great potential in cancer radiotherapy as theranostic drugs since, they serve simultaneously as contrast agents for medical imaging and as radio-therapy sensitizers. As with other anticancer drugs, intratumoral diffusion is one of the main limiting factors for therapeutic efficiency. To date, a few reports have investigated the intratumoral distribution of metallic nanoparticles. The aim of this study was to determine the quantitative distribution of gadolinium (Gd) nanoparticles after direct intratumoral injection within U87 human glioblastoma tumors grafted in mice, using micro-PIXE (Particle Induced X-ray Emission) imaging. AGuIX (Activation and Guiding of Irradiation by X-ray) 3 nm particles composed of a polysiloxane network surrounded by gadolinium chelates were used. PIXE results indicate that the direct injection of Gd nanoparticles in tumors results in their heterogeneous diffusion, probably related to variations in tumor density. All tumor regions contain Gd, but with markedly different concentrations, with a more than 250-fold difference. Also Gd can diffuse to the healthy adjacent tissue. This study highlights the usefulness of mapping the distribution of metallic nanoparticles at the intratumoral level, and proposes PIXE as an imaging modality to probe the quantitative distribution of metallic nanoparticles in tumors from experimental animal models with micrometer resolution. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. In Vivo Confocal Fluorescence Imaging of the Intratumor Distribution of the Photosensitizer Mono-l-Aspartylchlorin-e6

    Directory of Open Access Journals (Sweden)

    Soumya Mitra

    2008-05-01

    Full Text Available We present an in vivo fluorescence microscopic evaluation of intratumor distribution of the photosensitizer mono-l-aspartylchlorin-e6 (NPe6 in an intradermal mouse EMT6 tumor model. Although the identification of favorable photophysical and pharmacological properties has led to the development of new photosensitizers in photodynamic therapy, their intratumor distribution kinetics have remained relatively understudied. In this study, we used confocal fluorescence microscopy to follow the transport of NPe6 in vivo after systemic administration through the tail vein. Labeling of vasculature using fluorophore-conjugated anti-CD31 antibodies allows visualization of the uptake of NPe6 in tumor and normal vessels and its partitioning kinetics into the adjacent parenchyma for 3 hours after injection. During the initial 60 minutes after injection, the drug is predominantly confined to the vasculature. Subsequently, it significantly redistributes throughout the extravascular regions with no discernable difference in its extravasation rate between tumor and normal tissues. Further, we investigate the sensitizer’s altered intratumor distribution in response to photodynamic therapy irradiation and observe that treatment-induced changes in vessel permeability caused enhanced accumulation of NPe6 in the extravascular space. Our findings are of immediate clinical relevance and demonstrate the importance of an in vivo imaging approach to examine the dynamic process of intratumor drug distribution.

  17. Robust Intratumor Partitioning to Identify High-Risk Subregions in Lung Cancer: A Pilot Study

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Jia; Gensheimer, Michael F.; Dong, Xinzhe [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California (United States); Rubin, Daniel L. [Department of Radiology, Stanford University School of Medicine, Stanford, California (United States); Department of Medicine (Biomedical Informatics Research), Stanford University School of Medicine, Stanford, California (United States); Napel, Sandy [Department of Radiology, Stanford University School of Medicine, Stanford, California (United States); Diehn, Maximilian [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California (United States); Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California (United States); Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California (United States); Loo, Billy W. [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California (United States); Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California (United States); Li, Ruijiang, E-mail: rli2@stanford.edu [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California (United States); Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California (United States)

    2016-08-01

    Purpose: To develop an intratumor partitioning framework for identifying high-risk subregions from {sup 18}F-fluorodeoxyglucose positron emission tomography (FDG-PET) and computed tomography (CT) imaging and to test whether tumor burden associated with the high-risk subregions is prognostic of outcomes in lung cancer. Methods and Materials: In this institutional review board–approved retrospective study, we analyzed the pretreatment FDG-PET and CT scans of 44 lung cancer patients treated with radiation therapy. A novel, intratumor partitioning method was developed, based on a 2-stage clustering process: first at the patient level, each tumor was over-segmented into many superpixels by k-means clustering of integrated PET and CT images; next, tumor subregions were identified by merging previously defined superpixels via population-level hierarchical clustering. The volume associated with each of the subregions was evaluated using Kaplan-Meier analysis regarding its prognostic capability in predicting overall survival (OS) and out-of-field progression (OFP). Results: Three spatially distinct subregions were identified within each tumor that were highly robust to uncertainty in PET/CT co-registration. Among these, the volume of the most metabolically active and metabolically heterogeneous solid component of the tumor was predictive of OS and OFP on the entire cohort, with a concordance index or CI of 0.66-0.67. When restricting the analysis to patients with stage III disease (n=32), the same subregion achieved an even higher CI of 0.75 (hazard ratio 3.93, log-rank P=.002) for predicting OS, and a CI of 0.76 (hazard ratio 4.84, log-rank P=.002) for predicting OFP. In comparison, conventional imaging markers, including tumor volume, maximum standardized uptake value, and metabolic tumor volume using threshold of 50% standardized uptake value maximum, were not predictive of OS or OFP, with CI mostly below 0.60 (log-rank P>.05). Conclusion: We propose a robust

  18. Intratumoral macrophages contribute to epithelial-mesenchymal transition in solid tumors

    International Nuclear Information System (INIS)

    Bonde, Anne-Katrine; Tischler, Verena; Kumar, Sushil; Soltermann, Alex; Schwendener, Reto A

    2012-01-01

    Several stromal cell subtypes including macrophages contribute to tumor progression by inducing epithelial-mesenchymal transition (EMT) at the invasive front, a mechanism also linked to metastasis. Tumor associated macrophages (TAM) reside mainly at the invasive front but they also infiltrate tumors and in this process they mainly assume a tumor promoting phenotype. In this study, we asked if TAMs also regulate EMT intratumorally. We found that TAMs through TGF-β signaling and activation of the β-catenin pathway can induce EMT in intratumoral cancer cells. We depleted macrophages in F9-teratocarcinoma bearing mice using clodronate-liposomes and analyzed the tumors for correlations between gene and protein expression of EMT-associated and macrophage markers. The functional relationship between TAMs and EMT was characterized in vitro in the murine F9 and mammary gland NMuMG cells, using a conditioned medium culture approach. The clinical relevance of our findings was evaluated on a tissue microarray cohort representing 491 patients with non-small cell lung cancer (NSCLC). Gene expression analysis of F9-teratocarcinomas revealed a positive correlation between TAM-densities and mesenchymal marker expression. Moreover, immunohistochemistry showed that TAMs cluster with EMT phenotype cells in the tumors. In vitro, long term exposure of F9-and NMuMG-cells to macrophage-conditioned medium led to decreased expression of the epithelial adhesion protein E-cadherin, activation of the EMT-mediating β-catenin pathway, increased expression of mesenchymal markers and an invasive phenotype. In a candidate based screen, macrophage-derived TGF-β was identified as the main inducer of this EMT-associated phenotype. Lastly, immunohistochemical analysis of NSCLC patient samples identified a positive correlation between intratumoral macrophage densities, EMT markers, intraepithelial TGF-β levels and tumor grade. Data presented here identify a novel role for macrophages in EMT

  19. Intratumoral macrophages contribute to epithelial-mesenchymal transition in solid tumors

    Directory of Open Access Journals (Sweden)

    Bonde Anne-Katrine

    2012-01-01

    Full Text Available Abstract Background Several stromal cell subtypes including macrophages contribute to tumor progression by inducing epithelial-mesenchymal transition (EMT at the invasive front, a mechanism also linked to metastasis. Tumor associated macrophages (TAM reside mainly at the invasive front but they also infiltrate tumors and in this process they mainly assume a tumor promoting phenotype. In this study, we asked if TAMs also regulate EMT intratumorally. We found that TAMs through TGF-β signaling and activation of the β-catenin pathway can induce EMT in intratumoral cancer cells. Methods We depleted macrophages in F9-teratocarcinoma bearing mice using clodronate-liposomes and analyzed the tumors for correlations between gene and protein expression of EMT-associated and macrophage markers. The functional relationship between TAMs and EMT was characterized in vitro in the murine F9 and mammary gland NMuMG cells, using a conditioned medium culture approach. The clinical relevance of our findings was evaluated on a tissue microarray cohort representing 491 patients with non-small cell lung cancer (NSCLC. Results Gene expression analysis of F9-teratocarcinomas revealed a positive correlation between TAM-densities and mesenchymal marker expression. Moreover, immunohistochemistry showed that TAMs cluster with EMT phenotype cells in the tumors. In vitro, long term exposure of F9-and NMuMG-cells to macrophage-conditioned medium led to decreased expression of the epithelial adhesion protein E-cadherin, activation of the EMT-mediating β-catenin pathway, increased expression of mesenchymal markers and an invasive phenotype. In a candidate based screen, macrophage-derived TGF-β was identified as the main inducer of this EMT-associated phenotype. Lastly, immunohistochemical analysis of NSCLC patient samples identified a positive correlation between intratumoral macrophage densities, EMT markers, intraepithelial TGF-β levels and tumor grade. Conclusions Data

  20. Safety and Efficacy of Intratumoral Injections of Chimeric Antigen Receptor (CAR) T Cells in Metastatic Breast Cancer.

    Science.gov (United States)

    Tchou, Julia; Zhao, Yangbing; Levine, Bruce L; Zhang, Paul J; Davis, Megan M; Melenhorst, Jan Joseph; Kulikovskaya, Irina; Brennan, Andrea L; Liu, Xiaojun; Lacey, Simon F; Posey, Avery D; Williams, Austin D; So, Alycia; Conejo-Garcia, Jose R; Plesa, Gabriela; Young, Regina M; McGettigan, Shannon; Campbell, Jean; Pierce, Robert H; Matro, Jennifer M; DeMichele, Angela M; Clark, Amy S; Cooper, Laurence J; Schuchter, Lynn M; Vonderheide, Robert H; June, Carl H

    2017-12-01

    Chimeric antigen receptors (CAR) are synthetic molecules that provide new specificities to T cells. Although successful in treatment of hematologic malignancies, CAR T cells are ineffective for solid tumors to date. We found that the cell-surface molecule c-Met was expressed in ∼50% of breast tumors, prompting the construction of a CAR T cell specific for c-Met, which halted tumor growth in immune-incompetent mice with tumor xenografts. We then evaluated the safety and feasibility of treating metastatic breast cancer with intratumoral administration of mRNA-transfected c-Met-CAR T cells in a phase 0 clinical trial (NCT01837602). Introducing the CAR construct via mRNA ensured safety by limiting the nontumor cell effects (on-target/off-tumor) of targeting c-Met. Patients with metastatic breast cancer with accessible cutaneous or lymph node metastases received a single intratumoral injection of 3 × 10 7 or 3 × 10 8 cells. CAR T mRNA was detectable in peripheral blood and in the injected tumor tissues after intratumoral injection in 2 and 4 patients, respectively. mRNA c-Met-CAR T cell injections were well tolerated, as none of the patients had study drug-related adverse effects greater than grade 1. Tumors treated with intratumoral injected mRNA c-Met-CAR T cells were excised and analyzed by immunohistochemistry, revealing extensive tumor necrosis at the injection site, cellular debris, loss of c-Met immunoreactivity, all surrounded by macrophages at the leading edges and within necrotic zones. We conclude that intratumoral injections of mRNA c-Met-CAR T cells are well tolerated and evoke an inflammatory response within tumors. Cancer Immunol Res; 5(12); 1152-61. ©2017 AACR . ©2017 American Association for Cancer Research.

  1. The role of intratumoral and systemic IL-6 in breast cancer

    DEFF Research Database (Denmark)

    Dethlefsen, Christine; Højfeldt, Grith Westergaard; Hojman, Pernille

    2013-01-01

    Chronic low-grade inflammation plays an important role in the pathogenesis of several cancer forms including breast cancer. The pleiotropic cytokine IL-6 is a key player in systemic inflammation, regulating both the inflammatory response and tissue metabolism during acute stimulations. Here, we...... review the associations between IL-6 and breast cancer ranging from in vitro cell culture studies to clinical studies, covering the role of IL-6 in controlling breast cancer cell growth, regulation of cancer stem cell renewal, as well as breast cancer cell migration. Moreover, associations between......, while high circulating IL-6 levels are correlated with a poor prognosis in breast cancer patients. This discrepancy reflects distinct roles of IL-6, with elevated systemic levels being a biomarker for tumor burden, physical inactivity, and impaired metabolism, while local intratumoral IL-6 signaling...

  2. Tumor treatment by sustained intratumoral release of cisplatin: effects of drug alone and combined with radiation

    International Nuclear Information System (INIS)

    Yapp, Donald T.T.; Lloyd, David K.; Zhu, Julian; Lehnert, Shirley M.

    1997-01-01

    Purpose: The effect of intratumoral delivery of cisplatin to a mouse tumor model (RIF-1) by means of a biodegradable polymer implant with and without radiation was studied. Methods and Materials: The polymer bis(p-carboxyphenoxy)propane-sebacic acid (CPP:SA; 80:20) and its degradation products have been characterized. Polymer rods (8 x 0.5 mm) containing 17% cisplatin by weight were prepared by extrusion, and the in vitro degradation rate measured. The implants were placed into mouse tumors and their effect (with and without radiation) on tumor growth delay studied. The levels of Pt in the mouse kidney, tumor, and blood plasma at selected intervals after implant were also determined. These results were compared with those obtained when cisplatin was delivered systematically. Results: When cisplatin was delivered by the polymer implants, higher levels were present in the tumor for longer time periods (cf. systemic delivery of the drug). For both nonirradiated and irradiated tumors, those treated with the polymer implants had significantly longer tumor growth delays compared to nonimplanted controls and to systematically treated tumors. Conclusions: The results show that intratumoral delivery of cisplatin is more efficient than systemic delivery. Using the biodegradable polymer implant, higher doses of cisplatin can be tolerated by the animal as the drug is localized within the tumor, and the high levels of the drug in the tumor can be maintained for an extended period of time. When radiation is given in conjunction with cisplatin, the tumor response is supraadditive for all modes of cisplatin administration but is potentiated to a greater extent when cisplatin is delivered through the polymer implant. The greatest effect is seen for treatment with cisplatin delivered by polymer implant combined with fractionated radiation

  3. Pointwise mutual information quantifies intratumor heterogeneity in tissue sections labeled with multiple fluorescent biomarkers

    Directory of Open Access Journals (Sweden)

    Daniel M Spagnolo

    2016-01-01

    Full Text Available Background: Measures of spatial intratumor heterogeneity are potentially important diagnostic biomarkers for cancer progression, proliferation, and response to therapy. Spatial relationships among cells including cancer and stromal cells in the tumor microenvironment (TME are key contributors to heterogeneity. Methods: We demonstrate how to quantify spatial heterogeneity from immunofluorescence pathology samples, using a set of 3 basic breast cancer biomarkers as a test case. We learn a set of dominant biomarker intensity patterns and map the spatial distribution of the biomarker patterns with a network. We then describe the pairwise association statistics for each pattern within the network using pointwise mutual information (PMI and visually represent heterogeneity with a two-dimensional map. Results: We found a salient set of 8 biomarker patterns to describe cellular phenotypes from a tissue microarray cohort containing 4 different breast cancer subtypes. After computing PMI for each pair of biomarker patterns in each patient and tumor replicate, we visualize the interactions that contribute to the resulting association statistics. Then, we demonstrate the potential for using PMI as a diagnostic biomarker, by comparing PMI maps and heterogeneity scores from patients across the 4 different cancer subtypes. Estrogen receptor positive invasive lobular carcinoma patient, AL13-6, exhibited the highest heterogeneity score among those tested, while estrogen receptor negative invasive ductal carcinoma patient, AL13-14, exhibited the lowest heterogeneity score. Conclusions: This paper presents an approach for describing intratumor heterogeneity, in a quantitative fashion (via PMI, which departs from the purely qualitative approaches currently used in the clinic. PMI is generalizable to highly multiplexed/hyperplexed immunofluorescence images, as well as spatial data from complementary in situ methods including FISSEQ and CyTOF, sampling many different

  4. Intratumoral metabolic heterogeneity predicts invasive components in breast ductal carcinoma in situ

    Energy Technology Data Exchange (ETDEWEB)

    Yoon, Hai-Jeon [Ewha Womans University School of Medicine, Department of Nuclear Medicine, Yangchun-Ku, Seoul (Korea, Republic of); Kim, Yemi [Ewha Womans University, Clinical Research Institute, Seoul (Korea, Republic of); Kim, Bom Sahn [Ewha Womans University School of Medicine, Department of Nuclear Medicine, Yangchun-Ku, Seoul (Korea, Republic of); Ewha Womans University, Clinical Research Institute, Seoul (Korea, Republic of)

    2015-12-15

    This study investigated whether texture-based imaging parameters could identify invasive components of ductal carcinoma in situ (DCIS). We enrolled 65 biopsy-confirmed DCIS patients (62 unilateral, 3 bilateral) who underwent {sup 18}F-FDG PET, diffusion-weighted imaging (DWI), or breast-specific gamma imaging (BSGI). We measured SUV{sub max} and intratumoral metabolic heterogeneity by the area under the curve (AUC) of cumulative SUV histograms (CSH) on PET, tumour-to-normal ratio (TNR) and coefficient of variation (COV) as an index of heterogeneity on BSGI, minimum ADC (ADC{sub min}) and ADC difference (ADC{sub diff}) as an index of heterogeneity on DWI. After surgery, final pathology was categorized as pure-DCIS (DCIS-P), DCIS with microinvasion (DCIS-MI), or invasive ductal carcinoma (IDC). Clinicopathologic features of DCIS were correlated with final classification. Final pathology confirmed 44 DCIS-P, 14 DCIS-MI, and 10 IDC. The invasive component of DCIS was significantly correlated with higher SUV{sub max} (p = 0.017) and lower AUC-CSH (p < 0.001) on PET, higher TNR (p = 0.008) and COV (p = 0.035) on BSGI, lower ADC{sub min} (p = 0.016) and higher ADC{sub diff} (p = 0.009) on DWI, and larger pathologic size (p = 0.018). On multiple regression analysis, AUC-CSH was the only significant predictor of invasive components (p = 0.044). The intratumoral metabolic heterogeneity of {sup 18}F-FDG PET was the most important predictor of invasive components of DCIS. (orig.)

  5. The potentiation of the effect of radiation treatment by intratumoral delivery of cisplatin

    International Nuclear Information System (INIS)

    Yapp, Donald T.T.; Lloyd, David K.; Zhu, Julian; Lehnert, Shirley M.

    1998-01-01

    Purpose: To compare potentiation of the effects of acute or fractionated radiation by cisplatin when the drug was delivered intratumorally by implanted biodegradable polymer, by intraperitoneal injection, or by intraperitoneal osmotic pump. Methods and Materials: Radiation was delivered to a mouse tumor (RIF-1) either in a single dose or in a fractionated regime in conjunction with cisplatin delivered either as a bolus injection, with an osmotic pump, or with a biodegradable polymer rod containing cisplatin. The osmotic pump was implanted in the intraperitoneal cavity of the mouse while the polymer implants were placed directly in the tumor. As the polymer degrades, the drug is released at the treatment site leading to high local concentrations. The osmotic pump, in contrast, leads to prolonged systemic exposure to the drug at low concentrations. Tumor growth delay (TGD) was used as an endpoint in these experiments. Results: The most effective treatment protocol, in terms of potentiating the effects of radiation was cisplatin delivered by polymer implanted 2 days before an acute dose of radiation (growth modification factor [DMF] = 2.2). Comparison of single and multifraction regimes where polymer implant was on the same day as the commencement of treatment showed greater potentiation of the effect of fractionated than of acute radiation treatment with the DMF for fractionated treatment remaining relatively constant (1.5-1.9) for 5, 8, and 12 fraction treatments. Cisplatin delivered via the osmotic pump did not deliver a high enough dose of cisplatin to produce therapeutic effect in this mouse tumor model and had little impact on response to treatment. Conclusions: Our results indicated that cisplatin delivered intratumorally by biodegradable polymer implant was effective in potentiating the effect of both acute and fractionated radiation. For the fractionated treatments the effect was maintained with increasing fraction numbers and treatment time

  6. Intratumoral metabolic heterogeneity predicts invasive components in breast ductal carcinoma in situ

    International Nuclear Information System (INIS)

    Yoon, Hai-Jeon; Kim, Yemi; Kim, Bom Sahn

    2015-01-01

    This study investigated whether texture-based imaging parameters could identify invasive components of ductal carcinoma in situ (DCIS). We enrolled 65 biopsy-confirmed DCIS patients (62 unilateral, 3 bilateral) who underwent 18 F-FDG PET, diffusion-weighted imaging (DWI), or breast-specific gamma imaging (BSGI). We measured SUV max and intratumoral metabolic heterogeneity by the area under the curve (AUC) of cumulative SUV histograms (CSH) on PET, tumour-to-normal ratio (TNR) and coefficient of variation (COV) as an index of heterogeneity on BSGI, minimum ADC (ADC min ) and ADC difference (ADC diff ) as an index of heterogeneity on DWI. After surgery, final pathology was categorized as pure-DCIS (DCIS-P), DCIS with microinvasion (DCIS-MI), or invasive ductal carcinoma (IDC). Clinicopathologic features of DCIS were correlated with final classification. Final pathology confirmed 44 DCIS-P, 14 DCIS-MI, and 10 IDC. The invasive component of DCIS was significantly correlated with higher SUV max (p = 0.017) and lower AUC-CSH (p < 0.001) on PET, higher TNR (p = 0.008) and COV (p = 0.035) on BSGI, lower ADC min (p = 0.016) and higher ADC diff (p = 0.009) on DWI, and larger pathologic size (p = 0.018). On multiple regression analysis, AUC-CSH was the only significant predictor of invasive components (p = 0.044). The intratumoral metabolic heterogeneity of 18 F-FDG PET was the most important predictor of invasive components of DCIS. (orig.)

  7. Lymph Node Metastases in Papillary and Medullary Thyroid Carcinoma Are Independent of Intratumoral Lymphatic Vessel Density

    Science.gov (United States)

    Pereira, Filipe; Pereira, Sofia S.; Mesquita, Marta; Morais, Tiago; Costa, Madalena M.; Quelhas, Pedro; Lopes, Carlos; Monteiro, Mariana P.; Leite, Valeriano

    2017-01-01

    Background Blood and lymph vessel invasion are well-recognized markers of tumor aggressiveness, as these are the routes that lead to metastases. Thyroid tumors, depending on the histological variant, tend to have distinctive biological behaviors and use different vascular routes to metastasize, yet the mechanisms underlying the metastatic process are still poorly understood. Objectives The aim of this study was to assess how the lymph vessel density (LVD) in different histological types of thyroid tumors, and in their surrounding tissue, correlate with the presence of lymph node metastases (LNM) and tumor pathological features. Methods Lymph vessels of papillary thyroid carcinomas (PTC), of the classical (CVPTC, n = 50) and follicular variants (FVPTC, n = 18), and medullary thyroid carcinomas (MTC, n = 34) were immunohistochemically stained against antigen D2-40. The stained area was quantified using a computerized morphometric analysis tool and correlated with the tumor pathological characteristics. Results LVD within all analyzed thyroid tumor subtypes was significantly lower than in the surrounding thyroid tissues (p < 0.001). Despite intratumoral LVD being significantly higher in CVPTC than in FVPTC, and peritumoral LVD being significantly higher in MTC than in PTC (p < 0.05), no correlations were found between LVD (either intratumoral or peritumoral) and the presence of lymph node metastasis. Conclusions As no LVD differences were found amongst thyroid tumors with or without LNM, dissemination is more likely to depend on the tumor ability to invade the abundant lymph vessel network of the surrounding thyroid tissue than on the ability of the tumor to promote de novo lymphangiogenesis. PMID:28589086

  8. Intratumoral chemotherapy for lung cancer: re-challenge current targeted therapies

    Directory of Open Access Journals (Sweden)

    Hohenforst-Schmidt W

    2013-07-01

    through passive transport within the tumor. Recent advances have enhanced the diffusion of pharmaceuticals through active transport by using pharmaceuticals designed to target the genome of tumors. In the present study, five patients with non-small cell lung cancer epidermal growth factor receptor (EGFR negative stage IIIa–IV International Union Against Cancer 7 (UICC-7, and with Eastern Cooperative Oncology Group (ECOG 2 scores were administered platinum-based doublet chemotherapy using combined intratumoral-regional and intravenous route of administration. Cisplatin analogues were injected at 0.5%–1% concentration within the tumor lesion and proven malignant lymph nodes according to pretreatment histological/cytological results and the concentration of systemic infusion was decreased to 70% of a standard protocol. This combined intravenous plus intratumoral-regional chemotherapy is used as a first line therapy on this short series of patients. To the best of our knowledge this is the first report of direct treatment of involved lymph nodes with cisplatin by endobronchial ultrasound drug delivery with a needle without any adverse effects. The initial overall survival and local response are suggestive of a better efficacy compared to established doublet cisplatin–based systemic chemotherapy in (higher standard concentrations alone according to the UICC 7 database expected survival. An extensive search of the literature was performed to gather information of previously published literature of intratumoral chemo-drug administration and formulation for this treatment modality. Our study shows a favorable local response, more than a 50% reduction, for a massive tumor mass after administration of five sessions of intratumoral chemotherapy plus two cycles of low-dose intravenous chemotherapy according to our protocol. These encouraging results (even in very sick ECOG 2 patients with central obstructive non-small cell lung cancer having a worse prognosis and quality of

  9. Correlation of intra-tumor 18F-FDG uptake heterogeneity indices with perfusion CT derived parameters in colorectal cancer.

    Directory of Open Access Journals (Sweden)

    Florent Tixier

    Full Text Available Thirty patients with proven colorectal cancer prospectively underwent integrated 18F-FDG PET/DCE-CT to assess the metabolic-flow phenotype. Both CT blood flow parametric maps and PET images were analyzed. Correlations between PET heterogeneity and perfusion CT were assessed by Spearman's rank correlation analysis.Blood flow visualization provided by DCE-CT images was significantly correlated with 18F-FDG PET metabolically active tumor volume as well as with uptake heterogeneity for patients with stage III/IV tumors (|ρ|:0.66 to 0.78; p-value<0.02.The positive correlation found with tumor blood flow indicates that intra-tumor heterogeneity of 18F-FDG PET accumulation reflects to some extent tracer distribution and consequently indicates that 18F-FDG PET intra-tumor heterogeneity may be associated with physiological processes such as tumor vascularization.

  10. Spatial intratumoral heterogeneity of proliferation in immunohistochemical images of solid tumors

    International Nuclear Information System (INIS)

    Valous, Nektarios A.; Lahrmann, Bernd; Halama, Niels; Grabe, Niels; Bergmann, Frank; Jäger, Dirk

    2016-01-01

    Purpose: The interactions of neoplastic cells with each other and the microenvironment are complex. To understand intratumoral heterogeneity, subtle differences should be quantified. Main factors contributing to heterogeneity include the gradient ischemic level within neoplasms, action of microenvironment, mechanisms of intercellular transfer of genetic information, and differential mechanisms of modifications of genetic material/proteins. This may reflect on the expression of biomarkers in the context of prognosis/stratification. Hence, a rigorous approach for assessing the spatial intratumoral heterogeneity of histological biomarker expression with accuracy and reproducibility is required, since patterns in immunohistochemical images can be challenging to identify and describe. Methods: A quantitative method that is useful for characterizing complex irregular structures is lacunarity; it is a multiscale technique that exhaustively samples the image, while the decay of its index as a function of window size follows characteristic patterns for different spatial arrangements. In histological images, lacunarity provides a useful measure for the spatial organization of a biomarker when a sampling scheme is employed and relevant features are computed. The proposed approach quantifies the segmented proliferative cells and not the textural content of the histological slide, thus providing a more realistic measure of heterogeneity within the sample space of the tumor region. The aim is to investigate in whole sections of primary pancreatic neuroendocrine neoplasms (pNENs), using whole-slide imaging and image analysis, the spatial intratumoral heterogeneity of Ki-67 immunostains. Unsupervised learning is employed to verify that the approach can partition the tissue sections according to distributional heterogeneity. Results: The architectural complexity of histological images has shown that single measurements are often insufficient. Inhomogeneity of distribution depends

  11. Intratumor photosensitizer injection for photodynamic therapy: Pre-clinical experience with methylene blue, Pc 4, and Photofrin

    Science.gov (United States)

    Baran, Timothy M.; Foster, Thomas H.

    2016-03-01

    Intravenous administration of some photosensitizers, including the FDA-approved Photofrin, results in significant systemic photosensitivity and a 2-3-day drug-light interval. Direct intratumor injection of photosensitizer could potentially eliminate these negative aspects of photodynamic therapy (PDT), while requiring a lower photosensitizer dose to achieve comparable drug concentration in the target tissue. We performed PDT using intratumor injection of 3 photosensitizers, methylene blue (MB), Pc 4, and Photofrin, in mouse tumor models. After a 0-15 minute drug-light interval, illumination was delivered by appropriate diode lasers. For animals receiving MB or Pc 4, surface illumination was delivered using a microlens-terminated fiber. For animals receiving Photofrin, interstitial illumination was delivered by a 1 cm diffuser. In animals receiving MB or Pc 4, tumor dimensions were measured daily post-PDT, with a cure being defined as no palpable tumor 90 days post-treatment. For Photofrin, animals were sacrificed 24 hours post-PDT and tumors were excised, with samples HE stained to assess PDT-induced necrosis. 55% of tumors were cured with MB-PDT, and significant tumor growth delay (p=0.002) was observed for Pc 4. For Photofrin PDT, the mean necrosis radius was 3.4+/-0.8 mm, compared to 2.9+/-1.3 mm for systemic administration, which was not a significant difference (p=0.58). Intratumoral injection of the photosensitizers methylene blue, Pc 4, and Photofrin is feasible, and results in appreciable tumor response. Further investigation is necessary to optimize treatment protocols and assess the systemic photosensitivity induced by intratumor injection.

  12. A simple and effective approach for treatment of situs tumor and metastasis:to promote intratumor pus formation

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    Hong Li

    2015-12-01

    Full Text Available Purpose: The recent emergence of the tumor microenvironment as the critical determinant in cancer outcome opens a new routes to fight cancer, however, the clinical results of targeting microenvironment for treating human cancer have not met expectations. Our purpose is to investigate how to target microenvironment for treatment of situs tumor and metastasis.Methods : We suppose that tumor is a robber from times of anarchy and disorder and can be eradicated in flourishing age. We also suppose that carcinogenesis is largely attributed to physically weak that cann’t get rid of ulcer by pus formation. In vivo,the subcutaneous implant model and pulmonary metastasis model of lewis lung cancer were established. Tumor bearing mice were taken water decoction of Astragalus mongholicus(huangqi and Spina Gleditsiae (zaojiaoci by intragastric administration b.i.d for ten weeks, and the influences of Astragalus mongholicus and Spina Gleditsiae  on tumor progression were evaluated by body temperature,blood oxygen saturation,red cell ATPase,blood  rheology,intratumor hypoxia,capillary permeability, matrix metalloproteinase (MMPs and intratumor pus formation.  Results:We found that both of Astragalus mongholicus and Spina Gleditsiae could keep body temperature,blood oxygen saturation,red cell ATPase and blood rheology,and improve intratumor hypoxia,capillary permeability and MMPs in tumor bearing mice,which led to slower tumor growth and less metastasis. Astragalus mongholicus could remove body poison and stimulate immune responses, and Spina Gleditsiae  could  promote pus formation and proteolytic enzymes. The combination of  Astragalus mongholicus and Spina Gleditsiae favored the restoration of tumor immune responses and proteolytic activity at the tumor site, which not only result to an increase in aseptic pus formation, but also to a decrease in necrotic tissue accumulation, and finally caused a complete intratumor pus

  13. Prognostic value of preoperative intratumoral FDG uptake heterogeneity in patients with epithelial ovarian cancer

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Maria; Kim, Hee Seung; Chung, Hyun Hoon; Kim, Jae-Weon; Park, Noh-Hyun; Song, Yong Sang [Seoul National University College of Medicine, Department of Obstetrics and Gynecology, Cancer Research Institute, Seoul (Korea, Republic of); Lee, Hyunjong; Cheon, Gi Jeong [Seoul National University College of Medicine, Department of Nuclear Medicine, Cancer Research Institute, Seoul (Korea, Republic of)

    2017-01-15

    To investigate the prognostic value of intratumoral FDG uptake heterogeneity (IFH) derived from PET/CT in patients with epithelial ovarian cancer (EOC). We retrospectively reviewed patients with pathologically proven epithelial ovarian cancer who underwent preoperative {sup 18}F-FDG PET/CT scans. PET/CT parameters such as maximum and average standardized uptake values (SUV{sub max} and SUV{sub avg}), sum of all metabolic tumour volume (MTV), cumulative total lesion glycolysis (TLG) and IFH were assessed. Regression analyses were used to identify clinicopathological and imaging variables associated with disease-free survival (DFS). Clinicopathological data were reviewed for 61 eligible patients. The median duration of DFS was 13 months (range, 6-26 months), and 18 (29.5 %) patients experienced recurrence. High IFH values were associated with tumour recurrence (P = 0.005, hazard ratio 4.504, 95 % CI 1.572-12.902). The Kaplan-Meier survival graphs showed that DFS significantly differed in groups categorized based on IFH (P = 0.002, log-rank test). Moreover, there were significant differences in DFS (P = 0.009) and IFH (P = 0.040) between patients with and without recurrence. Preoperative IFH measured by {sup 18}F-FDG PET/CT was significantly associated with EOC recurrence. FDG-based heterogeneity could be a useful and potential predicator of EOC recurrence before treatment. (orig.)

  14. Intra-Tumor Genetic Heterogeneity in Wilms Tumor: Clonal Evolution and Clinical Implications

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    George D. Cresswell

    2016-07-01

    Full Text Available The evolution of pediatric solid tumors is poorly understood. There is conflicting evidence of intra-tumor genetic homogeneity vs. heterogeneity (ITGH in a small number of studies in pediatric solid tumors. A number of copy number aberrations (CNA are proposed as prognostic biomarkers to stratify patients, for example 1q+ in Wilms tumor (WT; current clinical trials use only one sample per tumor to profile this genetic biomarker. We multisampled 20 WT cases and assessed genome-wide allele-specific CNA and loss of heterozygosity, and inferred tumor evolution, using Illumina CytoSNP12v2.1 arrays, a custom analysis pipeline, and the MEDICC algorithm. We found remarkable diversity of ITGH and evolutionary trajectories in WT. 1q+ is heterogeneous in the majority of tumors with this change, with variable evolutionary timing. We estimate that at least three samples per tumor are needed to detect >95% of cases with 1q+. In contrast, somatic 11p15 LOH is uniformly an early event in WT development. We find evidence of two separate tumor origins in unilateral disease with divergent histology, and in bilateral WT. We also show subclonal changes related to differential response to chemotherapy. Rational trial design to include biomarkers in risk stratification requires tumor multisampling and reliable delineation of ITGH and tumor evolution.

  15. [Antitumor effect of intratumoral administration of a Coriolus preparation, PSK: inhibition of tumor invasion in vitro].

    Science.gov (United States)

    Ebina, T; Murata, K

    1994-09-01

    The antitumor effects of biological response modifiers (BRM) in an experimental mouse model, the "double grafted tumor system," were analysed. Intratumoral administration of PSK (polysaccharide Kureha), a Coriolus preparation into primary tumor induced a cure of not only the primary solid tumor but also the metastatic, distant tumor. The effect of PSK on in vitro invasion by murine RL male-1 leukemia cells was studied using Biocoat Matrigel Invasion Chamber (Becton Dickinson Labware). We determined the ability of tumor cells to penetrate matrigel-coated filters in the presence or absence of PSK. PSK (100 micrograms/ml) reduced to half the number of invasive tumor cells for 3 hr incubation. PSK inhibited tumor cell invasion of matrigel-coated filters in a dose-dependent manner. Matrigel includes laminin, collagen, fibronectin and heparan sulfate proteoglycan. It is possible, therefore, that PSK may inhibit enzymes which digest the components of basement membranes, extra cellular matrices (ECM). This phenomenon suggests that PSK also inhibits metastatic activity of tumor cells in vivo.

  16. MRI mediated, non-invasive tracking of intratumoral distribution of nanocarriers in rat glioma

    International Nuclear Information System (INIS)

    Karathanasis, Efstathios; Park, Jaekeun; Agarwal, Abhiruchi; Patel, Vijal; Zhao Fuqiang; Hu Xiaoping; Bellamkonda, Ravi V; Annapragada, Ananth V

    2008-01-01

    Nanocarrier mediated therapy of gliomas has shown promise. The success of systemic nanocarrier-based chemotherapy is critically dependent on the so-called leaky vasculature to permit drug extravasation across the blood-brain barrier. Yet, the extent of vascular permeability in individual tumors varies widely, resulting in a correspondingly wide range of responses to the therapy. However, there exist no tools currently for rationally determining whether tumor blood vessels are amenable to nanocarrier mediated therapy in an individualized, patient specific manner today. To address this need for brain tumor therapy, we have developed a multifunctional 100 nm scale liposomal agent encapsulating a gadolinium-based contrast agent for contrast-enhanced magnetic resonance imaging with prolonged blood circulation. Using a 9.4 T MRI system, we were able to track the intratumoral distribution of the gadolinium-loaded nanocarrier in a rat glioma model for a period of three days due to improved magnetic properties of the contrast agent being packaged in a nanocarrier. Such a nanocarrier provides a tool for non-invasively assessing the suitability of tumors for nanocarrier mediated therapy and then optimizing the treatment protocol for each individual tumor. Additionally, the ability to image the tumor in high resolution can potentially constitute a surgical planning tool for tumor resection

  17. Quantitative computed tomographic descriptors associate tumor shape complexity and intratumor heterogeneity with prognosis in lung adenocarcinoma.

    Directory of Open Access Journals (Sweden)

    Olya Grove

    Full Text Available Two CT features were developed to quantitatively describe lung adenocarcinomas by scoring tumor shape complexity (feature 1: convexity and intratumor density variation (feature 2: entropy ratio in routinely obtained diagnostic CT scans. The developed quantitative features were analyzed in two independent cohorts (cohort 1: n = 61; cohort 2: n = 47 of patients diagnosed with primary lung adenocarcinoma, retrospectively curated to include imaging and clinical data. Preoperative chest CTs were segmented semi-automatically. Segmented tumor regions were further subdivided into core and boundary sub-regions, to quantify intensity variations across the tumor. Reproducibility of the features was evaluated in an independent test-retest dataset of 32 patients. The proposed metrics showed high degree of reproducibility in a repeated experiment (concordance, CCC≥0.897; dynamic range, DR≥0.92. Association with overall survival was evaluated by Cox proportional hazard regression, Kaplan-Meier survival curves, and the log-rank test. Both features were associated with overall survival (convexity: p = 0.008; entropy ratio: p = 0.04 in Cohort 1 but not in Cohort 2 (convexity: p = 0.7; entropy ratio: p = 0.8. In both cohorts, these features were found to be descriptive and demonstrated the link between imaging characteristics and patient survival in lung adenocarcinoma.

  18. Comparison of detection pattern of HCC by ferumoxide-enhanced MRI and intratumoral blood flow pattern

    International Nuclear Information System (INIS)

    Itou, Naoki; Kotake, Fumio; Saitou, Kazuhiro; Abe, Kimihiko

    2000-01-01

    We compared the detection rate and pattern of ferumoxide-enhanced magnetic resonance imaging (Fe-MRI) with the intratumoral blood flow pattern determined by CT angiography (CTA) and CT portography (CTAP) in 124 nodes (34 cases) diagnosed as hepatocellular carcinoma (HCC) or borderline HCC, based on the clinical course. Sequences to obtain a T1-weighted images (T1W), proton density-weighted images (PDW), T2-weighted images (T2W), T2*-weighted images (T2*W) were used in Fe-MRI. In nodes shown to be hypervascular on CTA, the detection rate by Fe-MRI was 69.7%. In nodes shown to be avascular by CTAP, the detection rate by Fe-MRI was 67.3%. These rates were higher than with other flow patterns. In nodes showing high signal intensity (HSI) on any sequences, arterial blood flow was increased and portal blood flow decreased in comparison with nodes without high signal intensity. All nodes showing HSI, both on Fe-MRI T2W and T2*W, were hypervascular on CTA, and portal blood flow was absent on CTAP. Nodes showing HSI on both T2*W and T2W were considered to have greater arterial blood flow and decreased portal blood flow compared with nodes appearing as HSI on T2*W, but only as iso- or low signal intensity on T2W (Mann-Whitney U-test; p<0.05). (author)

  19. Regulatory Governance

    DEFF Research Database (Denmark)

    Kjær, Poul F.; Vetterlein, Antje

    2018-01-01

    , legal and cultural, on a global scale. Against this background, this special issue sets out to explore the multifaceted meaning, potential and impact as well as the social praxis of regulatory governance. Under the notions rules, resistance and responsibility the special issue pins out three overall......Regulatory governance frameworks have become essential building blocks of world society. From supply chains to the regimes surrounding international organizations, extensive governance frameworks have emerged which structure and channel a variety of social exchanges, including economic, political...

  20. Regulatory Anatomy

    DEFF Research Database (Denmark)

    Hoeyer, Klaus

    2015-01-01

    , legal documents, technological devices, organizational structures, and work practices aimed at minimizing risk. I use this term to reorient the analytical attention with respect to safety regulation. Instead of evaluating whether safety is achieved, the point is to explore the types of “safety” produced...... they arise. In short, I expose the regulatory anatomy of the policy landscape....

  1. MHC Intratumoral Heterogeneity May Predict Cancer Progression and Response to Immunotherapy.

    Science.gov (United States)

    Romero, Irene; Garrido, Cristina; Algarra, Ignacio; Chamorro, Virginia; Collado, Antonia; Garrido, Federico; Garcia-Lora, Angel M

    2018-01-01

    An individual tumor can present intratumoral phenotypic heterogeneity, containing tumor cells with different phenotypes that do not present irreversible genetic alterations. We have developed a mouse cancer model, named GR9, derived from a methylcholanthrene-induced fibrosarcoma that was adapted to tissue culture and cloned into different tumor cell lines. The clones showed diverse MHC-I phenotypes, ranging from highly positive to weakly positive MHC-I expression. These MHC-I alterations are due to reversible molecular mechanisms, because surface MHC-I could be recovered by IFN-γ treatment. Cell clones with high MHC-I expression demonstrated low local oncogenicity and high spontaneous metastatic capacity, whereas MHC-I-low clones showed high local oncogenicity and no spontaneous metastatic capacity. Although MHC-I-low clones did not metastasize, they produced MHC-I-positive dormant micrometastases controlled by the host immune system, i.e., in a state of immunodormancy. The metastatic capacity of each clone was directly correlated with the host T-cell subpopulations; thus, a strong decrease in cytotoxic and helper T lymphocytes was observed in mice with numerous metastases derived from MHC-I positive tumor clones but a strong increase was observed in those with dormant micrometastases. Immunotherapy was administered to the hosts after excision of the primary tumor, producing a recovery in their immune status and leading to the complete eradication of overt spontaneous metastases or their decrease. According to these findings, the combination of MHC-I surface expression in primary tumor and metastases with host T-cell subsets may be a decisive indicator of the clinical outcome and response to immunotherapy in metastatic disease, allowing the identification of responders to this approach.

  2. Multiple statistical analysis techniques corroborate intratumor heterogeneity in imaging mass spectrometry datasets of myxofibrosarcoma.

    Directory of Open Access Journals (Sweden)

    Emrys A Jones

    Full Text Available MALDI mass spectrometry can generate profiles that contain hundreds of biomolecular ions directly from tissue. Spatially-correlated analysis, MALDI imaging MS, can simultaneously reveal how each of these biomolecular ions varies in clinical tissue samples. The use of statistical data analysis tools to identify regions containing correlated mass spectrometry profiles is referred to as imaging MS-based molecular histology because of its ability to annotate tissues solely on the basis of the imaging MS data. Several reports have indicated that imaging MS-based molecular histology may be able to complement established histological and histochemical techniques by distinguishing between pathologies with overlapping/identical morphologies and revealing biomolecular intratumor heterogeneity. A data analysis pipeline that identifies regions of imaging MS datasets with correlated mass spectrometry profiles could lead to the development of novel methods for improved diagnosis (differentiating subgroups within distinct histological groups and annotating the spatio-chemical makeup of tumors. Here it is demonstrated that highlighting the regions within imaging MS datasets whose mass spectrometry profiles were found to be correlated by five independent multivariate methods provides a consistently accurate summary of the spatio-chemical heterogeneity. The corroboration provided by using multiple multivariate methods, efficiently applied in an automated routine, provides assurance that the identified regions are indeed characterized by distinct mass spectrometry profiles, a crucial requirement for its development as a complementary histological tool. When simultaneously applied to imaging MS datasets from multiple patient samples of intermediate-grade myxofibrosarcoma, a heterogeneous soft tissue sarcoma, nodules with mass spectrometry profiles found to be distinct by five different multivariate methods were detected within morphologically identical regions of

  3. Use and safety of intratumoral application of European mistletoe (Viscum album L) preparations in Oncology.

    Science.gov (United States)

    Steele, Megan L; Axtner, Jan; Happe, Antje; Kröz, Matthias; Matthes, Harald; Schad, Friedemann

    2015-03-01

    Intratumoral (IT) injection of European mistletoe (Viscum album L) preparations might induce local tumor response through combined cytotoxic and immunomodulatory actions of the preparations. Although promising in vitro and in vivo data, along with clinical case studies suggest the need for validation of this hypothesis in prospective trials, the safety of IT mistletoe injections has yet to be thoroughly assessed. The present study summarizes the practice and safety of off-label IT mistletoe therapy within the Network Oncology, a conjoint clinical registry of German hospitals and outpatients specialized in anthroposophic and integrative medicine. Demographic, diagnosis and treatment data of cancer patients who received IT mistletoe applications between 2007 and 2013 were assessed. Suspected adverse drug reactions (ADRs) were analyzed in terms of type, frequency, severity, seriousness and potential risk factors. A total of 123 cancer patients received 862 IT mistletoe injections (preparations from Abnoba, Helixor and Iscucin). The most commonly applied preparations were Abnoba viscum Fraxini (71 patients) and Helixor Mali (54 patients). Of the total patients, 26 patients (21.1%) experienced 74 ADRs. All ADRs were in response to either Abnoba viscum Fraxini (25.4% of exposed patients) or Helixor Mali (18.5% of exposed patients). ADRs were mostly body temperature or immune related and of mild (83.8%) or moderate (14.9%) intensity. Only one possible ADR was described as severe (hypertension) and no serious ADRs occurred. The frequency of ADRs to IT mistletoe injections was 3 times and 5 times higher than has previously been found for subcutaneous and intravenous applications of mistletoe, respectively. IT injection of mistletoe preparations resulted in a relatively high frequency of ADRs. Nearly all ADRs were mild to moderate however, and no serious ADRs occurred. Furthermore, it is possible that immune-related ADRs such as pyrexia and local inflammatory reactions might

  4. Whole genome sequence analysis suggests intratumoral heterogeneity in dissemination of breast cancer to lymph nodes.

    Directory of Open Access Journals (Sweden)

    Kevin Blighe

    Full Text Available Intratumoral heterogeneity may help drive resistance to targeted therapies in cancer. In breast cancer, the presence of nodal metastases is a key indicator of poorer overall survival. The aim of this study was to identify somatic genetic alterations in early dissemination of breast cancer by whole genome next generation sequencing (NGS of a primary breast tumor, a matched locally-involved axillary lymph node and healthy normal DNA from blood.Whole genome NGS was performed on 12 µg (range 11.1-13.3 µg of DNA isolated from fresh-frozen primary breast tumor, axillary lymph node and peripheral blood following the DNA nanoball sequencing protocol. Single nucleotide variants, insertions, deletions, and substitutions were identified through a bioinformatic pipeline and compared to CIN25, a key set of genes associated with tumor metastasis.Whole genome sequencing revealed overlapping variants between the tumor and node, but also variants that were unique to each. Novel mutations unique to the node included those found in two CIN25 targets, TGIF2 and CCNB2, which are related to transcription cyclin activity and chromosomal stability, respectively, and a unique frameshift in PDS5B, which is required for accurate sister chromatid segregation during cell division. We also identified dominant clonal variants that progressed from tumor to node, including SNVs in TP53 and ARAP3, which mediates rearrangements to the cytoskeleton and cell shape, and an insertion in TOP2A, the expression of which is significantly associated with tumor proliferation and can segregate breast cancers by outcome.This case study provides preliminary evidence that primary tumor and early nodal metastasis have largely overlapping somatic genetic alterations. There were very few mutations unique to the involved node. However, significant conclusions regarding early dissemination needs analysis of a larger number of patient samples.

  5. Salivary gland tumors of the parotid gland: CT and MR imaging findings with emphasis on intratumoral cystic components

    Energy Technology Data Exchange (ETDEWEB)

    Kato, Hiroki; Watanabe, Haruo [Gifu University School of Medicine, Department of Radiology, Gifu (Japan); Kanematsu, Masayuki [Gifu University School of Medicine, Department of Radiology, Gifu (Japan); Gifu University Hospital, High-Level Imaging Diagnosis Center, Gifu (Japan); Mizuta, Keisuke; Aoki, Mitsuhiro [Gifu University School of Medicine, Department of Otolaryngology, Gifu (Japan)

    2014-09-15

    The purpose of this study was to assess computed tomography (CT) and magnetic resonance (MR) imaging findings of salivary gland tumors of the parotid gland with emphasis on intratumoral cystic components. Seventy-two histopathologically confirmed salivary gland tumors of the parotid gland (44 benign and 28 malignant), which underwent both CT and MR imaging including contrast-enhanced study, were included in this study. We retrospectively reviewed images for the presence, number, occupying rate, margin characteristics, distribution, and predominant MR signal intensity of intratumoral cystic components. The prevalence of cystic components was greater in malignant than benign tumors (79 vs. 50 %, p < 0.05). The number and occupying rate were similar between benign and malignant tumors. The irregular margins were more frequent in malignant than benign tumors (73 vs. 27 %, p < 0.01). The frequency of eccentric location was greater in benign than malignant tumors (91 vs. 55 %, p < 0.01), whereas the frequency of centric location was greater in malignant than benign tumors (32 vs. 0 %, p < 0.01). On T1-weighted images, the frequency of hyperintensity was greater in benign than malignant tumors (50 vs. 9 %, p < 0.01), whereas that of isointensity was greater in malignant than benign tumors (50 vs. 0 %, p < 0.01). Multiple logistic regression analysis showed that the absence of irregular margins of cystic components only was significantly correlated with the presence of benign salivary gland tumors (p < 0.01). Imaging features of intratumoral cystic components may help to differentiate benign from malignant tumors of the parotid salivary gland. (orig.)

  6. Intratumoral administration of holmium-166 acetylacetonate microspheres: antitumor efficacy and feasibility of multimodality imaging in renal cancer.

    Directory of Open Access Journals (Sweden)

    Wouter Bult

    Full Text Available PURPOSE: The increasing incidence of small renal tumors in an aging population with comorbidities has stimulated the development of minimally invasive treatments. This study aimed to assess the efficacy and demonstrate feasibility of multimodality imaging of intratumoral administration of holmium-166 microspheres ((166HoAcAcMS. This new technique locally ablates renal tumors through high-energy beta particles, while the gamma rays allow for nuclear imaging and the paramagnetism of holmium allows for MRI. METHODS: (166HoAcAcMS were administered intratumorally in orthotopic renal tumors (Balb/C mice. Post administration CT, SPECT and MRI was performed. At several time points (2 h, 1, 2, 3, 7 and 14 days after MS administration, tumors were measured and histologically analyzed. Holmium accumulation in organs was measured using inductively coupled plasma mass spectrometry. RESULTS: (166HoAcAcMS were successfully administered to tumor bearing mice. A striking near-complete tumor-control was observed in (166HoAcAcMS treated mice (0.10±0.01 cm(3 vs. 4.15±0.3 cm(3 for control tumors. Focal necrosis and inflammation was present from 24 h following treatment. Renal parenchyma outside the radiated region showed no histological alterations. Post administration CT, MRI and SPECT imaging revealed clear deposits of (166HoAcAcMS in the kidney. CONCLUSIONS: Intratumorally administered (166HoAcAcMS has great potential as a new local treatment of renal tumors for surgically unfit patients. In addition to strong cancer control, it provides powerful multimodality imaging opportunities.

  7. Mammary lymphatic scintiscans by intratumoral injection in the assessment of breast cancer. 105 examinations in 100 patients

    International Nuclear Information System (INIS)

    Gabelle, P.; Comet, M.; Bodin, J.P.; Dupre, A; Carpentier, E.; Bolla, M.; Swiercz, P.

    1981-01-01

    One hundred and five scintiscans of the mammary lymphatic system were performed in 100 patients with breast cancer by intratumoral injection of 99m Tc-labelled colloidal rhenium. The progression of the radioactive colloidal agent was followed on a series of films taken 1, 2 and 4 hours after the injection, and the images obtained were compared with post-operative findings of lymph node involvement. Patients with more than 3 carcinomatous lymph nodes had less than 2 foci of activity, while those with less than 3 carcinomatous lymph nodes had more than 2 foci of activity, owing to more rapid progression of the compound. The difference was highly significant (p [fr

  8. Metaplastic thymoma with myasthenia gravis presumably caused by an accumulation of intratumoral immature T cells: a case report.

    Science.gov (United States)

    Tajima, Shogo; Yanagiya, Masahiro; Sato, Masaaki; Nakajima, Jun; Fukayama, Masashi

    2015-01-01

    Among human neoplasms, thymomas are well known for their association with paraneoplastic autoimmune diseases such as myasthenia gravis. However, regarding rare metaplastic thymoma, only one case of an association with myasthenia gravis has been reported. Here, we present the second case of a 44-year-old woman with metaplastic thymoma associated with myasthenia gravis. In metaplastic thymoma, intratumoral terminal deoxynucleotidyl transferase-positive T-cells (immature T-cells) are generally scarce, while they were abundant in the present case. We believe that these immature T-cells could be related to the occurrence of myasthenia gravis.

  9. Secondary Central Nerve System Lymphoma With Intratumoral Hemorrhage Suggested as Intravascular Lymphoma by Autopsy: A Case Report.

    Science.gov (United States)

    Suzuki, Yutaro; Tanaka, Hiroaki; Suyama, Kennichiro; Mochida, Hidetoshi; Suzuki, Yoshio

    2017-11-01

    Intravascular large B-cell lymphoma (IVL) is a rare type of extranodal diffuse large B-cell lymphoma (DLBCL), which often infiltrates the central nervous system (CNS) during the clinical course. Cerebral hemorrhage in patients with CNS lymphoma at presentation is rare. Herein, we describe a case of secondary CNS lymphoma with intratumoral hemorrhage, which was suggested as IVL from autopsy findings. A 76-year-old Japanese man with a history of treatment for B-cell non-Hodgkin's lymphoma was transferred to our hospital in an ambulance for generalized convulsions. Brain CT scan revealed a high-density tumor with edema and intratumoral hemorrhage in the left temporal lobes. He died in a rapid course, and autopsy revealed a focal hemorrhage with diffuse infiltration of lymphoma cells in the left temporal lobe and findings suggestive of IVL. Furthermore, the autopsy revealed a discrepancy in the CD20 immunostaining of lymphoma cells between the brain and other organs. Clinicians should not eliminate CNS lymphoma from the differential diagnosis of intracranial tumor with hemorrhage. Although many patients with IVL have rapidly progressive courses, it is very important to diagnose IVL at the initial onset, even in serious situations, to consider CNS prophylaxis.

  10. Intratumoral peripheral small papillary tufts: a diagnostic clue of renal tumors associated with Birt-Hogg-Dubé syndrome.

    Science.gov (United States)

    Kuroda, Naoto; Furuya, Mitsuko; Nagashima, Yoji; Gotohda, Hiroko; Moritani, Suzuko; Kawakami, Fumi; Imamura, Yoshiaki; Bando, Yoshimi; Takahashi, Masayuki; Kanayama, Hiro-omi; Ota, Satoshi; Michal, Michal; Hes, Ondrej; Nakatani, Yukio

    2014-06-01

    In this article, we searched for the common histologic characteristic of renal tumors in patients with Birt-Hogg-Dubé syndrome (BHDS). We selected 6 patients with histologically confirmed renal tumor in BHDS. Germline FLCN gene mutation has been identified in 5 patients. Multifocality and bilaterality of the renal tumors were pathologically or radiologically confirmed in 5 and 2 cases, respectively. Histologic subtypes of the dominant tumor included 3 previously described hybrid oncocytic tumors, one composite chromophobe/papillary/clear cell renal cell carcinoma (RCC) and one unclassified RCC resembling hybrid chromophobe/clear cell RCC. In one case, chromophobe RCC and clear cell RCC were separately observed. Small papillary lesions located in the peripheral area of the tumor, which we designated as intratumoral peripheral small papillary tufts, were identified in all patients. In conclusion, multifocality/bilaterality of renal tumors, discordance of histologic subtypes, and the presence of intratumoral peripheral small papillary tufts may be important clues to identify BHDS-associated renal tumors. Copyright © 2014 Elsevier Inc. All rights reserved.

  11. Multisite tumor sampling enhances the detection of intratumor heterogeneity at all different temporal stages of tumor evolution.

    Science.gov (United States)

    Erramuzpe, Asier; Cortés, Jesús M; López, José I

    2018-02-01

    Intratumor heterogeneity (ITH) is an inherent process of tumor development that has received much attention in previous years, as it has become a major obstacle for the success of targeted therapies. ITH is also temporally unpredictable across tumor evolution, which makes its precise characterization even more problematic since detection success depends on the precise temporal snapshot at which ITH is analyzed. New and more efficient strategies for tumor sampling are needed to overcome these difficulties which currently rely entirely on the pathologist's interpretation. Recently, we showed that a new strategy, the multisite tumor sampling, works better than the routine sampling protocol for the ITH detection when the tumor time evolution was not taken into consideration. Here, we extend this work and compare the ITH detections of multisite tumor sampling and routine sampling protocols across tumor time evolution, and in particular, we provide in silico analyses of both strategies at early and late temporal stages for four different models of tumor evolution (linear, branched, neutral, and punctuated). Our results indicate that multisite tumor sampling outperforms routine protocols in detecting ITH at all different temporal stages of tumor evolution. We conclude that multisite tumor sampling is more advantageous than routine protocols in detecting intratumor heterogeneity.

  12. A novel doxorubicin-loaded in situ forming gel based high concentration of phospholipid for intratumoral drug delivery.

    Science.gov (United States)

    Wu, Wenqi; Chen, Hui; Shan, Fengying; Zhou, Jing; Sun, Xun; Zhang, Ling; Gong, Tao

    2014-10-06

    The purpose of this study was to develop a safe and effective drug delivery system for local chemotherapy. A novel injectable in-situ-forming gel system was prepared using small molecule materials, including phospholipids, medium chain triglycerides (MCTs), and ethanol. Thus, this new sustained release system was named PME (first letter of phospholipids, MCT, and ethanol). PME has a well-defined molecule structure, a high degree of safety, and better biocompatible characteristics. It was in sol state with low viscosity in vitro and turned into a solid or semisolid gel in situ after injection. When loaded with doxorubicin (Dox), PME-D (doxorubicin-loaded PME) exhibited notably antitumor efficiency in S180 sarcoma tumors bearing mice after a single intratumoral injection. In vitro, PME-D had remarkable antiproliferative efficacies against MCF-7 breast cancer cells for over 5 days. Moreover, the initial burst effect can hardly be observed from PME system, which was different from many other in-situ-forming gels. The in vivo biodistribution study showed the high Dox concentration in tumors compared with other major organs after PME-D intratumoral administration. The strong signal in tumors was retained for more than 14 days after one single injection. The high concentration of Dox in tumor and long-term retention may explain the superior therapeutic efficacy and reduced side effects. The PME-D in-situ-forming gel system is a promising drug delivery system for local chemotherapy.

  13. TCR Repertoire Intratumor Heterogeneity in Localized Lung Adenocarcinomas: An Association with Predicted Neoantigen Heterogeneity and Postsurgical Recurrence.

    Science.gov (United States)

    Reuben, Alexandre; Gittelman, Rachel; Gao, Jianjun; Zhang, Jiexin; Yusko, Erik C; Wu, Chang-Jiun; Emerson, Ryan; Zhang, Jianhua; Tipton, Christopher; Li, Jun; Quek, Kelly; Gopalakrishnan, Vancheswaran; Chen, Runzhe; Vence, Luis M; Cascone, Tina; Vignali, Marissa; Fujimoto, Junya; Rodriguez-Canales, Jaime; Parra, Edwin R; Little, Latasha D; Gumbs, Curtis; Forget, Marie-Andrée; Federico, Lorenzo; Haymaker, Cara; Behrens, Carmen; Benzeno, Sharon; Bernatchez, Chantale; Sepesi, Boris; Gibbons, Don L; Wargo, Jennifer A; William, William N; Swisher, Stephen; Heymach, John V; Robins, Harlan; Lee, J Jack; Sharma, Padmanee; Allison, James P; Futreal, P Andrew; Wistuba, Ignacio I; Zhang, Jianjun

    2017-10-01

    Genomic intratumor heterogeneity (ITH) may be associated with postsurgical relapse of localized lung adenocarcinomas. Recently, mutations, through generation of neoantigens, were shown to alter tumor immunogenicity through T-cell responses. Here, we performed sequencing of the T-cell receptor (TCR) in 45 tumor regions from 11 localized lung adenocarcinomas and observed substantial intratumor differences in T-cell density and clonality with the majority of T-cell clones restricted to individual tumor regions. TCR ITH positively correlated with predicted neoantigen ITH, suggesting that spatial differences in the T-cell repertoire may be driven by distinct neoantigens in different tumor regions. Finally, a higher degree of TCR ITH was associated with an increased risk of postsurgical relapse and shorter disease-free survival, suggesting a potential clinical significance of T-cell repertoire heterogeneity. Significance: The present study provides insights into the ITH of the T-cell repertoire in localized lung adenocarcinomas and its potential biological and clinical impact. The results suggest that T-cell repertoire ITH may be tightly associated to genomic ITH and disease relapse. Cancer Discov; 7(10); 1088-97. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 1047 . ©2017 American Association for Cancer Research.

  14. Regulatory Physiology

    Science.gov (United States)

    Lane, Helen W.; Whitson, Peggy A.; Putcha, Lakshmi; Baker, Ellen; Smith, Scott M.; Stewart, Karen; Gretebeck, Randall; Nimmagudda, R. R.; Schoeller, Dale A.; Davis-Street, Janis

    1999-01-01

    As noted elsewhere in this report, a central goal of the Extended Duration Orbiter Medical Project (EDOMP) was to ensure that cardiovascular and muscle function were adequate to perform an emergency egress after 16 days of spaceflight. The goals of the Regulatory Physiology component of the EDOMP were to identify and subsequently ameliorate those biochemical and nutritional factors that deplete physiological reserves or increase risk for disease, and to facilitate the development of effective muscle, exercise, and cardiovascular countermeasures. The component investigations designed to meet these goals focused on biochemical and physiological aspects of nutrition and metabolism, the risk of renal (kidney) stone formation, gastrointestinal function, and sleep in space. Investigations involved both ground-based protocols to validate proposed methods and flight studies to test those methods. Two hardware tests were also completed.

  15. Differentiating intratumoral melanocytes from Langerhans cells in nonmelanocytic pigmented skin tumors in vivo by label-free third-harmonic generation microscopy

    Science.gov (United States)

    Weng, Wei-Hung; Liao, Yi-Hua; Tsai, Ming-Rung; Wei, Ming-Liang; Huang, Hsin-Yi; Sun, Chi-Kuang

    2016-07-01

    Morphology and distribution of melanocytes are critical imaging information for the diagnosis of melanocytic lesions. However, how to image intratumoral melanocytes noninvasively in pigmented skin tumors is seldom investigated. Third-harmonic generation (THG) is shown to be enhanced by melanin, whereas high accuracy has been demonstrated using THG microscopy for in vivo differential diagnosis of nonmelanocytic pigmented skin tumors. It is thus desirable to investigate if label-free THG microscopy was capable to in vivo identify intratumoral melanocytes. In this study, histopathological correlations of label-free THG images with the immunohistochemical images stained with human melanoma black (HMB)-45 and cluster of differentiation 1a (CD1a) were made. The correlation results indicated that the intratumoral THG-bright dendritic-cell-like signals were endogenously derived from melanocytes rather than Langerhans cells (LCs). The consistency between THG-bright dendritic-cell-like signals and HMB-45 melanocyte staining showed a kappa coefficient of 0.807, 84.6% sensitivity, and 95% specificity. In contrast, a kappa coefficient of -0.37, 21.7% sensitivity, and 30% specificity were noted between the THG-bright dendritic-cell-like signals and CD1a staining for LCs. Our study indicates the capability of noninvasive label-free THG microscopy to differentiate intratumoral melanocytes from LCs, which is not feasible in previous in vivo label-free clinical-imaging modalities.

  16. Intra-tumor heterogeneity of microRNA-92a, microRNA-375 and microRNA-424 in colorectal cancer

    DEFF Research Database (Denmark)

    Jepsen, Rikke Karlin; Novotny, Guy Wayne; Klarskov, Louise Laurberg

    2016-01-01

    Various microRNAs (miRNAs) have been investigated in order to improve diagnostics and risk assessment in colorectal cancer (CRC). To clarify the potential of miRNA profiling in CRC, knowledge of intra-tumor heterogeneity in expression levels is crucial. The study aim was to estimate the intra-tum...

  17. Intratumoral Heterogeneity of Breast Cancer Xenograft Models: Texture Analysis of Diffusion-Weighted MR Imaging

    Energy Technology Data Exchange (ETDEWEB)

    Yun, Bo La; Cho, Nariya; Li, Mulun; Song, In Chan; Moon, Woo Kyung [Dept. of Radiology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul (Korea, Republic of); Jang, Min Hye; Park, So Yeon; Kim, Bo Young [Seoul National University Bundang Hospital, Seongnam (Korea, Republic of); Kang, Ho Chul [Dept. of Computer Science and Engineering, Seoul National University, Seoul (Korea, Republic of)

    2014-10-15

    .464), kurtosis (r = -0.581, r = -0.389), contrast (r = -0.473, r = -0.549) and COR (r = 0.588, r = 0.580) correlated with MVDmean and MVDdiff (p < 0.05 for all). The texture analysis of ADC maps may help to determine the intratumoral spatial heterogeneity of necrosis patterns, amount of cellular proliferation and the vascularity in MCF-7 and MDA-MB-231 xenograft breast cancer models.

  18. A histological evaluation and in vivo assessment of intratumoral near infrared photothermal nanotherapy-induced tumor regression

    Directory of Open Access Journals (Sweden)

    Green HN

    2014-11-01

    Full Text Available Hadiyah N Green,1,2 Stephanie D Crockett,3 Dmitry V Martyshkin,1 Karan P Singh,2,4 William E Grizzle,2,5 Eben L Rosenthal,2,6 Sergey B Mirov11Department of Physics, Center for Optical Sensors and Spectroscopies, 2Comprehensive Cancer Center, 3Department of Pediatrics, Division of Neonatology, 4Department of Medicine, Division of Preventive Medicine, Biostatistics and Bioinformatics Shared Facility, 5Department of Pathology, 6Department of Surgery, Division of Otolaryngology, Head and Neck Surgery, The University of Alabama at Birmingham, Birmingham, AL, USAPurpose: Nanoparticle (NP-enabled near infrared (NIR photothermal therapy has realized limited success in in vivo studies as a potential localized cancer therapy. This is primarily due to a lack of successful methods that can prevent NP uptake by the reticuloendothelial system, especially the liver and kidney, and deliver sufficient quantities of intravenously injected NPs to the tumor site. Histological evaluation of photothermal therapy-induced tumor regression is also neglected in the current literature. This report demonstrates and histologically evaluates the in vivo potential of NIR photothermal therapy by circumventing the challenges of intravenous NP delivery and tumor targeting found in other photothermal therapy studies.Methods: Subcutaneous Cal 27 squamous cell carcinoma xenografts received photothermal nanotherapy treatments, radial injections of polyethylene glycol (PEG-ylated gold nanorods and one NIR 785 nm laser irradiation for 10 minutes at 9.5 W/cm2. Tumor response was measured for 10–15 days, gross changes in tumor size were evaluated, and the remaining tumors or scar tissues were excised and histologically analyzed.Results: The single treatment of intratumoral nanorod injections followed by a 10 minute NIR laser treatment also known as photothermal nanotherapy, resulted in ~100% tumor regression in ~90% of treated tumors, which was statistically significant in a

  19. Investigation of acupuncture-point injection combined with intratumor injection of radionuclide phosphorus 32 in treatment of metastatic carcinoma

    International Nuclear Information System (INIS)

    Chou, H.C.

    1986-01-01

    Seventeen patients with carcinoma and three patients with benign lesions of the head were studied by acupuncture-point injection combined with intratumor injection of radionuclide P-32 for treatment of metastatic carcinoma. The metastatic cervical nodules shrank to half their original sizes within 2-3 weeks in five cases of nasopharyngeal carcinoma. The injected dose ranged from 0.222 to 0.421 mCi, approximately 10 times less than that given by the ordinary method. The acupuncture points are selected according to the Theory of Channels and Collaterals of Chinese traditional medicine. The mechanism of therapeutic action of radionuclide P-32 is possibly by the delivery of destructive ionizing radiation from beta emission properties of P-32. This method appears to offer a low-dose means of P-32 treatment of metastatic carcinoma

  20. Intratumoral administration of IL2- and TNF-based fusion proteins cures cancer without establishing protective immunity.

    Science.gov (United States)

    Ziffels, Barbara; Pretto, Francesca; Neri, Dario

    2018-03-01

    The combination of tumor-targeting IL2- and TNF-based antibody-cytokine fusions has exhibited encouraging results in mouse and men. Here, we studied their combination to assess efficacy and mechanism of action in four different immunocompetent mouse models of cancer. Mice receiving a single intratumoral injection of F8-IL2, F8-TNF or the combination were investigated for tumor-infiltrating leukocytes and rechallenged when cured. In three models, a proportion of treated animals could be cured, most probably by infiltrating NK and CD8 + T cells. Most of the cured mice did not acquire protective immunity when rechallenged with the same tumor cell line. Immunocompetent mouse tumor models may not be adequate enough to predict the search for more efficacious therapy regimens.

  1. Intratumoral Injection of an Adenovirus Expressing Interleukin 2 Induces Regression and Immunity in a Murine Breast Cancer Model

    Science.gov (United States)

    Addison, Christina L.; Braciak, Todd; Ralston, Robert; Muller, William J.; Gauldie, Jack; Graham, Frank L.

    1995-08-01

    Rodent tumor cells engineered to secrete cytokines such as interleukin 2 (IL-2) or IL-4 are rejected by syngeneic recipients due to an enhanced antitumor host immune response. An adenovirus vector (AdCAIL-2) containing the human IL-2 gene has been constructed and shown to direct secretion of high levels of human IL-2 in infected tumor cells. AdCAIL-2 induces regression of tumors in a transgenic mouse model of mammary adenocarcinoma following intratumoral injection. Elimination of existing tumors in this way results in immunity against a second challenge with tumor cells. These findings suggest that adenovirus vectors expressing cytokines may form the basis for highly effective immunotherapies of human cancers.

  2. Intratumor genetic heterogeneity of breast carcinomas as determined by fine needle aspiration and TaqMan low density array

    DEFF Research Database (Denmark)

    Lyng, Maria B.; Laenkholm, Anne-Vibeke; Pallisgaard, Niels

    2007-01-01

    surgery were split in halves and FNAs were obtained from each half. A tissue biopsy of the tumors was also snap-frozen for comparison. Non-amplified RNA was investigated by the novel qRT-PCR-based technique, Low Density Array (LDA) using 4 reference genes and 44 target genes. RESULTS: Comparison of gene...... expression at the single gene level in the two FNA samples from each tumor demonstrated various degrees of heterogeneity. However, compared as gene expression profiles, intratumor correlations for 9/12 patients were high and these pairs could in a theoretical blinding of all the FNAs be correctly matched...... by statistical analysis. High correlations between the gene profiles of tumor FNAs and tissue biopsies from the same patient were observed for all patients. A cluster analysis identified clustering of both the two FNAs and the tissue biopsy of the same 9 patients. CONCLUSION: The overall genetic heterogeneity...

  3. Brachytherapy with Intratumoral Injections of Radiometal-Labeled Polymers That Thermoresponsively Self-Aggregate in Tumor Tissues.

    Science.gov (United States)

    Sano, Kohei; Kanada, Yuko; Kanazaki, Kengo; Ding, Ning; Ono, Masahiro; Saji, Hideo

    2017-09-01

    Brachytherapy is a type of radiotherapy wherein titanium capsules containing therapeutic radioisotopes are implanted within tumor tissues, enabling high-dose radioirradiation to tumor tissues around the seeds. Although marked therapeutic effects have been demonstrated, brachytherapy needs a complicated implantation technique under general anesthesia and the seeds could migrate to other organs. The aim of this study was to establish a novel brachytherapy using biocompatible, injectable thermoresponsive polymers (polyoxazoline [POZ]) labeled with 90 Y, which can self-aggregate above a specific transition temperature (Tt), resulting in long-term intratumoral retention of radioactivity and therapeutic effect. Therefore, we evaluated the tumor retention of radiolabeled POZ derivatives and their therapeutic effects. Methods: Using oxazoline derivatives with ethyl (Et), isopropyl (Isp), and propyl (Pr) side chains, we synthesized EtPOZ, IspPOZ, Isp-PrPOZ (heteropolymer), and PrPOZ and measured their characteristic Tts. The intratumoral retention of 111 In-labeled POZ was evaluated until 7 d after injection in nude mice bearing PC-3 human prostate cancer. The intratumoral localization of 111 In-labeled POZ derivatives was investigated by an autoradiographic study. Furthermore, a therapeutic study using 90 Y-labeled Isp-PrPOZ was performed, and tumor growth and survival rate were evaluated. Results: The Tts of EtPOZ, IspPOZ, Isp-PrPOZ, and PrPOZ (∼20 kDa) were greater than 70°C, 34°C, 25°C, and 19°C, respectively. In the intratumoral injection study, Isp-PrPOZ and PrPOZ (2,000 μM) with Tts lower than tumor temperature (33.5°C under anesthesia) showed a significantly higher retention of radioactivity at 1 d after injection (73.6% and 73.9%, respectively) than EtPOZ (5.6%) and IspPOZ (15.8%). Even at low injected dose (100 μM), Isp-PrPOZ exhibited high retention (68.3% at 1 d). The high level of radioactivity of Isp-PrPOZ was retained in the tumor 7 d after injection

  4. Effect of intra-tumoral magnetic nanoparticle hyperthermia and viral nanoparticle immunogenicity on primary and metastatic cancer

    Science.gov (United States)

    Hoopes, P. Jack; Mazur, Courtney M.; Osterberg, Bjorn; Song, Ailin; Gladstone, David J.; Steinmetz, Nicole F.; Veliz, Frank A.; Bursey, Alicea A.; Wagner, Robert J.; Fiering, Steven N.

    2017-02-01

    Although there is long association of medical hyperthermia and immune stimulation, the relative lack of a quantifiable and reproducible effect has limited the utility and advancement of this relationship in preclinical/clinical cancer and non-cancer settings. Recent cancer-based immune findings (immune checkpoint modulators etc.) including improved mechanistic understanding and biological tools now make it possible to modify and exploit the immune system to benefit conventional cancer treatments such as radiation and hyperthermia. Based on the prior experience of our research group including; cancer-based heat therapy, magnetic nanoparticle (mNP) hyperthermia, radiation biology, cancer immunology and Cowpea Mosaic Virus that has been engineered to over express antigenic proteins without RNA or DNA (eCPMV/VLP). This research was designed to determine if and how the intra-tumoral delivery of mNP hyperthermia and VLP can work together to improve local and systemic tumor treatment efficacy. Using the C3H mouse/MTG-B mammary adenocarcinoma cell model and the C57-B6 mouse/B-16-F10 melanoma cancer cell model, our data suggests the appropriate combination of intra-tumoral mNP heat (e.g. 43°C /30-60 minutes) and VLP (100 μg/200 mm3 tumor) not only result in significant primary tumor regression but the creation a systemic immune reaction that has the potential to retard secondary tumor growth (abscopal effect) and resist tumor rechallenge. Molecular data from these experiments suggest treatment based cell damage and immune signals such as Heat Shock Protein (HSP) 70/90, calreticulin, MTA1 and CD47 are potential targets that can be exploited to enhance the local and systemic (abscopal effect) immune potential of hyperthermia cancer treatment

  5. Doxorubicin-Loaded QuadraSphere Microspheres: Plasma Pharmacokinetics and Intratumoral Drug Concentration in an Animal Model of Liver Cancer

    International Nuclear Information System (INIS)

    Lee, Kwang-Hun; Liapi, Eleni A.; Cornell, Curt; Reb, Philippe; Buijs, Manon; Vossen, Josephina A.; Ventura, Veronica Prieto; Geschwind, Jean-Francois H.

    2010-01-01

    The purpose of this study was to evaluate, in vitro and in vivo, doxorubicin-loaded poly (vinyl alcohol-sodium acrylate) copolymer microspheres [QuadraSphere microspheres (QSMs)] for transcatheter arterial delivery in an animal model of liver cancer. Doxorubicin loading efficiency and release profile were first tested in vitro. In vivo, 15 rabbits, implanted with a Vx-2 tumor in the liver, were divided into three groups of five rabbits each, based on the time of euthanasia. Twenty-five milligrams of QSMs was diluted in 10 ml of a 10 mg/ml doxorubicin solution and 10 ml of nonionic contrast medium for a total volume of 20 ml. One milliliter of a drug-loaded QSM solution containing 5 mg of doxorubicin was injected into the tumor feeding artery. Plasma doxorubicin and doxorubicinol concentrations, and intratumoral and peritumoral doxorubicin tissue concentrations, were measured. Tumor specimens were pathologically evaluated to record tumor necrosis. As a control, one animal was blandly embolized with plain QSMs in each group. In vitro testing of QSM doxorubicin loadability and release over time showed 82-94% doxorubicin loadability within 2 h and 6% release within the first 6 h after loading, followed by a slow release pattern. In vivo, the doxorubicin plasma concentration declined at 40 min. The peak doxorubicin intratumoral concentration was observed at 3 days and remained detectable till the study's end point (7 days). Mean percentage tumor cell death in the doxorubicin QSM group was 90% at 7 days and 60% in the bland QSM embolization group. In conclusion, QSMs can be efficiently loaded with doxorubicin. Initial experiments with doxorubicin-loaded QSMs show a safe pharmacokinetic profile and effective tumor killing in an animal model of liver cancer.

  6. Genetic diversity in normal cell populations is the earliest stage of oncogenesis leading to intra-tumor heterogeneity

    Directory of Open Access Journals (Sweden)

    Cory L Howk

    2013-04-01

    Full Text Available Random mutations and epigenetic alterations provide a rich substrate for microevolutionary phenomena to occur in proliferating epithelial tissues. Genetic diversity resulting from random mutations in normal cells is critically important for understanding the genetic basis of oncogenesis. However, evaluation of the cell-specific role of individual (epi-genetic alterations in living tissues is extremely difficult from a direct experimental perspective. We have developed a theoretical model for uterine epithelial cell proliferation. Computational simulations have shown that a base-line mutation rate of two mutations per cell division is sufficient to explain sporadic endometrial cancer as a rare evolutionary consequence with an incidence similar to that reported in SEER data. Simulation of the entire oncogenic process has allowed us to analyze the features of the tumor initiating cells and their clonal expansion. Analysis of the malignant features of individual cancer cells, such as de-differentiation status, proliferation potential, and immortalization status, permits a mathematical characterization of malignancy and a comparison of intra-tumor heterogeneity between individual tumors. We found, under the conditions specified, that cancer stem cells account for approximately 7% of the total cancer cell population. Taken together, our mathematical modeling describes the genetic diversity and evolution in a normal cell population at the early stages of oncogenesis and characterizes intra-tumor heterogeneity. This model has explored the role of accumulation of a large number of genetic alterations in oncogenesis as an alternative to traditional biological approaches emphasizing the driving role of a small number of genetic mutations, and this accumulation, along with environmental factors, has a significant impact on the growth advantage of and selection pressure on individual cancer cells and the resulting tumor composition and progression.

  7. Intratumoral vaccination of adenoviruses expressing fusion protein RM4/tumor necrosis factor (TNF)-alpha induces significant tumor regression.

    Science.gov (United States)

    Wright, P; Zheng, C; Moyana, T; Xiang, J

    1998-01-01

    Recombinant adenovirus (AdV) vectors are highly efficient at in vitro and in vivo gene delivery. VKCK is a murine myeloma cell line expressing the light chain of the fusion protein RM4/tumor necrosis factor (TNF)-alpha. The in vitro transfection of VKCK cells with the AdV AdV5LacZ, which contains the marker gene beta-galactosidase, can reach a maximal 75% at a multiplicity of infection of 1000. Intratumoral injections of AdV5LacZ (2 x 10(9) plaque-forming units) resulted in substantial gene transfer in nearly 50% of VKCK tumors. The AdV pLpA/M4-TNF-alpha, which contains a fused gene M4-TNF-alpha that codes for the heavy chain of fusion protein RM4/TNF-alpha, was constructed. After the in vitro transfection of pLpA/M4-TNF-alpha at a multiplicity of infection of 1000, transfected VKCK cells showed significant secretion of RM4/TNF-alpha (36 ng/mL/10(6) cells) containing the functional TNF-alpha moiety in tissue culture. The secretion peaks at day 3 and is diminished at day 6 following the viral infection. These transfected VKCK cells also became more immunogenic with enhanced expression of major histocompatibility complex class I antigen. Intratumoral injections of 2 x 10(9) plaque-forming units of pLpA/M4-TNF-alpha virus with a repeated booster resulted in significant VKCK tumor regression in immune-competent mice, but not in athymic nude mice with a mean tumor weight of 0.07 g that were compared with 1.58 g and 1.70 g for tumors injected with AdV5LacZ and phosphate-buffered saline, respectively (P management of solid human tumors.

  8. Longitudinal immune monitoring of patients receiving intratumoral injection of a MART-1 T-cell receptor-transduced cell line (C-Cure 709)

    DEFF Research Database (Denmark)

    Køllgaard, Tania; Duval, Lone; Schmidt, Henrik

    2009-01-01

    BACKGROUND AIMS: Adoptive transfer of tumor-specific lymphocytes is a promising strategy in the treatment of cancer. We conducted intratumoral administration of an allogeneic irradiated continuous T-cell line (C-Cure 709) expressing an HLA-A2-restricted MART-1-specific T-cell receptor (TCR......) into HLA-A2(+) melanoma patients. The C-Cure 709 cell line is cytotoxic against MART-1(+) HLA-A2(+) melanoma cell lines and secretes several immune stimulatory cytokines upon stimulation. METHODS: Anti-tumor immune responses against the commonly expressed tumor antigen (Ag) MART-1 were longitudinally...... analyzed in peripheral blood by fluorescence-activated cell sorting (FACS) before and after intratumoral injection of C-Cure 709. RESULTS: No treatment-induced increase in Ag-specific T-cell frequencies was observed in peripheral blood, and the phenotype of MART-1-specific T cells was very stable during...

  9. Interleukin-33/ST2 axis promotes breast cancer growth and metastases by facilitating intratumoral accumulation of immunosuppressive and innate lymphoid cells.

    Science.gov (United States)

    Jovanovic, Ivan P; Pejnovic, Nada N; Radosavljevic, Gordana D; Pantic, Jelena M; Milovanovic, Marija Z; Arsenijevic, Nebojsa N; Lukic, Miodrag L

    2014-04-01

    The role of IL-33/ST2 pathway in antitumor immunity is unclear. Using 4T1 breast cancer model we demonstrate time-dependent increase of endogenous IL-33 at both the mRNA and protein levels in primary tumors and metastatic lungs during cancer progression. Administration of IL-33 accelerated tumor growth and development of lung and liver metastases, which was associated with increased intratumoral accumulation of CD11b(+) Gr-1(+) TGF-β1(+) myeloid-derived suppressor cells (MDSCs) that expressed IL-13α1R, IL-13-producing Lin(-) Sca-1(+) ST2(+) innate lymphoid cells (ILCs) and CD4(+) Foxp3(+) ST2(+) IL-10(+) Tregs compared to untreated mice. Higher incidence of monocytic vs. granulocytic MDSCs and plasmocytoid vs. conventional dendritic cells (DCs) was present in mammary tumors of IL-33-treated mice. Intratumoral NKp46(+) NKG2D(+) and NKp46(+) FasL(+) cells were markedly reduced after IL-33 treatment, while phosphate-buffered saline-treated ST2-deficient mice had increased frequencies of these tumoricidal natural killer (NK) cells compared to untreated wild-type mice. IL-33 promoted intratumoral cell proliferation and neovascularization, which was attenuated in the absence of ST2. Tumor-bearing mice given IL-33 had increased percentages of splenic MDSCs, Lin(-) Sca-1(+) ILCs, IL-10-expressing CD11c(+) DCs and alternatively activated M2 macrophages and higher circulating levels of IL-10 and IL-13. A significantly reduced NK cell, but not CD8(+) T-cell cytotoxicity in IL-33-treated mice was observed and the mammary tumor progression was not affected when CD8(+) T cells were in vivo depleted. We show a previously unrecognized role for IL-33 in promoting breast cancer progression through increased intratumoral accumulation of immunosuppressive cells and by diminishing innate antitumor immunity. Therefore, IL-33 may be considered as an important mediator in the regulation of breast cancer progression. © 2013 UICC.

  10. Intratumoral Infection with Murine Cytomegalovirus Synergizes with PD-L1 Blockade to Clear Melanoma Lesions and Induce Long-term Immunity

    Science.gov (United States)

    Erkes, Dan A; Xu, Guangwu; Daskalakis, Constantine; Zurbach, Katherine A; Wilski, Nicole A; Moghbeli, Toktam; Hill, Ann B; Snyder, Christopher M

    2016-01-01

    Cytomegalovirus is an attractive cancer vaccine platform because it induces strong, functional CD8+ T-cell responses that accumulate over time and migrate into most tissues. To explore this, we used murine cytomegalovirus expressing a modified gp100 melanoma antigen. Therapeutic vaccination by the intraperitoneal and intradermal routes induced tumor infiltrating gp100-specific CD8+ T-cells, but provided minimal benefit for subcutaneous lesions. In contrast, intratumoral infection of established tumor nodules greatly inhibited tumor growth and improved overall survival in a CD8+ T-cell-dependent manner, even in mice previously infected with murine cytomegalovirus. Although murine cytomegalovirus could infect and kill B16F0s in vitro, infection was restricted to tumor-associated macrophages in vivo. Surprisingly, the presence of a tumor antigen in the virus only slightly increased the efficacy of intratumoral infection and tumor-specific CD8+ T-cells in the tumor remained dysfunctional. Importantly, combining intratumoral murine cytomegalovirus infection with anti-PD-L1 therapy was synergistic, resulting in tumor clearance from over half of the mice and subsequent protection against tumor challenge. Thus, while a murine cytomegalovirus-based vaccine was poorly effective against established subcutaneous tumors, direct infection of tumor nodules unexpectedly delayed tumor growth and synergized with immune checkpoint blockade to promote tumor clearance and long-term protection. PMID:27434584

  11. A case of meningeal myxoid solitary fibrous tumor/hemangiopericytoma with unique NAB2-STAT6 fusion gene and symptomatic intratumoral hemorrhage

    Directory of Open Access Journals (Sweden)

    Takako Kihara, MD

    2017-11-01

    Full Text Available We experienced a case of meningeal solitary fibrous tumor (SFT/hemangiopericytoma (HPC with symptomatic intratumoral hemorrhage in a 67-year-old Japanese woman. Her chief complaints were sudden onset of motor aphasia and right hemiparesis. Brain computed tomography showed the hemorrhagic mass adjacent to the superior sagittal sinus. The mass was resected and pathological examination of the specimen revealed a tumor that is rich in vessels and accompanied with intratumoral hemorrhage. Short spindle tumor cells were proliferating with myxoid stroma. Tumor cells appeared to be arranged around the vessels and sometimes attached to the vessel wall directly. Although hyalinization of the vessel wall was observed, neither patternless pattern nor staghorn vessels were seen. Immunohistochemistry revealed that the tumor cells were positive for both CD34 and nuclear STAT6. Moreover, gene analyses revealed unique NAB2-STAT6 fusion. Immunohistochemical findings and fusion-gene analyses enabled us to make the definite diagnosis of meningeal myxoid SFT/HPC. The present case showed the three unique features such as clinically symptomatic intratumoral hemorrhage at the onset, rare variant of myxoid SFT/HPC, and unique NAB2-STAT6 fusion.

  12. Intratumoral Infection with Murine Cytomegalovirus Synergizes with PD-L1 Blockade to Clear Melanoma Lesions and Induce Long-term Immunity.

    Science.gov (United States)

    Erkes, Dan A; Xu, Guangwu; Daskalakis, Constantine; Zurbach, Katherine A; Wilski, Nicole A; Moghbeli, Toktam; Hill, Ann B; Snyder, Christopher M

    2016-08-01

    Cytomegalovirus is an attractive cancer vaccine platform because it induces strong, functional CD8(+) T-cell responses that accumulate over time and migrate into most tissues. To explore this, we used murine cytomegalovirus expressing a modified gp100 melanoma antigen. Therapeutic vaccination by the intraperitoneal and intradermal routes induced tumor infiltrating gp100-specific CD8(+) T-cells, but provided minimal benefit for subcutaneous lesions. In contrast, intratumoral infection of established tumor nodules greatly inhibited tumor growth and improved overall survival in a CD8(+) T-cell-dependent manner, even in mice previously infected with murine cytomegalovirus. Although murine cytomegalovirus could infect and kill B16F0s in vitro, infection was restricted to tumor-associated macrophages in vivo. Surprisingly, the presence of a tumor antigen in the virus only slightly increased the efficacy of intratumoral infection and tumor-specific CD8(+) T-cells in the tumor remained dysfunctional. Importantly, combining intratumoral murine cytomegalovirus infection with anti-PD-L1 therapy was synergistic, resulting in tumor clearance from over half of the mice and subsequent protection against tumor challenge. Thus, while a murine cytomegalovirus-based vaccine was poorly effective against established subcutaneous tumors, direct infection of tumor nodules unexpectedly delayed tumor growth and synergized with immune checkpoint blockade to promote tumor clearance and long-term protection.

  13. MRI-monitored intra-tumoral injection of iron-oxide labeled Clostridium novyi-NT anaerobes in pancreatic carcinoma mouse model.

    Directory of Open Access Journals (Sweden)

    Linfeng Zheng

    Full Text Available To validate the feasibility of labeling Clostridium novyi-NT (C.novyi-NT anaerobes with iron-oxide nanoparticles for magnetic resonance imaging (MRI and demonstrate the potential to use MRI to visualize intra-tumoral delivery of these iron-oxide labeled C.novyi-NT during percutaneous injection procedures.All studies were approved by IACUC. C.novyi-NT were labeled with hybrid iron-oxide Texas red nanoparticles. Growth of labeled and control samples were evaluated with optical density. Labeling was confirmed with confocal fluorescence and transmission electron microscopy (TEM. MRI were performed using a 7 Tesla scanner with T2*-weighted (T2*W sequence. Contrast-to-noise ratio (CNR measurements were performed for phantoms and signal-to-noise ratio (SNR measurements performed in C57BL/6 mice (n = 12 with Panc02 xenografts before and after percutaneous injection of iron-oxide labeled C.novyi-NT. MRI was repeated 3 and 7 days post-injection. Hematoxylin-eosin (HE, Prussian blue and Gram staining of tumor specimens were performed for confirmation of intra-tumoral delivery.Iron-oxide labeling had no influence upon C.novyi-NT growth. The signal intensity (SI within T2*W images was significantly decreased for iron-oxide labeled C.novyi-NT phantoms compared to unlabeled controls. Under confocal fluorescence microscopy, the iron-oxide labeled C.novyi-NT exhibited a uniform red fluorescence consistent with observed regions of DAPI staining and overall labeling efficiency was 100% (all DAPI stained C.novyi-NT exhibited red fluorescence. Within TEM images, a large number iron granules were observed within the iron-oxide labeled C.novyi-NT; these were not observed within unlabeled controls. Intra-procedural MRI measurements permitted in vivo visualization of the intra-tumoral distribution of iron-oxide labeled C.novyi-NT following percutaneous injection (depicted as punctate regions of SI reductions within T2*-weighted images; tumor SNR decreased

  14. Intratumoral lipids in 1H MRS in vivo in brain tumors: experience of the Siemens cooperative clinical trial.

    Science.gov (United States)

    Negendank, W; Sauter, R

    1996-01-01

    Fifteen institutions cooperated to examine the ability of 1H MRS to characterize metabolism in vivo in 102 primary brain tumors. Spectra were acquired from single 8 cc voxels in the tumor using a spin-echo method with an echo time of 135 ms. The most intense lipid signal was that of fatty acyl methylene protons at 1.3 ppm. Intratumoral lipid signals were not detected in oligodendrogliomas, ependymomas, or meningiomas and were evident in only 1 of 6 primitive neuroectodermal tumors. Among 75 astrocytic tumors, lipid signals occurred in 16% of low grade astrocytomas (AS), 36% of anaplastic astrocytomas (AA), and 44% of glioblastomas (GB). The amount of lipids, expressed as a ratio of the intensity of the methylene signal to that of choline, increased progressively with histopathological grade (p = 0.05). Greater amounts of mobile lipids in vivo in GB, which usually contain necrosis, is in accord with the recently discovered correlation between the fraction of microscopic necrosis and the intensity of the mobile lipid signal observed ex vivo using 1H MRS. The observation of lipid signals in AA, which do not contain necrosis, suggests that mobile fatty acids may appear at a stage of metabolic insult that precedes microscopic signs of cell death, and raises the possibility of an independent correlation between 1H MRS-detectable lipids and prognosis in patients with astrocytic tumors.

  15. In Situ Conversion of Melanoma Lesions into Autologous Vaccine by Intratumoral Injections of α-gal Glycolipids

    Directory of Open Access Journals (Sweden)

    Uri Galili

    2010-05-01

    Full Text Available Autologous melanoma associated antigens (MAA on murine melanoma cells can elicit a protective anti-tumor immune response following a variety of vaccine strategies. Most require effective uptake by antigen presenting cells (APC. APC transport and process internalized MAA for activation of anti-tumor T cells. One potential problem with clinical melanoma vaccines against autologous tumors may be that often tumor cells do not express surface markers that label them for uptake by APC. Effective uptake of melanoma cells by APC might be achieved by exploiting the natural anti-Gal antibody which constitutes ~1% of immunoglobulins in humans. This approach has been developed in a syngeneic mouse model using mice capable of producing anti-Gal. Anti-Gal binds specifically to α-gal epitopes (Galα1-3Galα1-4GlcNAc-R. Injection of glycolipids carrying α-gal epitopes (α-gal glycolipids into melanoma lesions results in glycolipid insertion into melanoma cell membranes, expression of α-gal epitopes on the tumor cells and binding of anti-Gal to these epitopes. Interaction between the Fc portions of bound anti-Gal and Fcγ receptors on APC induces effective uptake of tumor cells by APC. The resulting anti-MAA immune response can be potent enough to destroy distant micrometastases. A clinical trial is now open testing effects of intratumoral α-gal glycolipid injections in melanoma patients.

  16. A pilot study of the treatment of patients with recurrent malignant gliomas with intratumoral yttrium-90 radioimmunoconjugates

    International Nuclear Information System (INIS)

    Hopkins, K.; Chandler, C.; Bullimore, J.; Sandeman, D.; Coakham, H.; Kemshead, J.T.

    1995-01-01

    A pilot study of the treatment of patients with relapsed malignant gliomas with direct intratumoral injections of yttrium-90 ( 90 Y) radioimmunoconjugates has been completed. Patients were recruited following maximal tumour resection, and received 1-3 injections of 90 Y conjugated to a monoclonal antibody designated ERIC-1, which binds the neural cell-adhesion molecule. Data were collected to establish clinical toxicity, pharmacokinetics and radiation doses to the cavity wall and critical body organs. Twenty-three injections were completed in 15 patients, with a mean injected activity of 675 MBq (range 399-921). Early toxicity manifested as cerebral oedema and was readily controlled with dexamethasone. Delayed myelosuppression was observed but no intervention was required. Pharmacokinetic analysis confirmed prolonged retention of isotope in the cavity with correspondingly low activity in the bloodstream. These data were translated into estimates of absorbed radiation dose using the Medical Internal Radiation Dosimetry (MIRD) scheme. Mean doses, and dose rates, to the wall of the cavity, i.e. 'tumour,' were very high in comparison to normal tissue doses, with a further advantage if targeting was achieved

  17. [A Case of Intrahepatic Cholangiocarcinoma with Invasion to the Transverse Colon and Gallbladder, Forming an Intra-Tumor Abscess].

    Science.gov (United States)

    Okada, Nami; Kametaka, Hisashi; Koyama, Takashi; Seike, Kazuhiro; Makino, Hironobu; Fukada, Tadaomi; Sato, Yutaka; Miyazaki, Masaru

    2015-11-01

    An 81-year-old man was referred to our institution for evaluation of high fever and a liver tumor that had been detected by ultrasonography. Computed tomography revealed a low-density mass with peripheral ring-like enhancement in S5 of the liver. The liver mass was in contact with the gallbladder, and the boundary between the mass and the gallbladder was unclear. On the suspicion of liver abscess, percutaneous transhepatic drainage was performed. The cavity of the abscess communicated with the gallbladder. Because the cavity had no tendency to reduce in size, we performed surgical resection under a preoperative diagnosis of liver abscess or primary liver carcinoma invading to the gallbladder. Intraoperative findings revealed a liver tumor invading the transverse colon and gallbladder. Subsegmentectomy of S4a and S5 of the liver combined with gallbladder and transverse colon resection was performed. Histopathological findings indicated the growth of a mass forming type intrahepatic cholangiocarcinoma with invasion to the transverse colon and gallbladder, and the pathological stage of the tumor was pT3N0M0, fStage Ⅲ. Thus far, the patient is alive without recurrence 9 months after surgery. Here, we report an extremely rare case of intrahepatic cholangiocarcinoma that invaded other organs and was associated with an intra-tumor abscess.

  18. In Situ Conversion of Melanoma Lesions into Autologous Vaccine by Intratumoral Injections of α-gal Glycolipids

    Energy Technology Data Exchange (ETDEWEB)

    Galili, Uri, E-mail: Uri.Galili@umassmed.edu [Department of Surgery, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655 (United States); Albertini, Mark R.; Sondel, Paul M. [University of Wisconsin Carbone Cancer Center, Madison, WI. 53792 (United States); Wigglesworth, Kim; Sullivan, Mary; Whalen, Giles F. [Department of Surgery, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655 (United States)

    2010-05-04

    Autologous melanoma associated antigens (MAA) on murine melanoma cells can elicit a protective anti-tumor immune response following a variety of vaccine strategies. Most require effective uptake by antigen presenting cells (APC). APC transport and process internalized MAA for activation of anti-tumor T cells. One potential problem with clinical melanoma vaccines against autologous tumors may be that often tumor cells do not express surface markers that label them for uptake by APC. Effective uptake of melanoma cells by APC might be achieved by exploiting the natural anti-Gal antibody which constitutes ~1% of immunoglobulins in humans. This approach has been developed in a syngeneic mouse model using mice capable of producing anti-Gal. Anti-Gal binds specifically to α-gal epitopes (Galα1-3Galβ1-4GlcNAc-R). Injection of glycolipids carrying α-gal epitopes (α-gal glycolipids) into melanoma lesions results in glycolipid insertion into melanoma cell membranes, expression of α-gal epitopes on the tumor cells and binding of anti-Gal to these epitopes. Interaction between the Fc portions of bound anti-Gal and Fcγ receptors on APC induces effective uptake of tumor cells by APC. The resulting anti-MAA immune response can be potent enough to destroy distant micrometastases. A clinical trial is now open testing effects of intratumoral α-gal glycolipid injections in melanoma patients.

  19. From Chemotherapy to Combined Targeted Therapeutics: In Vitro and in Vivo Models to Decipher Intra-tumor Heterogeneity

    Directory of Open Access Journals (Sweden)

    Guido Gambara

    2018-02-01

    Full Text Available Recent advances in next-generation sequencing and other omics technologies capable to map cell fate provide increasing evidence on the crucial role of intra-tumor heterogeneity (ITH for cancer progression. The different facets of ITH, from genomic to microenvironmental heterogeneity and the hierarchical cellular architecture originating from the cancer stem cell compartment, contribute to the range of tumor phenotypes. Decoding these complex data resulting from the analysis of tumor tissue complexity poses a challenge for developing novel therapeutic strategies that can counteract tumor evolution and cellular plasticity. To achieve this aim, the development of in vitro and in vivo cancer models that resemble the complexity of ITH is crucial in understanding the interplay of cells and their (microenvironment and, consequently, in testing the efficacy of new targeted treatments and novel strategies of tailoring combinations of treatments to the individual composition of the tumor. This challenging approach may be an important cornerstone in overcoming the development of pharmaco-resistances during multiple lines of treatment. In this paper, we report the latest advances in patient-derived 3D (PD3D cell cultures and patient-derived tumor xenografts (PDX as in vitro and in vivo models that can retain the genetic and phenotypic heterogeneity of the tumor tissue.

  20. Monochromatic subdiffusive spatial frequency domain imaging provides in-situ sensitivity to intratumoral morphological heterogeneity in a murine model.

    Science.gov (United States)

    McClatchy, David M; Hoopes, P Jack; Pogue, Brian W; Kanick, Stephen Chad

    2017-02-01

    For the first time, spatially resolved quantitative metrics of light scattering recovered with sub-diffusive spatial frequency domain imaging (sd-SFDI) are shown to be sensitive to changes in intratumoral morphology and viability by direct comparison to histopathological analysis. Two freshly excised subcutaneous murine tumor cross-sections were measured with sd-SFDI, and recovered optical scatter parameter maps were co-registered to whole mount histology. Unique clustering of the optical scatter parameters μs' vs. γ (i.e. diffuse scattering vs. relative backscattering) evaluated at a single wavelength showed complete separation between regions of viable tumor, aggresive tumor with stromal growth, varying levels of necrotic tumor, and also peritumor muscle. The results suggest that with further technical development, sd-SFDI may represent a non-destructive screening tool for analysis of excised tissue or a non-invasive approach to investigate suspicious lesions without the need for exogenous labels or spectrally resolved imaging. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. Two-Step Delivery: Exploiting the Partition Coefficient Concept to Increase Intratumoral Paclitaxel Concentrations In vivo Using Responsive Nanoparticles

    Science.gov (United States)

    Colby, Aaron H.; Liu, Rong; Schulz, Morgan D.; Padera, Robert F.; Colson, Yolonda L.; Grinstaff, Mark W.

    2016-01-01

    Drug dose, high local target tissue concentration, and prolonged duration of exposure are essential criteria in achieving optimal drug performance. However, systemically delivered drugs often fail to effectively address these factors with only fractions of the injected dose reaching the target tissue. This is especially evident in the treatment of peritoneal cancers, including mesothelioma, ovarian, and pancreatic cancer, which regularly employ regimens of intravenous and/or intraperitoneal chemotherapy (e.g., gemcitabine, cisplatin, pemetrexed, and paclitaxel) with limited results. Here, we show that a “two-step” nanoparticle (NP) delivery system may address this limitation. This two-step approach involves the separate administration of NP and drug where, first, the NP localizes to tumor. Second, subsequent administration of drug then rapidly concentrates into the NP already stationed within the target tissue. This two-step method results in a greater than 5-fold increase in intratumoral drug concentrations compared to conventional “drug-alone” administration. These results suggest that this unique two-step delivery may provide a novel method for increasing drug concentrations in target tissues.

  2. Intratumor heterogeneous distribution of 10B-compounds suggested by the radiobiological findings from in vivo mouse studies

    International Nuclear Information System (INIS)

    Masunaga, S.; Ono, K.; Sakurai, Y.; Takagaki, M.; Kobayashi, T.; Kinashi, Y.; Akaboshi, M.; Akuta, K.

    2000-01-01

    After continuous labeling with or without 5-bromo-2'-deoxyuridine (BrdU), SCC VII tumor-bearing mice received one of the following treatments in vivo; 1) Tumor excision right after thermal neutron irradiation following sodium borocaptate- 10 B (BSH) or p-boronophenylalanine- 10 B (BPA) administration. 2) Tumor excision 5 min through 72 h after thermal neutron or γ-ray irradiation. 3) Determination of hypoxic fraction (HF) of implanted tumors by γ-ray test irradiation 5 min through 72 h after thermal neutron or γ-ray irradiation. 4) Determination of the tumor sensitivity to γ-rays 0-24 h after thermal neutron or γ-ray irradiation. The following results were obtained; 1) BSH and BPA sensitized quiescent (Q) and total (proliferating (P) + Q) tumor cells, respectively, and the use of 10 B-compound, especially BPA, widened the sensitivity difference between Q and total cells. 2) The use of 10 B-compound, especially BPA, increased the repair capacity from potentially lethal damage (PLDR) and induced PLDR pattern like post-γ-ray irradiation. 3) Reoxygenation after thermal neutron irradiation following 10 B-compound, especially BPA, administration occurred slowly, compared with after neutron irradiation only and looked like after γ-ray irradiation. 4) The use of 10 B-compound, especially BPA, promoted sublethal damage repair (SLDR) in total cells and the recruitment from Q to P state, compared with after thermal neutron irradiation alone. All these findings suggested the difficulty in distribution of 10 B-compound, especially BPA, in Q cells and the heterogeneity in intratumor distribution of 10 B-compound. (author)

  3. Intratumoral delivery of CpG-conjugated anti-MUC1 antibody enhances NK cell anti-tumor activity.

    Science.gov (United States)

    Schettini, Jorge; Kidiyoor, Amritha; Besmer, Dahlia M; Tinder, Teresa L; Roy, Lopamudra Das; Lustgarten, Joseph; Gendler, Sandra J; Mukherjee, Pinku

    2012-11-01

    Monoclonal antibodies (mAbs) against tumor-associated antigens are useful anticancer agents. Antibody-dependent cellular cytotoxicity (ADCC) is one of the major mechanisms responsible for initiating natural killer cell (NK)-mediated killing of tumors. However, the regulation of ADCC via NK cells is poorly understood. We have investigated the cytolytic activity of NK cells against pancreatic cancer cells that were coated with an antibody directed against the human tumor antigen, Mucin-1 designated HMFG-2, either alone or conjugated to CpG oligodeoxynucleotide (CpG ODN). Conjugated antibodies were tested for their ability to elicit ADCC in vitro and in vivo against pancreatic cancer cells. NK cells cultured in the presence of immobilized CpG ODN, HMFG-2 Ab, or CpG ODN-conjugated HMFG-2 Ab were able to up-regulate perforin similarly. Interestingly, a significant higher ADCC was observed when CpG ODN-conjugated HMFG-2-coated tumor cells were co-cultured with NK cells compared to unconjugated HMFG-2 Ab or CpG ODN alone. Moreover, MyD88-deficient NK cells can perform ADCC in vitro. Furthermore, intratumoral injections of CpG ODN-conjugated HMFG-2 induced a significant reduction in tumor burden in vivo in an established model of pancreatic tumor in nude mice compared to CpG ODN or the HMFG-2 alone. Depletion of macrophages or NK cells before treatment confirmed that both cells were required for the anti-tumor response in vivo. Results also suggest that CpG ODN and HMFG-2 Ab could be sensed by NK cells on the mAb-coated tumor cells triggering enhanced ADCC in vitro and in vivo.

  4. Challenging the Cancer Molecular Stratification Dogma: Intratumoral Heterogeneity Undermines Consensus Molecular Subtypes and Potential Diagnostic Value in Colorectal Cancer.

    Science.gov (United States)

    Dunne, Philip D; McArt, Darragh G; Bradley, Conor A; O'Reilly, Paul G; Barrett, Helen L; Cummins, Robert; O'Grady, Tony; Arthur, Ken; Loughrey, Maurice B; Allen, Wendy L; McDade, Simon S; Waugh, David J; Hamilton, Peter W; Longley, Daniel B; Kay, Elaine W; Johnston, Patrick G; Lawler, Mark; Salto-Tellez, Manuel; Van Schaeybroeck, Sandra

    2016-08-15

    A number of independent gene expression profiling studies have identified transcriptional subtypes in colorectal cancer with potential diagnostic utility, culminating in publication of a colorectal cancer Consensus Molecular Subtype classification. The worst prognostic subtype has been defined by genes associated with stem-like biology. Recently, it has been shown that the majority of genes associated with this poor prognostic group are stromal derived. We investigated the potential for tumor misclassification into multiple diagnostic subgroups based on tumoral region sampled. We performed multiregion tissue RNA extraction/transcriptomic analysis using colorectal-specific arrays on invasive front, central tumor, and lymph node regions selected from tissue samples from 25 colorectal cancer patients. We identified a consensus 30-gene list, which represents the intratumoral heterogeneity within a cohort of primary colorectal cancer tumors. Using a series of online datasets, we showed that this gene list displays prognostic potential HR = 2.914 (confidence interval 0.9286-9.162) in stage II/III colorectal cancer patients, but in addition, we demonstrated that these genes are stromal derived, challenging the assumption that poor prognosis tumors with stem-like biology have undergone a widespread epithelial-mesenchymal transition. Most importantly, we showed that patients can be simultaneously classified into multiple diagnostically relevant subgroups based purely on the tumoral region analyzed. Gene expression profiles derived from the nonmalignant stromal region can influence assignment of colorectal cancer transcriptional subtypes, questioning the current molecular classification dogma and highlighting the need to consider pathology sampling region and degree of stromal infiltration when employing transcription-based classifiers to underpin clinical decision making in colorectal cancer. Clin Cancer Res; 22(16); 4095-104. ©2016 AACRSee related commentary by Morris and

  5. Intratumoral Immunization by p19Arf and Interferon-β Gene Transfer in a Heterotopic Mouse Model of Lung Carcinoma

    Directory of Open Access Journals (Sweden)

    João Paulo Portela Catani

    2016-12-01

    Full Text Available Therapeutic strategies that act by eliciting and enhancing antitumor immunity have been clinically validated as an effective treatment modality but may benefit from the induction of both cell death and immune activation as primary stimuli. Using our AdRGD-PG adenovector platform, we show here for the first time that in situ gene transfer of p19Arf and interferon-β (IFNβ in the LLC1 mouse model of lung carcinoma acts as an immunotherapy. Although p19Arf is sufficient to induce cell death, only its pairing with IFNβ significantly induced markers of immunogenic cell death. In situ gene therapy with IFNβ, either alone or in combination with p19Arf, could retard tumor progression, but only the combined treatment was associated with a protective immune response. Specifically in the case of combined intratumoral gene transfer, we identified 167 differentially expressed genes when using microarray to evaluate tumors that were treated in vivo and confirmed the activation of CCL3, CXCL3, IL1α, IL1β, CD274, and OSM, involved in immune response and chemotaxis. Histologic evaluation revealed significant tumor infiltration by neutrophils, whereas functional depletion of granulocytes ablated the antitumor effect of our approach. The association of in situ gene therapy with cisplatin resulted in synergistic elimination of tumor progression. In all, in situ gene transfer with p19Arf and IFNβ acts as an immunotherapy involving recruitment of neutrophils, a desirable but previously untested outcome, and this approach may be allied with chemotherapy, thus providing significant antitumor activity and warranting further development for the treatment of lung carcinoma.

  6. Thymoma in Patient with Myasthenia Gravis Has Significantly Fewer Forkhead Box P3 Positive Lymphocytes than that without One.

    Science.gov (United States)

    Nishi, Tatsuya; Yokoyama, Shintaro; Takamori, Shinzo; Matsuo, Toshihiro; Murakami, Daigo; Akagi, Yoshito; Ohshima, Koichi

    2015-01-01

    Forkhead box P3 (FoxP3) is known as a pivotal and specific transcriptional factor of regulatory T cells, and are implicated in various immune diseases including myasthenia gravis (MG). The aim of this study was to investigate the relationships between FoxP3 expression of lymphocytes in thymoma and clinicopathological characteristics, particularly MG status in thymoma patients. We reviewed 83 thymoma specimens, including 22 from MG patients, and evaluated the FoxP3 expression of lymphocytes in thymoma using immunohistochemistry (IHC). Statistical association was evaluated using chi-square test and Fisher's exact test. Thirty-four cases (41.0%) were classified as FoxP3 positive. There were no statistical differences in sex (P=0.289), age (P=0.536), Masaoka stage (P=0.086), WHO histological classification (P=0.097), or Myasthenia Gravis Foundation of America (MGFA) Clinical Classification (P=0.117) between FoxP3 positive and negative cases. In contrast, thymoma in cases with MG showed significantly fewer FoxP3 positive lymphocytes than those in cases without MG (P=0.037). Moreover, cases with anti-acetylcholine receptor antibody titer equal to or greater than the normal limit also showed significantly fewer FoxP3 positive lymphocytes than cases within the normal limit (Pthymoma may lead to the development of MG and to an increase in anti-acetylcholine receptor antibodies. In addition, FoxP3 positive lymphocytes might be a useful biomarker for evaluation of the risk of MG onset, and could open the way to more effective therapeutic strategies in thymoma patients.

  7. Regulatory RNAs in Planarians.

    Science.gov (United States)

    Pawlicka, Kamila; Perrigue, Patrick M; Barciszewski, Jan

    2016-01-01

    The full scope of regulatory RNA evolution and function in epigenetic processes is still not well understood. The development of planarian flatworms to be used as a simple model organism for research has shown a great potential to address gaps in the knowledge in this field of study. The genomes of planarians encode a wide array of regulatory RNAs that function in gene regulation. Here, we review planarians as a suitable model organism for the identification and function of regulatory RNAs.

  8. CT-guided percutaneous intratumoral chemotherapy with a novel cisplatin/epinephrine injectable gel for the treatment of unresectable malignant liver tumors

    International Nuclear Information System (INIS)

    Engelmann, K.; Mack, M.G.; Straub, R.; Eichler, K.; Zangos, S.; Vogl, T.J.

    2000-01-01

    Purpose: To evaluate prospectively the volumetric changes of tumor and necrosis in unresectable malignant liver tumors and the clinical aspects after CT-guided direct intratumoral administration of a novel cisplatin/epinephrine injectable gel in a clinical phase II study. Patients and methods: 8 patients with 17 colorectal liver metastases with a mean volume of 42 ml were treated with a mean of 5.1 injections and 8 patients with 11 HCC nodules (mean volume of 22.1 ml) with a mean of 3.25 treatments with CT-guided local administration of a novel cisplatin/epinephrine gel. This method of administration provides a higher local and lower systemic drug concentration. Volumes of tumor and necrosis prior to and after treatment were measured by computer-generated volumetric analysis. Results: Contrast-enhanced studies verified pretherapeutic tumor necrosis with a value of 12.6% in the metastases and 0.6% in the HCC nodules. Intratumoral drug administration resulted in a necrotic volume of 110% in metastases and 128% in HCC versus the mean initial tumor volume, at least 4 treatments resulted in 122% necrosis in metastases and 130% in HCC. Local therapy control rate for the follow-up to 6 months was 38% and 83.3% for the group of metastases and HCC, respectively. Conclusions: Direct intratumoral injection of a novel cisplatin/epinephrine injectable gel results in an induction of a relevant necrosis in malignant liver tumors, with a substantially higher local therapy control rate for HCC compared to colorectal metastases. (orig.) [de

  9. Comparison of intratumoral FDG and Cu-ATSM distributions in cancer tissue originated spheroid (CTOS) xenografts, a tumor model retaining the original tumor properties

    International Nuclear Information System (INIS)

    Furukawa, Takako; Yuan, Qinghua; Jin, Zhao-Hui; Aung, Winn; Yoshii, Yukie; Hasegawa, Sumitaka; Endo, Hiroko; Inoue, Masahiro; Zhang, Ming-Rong; Fujibayashi, Yasuhisa; Saga, Tsuneo

    2014-01-01

    Introduction: The intratumoral distributions of [ 18 F]FDG and [ 64 Cu]Cu-ATSM have been reported to be similar in adenocarcinomas but different in squamous cell carcinoma (SCC) in clinical studies. In the present study, we compared the intratumoral distributions of these two tracers in cancer tissue originated spheroid (CTOS) xenografts derived from adenocarcinoma and SCC, which retain the histological characteristics of the original tumors, and in cancer cell line xenografts of corresponding origin, to investigate the underlying mechanism of the distinct FDG and Cu-ATSM distribution patterns in adenocarcinoma and SCC. Methods: CTOSs derived from colon adenocarcinoma and lung SCC and cell lines established from colon adenocarcinoma and lung SCC, which were used for comparison, were subcutaneously transplanted into immunodeficient mice. One hour after administering [ 14 C]FDG and [ 64 Cu]Cu-ATSM, the intratumoral distributions were compared in the xenografts by using dual-tracer autoradiography. Adjacent sections were evaluated for necrosis, vasculature anatomy, Ki-67 antigen, and pimonidazole adducts using hematoxylin and eosin and immunohistochemical staining. Results: There was a higher regional overlap of high FDG and Cu-ATSM accumulations in the adenocarcinoma CTOS xenografts than in the SCC CTOS xenografts, while the overlap in the adenocarcinoma cell line xenograft was lower than that observed in the SCC cell line. High FDG accumulation occurred primarily in proximity to necrotic or pimonidazole adduct positive regions, while high Cu-ATSM accumulation occurred primarily in live cell regions separate from the necrotic regions. The adenocarcinoma CTOS xenograft had the stereotypical glandular structure, resulting in more intricately mixed regions of live and necrotic cells compared to those observed in the SCC CTOS or the cell line xenografts. Conclusion: Tumor morphological characteristics, specifically the spatial distribution of live and necrotic cell

  10. Intratumoral and peritumoral radiomics for the pretreatment prediction of pathological complete response to neoadjuvant chemotherapy based on breast DCE-MRI.

    Science.gov (United States)

    Braman, Nathaniel M; Etesami, Maryam; Prasanna, Prateek; Dubchuk, Christina; Gilmore, Hannah; Tiwari, Pallavi; Plecha, Donna; Madabhushi, Anant

    2017-05-18

    In this study, we evaluated the ability of radiomic textural analysis of intratumoral and peritumoral regions on pretreatment breast cancer dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to predict pathological complete response (pCR) to neoadjuvant chemotherapy (NAC). A total of 117 patients who had received NAC were retrospectively analyzed. Within the intratumoral and peritumoral regions of T1-weighted contrast-enhanced MRI scans, a total of 99 radiomic textural features were computed at multiple phases. Feature selection was used to identify a set of top pCR-associated features from within a training set (n = 78), which were then used to train multiple machine learning classifiers to predict the likelihood of pCR for a given patient. Classifiers were then independently tested on 39 patients. Experiments were repeated separately among hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR + , HER2 - ) and triple-negative or HER2 + (TN/HER2 + ) tumors via threefold cross-validation to determine whether receptor status-specific analysis could improve classification performance. Among all patients, a combined intratumoral and peritumoral radiomic feature set yielded a maximum AUC of 0.78 ± 0.030 within the training set and 0.74 within the independent testing set using a diagonal linear discriminant analysis (DLDA) classifier. Receptor status-specific feature discovery and classification enabled improved prediction of pCR, yielding maximum AUCs of 0.83 ± 0.025 within the HR + , HER2 - group using DLDA and 0.93 ± 0.018 within the TN/HER2 + group using a naive Bayes classifier. In HR + , HER2 - breast cancers, non-pCR was characterized by elevated peritumoral heterogeneity during initial contrast enhancement. However, TN/HER2 + tumors were best characterized by a speckled enhancement pattern within the peritumoral region of nonresponders. Radiomic features were found to strongly predict pCR independent of

  11. 3 CFR - Regulatory Review

    Science.gov (United States)

    2010-01-01

    ... Departments and Agencies For well over two decades, the Office of Information and Regulatory Affairs (OIRA) at... opportunities and security. While recognizing the expertise and authority of executive branch departments and... as a means of promoting regulatory goals. The fundamental principles and structures governing...

  12. NRC Regulatory Agenda

    International Nuclear Information System (INIS)

    1991-10-01

    The NRC Regulatory Agenda is a compilation of all rules on which the NRC has recently completed action, or has proposed action, or is considering action, and all petitions for rulemaking which have been received by the Commission and are pending disposition by the Commission. The Regulatory Agenda is updated and issued each quarter

  13. NRC Regulatory Agenda

    International Nuclear Information System (INIS)

    1991-08-01

    The NRC Regulatory Agenda is a compilation of all rules on which the NRC has recently completed action or has proposed, or is considering action and all petitions for rulemaking which have been received by the commission and are pending disposition by the Commission. The Regulatory Agenda is updated and issued each quarter

  14. NRC regulatory agenda

    International Nuclear Information System (INIS)

    1991-04-01

    The NRC Regulatory Agenda is a compilation of all rules on which the NRC has recently completed action or has proposed, or is considering action and all petitions for rulemaking which have been received by the Commission and are pending disposition by the Commission. The Regulatory Agenda is updated and issued each quarter

  15. Nuclear Regulatory legislation

    International Nuclear Information System (INIS)

    1984-06-01

    This compilation of statutes and material pertaining to nuclear regulatory legislation through the 97th Congress, 2nd Session, has been prepared by the Office of the Executive Legal Director, U.S. Nuclear Regulatory Commission, with the assistance of staff, for use as an internal resource document

  16. NRC regulatory agenda

    International Nuclear Information System (INIS)

    1993-04-01

    The NRC Regulatory Agenda is a compilation of all rules on which the NRC has recently completed action, or has proposed action, or is considering action, and all petitions for rulemaking which have been received by the Commission and are pending disposition by the Commission. The Regulatory Agenda is updated and issued each quarter

  17. NRC regulatory agenda

    International Nuclear Information System (INIS)

    1990-01-01

    The NRC Regulatory Agenda is a compilation of all rules on which the NRC has proposed or is considering action and all petitions for rulemaking which have been received by the Commission and are pending disposition by the Commission. The Regulatory Agenda is updated and issued each quarter

  18. Clinical Significance of Programmed Death Ligand‑1 and Intra-Tumoral CD8+ T Lymphocytes in Ovarian Carcinosarcoma.

    Science.gov (United States)

    Zhu, Jun; Wen, Hao; Ju, Xingzhu; Bi, Rui; Zuo, Wenjia; Wu, Xiaohua

    2017-01-01

    Ovarian carcinosarcoma (OCS) accounts for high mortality and lacks effective therapeutic methods. So far, we lack reliable biomarkers capable of predicting the risk of aggressive course of the disease. Programmed death ligand-1 (PD-L1) is expressed in various tumors, and antibodies targeting its receptor programmed cell death 1 (PD-1) are emerging cancer therapeutics. This study was designed to evaluate the expression of PD-L1 and intratumoral CD8+ T lymphocytes by immunohistochemistry from 19 OCS patients who underwent primary surgery at Fudan University Shanghai Cancer Center. The correlations between PD-L1 expression and CD8+ T lymphocytes as well as the patients' clinicopathologic characteristics were integrated and statistically analyzed. PD-L1-positive expression was observed in 52.6% of intraepithelial tissues and 47.4% of mesenchymal tissues (p = 0.370). Meanwhile, intraepithelial and mesenchymal CD8+ T lymphocytes were positive in 36.8% and 84.2% of OCS, respectively (p = 0.628). A significantly negative correlation was found between mesenchymal CD8+ T lymphocytes and PD-L1 expression (r = -0.630, p = 0.011). Intraepithelial PD-L1-positive expression was associated only with positive ascitic fluid (p = 0.008). Mesenchymal PD-L1-positive patients had a poorer survival than those with negative expression (p = 0.036). Meanwhile, intraepithelial PD-L1-positive patients had a better survival trend than PD-L1-negative patients, though no statistical significance was found (p = 0.061). There was a better postoperative survival noted in mesenchymal CD8-positive patients (p = 0.024), and allthough a better trend of OS was observed in intraepithelial CD8-positive patients, no statistical significance was found (p = 0.382). Positive tumoral CD8+ T lymphocytes and mesenchymal PD-L1-negative expression seem to be associated with better survival in OCS. It is possible that immunotherapy targeting PD-L1 pathway could be used in OCS.

  19. Volume of high-risk intratumoral subregions at multi-parametric MR imaging predicts overall survival and complements molecular analysis of glioblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Cui, Yi; Li, Ruijiang [Stanford University, Department of Radiation Oncology, Palo Alto, CA (United States); Hokkaido University, Global Station for Quantum Medical Science and Engineering, Global Institution for Collaborative Research and Education, Hokkaido (Japan); Ren, Shangjie [Tianjin University, School of Electrical Engineering and Automation, Tianjin Shi (China); Tha, Khin Khin; Shirato, Hiroki [Hokkaido University, Global Station for Quantum Medical Science and Engineering, Global Institution for Collaborative Research and Education, Hokkaido (Japan); Hokkaido University, Department of Radiology and Nuclear Medicine, Hokkaido (Japan); Wu, Jia [Stanford University, Department of Radiation Oncology, Palo Alto, CA (United States)

    2017-09-15

    To develop and validate a volume-based, quantitative imaging marker by integrating multi-parametric MR images for predicting glioblastoma survival, and to investigate its relationship and synergy with molecular characteristics. We retrospectively analysed 108 patients with primary glioblastoma. The discovery cohort consisted of 62 patients from the cancer genome atlas (TCGA). Another 46 patients comprising 30 from TCGA and 16 internally were used for independent validation. Based on integrated analyses of T1-weighted contrast-enhanced (T1-c) and diffusion-weighted MR images, we identified an intratumoral subregion with both high T1-c and low ADC, and accordingly defined a high-risk volume (HRV). We evaluated its prognostic value and biological significance with genomic data. On both discovery and validation cohorts, HRV predicted overall survival (OS) (concordance index: 0.642 and 0.653, P < 0.001 and P = 0.038, respectively). HRV stratified patients within the proneural molecular subtype (log-rank P = 0.040, hazard ratio = 2.787). We observed different OS among patients depending on their MGMT methylation status and HRV (log-rank P = 0.011). Patients with unmethylated MGMT and high HRV had significantly shorter survival (median survival: 9.3 vs. 18.4 months, log-rank P = 0.002). Volume of the high-risk intratumoral subregion identified on multi-parametric MRI predicts glioblastoma survival, and may provide complementary value to genomic information. (orig.)

  20. Intra-tumoral Heterogeneity of KRAS and BRAF Mutation Status in Patients with Advanced Colorectal Cancer (aCRC and Cost-Effectiveness of Multiple Sample Testing

    Directory of Open Access Journals (Sweden)

    Susan D. Richman

    2011-01-01

    Full Text Available KRAS mutation status is established as a predictive biomarker of benefit from anti-EGFr therapies. Mutations are normally assessed using DNA extracted from one formalin-fixed, paraffin-embedded (FFPE tumor block. We assessed heterogeneity of KRAS and BRAF mutation status intra-tumorally (multiple blocks from the same primary tumor. We also investigated the utility and efficiency of genotyping a ‘DNA cocktail’ prepared from multiple blocks. We studied 68 consenting patients in two randomized clinical trials. DNA was extracted, from ≥2 primary tumor FFPE blocks per patient. DNA was genotyped by pyrosequencing for KRAS codons 12, 13 and 61 and BRAF codon 600. In patients with heterogeneous mutation status, DNA cocktails were prepared and genotyped. Among 69 primary tumors in 68 patients, 7 (10.1% showed intratumoral heterogeneity; 5 (7.2% at KRAS codons 12, 13 and 2 (2.9% at BRAF codon 600. In patients displaying heterogeneity, the relevant KRAS or BRAF mutation was also identified in ‘DNA cocktail’ samples when including DNA from mutant and wild-type blocks. Heterogeneity is uncommon but not insignificant. Testing DNA from a single block will wrongly assign wild-type status to 10% patients. Testing more than one block, or preferably preparation of a ‘DNA cocktail’ from two or more tumor blocks, improves mutation detection at minimal extra cost.

  1. Quantitative evaluation of oxygen metabolism in the intratumoral hypoxia: 18F-fluoromisonidazole and 15O-labelled gases inhalation PET.

    Science.gov (United States)

    Watabe, Tadashi; Kanai, Yasukazu; Ikeda, Hayato; Horitsugi, Genki; Matsunaga, Keiko; Kato, Hiroki; Isohashi, Kayako; Abe, Kohji; Shimosegawa, Eku; Hatazawa, Jun

    2017-12-01

    Intratumoral hypoxia is one of the resistant factors in radiotherapy and chemotherapy for cancer. Although it is detected by 18 F-fluoromisonidazole (FMISO) PET, the relationship between intratumoral hypoxia and oxygen metabolism has not been studied. The purpose of this study was to evaluate the intratumoral perfusion and oxygen metabolism in hypoxic regions using the rat xenograft model. Ten male Fischer rats with C6 glioma (body weight = 220 ± 15 g) were investigated with 18 F-FMISO PET and steady-state inhalation method of 15 O-labelled gases PET. The tumoral blood flow (TBF), tumoral metabolic rate of oxygen (TMRO 2 ), oxygen extraction fraction (OEF), and tumoral blood volume (TBV) were measured under artificial ventilation with 15 O-CO 2 , 15 O-O 2 , and 15 O-CO gases. Multiple volumes of interest (1-mm diameter sphere) were placed on the co-registered 18 F-FMISO (3 h post injection) and functional 15 O-labelled gases PET images. The TBF, TMRO 2 , OEF, and TBV values were compared among the three groups classified by the 18 F-FMISO uptake as follows: group Low (L), less than 1.0; group Medium (M), between 1.0 and 2.0; and group High (H), more than 2.0 in the 18 F-FMISO standardized uptake value (SUV). There were moderate negative correlations between 18 F-FMISO SUV and TBF (r = -0.56 and p < 0.01), and weak negative correlations between 18 F-FMISO SUV and TMRO 2 (r = -0.38 and p < 0.01) and 18 F-FMISO SUV and TBV (r = -0.38 and p < 0.01). Quantitative values were as follows: TBF, (L) 55 ± 30, (M) 32 ± 17, and (H) 30 ± 15 mL/100 mL/min; OEF, (L) 33 ± 14, (M) 36 ± 17, and (H) 41 ± 16%; TMRO 2 , (L) 2.8 ± 1.3, (M) 1.9 ± 1.0, and (H) 2.1 ± 1.1 mL/100 mL/min; and TBV, (L) 5.7 ± 2.1, (M) 4.3 ± 1.9, and (H) 3.9 ± 1.2 mL/100 mL, respectively. Intratumoral hypoxic regions (M and H) showed significantly lower TBF, TMRO 2 , and TBV values than non-hypoxic regions (L). OEF

  2. Intratumoral Delivery of Doxorubicin on Folate-Conjugated Graphene Oxide by In-Situ Forming Thermo-Sensitive Hydrogel for Breast Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Yi Teng Fong

    2017-11-01

    Full Text Available By taking advantage of the pH-sensitive drug release property of graphene oxide (GO after intracellular uptake, we prepared folic acid (FA-conjugated GO (GOFA for targeted delivery of the chemotherapeutic drug doxorubicin (DOX. GOFA-DOX was further encapsulated in an injectable in-situ forming thermo-sensitive hyaluronic acid-chitosan-g-poly(N-isopropylacrylamide (HACPN hydrogel for intratumoral delivery of DOX. As the degradation time of HACPN could be extended up to 3 weeks, intratumoral delivery of GOFA-DOX/HACPN could provide controlled and targeted delivery of DOX through slow degradation HACPN and subsequent cellular uptake of released GOFA-DOX by tumor cells through interactions of GOFA with folate receptors on the tumor cell’s surface. GOFA nano-carrier and HACPN hydrogel were first characterized for the physico-chemical properties. The drug loading experiments indicated the best preparation condition of GOFA-DOX was by reacting 0.1 mg GOFA with 2 mg DOX. GOFA-DOX showed pH-responsive drug release with ~5 times more DOX released at pH 5.5 than at pH 7.4 while only limited DOX was released from GOFA-DOX/HACPN at pH 7.4. Intracellular uptake of GOFA by endocytosis and release of DOX from GOFA-DOX in vitro could be confirmed from transmission electron microscopic and confocal laser scanning microscopic analysis with MCF-7 breast cancer cells. The targeting effect of FA was revealed when intracellular uptake of GOFA was blocked by excess FA. This resulted in enhanced in vitro cytotoxicity as revealed from the lower half maximal inhibitory concentration (IC50 value of GOFA-DOX (7.3 μg/mL compared with that of DOX (32.5 μg/mL and GO-DOX (10 μg/mL. The flow cytometry analysis indicated higher apoptosis rates for cells treated with GOFA-DOX (30% compared with DOX (8% and GO-DOX (11%. Animal studies were carried out with subcutaneously implanted MCF-7 cells in BALB/c nude mice and subject to intratumoral administration of drugs. The relative

  3. Regulatory guidance document

    International Nuclear Information System (INIS)

    1994-05-01

    The Office of Civilian Radioactive Waste Management (OCRWM) Program Management System Manual requires preparation of the OCRWM Regulatory Guidance Document (RGD) that addresses licensing, environmental compliance, and safety and health compliance. The document provides: regulatory compliance policy; guidance to OCRWM organizational elements to ensure a consistent approach when complying with regulatory requirements; strategies to achieve policy objectives; organizational responsibilities for regulatory compliance; guidance with regard to Program compliance oversight; and guidance on the contents of a project-level Regulatory Compliance Plan. The scope of the RGD includes site suitability evaluation, licensing, environmental compliance, and safety and health compliance, in accordance with the direction provided by Section 4.6.3 of the PMS Manual. Site suitability evaluation and regulatory compliance during site characterization are significant activities, particularly with regard to the YW MSA. OCRWM's evaluation of whether the Yucca Mountain site is suitable for repository development must precede its submittal of a license application to the Nuclear Regulatory Commission (NRC). Accordingly, site suitability evaluation is discussed in Chapter 4, and the general statements of policy regarding site suitability evaluation are discussed in Section 2.1. Although much of the data and analyses may initially be similar, the licensing process is discussed separately in Chapter 5. Environmental compliance is discussed in Chapter 6. Safety and Health compliance is discussed in Chapter 7

  4. Managing Regulatory Body Competence

    International Nuclear Information System (INIS)

    2013-01-01

    In 2001, the IAEA published TECDOC 1254, which examined the way in which the recognized functions of a regulatory body for nuclear facilities results in competence needs. Using the systematic approach to training (SAT), TECDOC 1254 provided a framework for regulatory bodies for managing training and developing and their maintaining their competence. It has been successfully used by many regulators. The IAEA has also introduced a methodology and an assessment tool - Guidelines for Systematic Assessment of Regulatory Competence Needs (SARCoN) - which provides practical guidance on analysing the training and development needs of a regulatory body and, through a gap analysis, guidance on establishing competence needs and how to meet them. In 2009, the IAEA established a steering committee (supported by a bureau) with the mission to advise the IAEA on how it could best assist Member States to develop suitable competence management systems for their regulatory bodies. The committee recommended the development of a safety report on managing staff competence as an integral part of a regulatory body's management system. This Safety Report was developed in response to this request. It supersedes TECDOC 1254, broadens its application to regulatory bodies for all facilities and activities, and builds upon the experience gained through the application of TECDOC 1254 and SARCoN and the feedback received from Member States. This Safety Report applies to the management of adequate competence as needs change, and as such is equally applicable to the needs of States 'embarking' on a nuclear power programme. It also deals with the special case of building up the competence of regulatory bodies as part of the overall process of establishing an 'embarking' State's regulatory system

  5. Disparities in Intratumoral Steroidogenesis

    Science.gov (United States)

    2017-12-01

    cancer. The reasons for this racial disparity in prostate cancer incidence and mortality are unknown but may stem from economic, social, psychological ...One aspect of our experimental approach is to test whether therapeutically targeting cholesterol using heart healthy diets and FDA approved, safe and...of the racial differences seen in incidence and mortality. We sought to test this using preclinical models (done by Dr. Solomon for which no data

  6. Disparities in Intratumoral Steroidogenesis

    Science.gov (United States)

    2013-07-01

    their cancers progress after adjusting for disease characteristics22. Moreover, multiple studies determined allelic variants in chromosomal regions...especially 3 separate regions (risk-regions) of chromosome 8q24 spanning ≈600kb are associated with a higher risk of PCa or of metastatic prostate...Steroidogenesis Duke University Medical Center   Page 15 of 22    - Fatal - Life-threatening - Constitutes a congenital anomaly or birth defect

  7. NRC regulatory agenda

    International Nuclear Information System (INIS)

    1990-04-01

    The Regulatory Agenda is a quarterly compilation of all rules on which the NRC has recently completed action or has proposed, or is considering action and of all petitions for rulemaking that the NRC has received that are pending disposition

  8. NRC regulatory agenda

    International Nuclear Information System (INIS)

    1990-10-01

    The Regulatory Agenda is a quarterly compilation of all rules on which the NRC has recently completed action or has proposed, or is considering action and of all petitions for rulemaking that the NRC has received that are pending disposition

  9. Investigating intra-tumor heterogeneity and expression gradients of miR-21, miR-92a and miR-200c and their potential of predicting lymph node metastases in early colorectal cancer

    DEFF Research Database (Denmark)

    Jepsen, Rikke Karlin; Novotny, Guy Wayne; Klarskov, Louise Laurberg

    2016-01-01

    Introduction miR-21, miR-92a and miR-200c are regulators of pathways involved in migration, intravasation and metastasis, and their tumor expression levels have been proposed as potential prognostic markers in colorectal cancer (CRC). In two parallel cohorts we examine intra-tumor expression leve...

  10. The intratumoral administration of ferucarbotran conjugated with doxorubicin improved therapeutic effect by magnetic hyperthermia combined with pharmacotherapy in a hepatocellular carcinoma model.

    Science.gov (United States)

    Jeon, Min Jeong; Ahn, Cheol-Hee; Kim, Hyeonjin; Chung, In Jae; Jung, Seulhee; Kim, Young-Hwa; Youn, Hyewon; Chung, Jin Wook; Kim, Young Il

    2014-07-18

    Local hyperthermia of tumor in conjunction with chemotherapy is a promising strategy for cancer treatment. The aim of this study was to evaluate the efficacy of intratumoral delivery of clinically approved magnetic nanoparticles (MNPs) conjugated with doxorubicin to simultaneously induce magnetic hyperthermia and drug delivery in a hepatocellular carcinoma (HCC) model. HCC cells expressing luciferase were implanted into the flank of BALB/c-nu mice (n = 19). When the tumor diameter reached 7-8 mm, the animals were divided into four groups according to the injected agents: group A (normal saline, n = 4), group B (doxorubicin, n = 5), group C (MNP, n = 5), and group D (MNP/doxorubicin complex, n = 5). Animals were exposed to an alternating magnetic field (AMF) to receive magnetic hyperthermia, and intratumoral temperature changes were measured. The rise in temperature of the tumors was 1.88 ± 0.21°C in group A, 0.96 ± 1.05°C in B, 7.93 ± 1.99°C in C, and 8.95 ± 1.31°C in D. The RSI of the tumors at day 14 post-treatment was significantly lower in group D (0.31 ± 0.20) than in group A (2.23 ± 1.14), B (0.94 ± 0.47), and C (1.02 ± 0.21). The apoptosis rates of the tumors were 11.52 ± 3.10% in group A, 23.0 ± 7.68% in B, 25.4 ± 3.36% in C, and 39.0 ± 13.2% in D, respectively. The intratumoral injection of ferucarbotran conjugated with doxorubicin shows an improved therapeutic effect compared with doxorubicin or ferucarbotran alone when the complex is injected into HCC tissues exposed to AMF for magnetic hyperthermia. This strategy of combining doxorubicin and MNP-induced magnetic hyperthermia exhibits a synergic effect on inhibiting tumor growth in an HCC model.

  11. SU-D-207B-05: Robust Intra-Tumor Partitioning to Identify High-Risk Subregions for Prognosis in Lung Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Wu, J; Gensheimer, M; Dong, X; Rubin, D; Napel, S; Diehn, M; Loo, B; Li, R [Stanford University, Palo Alto, CA (United States)

    2016-06-15

    Purpose: To develop an intra-tumor partitioning framework for identifying high-risk subregions from 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) and CT imaging, and to test whether tumor burden associated with the high-risk subregions is prognostic of outcomes in lung cancer. Methods: In this institutional review board-approved retrospective study, we analyzed the pre-treatment FDG-PET and CT scans of 44 lung cancer patients treated with radiotherapy. A novel, intra-tumor partitioning method was developed based on a two-stage clustering process: first at patient-level, each tumor was over-segmented into many superpixels by k-means clustering of integrated PET and CT images; next, tumor subregions were identified by merging previously defined superpixels via population-level hierarchical clustering. The volume associated with each of the subregions was evaluated using Kaplan-Meier analysis regarding its prognostic capability in predicting overall survival (OS) and out-of-field progression (OFP). Results: Three spatially distinct subregions were identified within each tumor, which were highly robust to uncertainty in PET/CT co-registration. Among these, the volume of the most metabolically active and metabolically heterogeneous solid component of the tumor was predictive of OS and OFP on the entire cohort, with a concordance index or CI = 0.66–0.67. When restricting the analysis to patients with stage III disease (n = 32), the same subregion achieved an even higher CI = 0.75 (HR = 3.93, logrank p = 0.002) for predicting OS, and a CI = 0.76 (HR = 4.84, logrank p = 0.002) for predicting OFP. In comparison, conventional imaging markers including tumor volume, SUVmax and MTV50 were not predictive of OS or OFP, with CI mostly below 0.60 (p < 0.001). Conclusion: We propose a robust intra-tumor partitioning method to identify clinically relevant, high-risk subregions in lung cancer. We envision that this approach will be applicable to identifying useful

  12. Computed Tomography Demonstration of the Production and Distribution of Oxygen Gas Following Intratumoral Injection of a New Radiosensitizer (KORTUC) for Patients with Breast Cancer-Is Intratumoral Injection Not an Ideal Approach to Solve the Major Problem of Tumor Hypoxia in Radiotherapy?

    Science.gov (United States)

    Hayashi, Naoya; Ogawa, Yasuhiro; Kubota, Kei; Okino, Kazuhiro; Akima, Ryo; Morita-Tokuhiro, Shiho; Tsuzuki, Akira; Yaogawa, Shin; Nishioka, Akihito; Miyamura, Mitsuhiko

    2016-04-01

    We previously developed a new enzyme-targeting radiosensitization treatment named Kochi Oxydol-Radiation Therapy for Unresectable Carcinomas, Type II (KORTUC II), which contains hydrogen peroxide and sodium hyaluronate for injection into various types of tumors. For breast cancer treatment, the radiosensitization agent was injected into the tumor tissue twice a week under ultrasonographic guidance, immediately prior to each administration of radiation therapy. At approximately three hours after the second or third injection, computed tomography (CT) was performed to confirm the production and distribution of oxygen gas generated from the KORTUC radiosensitization agent by catalysis of peroxidases contained mainly in tumor tissue. The purpose of this study was to demonstrate that tumor hypoxia could be overcome by such a procedure and to evaluate the method of intratumoral injection in terms of confirming oxygen distribution in the target tumor tissue and around the tumor to be visualized on dedicated CT imaging. Three-dimensional reconstructed maximum intensity projection imaging of contrast-enhanced breast magnetic resonance imaging was used to compare the position of the tumor and that of the generated oxygen. Distributed oxygen gas was confirmed in the tumor tissue and around it in all 10 patients examined in the study. A region of oxygen gas was measured as an average value of -457.2 Hounsfield units (HU) as a region of interest. A slightly increased HU value compared to the density of air or oxygen was considered due to the presence of tumor tissue in the low-density area on 5-mm-thick reconstructed CT imaging. The results of this study showed that intratumoral oxygen was successfully produced by intratumoral KORTUC injection under ultrasonographic guidance, and that tumor hypoxia, which is considered a main cause of radioresistance in currently used Linac (linear accelerator) radiation therapy for malignant neoplasms, could be resolved by this method.

  13. Perceptions of regulatory approaches

    International Nuclear Information System (INIS)

    Halin, Magnus; Leinonen, Ruusaliisa

    2012-01-01

    Ms. Ruusaliisa Leinonen and Mr. Magnus Halin from Fortum gave a joint presentation on industry perceptions of regulatory oversight of LMfS/SC. It was concluded that an open culture of discussion exists between the regulator (STUK) and the licensee, based on the common goal of nuclear safety. An example was provided of on how regulatory interventions helped foster improvements to individual and collective dose rate trends, which had remained static. Regulatory interventions included discussions on the ALARA concept to reinforce the requirement to continuously strive for improvements in safety performance. Safety culture has also been built into regulatory inspections in recent years. Training days have also been organised by the regulatory body to help develop a shared understanding of safety culture between licensee and regulatory personnel. Fortum has also developed their own training for managers and supervisors. Training and ongoing discussion on LMfS/SC safety culture is considered particularly important because both Fortum and the regulatory body are experiencing an influx of new staff due to the demographic profile of their organisations. It was noted that further work is needed to reach a common understanding of safety culture on a practical level (e.g., for a mechanic setting to work), and in relation to the inspection criteria used by the regulator. The challenges associated with companies with a mix of energy types were also discussed. This can make it more difficult to understand responsibilities and decision making processes, including the role of the parent body organisation. It also makes communication more challenging due to increased complexity and a larger number of stakeholders

  14. Association of FOXP3 Gene Polymorphism with Chronic Hepatitis B in Chinese Population

    Directory of Open Access Journals (Sweden)

    Chen Yan-hui

    2012-12-01

    Full Text Available Objective The forkhead transcription factor FOXP3 is a key molecular which can mediate regulatory T cells immune-related inhibitory functions. Increased levels of FOXP3-positive Tregs in peripheral blood have been proved to be associated with a less favorable prognosis in various inflammatory diseases. It is of great interest to investigate the correlation between single nucleotide polymorphism (SNP of FOXP3 gene and the susceptibility of chronic hepatitis B (CHB.

  15. Federal Reserve System Semiannual Regulatory Agenda

    Science.gov (United States)

    2010-12-20

    ... [The Regulatory Plan and Unified Agenda of Federal Regulatory and Deregulatory Actions] [Federal Reserve System Semiannual Regulatory Agenda ] Part XXI Federal Reserve System Semiannual Regulatory Agenda... Flexibility Agenda AGENCY: Board of Governors of the Federal Reserve System. ACTION: Semiannual regulatory...

  16. Intratumoral interleukin-21 increases antitumor immunity, tumor-infiltrating CD8+ T-cell density and activity, and enlarges draining lymph nodes

    DEFF Research Database (Denmark)

    Søndergaard, Henrik; Galsgaard, Elisabeth D; Bartholomaeussen, Monica

    2010-01-01

    Interleukin (IL)-21 is a novel cytokine in clinical development for the treatment of cancer. In this study, we have compared the efficacy of subcutaneous and intratumoral (IT) administration of IL-21 protein in two syngeneic mouse tumor models, RenCa renal cell carcinoma and B16 melanoma......, and investigated the mechanisms by which IL-21 enhances CD8 T-cell-mediated antitumor immunity. We found that in comparison to subcutaneous administration, IT administration of IL-21 more potently inhibited tumor growth and increased survival. This correlated with increased densities of tumor-infiltrating CD8...... and CD4CD25 T cells, but not CD4CD25FoxP3 T cells. Furthermore, IT administration of IL-21 increased degranulation, and expression of interferon-gamma and granzyme B in tumor-infiltrating CD8 T cells. Tumors injected with IL-21 grew slower than contralateral tumors, suggesting that the increased efficacy...

  17. Intratumoral Interleukin-21 Increases Antitumor Immunity, Tumor-infiltrating CD8(+) T-cell Density and Activity, and Enlarges Draining Lymph Nodes

    DEFF Research Database (Denmark)

    Sondergaard, H.; Galsgaard, E.D.; Bartholomaeussen, M.

    2010-01-01

    Interleukin (IL)-21 is a novel cytokine in clinical development for the treatment of cancer. In this study, we have compared the efficacy of subcutaneous and intratumoral (IT) administration of IL-21 protein in two syngeneic mouse tumor models, RenCa renal cell carcinoma and B16 melanoma......, and investigated the mechanisms by which IL-21 enhances CD8(+) T-cell-mediated antitumor immunity. We found that in comparison to subcutaneous administration, IT administration of IL-21 more potently inhibited tumor growth and increased survival. This correlated with increased densities of tumor-infiltrating CD8......(+) and CD4(+) CD25(-) T cells, but not CD4(+) CD25(+) FoxP3(+) T cells. Furthermore, IT administration of IL-21 increased degranulation, and expression of interferon-gamma and granzyme B in tumor-infiltrating CD8(+) T cells. Tumors injected with IL-21 grew slower than contralateral tumors, suggesting...

  18. Nuclear regulatory decision making

    International Nuclear Information System (INIS)

    Wieland, Patricia; Almeida, Ivan Pedro Salati de

    2011-01-01

    The scientific considerations upon which the nuclear regulations are based provide objective criteria for decisions on nuclear safety matters. However, the decisions that a regulatory agency takes go far beyond granting or not an operating license based on assessment of compliance. It may involve decisions about hiring experts or research, appeals, responses to other government agencies, international agreements, etc.. In all cases, top management of the regulatory agency should hear and decide the best balance between the benefits of regulatory action and undue risks and other associated impacts that may arise, including issues of credibility and reputation. The establishment of a decision framework based on well established principles and criteria ensures performance stability and consistency, preventing individual subjectivity. This article analyzes the challenges to the decision-making by regulatory agencies to ensure coherence and consistency in decisions, even in situations where there is uncertainty, lack of reliable information and even divergence of opinions among experts. The article explores the basic elements for a framework for regulatory decision-making. (author)

  19. Minimal-invasive magnetic heating of tumors does not alter intra-tumoral nanoparticle accumulation, allowing for repeated therapy sessions: an in vivo study in mice

    International Nuclear Information System (INIS)

    Kettering, Melanie; Kaiser, Werner Alois; Hilger, Ingrid; Richter, Heike; Wiekhorst, Frank; Trahms, Lutz; Bremer-Streck, Sibylle

    2011-01-01

    Localized magnetic heating treatments (hyperthermia, thermal ablation) using superparamagnetic iron oxide nanoparticles (MNPs) continue to be an active area of cancer research. For generating the appropriate heat to sufficiently target cell destruction, adequate MNP concentrations need to be accumulated into tumors. Furthermore, the knowledge of MNP bio-distribution after application and additionally after heating is significant, firstly because of the possibility of repeated heating treatments if MNPs remain at the target region and secondly to study potential adverse effects dealing with MNP dilution from the target region over time. In this context, little is known about the behavior of MNPs after intra-tumoral application and magnetic heating. Therefore, the present in vivo study on the bio-distribution of intra-tumorally injected MNPs in mice focused on MNP long term monitoring of pre and post therapy over seven days using multi-channel magnetorelaxometry (MRX). Subsequently, single-channel MRX was adopted to study the bio-distribution of MNPs in internal organs and tumors of sacrificed animals. We found no distinct change of total MNP amounts in vivo during long term monitoring. Most of the MNP amounts remained in the tumors; only a few MNPs were detected in liver and spleen and less than 1% of totally injected MNPs were excreted. Apparently, the application of magnetic heating and the induction of apoptosis did not affect MNP accumulation. Our results indicate that MNP mainly remained within the injection side after magnetic heating over a seven-days-observation and therefore not affecting healthy tissue. As a consequence, localized magnetic heating therapy of tumors might be applied periodically for a better therapeutic outcome.

  20. Peripheral Leukocytosis Is Inversely Correlated with Intratumoral CD8+ T-Cell Infiltration and Associated with Worse Outcome after Chemoradiotherapy in Anal Cancer

    Directory of Open Access Journals (Sweden)

    Daniel Martin

    2017-09-01

    Full Text Available Peripheral blood leukocytosis has been implicated in promoting tumor progression leading to worse survival, but the mechanisms behind this phenomenon remain unexplored. Here, we examined the prognostic role of pretreatment white blood cell (WBC count and clinicopathologic parameters in the context of CD8+ tumor-infiltrating lymphocytes (TIL and myeloperoxidase+ tumor-associated neutrophils (TANs in patients with anal squamous cell carcinoma (ASCC treated with definitive chemoradiotherapy (CRT. After a median follow-up of 26 months, leukocytosis correlated with advanced T-stage (p < 0.001 and N-stage (p < 0.001, and predicted for worse distant-metastasis-free survival (p = 0.006, disease-free-survival (DFS, p = 0.029, and overall survival (p = 0.013. Importantly, leukocytosis was associated with a lower intraepithelial CD8+ TIL density (p = 0.014, whereas low CD8+ TIL expression in the intraepithelial compartment was associated with worse DFS (p = 0.028. Additionally, high TAN expression in the peritumoral compartment was associated with a significantly lower density of CD8+ TIL (p = 0.039, albeit, TAN expression lacked prognostic value. In conclusion, leukocytosis constitutes an important prognostic marker in ASCC patients treated with CRT. In conjunction with intratumoral TIL and TAN, these data provide for the first time important insight on the correlation of peripheral blood leukocytosis with the intratumoral immune contexture and could be relevant for future patient stratification using immunotherapies in ASCC.

  1. A phase I study of Onyx-015, an E1B attenuated adenovirus, administered intratumorally to patients with recurrent head and neck cancer.

    Science.gov (United States)

    Ganly, I; Kirn, D; Eckhardt, G; Rodriguez, G I; Soutar, D S; Otto, R; Robertson, A G; Park, O; Gulley, M L; Heise, C; Von Hoff, D D; Kaye, S B; Eckhardt, S G

    2000-03-01

    An E1B 55 kDa gene-deleted adenovirus, Onyx-015, which reportedly selectively replicates in and lyses p53-deficient cells, was administered by a single intratumoral injection to a total of 22 patients with recurrent head and neck cancer. The objectives of this Phase I study were to determine the safety, feasibility, and efficacy of this therapy and determine any correlation to p53 status. Six cohorts were investigated with a dose escalation from 10(7)-10(11) plaque-forming units. Toxicity was assessed using NCIC criteria. Tumor response was assessed by clinical and radiological measurement. Blood samples were taken to detect adenovirus DNA and neutralizing antibody to adenovirus. Tumor biopsies were taken to detect adenovirus by in situ hybridization. Treatment was well tolerated, with the main toxicity being grade 1/2 flu-like symptoms. Dose-limiting toxicity was not reached at the highest dose of 10(11) plaque-forming units. Twenty-one of the 22 patients treated showed an increase in neutralizing antibody to adenovirus. In situ hybridization showed viral replication in 4 of 22 patients treated, all of whom had mutant p53 tumors. Using conventional response criteria, no objective responses were observed. However, magnetic resonance imaging scans were suggestive of tumor necrosis at the site of viral injection in five patients, three of whom were classified using nonconventional criteria as partial responders, and two of whom were classified using nonconventional criteria as minor responders. Of these five cases, four had mutant p53 tumors. The response duration for the three partial responders was 4, 8, and 12 weeks. An additional eight patients had stable disease in the injected tumors lasting from 4-8 weeks. These preliminary results show that intratumoral administration of Onyx-015 is feasible, well tolerated, and associated with biological activity. Further investigation of Onyx-015, particularly with a more frequent injection protocol and in combination with

  2. Expression of inhibitory receptors on intratumoral T cells modulates the activity of a T cell-bispecific antibody targeting folate receptor

    Science.gov (United States)

    Schreiner, Jens; Thommen, Daniela S.; Herzig, Petra; Bacac, Marina; Klein, Christian; Roller, Andreas; Belousov, Anton; Levitsky, Victor; Savic, Spasenija; Moersig, Wolfgang; Uhlenbrock, Franziska; Heinzelmann-Schwarz, Viola A.; Umana, Pablo; Pisa, Pavel; von Bergwelt-Baildon, M.; Lardinois, Didier; Müller, Philipp; Karanikas, Vaios; Zippelius, Alfred

    2016-01-01

    ABSTRACT T-cell bispecific antibodies (TCBs) are a novel therapeutic tool designed to selectively recruit T-cells to tumor cells and simultaneously activate them. However, it is currently unknown whether the dysfunctional state of T-cells, embedded into the tumor microenvironment, imprints on the therapeutic activity of TCBs. We performed a comprehensive analysis of activation and effector functions of tumor-infiltrating T-cells (TILs) in different tumor types, upon stimulation by a TCB targeting folate receptor 1 and CD3 (FolR1-TCB). We observed a considerable heterogeneity in T-cell activation, cytokine production and tumor cell killing upon exposure to FolR1-TCB among different FolR1-expressing tumors. Of note, tumors presenting with a high frequency of PD-1hi TILs displayed significantly impaired tumor cell killing and T-cell function. Further characterization of additional T-cell inhibitory receptors revealed that PD-1hi TILs defined a T-cell subset with particularly high levels of multiple inhibitory receptors compared with PD-1int and PD-1neg T-cells. PD-1 blockade could restore cytokine secretion but not cytotoxicity of TILs in a subset of patients with scarce PD-1hi expressing cells; in contrast, patients with abundance of PD-1hi expressing T-cells did not benefit from PD-1 blockade. Our data highlight that FolR1-TCB is a promising novel immunotherapeutic treatment option which is capable of activating intratumoral T-cells in different carcinomas. However, its therapeutic efficacy may be substantially hampered by a pre-existing dysfunctional state of T-cells, reflected by abundance of intratumoral PD-1hi T-cells. These findings present a rationale for combinatorial approaches of TCBs with other therapeutic strategies targeting T-cell dysfunction. PMID:27057429

  3. Nuclear Regulatory Legislation

    International Nuclear Information System (INIS)

    1989-08-01

    This compilation of statutes and material pertaining to nuclear regulatory legislation through the 100th Congress, 2nd Session, has been prepared by the Office of the General Counsel, US Nuclear Regulatory Commission, with the assistance of staff, for use as an internal resource document. Persons using this document are placed on notice that it may not be used as an authoritative citation in lieu of the primary legislative sources. Furthermore, while every effort has been made to ensure the completeness and accuracy of this material, neither the United States Government, the Nuclear Regulatory Commission, nor any of their employees makes any expressed or implied warranty or assumes liability for the accuracy or completeness of the material presented in this compilation

  4. Regulatory and licensee surveys

    International Nuclear Information System (INIS)

    2009-01-01

    Prior to the workshop two CSNI/WGHOF surveys were distributed. One survey was directed at regulatory bodies and the other was directed at plant licensees. The surveys were: 1 - Regulatory Expectations of Licensees' Arrangements to Ensure Suitable Organisational Structure, Resources and Competencies to Manage Safety (sent to WGHOF regulatory members). The survey requested that the respondents provide a brief overview of the situation related to plant organisations in their country, their regulatory expectations and their formal requirements. The survey addressed three subjects: the demonstration and documentation of organisational structures, resources and competencies, organisational changes, issues for improvement (for both current and new plants). Responses were received from eleven regulatory bodies. 2 - Approaches to Justify Organisational Suitability (sent to selected licensees). The purpose of the survey to was to gain an understanding of how licensees ensure organisational suitability, resources and competencies. This information was used to assist in the development of the issues and subjects that were addressed at the group discussion sessions. Responses were received from over fifteen licensees from nine countries. The survey requested that the licensees provide information on how they ensure effective organisational structures at their plants. The survey grouped the questions into the following four categories: organisational safety functions, resource and competence, decision-making and communication, good examples and improvement needs. The findings from these surveys were used in conjunction with other factors to identify the key issues for the workshop discussion sessions. The responses from these two surveys are discussed briefly in Sections 4 and 5 of this report. More extensive reviews of the regulatory and licensee responses are provided in Appendix 1

  5. Balanced Integrated Regulatory Oversight

    International Nuclear Information System (INIS)

    Borchardt, R.W.

    2010-01-01

    Reactor safety, protecting the public health and safety, and protecting the environment must always be the nuclear regulator's top priorities. Enabling the use of nuclear power for the benefit of society, while protecting the public and the environment requires the regulator to balance many factors. In addition, the regulator is only one part of the overall government that must consider many factors as it carries out its societal responsibilities. Some of the factors that must be balanced and the practical impacts on how the regulator carries out its responsibilities will be addressed. The first International Conference on Effective Regulatory Systems, held in Moscow, Russian Federation, in 2006, focused on safety and security challenges with a goal of improving regulatory effectiveness through cooperation and sharing of information and best practices. The challenge of meeting both safety and security objectives is one example of potentially competing programmes that must be balanced. Other balances that must be evaluated include the benefits of safety improvements compared to the cost of implementation, the use of deterministic and probabilistic approaches, communication openness balanced with the protection of information that could be used for detrimental purposes, and timeliness of regulatory decision making balanced with the need to perform quality work in support of oversight responsibilities. A balanced and integrated approach to regulatory oversight is vital to ensuring that the regulatory body remains effective in its mission to enable the use of nuclear power while protecting the public and the environment. This concept is applicable to nations beginning a nuclear programme as well as established and experienced regulatory bodies. (author)

  6. Regulatory stability and credibility

    International Nuclear Information System (INIS)

    Lee, B. Jr.

    1988-01-01

    The author discusses programs within the nuclear industry dedicated to enhancing the utilities' role in achieving operational excellence. The activities of the Nuclear Management and Resources Council (NUMARC), INPO, and EPRI are described. NRC regulations are addressed. The author identifies and focuses on the importance of a stable and credible regulatory process for the achievement of operational excellence

  7. NRC Regulatory Agenda

    International Nuclear Information System (INIS)

    1989-07-01

    This document is a compilation of all rules on which the NRC has proposed or is considering action and all petitions for rulemaking which have been received by the Commission and are pending disposition by the Commission. The Regulatory Agenda is updated and issued each quarter

  8. Developing regulatory approaches

    International Nuclear Information System (INIS)

    Axelsson, Lars

    2012-01-01

    Lars Axelsson presented SSM progress on oversight of LMfS/SC since the Chester 1 Workshop in 2007. Current SSM approaches for safety culture oversight include targeted safety management and safety culture inspections, compliance inspections which cover aspects of safety management/safety culture and multi-disciplinary team inspections. Examples of themes for targeted inspections include management of ambiguous operational situations or other weak signals, understanding of and attitudes to Human Performance tools, the Safety Department's role and authority and Leadership for safety. All regulatory activities provide inputs for the SSM yearly safety evaluation of each licensee. A form has been developed to capture safety culture observations from inspections and other interactions with licensees. Analysis will be performed to identify patterns and provide information to support planning of specific Safety Culture activities. Training has been developed for regulatory staff to enhance the quality of regulatory interventions on safety culture. This includes a half-day seminar to provide an overview of safety culture, and a workshop which provides more in-depth discussion on cultural issues and how to capture those during regulatory activities. Future plans include guidance for inspectors, and informal seminars on safety culture with licensees

  9. Comments on regulatory reform

    International Nuclear Information System (INIS)

    Hendrie, J.M.

    1982-01-01

    Nuclear regulatory reform is divided into two parts. The first part contains all those matters for which new legislation is required. The second part concerns all those matters that are within the power of the Commission under existing statutes. Recommendations are presented

  10. OAR Regulatory Reform

    Science.gov (United States)

    The U.S. EPA's Office of Air and Radiation is hosting a public teleconference to solicit input on specific air and radiation actions that should be considered for “repeal, replacement, or modification” to reduce regulatory burden consistent with EO 13777.

  11. NRC regulatory agenda

    International Nuclear Information System (INIS)

    1993-02-01

    This document is a compilation of all rules on which the NRC has recently completed action, or has proposed action, or is considered action, and all petitions for rulemaking which have been received by the Commission and are pending disposition by the Commission. The Regulatory Agenda is updated and issued each quarter

  12. NRC Regulatory Agenda

    International Nuclear Information System (INIS)

    1992-07-01

    This document compilation of all rules on which the NRC has recently completed action, or has proposed action, or is considering action, and all petitions for rule making which have been received by the Commission and are pending disposition by the Commission. The Regulatory Agenda is updated and issued each quarter

  13. Prediction of regulatory elements

    DEFF Research Database (Denmark)

    Sandelin, Albin

    2008-01-01

    Finding the regulatory mechanisms responsible for gene expression remains one of the most important challenges for biomedical research. A major focus in cellular biology is to find functional transcription factor binding sites (TFBS) responsible for the regulation of a downstream gene. As wet-lab...

  14. NRC regulatory agenda

    International Nuclear Information System (INIS)

    1992-11-01

    This document provides a compilation of all rules on which the NRC has recently completed action, or has proposed action, or is considering action, and all petitions for rulemaking which have been received by the Commission and are pending disposition by the Commission. The Regulatory Agenda is updated and issued each quarter

  15. Perioperative dynamic alterations in peripheral regulatory T and B cells in patients with hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Chen Tianxiang

    2012-01-01

    Full Text Available Abstract Background Intratumoral and circulating regulatory T cells (Tregs have been shown to be critical in the pathogenesis of hepatocellular carcinoma (HCC. However there is limited knowledge on the alterations of regulatory B cells (Bregs. We here investigated perioperative dynamic alterations of peripheral circulating Tregs and Bregs in HCC patients to reveal the relationship between regulatory lymphocytes and its clinical implications. Methods 36 patients with HCC, 6 with chronic hepatitis B infection and 10 healthy donors were enrolled for this study. Frequencies of peripheral Tregs and Bregs were measured by flow cytometry with antibodies against CD4, CD25, CD127, CD19 and IL-10 before, and after radical surgery. Then, clinical informatics of HCC patients was achieved through Digital Evaluation Score System (DESS for the assessment of disease severity. Finally, we analysed correlations between digitalized clinical features and kinetics of circulating regulatory lymphocytes. Results Level of circulating CD4+CD25+CD127- Tregs in HCC patients was significantly lower than that in healthy donors and patients with chronic hepatitis B infection before surgery, but was increased after surgery. Preoperative level of CD19+ IL-10+ Bregs in HCC patients was also significantly lower than the other groups. However it dramatically was elevated right after surgery and remained elevated compared to controls (about 7 days after surgery, P = 0.04. Frequency of circulating Tregs was correlated with circulating leukocytes, ferritin, and clinical features suggesting tumor aggressiveness including portal vein thrombosis, hepatic vein involvement and advanced clinical stages. Frequency of circulating Bregs was associated with Hepatitis B e Antigen (HBeAg and Hepatitis B virus (HBV DNA copy number. In addition, DESS was significantly and positively correlated with other staging systems. Conclusion Frequencies of peripheral Tregs and Bregs in HCC patients

  16. Functional footprinting of regulatory DNA.

    Science.gov (United States)

    Vierstra, Jeff; Reik, Andreas; Chang, Kai-Hsin; Stehling-Sun, Sandra; Zhou, Yuanyue; Hinkley, Sarah J; Paschon, David E; Zhang, Lei; Psatha, Nikoletta; Bendana, Yuri R; O'Neil, Colleen M; Song, Alexander H; Mich, Andrea K; Liu, Pei-Qi; Lee, Gary; Bauer, Daniel E; Holmes, Michael C; Orkin, Stuart H; Papayannopoulou, Thalia; Stamatoyannopoulos, George; Rebar, Edward J; Gregory, Philip D; Urnov, Fyodor D; Stamatoyannopoulos, John A

    2015-10-01

    Regulatory regions harbor multiple transcription factor (TF) recognition sites; however, the contribution of individual sites to regulatory function remains challenging to define. We describe an approach that exploits the error-prone nature of genome editing-induced double-strand break repair to map functional elements within regulatory DNA at nucleotide resolution. We demonstrate the approach on a human erythroid enhancer, revealing single TF recognition sites that gate the majority of downstream regulatory function.

  17. Consistent Regulatory Policy under Uncertainty

    OpenAIRE

    Michael J. Brennan; Eduardo S. Schwartz

    1982-01-01

    This article is concerned with the effects of regulation on the risk and value of the regulated firm in a dynamic context. Current regulatory practice is shown to be logically deficient, since it ignores the effect of regulatory policy on the cost of capital and therefore on the appropriate allowed rate of return. A notion of consistency in regulatory policy is developed, and it is shown how consistent regulatory policies may be implemented once the valuation problem is solved.

  18. Nuclear Regulatory Commission information digest

    Energy Technology Data Exchange (ETDEWEB)

    None,

    1990-03-01

    The Nuclear Regulatory Commission information digest provides summary information regarding the US Nuclear Regulatory Commission, its regulatory responsibilities, and areas licensed by the commission. This is an annual publication for the general use of the NRC Staff and is available to the public. The digest is divided into two parts: the first presents an overview of the US Nuclear Regulatory Commission and the second provides data on NRC commercial nuclear reactor licensees and commercial nuclear power reactors worldwide.

  19. NRC regulatory agenda

    International Nuclear Information System (INIS)

    1993-07-01

    The NRC Regulatory Agenda is a compilation of all rules on which the NRC has recently completed action, or has proposed action, or is considering action, and all petitions for rulemaking which have been received by the Commission and are pending disposition by the Commission. The Regulatory Agenda is updated and issued each quarter. The rules on which final action has been taken since March 31, 1993 are: Repeal of NRC standards of conduct; Fitness-for-duty requirements for licensees who possess, use, or transport Category I material; Training and qualification of nuclear power plant personnel; Monitoring the effectiveness of maintenance at nuclear power plants; Licensing requirements for land disposal of radioactive wastes; and Licensees' announcements of safeguards inspections

  20. A flexible regulatory framework

    International Nuclear Information System (INIS)

    Silvennoinen, T.

    2000-01-01

    Regulatory reform of the Finnish electricity market meant opening up potentially competitive parts of the electricity sector to competition and eliminating all unnecessary forms of regulation covering generation, wholesale supply, retail supply, and foreign trade in electricity. New types of control and regulatory mechanisms and institutions were set up for those parts of the electricity industry that were excluded from competition, such as network operations. Network activities now have to be licensed, whereas no licence is needed for generation or supply. A new sector-specific regulatory authority was established in 1995 to coincide with the implementation of the Electricity Market Act, known as the Electricity Market Authority. This is responsible for regulating network activities and retail supply to captive customers. The core function of the authority, which employs some 14 people, is to promote the smooth operation of the Finnish electricity market and to oversee the implementation of the Electricity Market Act and its provisions. Its most important duties are linked to overseeing the process by which network companies price their electricity. As price regulation no longer exists, all the companies in the electricity sector set their tariffs independently, even network companies. The job of controlling the pricing of network services is handed by the Electricity Market Authority, following the principles of competition control. Pricing control takes place ex post - after a pricing system has been adopted by a company and concentrates on individual cases and companies. There is no ex ante system of setting or approving prices and tariffs by the regulator. The tariffs and pricing of network services can be evaluated, however, by both the Electricity Market Authority and the Finnish Competition Authority, which have overlapping powers as regards the pricing of network activities. The Finnish regulatory framework can be described as a system of light

  1. Essays in Regulatory Economics

    OpenAIRE

    Guerrero, Santiago

    2011-01-01

    This dissertation consists of three essays. The objective of the essays is to study the impacts of different regulations on the behavior of regulated agents. The first two essays focus on the analysis of non-traditional regulatory policies that complement traditional regulations consisting of inspections and fines for plants that violate regulations. The third essay studies the impacts of the Minimum Legal Drinking Age regulation on alcohol and marijuana consumption. The first essay of this d...

  2. Regulatory aspects of radiopharmaceuticals

    International Nuclear Information System (INIS)

    Kristensen, K.

    1985-01-01

    Regulatory systems in the field of radiopharmaceuticals have two main purposes: efficacy and safety. Efficacy expresses the quality of the diagnostic and therapeutic process for the patient. Safety involves the patient, the staff, and the environment. The world situation regarding regulations for radiopharmaceuticals is reviewed on the basis of a survey in WHO Member States. The main content of such regulations is discussed. The special properties of radiopharmaceuticals compared with ordinary drugs may call for modified regulations. Several countries are preparing such regulations. Close co-operation and good understanding among scientists working in hospital research, industry and regulatory bodies will be of great importance for the fast and safe introduction of new radiopharmaceuticals for the benefit of the patient. Before introducing new legislation in this field, a radiopharmaceutical expert should analyse the situation in the country and the relationship to the existing regulations. It is expected that the most important factor in promoting the fast introduction of new, safe and effective radiopharmaceuticals will be the training of people working within the regulatory bodies. It is foreseen that the IAEA and WHO will have an important role to play by providing expert advice and training in this area. (author)

  3. The changing regulatory environment

    International Nuclear Information System (INIS)

    Caron, G.

    1999-01-01

    The role and value of regulation in the energy sector was discussed, demonstrating how, despite common perception, regulation is an essential part of Canada's strategy to find and develop new opportunities. The future vision of regulation for industry participants was presented with particular focus on issues related to streamlining the regulatory process. As far as pipelines are concerned, regulatory actions are necessary to facilitate capacity increases and to ensure the line's integrity, safety and environmental record. Furthermore, regulation provides economic solutions where market forces cannot provide them, as for example where business has elements of monopoly. It arbitrates interests of landowners, business, consumers, and environmental groups. It looks for ways to ensure conditions under which competition can flourish. It acts as the guardian of citizens' rights in a democratic society by providing citizens with an opportunity to be heard on the building or expansion of pipelines and associated facilities. As citizens become more and more concerned about their property and the land that surrounds them, citizen involvement in decision making about how industry activity affects their quality of life will become correspondingly more important. Regulatory agencies are committed to facilitate this engagement by flexible hearing procedures and by making use of evolving communication and information technology

  4. Genomic profiling of malignant phyllodes tumors reveals aberrations in FGFR1 and PI-3 kinase/RAS signaling pathways and provides insights into intratumoral heterogeneity.

    Science.gov (United States)

    Liu, Su-Yang; Joseph, Nancy M; Ravindranathan, Ajay; Stohr, Bradley A; Greenland, Nancy Y; Vohra, Poonam; Hosfield, Elizabeth; Yeh, Iwei; Talevich, Eric; Onodera, Courtney; Van Ziffle, Jessica A; Grenert, James P; Bastian, Boris C; Chen, Yunn-Yi; Krings, Gregor

    2016-09-01

    Malignant phyllodes tumors of the breast are poorly understood rare neoplasms with potential for aggressive behavior. Few efficacious treatment options exist for progressed or metastatic disease. The molecular features of malignant phyllodes tumors are poorly defined, and a deeper understanding of the genetics of these tumors may shed light on pathogenesis and progression and potentially identify novel treatment approaches. We sequenced 510 cancer-related genes in 10 malignant phyllodes tumors, including 5 tumors with liposarcomatous differentiation and 1 with myxoid chondrosarcoma-like differentiation. Intratumoral heterogeneity was assessed by sequencing two separate areas in 7 tumors, including non-heterologous and heterologous components of tumors with heterologous differentiation. Activating hotspot mutations in FGFR1 were identified in 2 tumors. Additional recurrently mutated genes included TERT promoter (6/10), TP53 (4/10), PIK3CA (3/10), MED12 (3/10), SETD2 (2/10) and KMT2D (2/10). Together, genomic aberrations in FGFR/EGFR PI-3 kinase and RAS pathways were identified in 8 (80%) tumors and included mutually exclusive and potentially actionable activating FGFR1, PIK3CA and BRAF V600E mutations, inactivating TSC2 mutation, EGFR amplification and PTEN loss. Seven (70%) malignant phyllodes tumors harbored TERT aberrations (six promoter mutations, one amplification). For comparison, TERT promoter mutations were identified by Sanger sequencing in 33% borderline (n=12) and no (0%, n=8) benign phyllodes tumors (P=0.391 and P=0.013 vs malignant tumors, respectively). Genetic features specific to liposarcoma, including CDK4/MDM2 amplification, were not identified. Copy number analysis revealed intratumoral heterogeneity and evidence for divergent tumor evolution in malignant phyllodes tumors with and without heterologous differentiation. Tumors with liposarcomatous differentiation revealed more chromosomal aberrations in non-heterologous components compared with

  5. 75 FR 21955 - Semiannual Regulatory Agenda

    Science.gov (United States)

    2010-04-26

    ... Part XXI National Credit Union Administration ###Semiannual Regulatory Agenda### [[Page 21956... Regulatory Agenda AGENCY: National Credit Union Administration (NCUA). ACTION: Semiannual regulatory agenda... included in the Unified Agenda of Federal Regulatory and Deregulatory Actions. DATES: This information is...

  6. 78 FR 1698 - Semiannual Regulatory Flexibility Agenda

    Science.gov (United States)

    2013-01-08

    ...: Regulatory Capital, Implementation of Basel III, Minimum Regulatory Capital Ratios, Capital Adequacy, and...--Regulatory Capital Rules: Regulatory Capital, Implementation of Basel III, Minimum Regulatory Capital Ratios... Supervision (BCBS) in ``Basel III: A Global Regulatory Framework for More Resilient Banks and Banking Systems...

  7. Combined treatment with ipilimumab and intratumoral interleukin-2 in pretreated patients with stage IV melanoma-safety and efficacy in a phase II study.

    Science.gov (United States)

    Weide, Benjamin; Martens, Alexander; Wistuba-Hamprecht, Kilian; Zelba, Henning; Maier, Ludwig; Lipp, Hans-Peter; Klumpp, Bernhard D; Soffel, Daniel; Eigentler, Thomas K; Garbe, Claus

    2017-04-01

    Treatment of advanced melanoma patients with ipilimumab results in improved survival. However, only about 20% of treated patients experience long-term benefit. Combining treatment of ipilimumab with other drugs may improve immune activation and potentially enhance clinical efficacy. The aims of the phase II clinical trial reported here were to investigate tolerability and efficacy of a combined immunotherapeutic strategy comprising standard systemic ipilimumab at 3 mg/kg four times at 3-week intervals and intratumorally injected IL-2 at 9 MIU daily twice weekly for four weeks in pretreated melanoma patients with distant metastasis. The primary endpoint was the disease control rate according to immune-related response criteria at week 12; tolerability according to Common Terminology Criteria for Adverse Events criteria was secondary endpoint. No objective responses were observed in the 15 enrolled patients. Three patients had stable disease 12 weeks after starting treatment, yielding a disease control rate of 20%. Tolerability of this combination treatment was acceptable. Observed adverse events were those expected from the respective monotherapies. Autoimmune colitis was observed in two patients. Grade III/IV adverse events were observed in 40% of patients, and no treatment-related deaths occurred. Thus, this combined immunotherapy is associated with adverse events similar to those associated with the respective monotherapies. However, this study does not provide any evidence of improved efficacy of the combination over ipilimumab alone.

  8. Synthesis of Poly[APMA]-DOTA-64Cu Conjugates for Interventional Radionuclide Therapy of Prostate Cancer: Assessment of Intratumoral Retention by Micro–Positron Emission Tomography

    Directory of Open Access Journals (Sweden)

    Jianchao Yuan

    2007-01-01

    Full Text Available To develop new radiopharmaceuticals for interventional radionuclide therapy of locally recurrent prostate cancer, poly[N-(3-aminopropylmethacrylamide] [poly(APMA] polymers were synthesized by free radical precipitation polymerization in acetonedimethylsulfoxide using N,N‘-azobis(isobutyronitrile as the initiator. The polymers were characterized with nuclear magnetic resonance, size exclusion chromatography, and dynamic light scattering (Mn 5 2.40 × 104, Mw/Mn = 1.87. Subsequently, poly[APMA] was coupled with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA using 1-(3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride as an activator, followed by conjugation with 64Cu radionuclide. Prolonged retention of poly[APMA]-DOTA-64Cu conjugates within the tumor tissues was demonstrated by micro–positron emission tomography at 24 hours following intra-tumoral injection of the conjugates to human prostate xenografts in mice. The data suggest that the poly[APMA]-DOTA-64Cu conjugates might be useful for interventional radionuclide therapy of locally recurrent prostate cancer in humans.

  9. Volume of high-risk intratumoral subregions at multi-parametric MR imaging predicts overall survival and complements molecular analysis of glioblastoma.

    Science.gov (United States)

    Cui, Yi; Ren, Shangjie; Tha, Khin Khin; Wu, Jia; Shirato, Hiroki; Li, Ruijiang

    2017-09-01

    To develop and validate a volume-based, quantitative imaging marker by integrating multi-parametric MR images for predicting glioblastoma survival, and to investigate its relationship and synergy with molecular characteristics. We retrospectively analysed 108 patients with primary glioblastoma. The discovery cohort consisted of 62 patients from the cancer genome atlas (TCGA). Another 46 patients comprising 30 from TCGA and 16 internally were used for independent validation. Based on integrated analyses of T1-weighted contrast-enhanced (T1-c) and diffusion-weighted MR images, we identified an intratumoral subregion with both high T1-c and low ADC, and accordingly defined a high-risk volume (HRV). We evaluated its prognostic value and biological significance with genomic data. On both discovery and validation cohorts, HRV predicted overall survival (OS) (concordance index: 0.642 and 0.653, P parametric MRI predicts glioblastoma survival, and may provide complementary value to genomic information. • High-risk volume (HRV) defined on multi-parametric MRI predicted GBM survival. • The proneural molecular subtype tended to harbour smaller HRV than other subtypes. • Patients with unmethylated MGMT and high HRV had significantly shorter survival. • HRV complements genomic information in predicting GBM survival.

  10. Immunological, anti-angiogenic and clinical effects of intratumoral interleukin 12 electrogene therapy combined with metronomic cyclophosphamide in dogs with spontaneous cancer: A pilot study.

    Science.gov (United States)

    Cicchelero, Laetitia; Denies, Sofie; Vanderperren, Katrien; Stock, Emmelie; Van Brantegem, Leen; de Rooster, Hilde; Sanders, Niek N

    2017-08-01

    The immunological, anti-angiogenic and clinical effects of metronomic cyclophosphamide and 3 consecutive intratumoral interleukin (IL)-12 gene therapy (electrogene therapy (EGT)) treatments were evaluated in 6 dogs with spontaneous cancer. In all dogs, a decrease in peripheral leukocytes 2 days after IL-12 EGT coincided with erythema and swelling of the tumor. In the tumor, a transient increase in IL-12 levels was measured, whereas a continuous increase in interferon γ (IFNγ) and thrombospondin 1 (TSP-1) were determined in contrast to a continuous decrease in vascular endothelial growth factor (VEGF). In the serum, a transient increase in IL-12 and IL-10 levels were noted in contrast to a transient decrease in VEGF and TSP-1. The treatment resulted in a significant anti-angiogenic effect. Although all primary tumors continued to progress in time, this progression was slower than before treatment according to the contrast-enhanced ultrasound data. Besides the encouraging immunostimulatory and anti-angiogenic effects observed in all dogs we also noticed in 4 out of 6 dogs clinically relevant improvements in quality of life and weight. These results hold great promise for combinatorial strategies of IL-12 EGT and metronomic chemotherapy with conventional antitumor (immuno)therapies. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  11. Expression of Intratumoral IGF-II Is Regulated by the Gene Imprinting Status in Triple Negative Breast Cancer from Vietnamese Patients

    Directory of Open Access Journals (Sweden)

    Vinodh Kumar Radhakrishnan

    2015-01-01

    Full Text Available African American women suffer higher incidence and mortality of triple negative breast cancer (TNBC than Caucasian women. TNBC is very aggressive, causing the worst clinical outcome. We previously demonstrated that tumors from these patients express high IGF-II and exhibit high activation of the IGF signaling pathways. IGF-II gene expression is imprinted (monoallelic, promotes tumor progression, and metastasis and regulates Survivin, a TNBC prognostic marker. Since BC mortality has increased among young Vietnamese women, we analyzed 48 (paired TNBC samples from Vietnamese patients to assess IGF-II expression. We analyzed all samples by qrtPCR for identification of IGF-II heterozygosity and to determine allelic expression of the IGF-II gene. We also analyzed the tissues for proIGF-II and Survivin by RT-PCR and Western blotting. A total of 28 samples displayed IGF-II heterozygosity of which 78% were biallelic. Tumors with biallelic IGF-II gene expression exhibited the highest levels of proIGF-II and Survivin. Although 100% of these tissues corresponding normal samples were biallelic, they expressed significantly lower levels of or no proIGF-II and Survivin. Thus, IGF-II biallelic gene expression is differentially regulated in normal versus tumor tissues. We propose that intratumoral proIGF-II is dependent on the IGF-II gene imprinting status and it will promote a more aggressive TNBC.

  12. Politically Induced Regulatory Risk and Independent Regulatory Agencies

    OpenAIRE

    Strausz, Roland

    2015-01-01

    Uncertainty in election outcomes generates politically induced regulatory risk. Political parties' risk attitudes towards such risk depend on a fluctuation effect that hurts both parties and an output--expansion effect that benefits at least one party. Notwithstanding the parties' risk attitudes, political parties have incentives to negotiate away all regulatory risk by pre-electoral bargaining. Efficient pre-electoral bargaining outcomes fully eliminate politically induced regulatory risk. P...

  13. Assessment of regulatory effectiveness. Peer discussions on regulatory practices

    International Nuclear Information System (INIS)

    1999-09-01

    This report arises from the seventh series of peer discussions on regulatory practices entitled 'Assessment of Regulatory Effectiveness'. The term 'regulatory effectiveness' covers the quality of the work and level of performance of a regulatory body. In this sense, regulatory effectiveness applies to regulatory body activities aimed at preventing safety degradation and ensuring that an acceptable level of safety is being maintained by the regulated operating organizations. In addition, regulatory effectiveness encompasses the promotion of safety improvements, the timely and cost effective performance of regulatory functions in a manner which ensures the confidence of the operating organizations, the general public and the government, and striving for continuous improvements to performance. Senior regulators from 22 Member States participated in two peer group discussions during March and May 1999. The discussions were focused on the elements of an effective regulatory body, possible indicators of regulatory effectiveness and its assessment. This report presents the outcome of these meetings and recommendations of good practices identified by senior regulators, which do not necessarily reflect those of the governments of the nominating Member States, the organizations they belong to, or the International Atomic Energy Agency. In order to protect people and the environment from hazards associated with nuclear facilities, the main objective of a nuclear regulatory body is to ensure that a high level of safety in the nuclear activities under its jurisdiction is achieved, maintained and within the control of operating organizations. Even if it is possible to directly judge objective safety levels at nuclear facilities, such safety levels would not provide an exclusive indicator of regulatory effectiveness. The way the regulatory body ensures the safety of workers and the public and the way it discharges its responsibilities also determine its effectiveness. Hence the

  14. Visions of regulatory renewal

    International Nuclear Information System (INIS)

    Edgeworth, A.

    1998-01-01

    The economic contribution of the CEPA (Canadian Energy Pipeline Association) member companies to Canada's trade balance was discussed. CEPA member companies transport 95 per cent of the crude oil and natural gas produced in Canada to domestic and export markets. This represents a total of 5.6 Tcf of gas annually. Half of Canada's natural gas and oil production is exported to U.S. markets. All of these exports are transported by pipeline. CEPA member companies operate 90,000 km of pipeline from British Columbia to Quebec. Expansions are needed as a result of a significant increase in demand for natural gas and crude oil since 1990. Several issues exist for regulatory renewal. They include the need to create a level playing field, the overseeing of tolls and contract renewal terms, changing risk/reward trade-offs, the right to confidentiality of information and price discovery mechanism. The drivers for regulatory reform at Westcoast Energy are the need for pricing flexibility, customers desire for toll certainty, decontracting and opposition to rolled-in expansions for gathering and processing. An overview of Westcoast Energy's negotiated toll settlement, its implications, and the components of Westcoast Energy's 'light handed regulation' (LHR) was presented

  15. The regulatory dynamic

    International Nuclear Information System (INIS)

    Dybwad, C.

    2001-01-01

    An outline of the activities and efforts expanded by the National Energy Board to adjust to the changing natural gas market was provided in this presentation. The author began by defining the role of the National Energy Board in energy markets. It must ensure the adoption of rules and procedures that result in a more competitive and efficient market. Light-handed regulatory techniques are the norm, and the National Energy Board is now committed to facilitating the availability and flow of information so that all parties know where opportunities exist, the terms offered to buy or sell goods and services, their quality and costs. It will specialize in providing new participants with information on the workings of the market, who the players are, the regulatory processes in place, and how, when and where the market can be accessed. The manner in which the Board deals with information was reviewed, providing examples along the way to clarify some points. Some of the documents produced by the National Energy Board are being reviewed with the intent of making them easier to read and understand. Audio streaming over the Internet is another avenue being pursued to ensure individuals can listen in real time to hearings without having to be present in the room. The National Energy Board is also exploring alternative dispute resolution techniques. Consultation with energy market participants represents another facet of these efforts to be more accessible and responsive

  16. National legislative and regulatory activities

    International Nuclear Information System (INIS)

    2012-01-01

    This section gathers the following national legislative and regulatory activities sorted by country: Bulgaria: General legislation; Czech Republic: General legislation; France: General legislation, Regulatory infrastructure and activity; Germany: General legislation; India: Liability and compensation, Organisation and structure; Ireland: Radiation protection, General legislation; Korea (Republic of): Organisation and structure; Lithuania: Regulatory infrastructure and activity, Radioactive waste management, Radiation protection, international cooperation, Nuclear safety; Poland: General legislation; Romania: Environmental protection; Russian Federation: Radioactive waste management; Slovenia: Nuclear safety; Spain: Liability and compensation, Nuclear security; Sweden: Nuclear safety; Turkey: Radiation protection, Regulatory infrastructure and activity, Nuclear safety, Liability and compensation; United States: General legislation

  17. Nuclear Regulatory Commission Issuances

    International Nuclear Information System (INIS)

    1992-01-01

    This is the thirty-sixth volume of issuances (1-396) of the Nuclear Regulatory Commission and its Atomic Safety and Licensing Boards, Administrative Law Judges, and Office Directors. It covers the period from July 1, 1992-December 31, 1992. Atomic Safety and Licensing Boards are authorized by Section 191 of the Atomic Energy Act of 1954. These Boards, comprised of three members conduct adjudicatory hearings on applications to construct and operate nuclear power plants and related facilities and issue initial decisions which, subject to internal review and appellate procedures, become the final Commission action with respect to those applications. Boards are drawn from the Atomic Safety and Licensing Board Panel, comprised of lawyers, nuclear physicists and engineers, environmentalists, chemists, and economists. The Atomic Energy Commission first established Licensing Boards in 1962 and the Panel in 1967

  18. Regulatory mark; Marco regulatorio

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2009-10-15

    This chapter is based on a work performed in distinct phases. The first phase consisted in of the analysis regulatory legislation existent in Brazil for the sugar-alcohol sector since the beginning of the X X century. This analysis allowed the identification of non existent points and legal devices related to the studied aspects, and that were considered as problematic for the sector expansion. In the second phase, related treaties and international agreements was studied and possible obstacles for the brazilian bio ethanol exportation for the international market. Initiatives were examined at European Union, United States of America, Caribbean and countries of the sub-Saharan Africa. In this phase, policies were identified related to the incentives and adoption of use of bio fuels added to the gasoline in countries or group of countries considered as key for the consolidation of bio ethanol as a world commodity.

  19. Regulatory actions post - Fukushima

    International Nuclear Information System (INIS)

    Ciurea Ercau, C.

    2013-01-01

    The paper presents the results of the safety reviews performed in Romania after the Fukushima accident and the resulting actions for improving the safety. The actions taken by the National Commission for Nuclear Activities Control (CNCAN) to improve the regulatory framework include the development of new regulations and the enhancement of inspection practices, taking account of the lessons learned from the Fukushima accident. A regulation on the response to transients, accidents and emergency situations at nuclear power plants has been developed, which includes requirements on transient and accident scenarios that have to be covered by the Emergency Operating Procedures (EOPs), accident scenarios to be covered by the Severe Accident Management Guidelines (SAMGs), emergency situations to be covered by the on-site emergency response plan and emergency response procedures. (authors)

  20. Regulatory considerations for biosimilars

    Directory of Open Access Journals (Sweden)

    Ranjani Nellore

    2010-01-01

    Full Text Available Currently there is considerable interest in the legislative debate around generic biological drugs or "biosimilars" in the EU and US due to the large, lucrative market that it offers to the industry. While some countries have issued a few regulatory guidelines as well as product specific requirements, there is no general consensus as to a single, simple mechanism similar to the bioequivalence determination that leads to approval of generic small molecules all over the world. The inherent complex nature of the molecules, along with complicated manufacturing and analytical techniques to characterize them make it difficult to rely on a single human pharmacokinetic study for assurance of safety and efficacy. In general, the concept of comparability has been used for evaluation of the currently approved "similar" biological where a step by step assessment on the quality, preclinical and clinical aspects is made. In India, the focus is primarily on the availability and affordability of life-saving drugs. In this context every product needs to be evaluated on its own merit irrespective of the innovator brand. The formation of the National Biotechnology Regulatory Authority may provide a step in the right direction for regulation of these complex molecules. However, in order to have an efficient machinery for initial approval and ongoing oversight with a country-specific focus, cooperation with international authorities for granting approvals and continuous risk-benefit review is essential. Several steps are still needed for India to be perceived as a country that leads the world in providing quality biological products.

  1. Regulatory T Cells in Colorectal Cancer: From Biology to Prognostic Relevance

    Directory of Open Access Journals (Sweden)

    Dimitrios Mougiakakos

    2011-03-01

    Full Text Available Regulatory T cells (Tregs were initially described as "suppressive" lymphocytes in the 1980s. However, it took almost 20 years until the concept of Treg-mediated immune control in its present form was finally established. Tregs are obligatory for self-tolerance and defects within their population lead to severe autoimmune disorders. On the other hand Tregs may promote tolerance for tumor antigens and even hamper efforts to overcome it. Intratumoral and systemic accumulation of Tregs has been observed in various types of cancer and is often linked to worse disease course and outcome. Increase of circulating Tregs, as well as their presence in mesenteric lymph nodes and tumor tissue of patients with colorectal cancer de facto suggests a strong involvement of Tregs in the antitumor control. This review will focus on the Treg biology in view of colorectal cancer, means of Treg accumulation and the controversies regarding their prognostic significance. In addition, a concise overview will be given on how Tregs and their function can be targeted in cancer patients in order to bolster an inherent immune response and/or increase the efficacy of immunotherapeutic approaches.

  2. Regulatory focus in groupt contexts

    NARCIS (Netherlands)

    Faddegon, Krispijn Johannes

    2009-01-01

    The thesis examines the influence of group processes on the regulatory focus of individual group members. It is demonstrated that the group situation can affect group members' regulatory focus both in a top-down fashion (via the identitiy of the group) and in a bottom-up fashion (emerging from the

  3. Regulatory Quality and Competition Policy

    OpenAIRE

    International Finance Corporation; Multilateral Investment Guarantee Agency; World Bank

    2010-01-01

    Regulatory reform and competition policy are two important and inter-related areas of regulatory policy and public administration. Both can play a key role in improving the quality of regulation, and creating healthy and competitive markets and an attractive investment climate. This in turn leads to greater economic growth, employment and incomes. Part one of this paper discusses definitio...

  4. Reconsidering Styles of Regulatory Enforcement

    DEFF Research Database (Denmark)

    May, Peter J.; Winter, Søren

    2000-01-01

    This study addresses enforcement styles of regulatory inspectors, based on an examination of the municipal enforcement of agro-environmental policies in Denmark. Our findings make three contributions to the regulatory literature. One contribution is to add empirical support for theorizing about...

  5. A methodology for comprehensive breast cancer Ki67 labeling index with intra-tumor heterogeneity appraisal based on hexagonal tiling of digital image analysis data.

    Science.gov (United States)

    Plancoulaine, Benoit; Laurinaviciene, Aida; Herlin, Paulette; Besusparis, Justinas; Meskauskas, Raimundas; Baltrusaityte, Indra; Iqbal, Yasir; Laurinavicius, Arvydas

    2015-10-19

    Digital image analysis (DIA) enables higher accuracy, reproducibility, and capacity to enumerate cell populations by immunohistochemistry; however, the most unique benefits may be obtained by evaluating the spatial distribution and intra-tissue variance of markers. The proliferative activity of breast cancer tissue, estimated by the Ki67 labeling index (Ki67 LI), is a prognostic and predictive biomarker requiring robust measurement methodologies. We performed DIA on whole-slide images (WSI) of 302 surgically removed Ki67-stained breast cancer specimens; the tumour classifier algorithm was used to automatically detect tumour tissue but was not trained to distinguish between invasive and non-invasive carcinoma cells. The WSI DIA-generated data were subsampled by hexagonal tiling (HexT). Distribution and texture parameters were compared to conventional WSI DIA and pathology report data. Factor analysis of the data set, including total numbers of tumor cells, the Ki67 LI and Ki67 distribution, and texture indicators, extracted 4 factors, identified as entropy, proliferation, bimodality, and cellularity. The factor scores were further utilized in cluster analysis, outlining subcategories of heterogeneous tumors with predominant entropy, bimodality, or both at different levels of proliferative activity. The methodology also allowed the visualization of Ki67 LI heterogeneity in tumors and the automated detection and quantitative evaluation of Ki67 hotspots, based on the upper quintile of the HexT data, conceptualized as the "Pareto hotspot". We conclude that systematic subsampling of DIA-generated data into HexT enables comprehensive Ki67 LI analysis that reflects aspects of intra-tumor heterogeneity and may serve as a methodology to improve digital immunohistochemistry in general.

  6. Alteration of sensitivity of intratumor quiescent and total cells to γ-rays following thermal neutron irradiation with or without 10B-compound

    International Nuclear Information System (INIS)

    Masunaga, Shin-ichiro; Ono, Koji; Suzuki, Minoru; Sakurai, Yoshinori; Kobayashi, Tooru; Takagaki, Masao; Kinashi, Yuko; Akaboshi, Mitsuhiko

    2000-01-01

    Purpose: Changes in the sensitivity of intratumor quiescent (Q) and total cells to γ-rays following thermal neutron irradiation with or without 10 B-compound were examined. Methods and Materials: 5-Bromo-2'-deoxyuridine (BrdU) was injected to SCC VII tumor-bearing mice intraperitoneally 10 times to label all the proliferating (P) tumor cells. As priming irradiation, thermal neutrons alone or thermal neutrons with 10 B-labeled sodium borocaptate (BSH) or dl-p-boronophenylalanine (BPA) were administered. The tumor-bearing mice then received a series of γ-ray radiation doses, 0 through 24 h after the priming irradiation. During this period, no BrdU was administered. Immediately after the second irradiation, the tumors were excised, minced, and trypsinized. Following incubation of tumor cells with cytokinesis blocker, the micronucleus (MN) frequency in cells without BrdU labeling (= Q cells at the time of priming irradiation) was determined using immunofluorescence staining for BrdU. The MN frequency in the total (P + Q) tumor cells was determined from the tumors that were not pretreated with BrdU before the priming irradiation. To determine the BrdU-labeled cell ratios in the tumors at the time of the second irradiation, each group also included mice that were continuously administered BrdU until just before the second irradiation using mini-osmotic pumps which had been implanted subcutaneously 5 days before the priming irradiation. Results: In total cells, during the interval between the two irradiations, the tumor sensitivity to γ-rays relative to that immediately after priming irradiation decreased with the priming irradiation ranking in the following order: thermal neutrons only > thermal neutrons with BSH > thermal neutrons with BPA. In contrast, in Q cells, during that time the sensitivity increased in the following order: thermal neutrons only 10 B-compound, especially BPA, in thermal neutron irradiation causes the recruitment from the Q to P population

  7. Three-dimensional susceptibility-weighted imaging and two-dimensional T2*-weighted gradient-echo imaging of intratumoral hemorrhages in pediatric diffuse intrinsic pontine glioma

    International Nuclear Information System (INIS)

    Loebel, Ulrike; Sedlacik, Jan; Sabin, Noah D.; Hillenbrand, Claudia M.; Patay, Zoltan; Kocak, Mehmet; Broniscer, Alberto

    2010-01-01

    We compared the sensitivity and specificity of T2*-weighted gradient-echo imaging (T2*-GRE) and susceptibility-weighted imaging (SWI) in determining prevalence and cumulative incidence of intratumoral hemorrhages in children with diffuse intrinsic pontine glioma (DIPG) undergoing antiangiogenic and radiation therapy. Patients were recruited from an institutional review board-approved prospective phase I trial of vandetanib administered in combination with radiation therapy. Patient consent was obtained before enrollment. Consecutive T2*-GRE and SWI exams of 17 patients (F/M: 9/8; age 3-17 years) were evaluated. Two reviewers (R1 and R2) determined the number and size of hemorrhages at baseline and multiple follow-ups (92 scans, mean 5.4/patient). Statistical analyses were performed using descriptive statistics, graphical tools, and mixed-effects Poisson regression models. Prevalence of hemorrhages at diagnosis was 41% and 47%; the cumulative incidences of hemorrhages at 6 months by T2*-GRE and SWI were 82% and 88%, respectively. Hemorrhages were mostly petechial; 9.7% of lesions on T2*-GRE and 5.2% on SWI were hematomas (>5 mm). SWI identified significantly more hemorrhages than T2*-GRE did. Lesions were missed or misinterpreted in 36/39 (R1/R2) scans by T2*-GRE and 9/3 scans (R1/R2) by SWI. Hemorrhages had no clinically significant neurological correlates in patients. SWI is more sensitive than T2*-GRE in detecting hemorrhages and differentiating them from calcification, necrosis, and artifacts. Also, petechial hemorrhages are more common in DIPG at diagnosis than previously believed and their number increases during the course of treatment; hematomas are rare. (orig.)

  8. Virginia Power's regulatory reduction program

    International Nuclear Information System (INIS)

    Miller, G.D.

    1996-01-01

    Virginia Power has two nuclear plants, North Anna and Surry Power Stations, which have two units each for a total of four nuclear units. In 1992, the Nuclear Regulatory Commission solicited comments from the nuclear industry to obtain their ideas for reducing the regulatory burden on nuclear facilities. Pursuant to the new regulatory climate, Virginia Power developed an internal program to evaluate and assess the regulatory and self-imposed requirements to which they were committed, and to pursue regulatory relief or internal changes where possible and appropriate. The criteria were that public safety must be maintained, and savings must be significant. Up to the date of the conference, over US$22 million of one-time saving had been effected, and US$2.75 million in annual savings

  9. Anti-regulatory T cells

    DEFF Research Database (Denmark)

    Andersen, Mads Hald

    2017-01-01

    Our initial understanding of immune-regulatory cells was based on the discovery of suppressor cells that assure peripheral T-cell tolerance and promote immune homeostasis. Research has particularly focused on the importance of regulatory T cells (Tregs) for immune modulation, e.g. directing host...... responses to tumours or inhibiting autoimmunity development. However, recent studies report the discovery of self-reactive pro-inflammatory T cells—termed anti-regulatory T cells (anti-Tregs)—that target immune-suppressive cells. Thus, regulatory cells can now be defined as both cells that suppress immune...... reactions as well as effector cells that counteract the effects of suppressor cells and support immune reactions. Self-reactive anti-Tregs have been described that specifically recognize human leukocyte antigen-restricted epitopes derived from proteins that are normally expressed by regulatory immune cells...

  10. Regulatory Streamlining and Improvement

    Energy Technology Data Exchange (ETDEWEB)

    Mark A. Carl

    2006-07-11

    The Interstate Oil and Gas Compact Commission (IOGCC) engaged in numerous projects outlined under the scope of work discussed in the United States Department of Energy (DOE) grant number DE-FC26-04NT15456 awarded to the IOGCC. Numerous projects were completed that were extremely valuable to state oil and gas agencies as a result of work performed utilizing resources provided by the grant. There are numerous areas in which state agencies still need assistance. This additional assistance will need to be addressed under future scopes of work submitted annually to DOE's Project Officer for this grant. This report discusses the progress of the projects outlined under the grant scope of work for the 2005-2006 areas of interest, which are as follows: Area of Interest No. 1--Regulatory Streamlining and Improvement: This area of interest continues to support IOGCC's regulatory streamlining efforts that include the identification and elimination of unnecessary duplications of efforts between and among state and federal programs dealing with exploration and production on public lands. Area of Interest No. 2--Technology: This area of interest seeks to improve efficiency in states through the identification of technologies that can reduce costs. Area of Interest No. 3--Training and Education: This area of interest is vital to upgrading the skills of regulators and industry alike. Within the National Energy Policy, there are many appropriate training and education opportunities. Education was strongly endorsed by the President's National Energy Policy Development group. Acting through the governors offices, states are very effective conduits for the dissemination of energy education information. While the IOGCC favors the development of a comprehensive, long-term energy education plan, states are also supportive of immediate action on important concerns, such as energy prices, availability and conservation. Area of Interest No. 4--Resource Assessment and

  11. 76 FR 32878 - Draft Regulatory Guide: Issuance, Availability

    Science.gov (United States)

    2011-06-07

    ...; ] NUCLEAR REGULATORY COMMISSION 10 CFR Part 50 Draft Regulatory Guide: Issuance, Availability AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Draft Regulatory Guide, DG...

  12. Regulatory risk coherence

    International Nuclear Information System (INIS)

    Remick, F.J.

    1992-01-01

    As one of the most progressive users of risk assessment in decision making, the US Nuclear Regulatory Commission (NRC) is in a position to play an important role in influencing the development of standard government wide policies for the application of risk assessment in decision making. The NRC, with the support of the nuclear industry, should use the opportunity provided by its experience with risk assessment to actively encourage the adoption of standard national and international health-based safety goals and at the same time accelerate its own efforts to implement the safety goals it has already developed for itself. There are signs of increased recognition of the need for consistency and coherence in the application of risk assessment in government decision making. The NRC and the nuclear industry have recently taken a great step toward establishing a consistant and coherent risk assessment-based culture in the US nuclear industry. As a result of Generic Letter 88-20, which asks each commercial nuclear power plant licensee to perform an individual plant examination by September 1992, for the first time a risk assessment characterizing initiating events in each plant will exist

  13. Internationalization of regulatory requirements.

    Science.gov (United States)

    Juillet, Y

    2003-02-01

    The aim of harmonisation of medicines regulatory requirements is to allow the patient quicker access to new drugs and to avoid animal and human duplications. Harmonisation in the European Union (EU) is now completed, and has led to the submission of one dossier in one language study leading to European marketing authorizations, thanks in particular to efficacy guidelines published at the European level. With the benefit of the European experience since 1989, more than 40 guidelines have been harmonised amongst the EU, Japan and the USA through the International Conference on Harmonisation (ICH). ICH is a unique process gathering regulators and industry experts from the three regions. Its activity is built on expertise and trust. The Common Technical Document (CTD), an agreed common format for application in the three regions, is a logical follow-up to the ICH first phase harmonising the content of the dossier. The CTD final implementation in July 2003 will have considerable influence on the review process and on the exchange of information in the three regions.

  14. Strengthening Regulatory Competence in Pakistan

    International Nuclear Information System (INIS)

    Sadiq, M.

    2016-01-01

    Capacity building of Pakistan Nuclear Regulatory Authority is considered an essential element in pursuit of its vision to become a world class regulatory body. Since its inception in 2001, PNRA has continuously endeavoured to invest in its people, develop training infrastructure and impart sound knowledge and professional skills with the aim to improve its regulatory effectiveness. The use of nuclear and radioactive material in Pakistan has increased manifold in recent years, thus induction of more manpower was needed for regulatory oversight. PNRA adopted two pronged approach for meeting the manpower demand (a) employment of university graduates through fast track recruitment drive and (b) induction of graduates by offering fellowships for Master degree programs. Although, the newly employed staff was selected on the basis of their excellent academic qualifications in basic and applied sciences, but they required rigorous knowledge and skills in regulatory perspectives. In order to implement a structured training program, PNRA conducted Training Needs Assessment (TNA) and identified competency gaps of the regulatory staff in legal, technical, regulatory practice and behavioural domains. PNRA took several initiatives for capacity building which included establishment of a training centre for sustainability of trainings, initiation of a fellowship scheme for Master program, attachment of staff at local institutes for on-the-job training and placement at foreign regulatory bodies and organizations for technical development with the assistance of IAEA. The above strategies have been very beneficial in competence building of the PNRA staff to perform all regulatory activities indigenously for nuclear power plants, research reactors and radiation facilities. Provision of vibrant technical support to IAEA and Member States in various programs by PNRA is a landmark of these competence development efforts. This paper summarizes PNRA initiatives and the International Atomic

  15. The Danish Regulatory Reform of Telecommunications

    DEFF Research Database (Denmark)

    Skouby, Knud Erik

    1998-01-01

    An overview of the liberalisation process and regulatory reform of telecommunications in Denmark......An overview of the liberalisation process and regulatory reform of telecommunications in Denmark...

  16. International regulatory activities

    International Nuclear Information System (INIS)

    Anon.

    2004-01-01

    The 48. session of the IAEA general conference was held in Vienna from 20 to 24 september 2004 with the participation of delegates from 125 members states and representatives of various international organisations. A number of resolutions were adopted by the conference in the following fields: nuclear safety, radiation, transport and waste safety. The general conference also adopted a resolution on measures to protect against nuclear terrorism. The Director General decided in 2003 to appoint a group of experts to explore and advise on issues related to nuclear liability. This group called the International Expert Group on Nuclear Liability (I.N.L.E.X.) consists of 20 experts members from nuclear power and non nuclear power countries and from shipping and non shipping states. It serves three major functions: to create a forum of expertise to explore and advise on issues related to nuclear liability; to enhance global adherence by nuclear and non nuclear states to an effective nuclear liability regime, inter alia, on the basis of the convention on supplementary compensation for nuclear damage and the annex thereto, the Vienna convention on civil liability for nuclear damage, the Paris convention on third party liability in the field of nuclear energy, the joint protocol relating to the application of the vienna convention and the paris convention and the amendments thereto; and to assist in the development and strengthening of the national nuclear liability legal frameworks in IAEA members states to protect the public and the environment and to enhance nuclear safety. The second part of international regulatory concerns a directive on public access to environmental information made by the European Parliament. (N.C.)

  17. Regulatory Snapshots: integrative mining of regulatory modules from expression time series and regulatory networks.

    Directory of Open Access Journals (Sweden)

    Joana P Gonçalves

    Full Text Available Explaining regulatory mechanisms is crucial to understand complex cellular responses leading to system perturbations. Some strategies reverse engineer regulatory interactions from experimental data, while others identify functional regulatory units (modules under the assumption that biological systems yield a modular organization. Most modular studies focus on network structure and static properties, ignoring that gene regulation is largely driven by stimulus-response behavior. Expression time series are key to gain insight into dynamics, but have been insufficiently explored by current methods, which often (1 apply generic algorithms unsuited for expression analysis over time, due to inability to maintain the chronology of events or incorporate time dependency; (2 ignore local patterns, abundant in most interesting cases of transcriptional activity; (3 neglect physical binding or lack automatic association of regulators, focusing mainly on expression patterns; or (4 limit the discovery to a predefined number of modules. We propose Regulatory Snapshots, an integrative mining approach to identify regulatory modules over time by combining transcriptional control with response, while overcoming the above challenges. Temporal biclustering is first used to reveal transcriptional modules composed of genes showing coherent expression profiles over time. Personalized ranking is then applied to prioritize prominent regulators targeting the modules at each time point using a network of documented regulatory associations and the expression data. Custom graphics are finally depicted to expose the regulatory activity in a module at consecutive time points (snapshots. Regulatory Snapshots successfully unraveled modules underlying yeast response to heat shock and human epithelial-to-mesenchymal transition, based on regulations documented in the YEASTRACT and JASPAR databases, respectively, and available expression data. Regulatory players involved in

  18. Recent regulatory issues in Finland

    International Nuclear Information System (INIS)

    Laaksonen, J.; Tiipana, P.

    2001-01-01

    This paper presents general regulatory issues from Finland since the last WWER Regulators Forum meeting in Odessa 11-13 October 2000. More specific issues concerning Loviisa NPP are described in the Annex of this paper. (author)

  19. Quality assurance within regulatory bodies

    International Nuclear Information System (INIS)

    1999-06-01

    The IAEA directed extensive efforts during the years 1991 to 1995 to the integral revision of all NUSS quality assurance publications, which were approved and issued as Safety Series No.50-C/SG-Q, Quality Assurance for Safety in Nuclear Power Plants and other Nuclear Installations (1996). When these quality assurance publications were developed, their prime focus was on requirements against which work performed by the licensees could be measured and assessed by the regulatory bodies. In this way, they only helped to facilitate the functions of regulators. No requirements or recommendations were provided on how the regulators should ensure the effective implementation of their own activities. The present publication is a first attempt to collect, integrate and offer available experience to directly support performance of regulatory activities. It presents a comprehensive compilation on the application of quality assurance principles and methods by regulatory bodies to their activities. The aim is consistent good performance of regulatory activities through a systematic approach

  20. [Regulatory science researches of nanomedicines].

    Science.gov (United States)

    Sakai-Kato, Kumiko; Goda, Yukihiro

    2014-01-01

    Recently, the development of nanomedicines is progressing. These are designed to ensure high stability and to optimize the pharmacokinetics in vivo. The polymeric micelles and lipid nanoparticles are typical such examples. Because the unique size-specific interaction with biological systems or biodistribution may have significant impacts on the efficacy and safety of nanomedicines, regulatory science researches of nanomedicines are required. In this review, the authors introduce our initiatives of the regulatory science researches of nanomedicines.

  1. Regulatory facility guide for Ohio

    Energy Technology Data Exchange (ETDEWEB)

    Anderson, S.S.; Bock, R.E.; Francis, M.W.; Gove, R.M.; Johnson, P.E.; Kovac, F.M.; Mynatt, J.O. [Oak Ridge National Lab., TN (United States); Rymer, A.C. [Transportation Consulting Services, Knoxville, TN (United States)

    1994-02-28

    The Regulatory Facility Guide (RFG) has been developed for the DOE and contractor facilities located in the state of Ohio. It provides detailed compilations of international, federal, and state transportation-related regulations applicable to shipments originating at destined to Ohio facilities. This RFG was developed as an additional resource tool for use both by traffic managers who must ensure that transportation operations are in full compliance with all applicable regulatory requirements and by oversight personnel who must verify compliance activities.

  2. Sodium Iodide Symporter (NIS)-Mediated Radionuclide (131I, 188Re) Therapy of Liver Cancer After Transcriptionally Targeted Intratumoral in Vivo NIS Gene Delivery

    Science.gov (United States)

    Klutz, Kathrin; Willhauck, Michael J.; Wunderlich, Nathalie; Zach, Christian; Anton, Martina; Senekowitsch-Schmidtke, Reingard; Göke, Burkhard

    2011-01-01

    Abstract We reported the therapeutic efficacy of 131I in hepatocellular carcinoma (HCC) cells stably expressing the sodium iodide symporter (NIS) under the control of the tumor-specific α-fetoprotein (AFP) promoter. In the current study we investigated the efficacy of adenovirus-mediated in vivo NIS gene transfer followed by 131I and 188Re administration for the treatment of HCC xenografts. We used a replication-deficient adenovirus carrying the human NIS gene linked to the mouse AFP promoter (Ad5-AFP-NIS) for in vitro and in vivo NIS gene transfer. Functional NIS expression was confirmed by in vivo γ-camera imaging, followed by analysis of NIS protein and mRNA expression. Human HCC (HepG2) cells infected with Ad5-AFP-NIS concentrated 50% of the applied activity of 125I, which was sufficiently high for a therapeutic effect in an in vitro clonogenic assay. Four days after intratumoral injection of Ad5-AFP-NIS (3×109 plaque-forming units) HepG2 xenografts accumulated 14.5% injected dose (ID)/g 123I with an effective half-life of 13 hr (tumor-absorbed dose, 318 mGy/MBq 131I). In comparison, 9.2% ID/g 188Re was accumulated in tumors with an effective half-life of 12.8 hr (tumor-absorbed dose, 545 mGy/MBq). After adenovirus-mediated NIS gene transfer in HepG2 xenografts administration of a therapeutic dose of 131I or 188Re (55.5 MBq) resulted in a significant delay in tumor growth and improved survival without a significant difference between 188Re and 131I. In conclusion, a therapeutic effect of 131I and 188Re was demonstrated in HepG2 xenografts after tumor-specific adenovirus-mediated in vivo NIS gene transfer. PMID:21488714

  3. Relationship between intratumoral expression of genes coding for xenobiotic-metabolizing enzymes and benefit from adjuvant tamoxifen in estrogen receptor alpha-positive postmenopausal breast carcinoma

    International Nuclear Information System (INIS)

    Bièche, Ivan; Girault, Igor; Urbain, Estelle; Tozlu, Sengül; Lidereau, Rosette

    2004-01-01

    Little is known of the function and clinical significance of intratumoral dysregulation of xenobiotic-metabolizing enzyme expression in breast cancer. One molecular mechanism proposed to explain tamoxifen resistance is altered tamoxifen metabolism and bioavailability. To test this hypothesis, we used real-time quantitative RT-PCR to quantify the mRNA expression of a large panel of genes coding for the major xenobiotic-metabolizing enzymes (12 phase I enzymes, 12 phase II enzymes and three members of the ABC transporter family) in a small series of normal breast (and liver) tissues, and in estrogen receptor alpha (ERα)-negative and ERα-positive breast tumors. Relevant genes were further investigated in a well-defined cohort of 97 ERα-positive postmenopausal breast cancer patients treated with primary surgery followed by adjuvant tamoxifen alone. Seven of the 27 genes showed very weak or undetectable expression in both normal and tumoral breast tissues. Among the 20 remaining genes, seven genes (CYP2A6, CYP2B6, FMO5, NAT1, SULT2B1, GSTM3 and ABCC11) showed significantly higher mRNA levels in ERα-positive breast tumors than in normal breast tissue, or showed higher mRNA levels in ERα-positive breast tumors than in ERα-negative breast tumors. In the 97 ERα-positive breast tumor series, most alterations of these seven genes corresponded to upregulations as compared with normal breast tissue, with an incidence ranging from 25% (CYP2A6) to 79% (NAT1). Downregulation was rare. CYP2A6, CYP2B6, FMO5 and NAT1 emerged as new putative ERα-responsive genes in human breast cancer. Relapse-free survival was longer among patients with FMO5-overexpressing tumors or NAT1-overexpressing tumors (P = 0.0066 and P = 0.000052, respectively), but only NAT1 status retained prognostic significance in Cox multivariate regression analysis (P = 0.0013). Taken together, these data point to a role of genes coding for xenobiotic-metabolizing enzymes in breast tumorigenesis, NAT1 being an

  4. In depth evaluation of the prognostic and predictive utility of PTEN immunohistochemistry in colorectal carcinomas: performance of three antibodies with emphasis on intracellular and intratumoral heterogeneity.

    Science.gov (United States)

    Ágoston, Emese Irma; Micsik, Tamás; Ács, Balázs; Fekete, Krisztina; Hahn, Oszkár; Baranyai, Zsolt; Dede, Kristóf; Bodoky, György; Bursics, Attila; Kulka, Janina; Krenács, Tibor; Győrffy, Balázs; Harsányi, László; Szász, A Marcell

    2016-07-08

    Phosphatase and tensin homolog deleted in chromosome 10 (PTEN) loss of function is frequently detected in advanced colorectal cancer. Its detection is thought to have prognostic significance and it is being considered to predict responsiveness to anti-EGFR therapy. Unfortunately, while immunohistochemical assessment of PTEN expression is widespread, it lacks standardization and the results are hardly comparable across the available publications. Retrospectively collected, formalin-fixed and paraffin-embedded colorectal tumor tissue samples from 55 patients were combined into tissue microarray (TMA) blocks. We used three different PTEN antibodies to determine the frequency, intensity and intracellular pattern of PTEN immunohistochemical labeling: Neomarkers, Dako and CellSignaling. We evaluated the aforementioned parameters in selected regions of colorectal cancers and in their lymph node metastases by using three scoring methods that take into consideration both staining frequency and intensity (H1-H3-score). We also evaluated intracellular localization. The Dako and CellSignaling antibodies stained predominantly cytoplasms, while the Neomarkers antibody specifically stained cell nuclei. PTEN H-scores were significantly lower in all tumor areas as compared to the normal colonic mucosa based on staining with the DAKO and CellSignaling antibodies. Intratumoral regional differences or differences between matching tumors and metastases were not detected with any of the antibodies. Neither Dako, neither CellSignaling, nor the Neomarkers antibodies revealed a significant correlation between PTEN expression and pT, Dukes/MAC and clinical stage. KRAS status, histological grade correlated with PTEN H-scores based on staining with the Neomarkers antibody. PTEN H-scores did not correlate with MMR status. PTEN H-scores did not show any correlation with relapse-free survival based on staining with either antibody. While PTEN expression decreased in colorectal cancer according

  5. T2-weighted images are superior to other MR image types for the determination of diffuse intrinsic pontine glioma intratumoral heterogeneity.

    Science.gov (United States)

    Harward, Stephen; Harrison Farber, S; Malinzak, Michael; Becher, Oren; Thompson, Eric M

    2018-03-01

    Diffuse intrinsic pontine glioma (DIPG) remains the main cause of death in children with brain tumors. Given the inefficacy of numerous peripherally delivered agents to treat DIPG, convection enhanced delivery (CED) of therapeutic agents is a promising treatment modality. The purpose of this study was to determine which MR imaging type provides the best discrimination of intratumoral heterogeneity to guide future stereotactic implantation of CED catheters into the most cellular tumor regions. Patients ages 18 years or younger with a diagnosis of DIPG from 2000 to 2015 were included. Radiographic heterogeneity index (HI) of the tumor was calculated by measuring the standard deviation of signal intensity of the tumor (SD Tumor ) normalized to the genu of the corpus callosum (SD Corpus Callosum ). Four MR image types (T2-weighted, contrast-enhanced T1-weighted, FLAIR, and ADC) were analyzed at several time points both before and after radiotherapy and chemotherapy. HI values across these MR image types were compared and correlated with patient survival. MR images from 18 patients with DIPG were evaluated. The mean survival ± standard deviation was 13.8 ± 13.7 months. T2-weighted images had the highest HI (mean ± SD, 5.1 ± 2.5) followed by contrast-enhanced T1-weighted images (3.7 ± 1.5), FLAIR images (3.0 ± 1.1), and ADC maps (1.6 ± 0.4). ANOVA demonstrated that HI values were significantly higher for T2-weighted images than FLAIR (p values increased, while FLAIR and ADC HI values decreased. Univariate and multivariate analyses did not reveal a relationship between HI values and patient survival (p > 0.05). For children with DIPG, T2-weighted MRI demonstrates the greatest signal intensity variance suggesting tumor heterogeneity. Within this heterogeneity, T2-weighted signal hypointensity is known to correlate with increased cellularity and thus may represent a putative target for CED catheter placement in future clinical trials.

  6. Assessment of intratumor non-antibody directed iron oxide nanoparticle hyperthermia cancer therapy and antibody directed IONP uptake in murine and human cells

    Science.gov (United States)

    Hoopes, P. J.; Tate, J. A.; Ogden, J. A.; Strawbridge, R. R.; Fiering, S. N.; Petryk, A. A.; Cassim, S. M.; Giustini, A. J.; Demidenko, E.; Ivkov, R.; Barry, S.; Chinn, P.; Foreman, A.

    2009-02-01

    Hyperthermia, as an independent modality or in combination with standard cancer treatments such as chemotherapy and radiation, has been established in vitro and in vivo as an effective cancer treatment. However, despite efforts over the past 25 years, such therapies have never been optimized or widelyaccepted clinically. Although methods continue to improve, conventionally-delivered heat (RF, ultrasound, microwave etc) can not be delivered in a tumor selective manner. The development of antibody-targeted, or even nontargeted, biocompatible iron oxide nanoparticles (IONP) now allows delivery of cytotoxic heat to individual cancer cells. Using a murine mouse mammary adenocarcinoma (MTGB) and human colon carcinoma (HT29) cells, we studied the biology and treatment of IONP hyperthermia tumor treatment. Methods: Cancer cells (1 x 106) with or without iron oxide nanoparticles (IONP) were studied in culture or in vivo via implanted subcutaneously in female C3H mice, Tumors were grown to a treatment size of 150 mm3 and tumors volumes were measured using standard 3-D caliper measurement techniques. Mouse tumors were heated via delivery of an alternating magnetic field, which activated the nanoparticles, using a cooled 36 mm diameter square copper tube induction coil which provided optimal heating in 1.5 cm wide region of the coil. The IONPs were dextran coated and had a hydrodynamic radius of approximately 100 nm. For the in vivo studies, intra-tumor, peritumor and rectal (core body) temperatures were continually measured throughout the treatment period. Results: Although some eddy current heating was generated in non-target tissues at the higher field strengths, our preliminary IONP hyperthermia studies show that whole mouse AMF exposure @160 KHz and 400 or 550 Oe, for a 20 minutes (heat-up and protocol heating), provides a safe and efficacious tumor treatment. Initial electron and light microscopic studies (in vitro and in vivo) showed the 100 nm used in our studies are

  7. 78 FR 44399 - Semiannual Regulatory Flexibility Agenda

    Science.gov (United States)

    2013-07-23

    ... of Basel III, Minimum Regulatory Capital Ratios, Capital Adequacy, and Transition Provisions. (Docket.... Regulations H and Y--Regulatory Capital Rules: Regulatory Capital, Implementation of Basel III, Minimum... Committee on Banking Supervision (BCBS) in ``Basel III: A Global Regulatory Framework for More Resilient...

  8. 75 FR 61530 - Issuance of Regulatory Guides

    Science.gov (United States)

    2010-10-05

    ... NUCLEAR REGULATORY COMMISSION [NRC-2010-0312] Issuance of Regulatory Guides AGENCY: Nuclear... of the issuance and availability of Regulatory Guides 1.84, Rev. 35, ``Design, Fabrication, and... . SUPPLEMENTARY INFORMATION: I. Introduction The NRC is issuing two final Regulatory Guides (RGs) in the agency's...

  9. The Regulatory Independence of FANR

    International Nuclear Information System (INIS)

    ALNuaimi, Fatema; Choi, Kwang Shik

    2012-01-01

    Regulatory independence is meant to provide a conservative system of policy making in order to comply with the problems that are forecasted upon the basis of assumptions. The Federal Authorization of Nuclear Regulation (FANR) is a regulatory commission that was formed to be regulatory body that governs the generation of nuclear power in United Arab Emirates. It was established under the UAE nuclear law (9/2009) as an independent regulatory body that was tasked with the regulation of all nuclear activities in the United Arab Emirates. As an independent body, FANR was tasked with ensuring that the regulation of the nuclear sector is done in effective and transparent manner to ensure its accountability to the people. Being independent, the regulatory body develops national nuclear regulations based on laid down safety standards by the International Atomic Energy Agency, ensuring that they are based on scientific and proven technologies The role of FANR is to ensure that the all corporations that undertake nuclear activities follow the laid down procedures and objectives and ensure safety measures are taken keenly to ensure the safety of the workers and the general public while at the same time ensuring the environment is free from nuclear radiations

  10. Regulatory Expectations for Safety Culture

    International Nuclear Information System (INIS)

    Jung, Su Jin; Oh, Jang Jin; Choi, Young Sung

    2014-01-01

    The oversight of licensee's safety culture becomes an important issue that attracts great public and political concerns recently in Korea. Beginning from the intended violation of rules, a series of corruptions, documents forgery and disclosure of wrong-doings made the public think that the whole mindset of nuclear workers has been inadequate. Thus, they are demanding that safety culture shall be improved and that regulatory body shall play more roles and responsibilities for the improvements and oversight for them. This paper introduces, as an effort of regulatory side, recent changes in the role of regulators in safety culture, regulatory expectations on the desired status of licensee's safety culture, the pilot inspection program for safety culture and research activity for the development of oversight system. After the Fukushima accident in Japan 2011, many critics has searched for cultural factors that caused the unacceptable negligence pervaded in Japan nuclear society and the renewed emphasis has been placed on rebuilding safety culture by operators, regulators, and relevant institutions globally. Significant progress has been made in how to approach safety culture and led to a new perspective different from the existing normative assessment method both in operators and regulatory side. Regulatory expectations and oversight of them are based on such a new holistic concept for human, organizational and cultural elements to maintain and strengthen the integrity of defense in depth and consequently nuclear safety

  11. Regulatory Expectations for Safety Culture

    Energy Technology Data Exchange (ETDEWEB)

    Jung, Su Jin; Oh, Jang Jin; Choi, Young Sung [Korea Institute of Nuclear Safety, Daejeon (Korea, Republic of)

    2014-05-15

    The oversight of licensee's safety culture becomes an important issue that attracts great public and political concerns recently in Korea. Beginning from the intended violation of rules, a series of corruptions, documents forgery and disclosure of wrong-doings made the public think that the whole mindset of nuclear workers has been inadequate. Thus, they are demanding that safety culture shall be improved and that regulatory body shall play more roles and responsibilities for the improvements and oversight for them. This paper introduces, as an effort of regulatory side, recent changes in the role of regulators in safety culture, regulatory expectations on the desired status of licensee's safety culture, the pilot inspection program for safety culture and research activity for the development of oversight system. After the Fukushima accident in Japan 2011, many critics has searched for cultural factors that caused the unacceptable negligence pervaded in Japan nuclear society and the renewed emphasis has been placed on rebuilding safety culture by operators, regulators, and relevant institutions globally. Significant progress has been made in how to approach safety culture and led to a new perspective different from the existing normative assessment method both in operators and regulatory side. Regulatory expectations and oversight of them are based on such a new holistic concept for human, organizational and cultural elements to maintain and strengthen the integrity of defense in depth and consequently nuclear safety.

  12. Radioactive waste below regulatory concern

    International Nuclear Information System (INIS)

    Neuder, S.M.

    1987-01-01

    The U.S. Nuclear Regulatory Commission (NRC) published two notices in the Federal Register concerning radioactive waste below regulatory concern. The first, a Commission Policy Statement and Implementation Plan published August 29, 1986, concerns petition to exempt specific radioactive waste streams from the regulations. The second, an Advanced Notice of Proposed Rulemaking published Decemger 2, 1986, addresses the concept of generic rulemaking by the NRC on radioactive wastes that are below regulatory concern. Radioactive waste determined to be below regulatory concern would not be subject to regulatory control and would not need to go to a licensed low-level radioactive waste disposal site. The Policy Statement and Implementation Plan describe (1) the information a petitioner should file in support of a petition to exempt a specific waste stream, (2) the decision criteria the Commission intends to use for judging the petition, and (3) the internal administrative procedures to use be followed in order to permit the Commission to act upon the petition in an expedited manner

  13. Regulatory authority information system RAIS

    International Nuclear Information System (INIS)

    Ortiz, P.; Mrabit, K.; Miaw, S.

    2000-01-01

    In this lecture the principles of the regulatory authority information system (RAIS) are presented. RAIS is a tool currently being developed by the IAEA for the Regulatory Authorities. It is a part of a set of supporting actions designed to assist member states in achieving the objectives of the Model project on radiation and waste safety infrastructure. RAIS is a tool that provides the management of the Regulatory Authority with the key information needed for the planning and implementation of activities and to ensure confidence that resources are optimally used. The RAIS contains five modules: Inventory of installations and radiation sources; Authorization process; Inspection and follow-up actions; Information on personal dosimetry; Assessment of effectiveness by means of performance indicators

  14. Regulatory authority infrastructure for Namibia

    International Nuclear Information System (INIS)

    Shangula, K.

    2001-01-01

    The Republic of Namibia is participating in the International Atomic Energy Agency's Model Project for the Improvement of National Regulatory Authority Infrastructures in Member States. The paper illustrates our experience in solving problems and difficulties confronted in establishing an effective regulatory authority operating within the existing national infrastructure that should be supported by the Government. An effective regulatory authority is seen as part of the wider administrative scope of our Government through ministerial mandates given by the State from time to time, guaranteeing its independence when implementing legal provisions under statutes. Sections of the report illustrate our experience in the following areas: 1. National radiation protection policy 2. Structure of our national regulatory authority 3. Laws and regulations 4. Provisions for notification, authorization and registration 5. In-depth security measures for radiation sources and radioactive material 6. Systems for the inspection of radiation sources, radioactive materials, enforcement of legal provisions 7. Extent of the applications of radiation sources and radioactive materials in the country. The paper provides information regarding existing Government policy on radiation protection; structure and legal aspects of the national regulatory, including statutes and regulations; the extent of application and uses of radiation sources and security of radioactive materials; human resources: strengths and constraints; management practices and financing of regulatory authority; and plans for emergency recovery of orphan sources. National plans for management of disused sources, recovery of orphan sources, abnormal emergencies, communication of information to affected persons on exposure effects, and the safety training of persons using these applications are discussed. the paper provides a summary and some suggestions of the way forward for Namibia. (author)

  15. Regulatory processes in Aspergillus niger

    DEFF Research Database (Denmark)

    Poulsen, Lars

    some disadvantages as well, those are byproduct formation, secretion of proteolytic enzymes and formation of mycotoxins. The aim of this project was to reduce these disadvantages, though investigating the regulatory processes. The first objective was to study the regulatory events leading to A. niger...... characteristics, as a lower oxalic ii acid formation and wild type growth performance; it was therefore argued that this strain could be an attractive alternative to ΔprtT. Finally, in order to characterize the formation of the carcinogenic mycotoxin fumonisin, a reporter strain of A. niger was constructed, where...

  16. National legislative and regulatory activities

    International Nuclear Information System (INIS)

    2014-01-01

    This section treats of the following activities sorted by country: 1 - Belarus: International cooperation, Organisation and structure, Licensing and regulatory infrastructure, Nuclear safety and radiological protection; 2 - France: Nuclear safety and radiological protection, Radioactive waste management, Environmental protection, Liability and compensation, International co-operation; 3 - Hungary: General legislation, Radioactive waste management, Nuclear security; 4 - Ireland: Nuclear safety and radiological protection (including emergency planning); 5 - Lithuania: Licensing and regulatory infrastructure; 6 - Moldova: Nuclear safety and radiological protection; 7 - Portugal: Radioactive waste management, Nuclear safety and radiological protection; 8 - Slovak Republic: Radioactive waste management, Liability and compensation; 9 - Spain: Radioactive waste management; 10 - Ukraine: Radioactive waste management; 11 - United Kingdom: Organisation and structure

  17. Regulatory Control of Radiation Sources. Safety Guide

    International Nuclear Information System (INIS)

    2009-01-01

    This Safety Guide is intended to assist States in implementing the requirements established in Safety Standards Series No. GS-R-1, Legal and Governmental Infrastructure for Nuclear, Radiation, Radioactive Waste and Transport Safety, for a national regulatory infrastructure to regulate any practice involving radiation sources in medicine, industry, research, agriculture and education. The Safety Guide provides advice on the legislative basis for establishing regulatory bodies, including the effective independence of the regulatory body. It also provides guidance on implementing the functions and activities of regulatory bodies: the development of regulations and guides on radiation safety; implementation of a system for notification and authorization; carrying out regulatory inspections; taking necessary enforcement actions; and investigating accidents and circumstances potentially giving rise to accidents. The various aspects relating to the regulatory control of consumer products are explained, including justification, optimization of exposure, safety assessment and authorization. Guidance is also provided on the organization and staffing of regulatory bodies. Contents: 1. Introduction; 2. Legal framework for a regulatory infrastructure; 3. Principal functions and activities of the regulatory body; 4. Regulatory control of the supply of consumer products; 5. Functions of the regulatory body shared with other governmental agencies; 6. Organization and staffing of the regulatory body; 7. Documentation of the functions and activities of the regulatory body; 8. Support services; 9. Quality management for the regulatory system.

  18. 78 FR 62417 - Regulatory Capital Rules: Regulatory Capital, Implementation of Basel III, Capital Adequacy...

    Science.gov (United States)

    2013-10-22

    ... Capital, Implementation of Basel III, Capital Adequacy, Transition Provisions, Prompt Corrective Action..., 2013 (78 FR 55340), regarding Regulatory Capital Rules: Regulatory Capital, Implementation of Basel III...

  19. Regulatory perspectives of concept assessment

    International Nuclear Information System (INIS)

    Flavelle, Peter A.

    1987-09-01

    The Atomic Energy Control Board is the head agency for the regulatory review of the Assessment of the Canadian Concept for Nuclear Fuel Waste Disposal being done by Atomic Energy of Canada Limited and Ontario Hydro. This paper describes the regulatory perspective of how the Concept Assessment could demonstrate the feasibility of a disposal conforming to regulatory requirements. The long-term aspects of Concept Assessment encourage the use of various predictive techniques for different time scales. Each technique will have a different potential for establishing confidence in the predictions. The predicted performance of a facility during operation should have a very high confidence, as it can be based on standard engineering calculations and the predictions can be validated later by monitoring during operation. The predictions of the transient period following closure of the facility should achieve a medium level of confidence, since they can be based on extrapolations of predictions of operational performance, using models that can be calibrated with monitoring data and with averaged input data derived from natural analog studies. Predictions based on fundamental processes will have a medium level of confidence when made to intermediate times after closure. Long-term predictions using generic or typical input data or Monte Carlo calculations of simplified models will have the least confidence and yet they can still contribute to the confidence that the disposal concept will conform to regulatory requirements

  20. NRC regulatory information conference: Proceedings

    International Nuclear Information System (INIS)

    1989-09-01

    This volume of the report provides the proceedings from the Nuclear Regulatory Commission (NRC) Regulatory Information Conference that was held at the Mayflower Hotel, Washington, DC, on April 18, 19, and 20, 1989. This conference was held by the NRC and chaired by Dr. Thomas E. Mosley, Director, Office of Nuclear Reactor Regulations (NRR) and coordinated by S. Singh Bajwa, Chief, Technical Assistance Management Section, NRR. There were approximately 550 participants from nine countries at the conference. The countries represented were Canada, England, Italy, Japan, Mexico, Spain, Taiwan, Yugoslavia, and the United States. The NRC staff discussed with nuclear industry its regulatory philosophy and approach and the bases on which they have been established. Furthermore, the NRC staff discussed several initiatives that have been implemented recently and their bases as well as NRC's expectations for new initiatives to further improve safety. The figures contained in Appendix A to the volume correspond to the slides that were shown during the presentations. Volume 2 of this report contains the formal papers that were distributed at the beginning of the Regulatory Information Conference and other information about the conference

  1. 78 FR 1574 - Regulatory Agenda

    Science.gov (United States)

    2013-01-08

    ... Standard Menu Items in Restaurants and Similar Retail Food Establishments (Reg Plan Seq No. 41). References... advancements in technology. Timetable: Action Date FR Cite NPRM 12/00/12 Regulatory Flexibility Analysis... and Accessible Medical Technology Specialist, Department of Health and Human Services, Food and Drug...

  2. Private Equity and Regulatory Capital

    NARCIS (Netherlands)

    Bongaerts, D.; Charlier, E.

    2008-01-01

    Regulatory Capital requirements for European banks have been put forward in the Basel II Capital Framework and subsequently in the Capital Requirements Directive (CRD) of the EU. We provide a detailed discussion of the capital requirements for private equity investments under the simple risk weight

  3. Radiation practices and regulatory control

    International Nuclear Information System (INIS)

    1997-01-01

    The general principles to be observed in the regulatory control of ionizing radiation use and practices are specified in the guide. It also takes into account of additions and alterations needed for for compliance with the European Union (EU) directives that have not been mentioned in other STUK/ST-guides. (6 refs.)

  4. Management systems for regulatory authorities

    International Nuclear Information System (INIS)

    Mpandanyama, Rujeko Lynette

    2015-02-01

    For a regulatory body to fulfil its statutory obligations, there is need to develop and implement a regulatory management system that has the necessary arrangements for achieving and maintaining high quality performance in regulating the safety of nuclear and radiation facilities under its authority. Hence, the regulatory management system needs to fully integrate the human resources, processes and physical resources of the organization. This study sought to provide an understanding of the concept, principles, policies and fundamentals of management systems as they relate to regulatory systems in the field of radiation protection and to make appropriate recommendations to ensure that an effective management system exists for the control of ionizing radiation and radiation sources and addresses all relevant stakeholders in Zimbabwe. A comparative analysis was done on the current management status and the ideal management system, which led to the identification of the gaps existing. The main key that was found to be of significance was lack of linkages between processes and management tools within the institution. (au)

  5. Regulatory/policy-panel A

    Energy Technology Data Exchange (ETDEWEB)

    Barr, M.R.; Grano, D.; Ruyter, J.C. de; Jernigan, R.; Carney, M.V.; Schulze, R.A.

    1995-08-01

    The status of various bills in Congress is outlined. The bills include those included in the {open_quotes}Contract with America,{close_quotes} limits on federal regulations, the Regulatory Transition Act of 1995, and the Job Creation and Wage Enhancement Act of 1995.

  6. 75 FR 70044 - Withdrawal of Regulatory Guide 1.39

    Science.gov (United States)

    2010-11-16

    ... NUCLEAR REGULATORY COMMISSION [NRC-2010-0354] Withdrawal of Regulatory Guide 1.39 AGENCY: Nuclear Regulatory Commission. ACTION: Withdrawal of a Regulatory Guide: Regulatory Guide 1.39, ``Housekeeping... U.S. Nuclear Regulatory Commission (NRC) is withdrawing Regulatory Guide 1.39, ``Housekeeping...

  7. Cancerous HLA class I expression and regulatory T cell infiltration in gastric cancer.

    Science.gov (United States)

    Ishigami, Sumiya; Arigami, Takaaki; Uenosono, Yoshikazu; Matsumoto, Masataka; Okumura, Hiroshi; Uchikado, Yasuto; Kita, Yoshiaki; Nishizono, Yuka; Maemura, Kosei; Kijima, Yuko; Nakajo, Akihiro; Owaki, Tetsuhiro; Ueno, Shinichi; Hokita, Shuichi; Natsugoe, Shoji

    2012-10-01

    Since antitumor immune reactions between tumors and intratumoral immunocytes have been verified in several human tumors, immunological therapeutic strategies must be considered to obtain the proper efficacy of tumor shrinkage under these conditions. Human leukocyte antigen (HLA) class I expression in cancer cells and degree of infiltration of regulatory T cells (Tregs) in the stroma have been regarded as important markers of antitumor immune reactions in the context of independent immunological mechanisms. In the current study, we investigated HLA class I expression and Treg cells infiltration in gastric cancer and discussed the clinical implications of this combinatory analysis in gastric cancer. A total of 141 gastric cancer patients who received R0 gastrectomy at Kagoshima University Hospital were studied. Immunohistochemically, in 141 gastric cancer patients, HLA class I expression and Treg cell infiltration in cancerous tissue were evaluated using HLA class I (EMR8-5) and forkhead box p3 (FOXP3) monoclonal antibodies. The correlation between clinical factors and tumor-infiltrating Treg cells was analyzed. HLA class I expression was positively associated with depth of tumor invasion (P HLA class I expression had no association with Treg cell infiltration (r = 0.04). A better postoperative outcome was associated with fewer numbers of Treg infiltration (P = 0.034). A combination of HLA and Treg analysis may lead to a more accurate prediction of postoperative outcome (P = 0.02). Two different antitumor immunological markers, Treg infiltration and HLA class I expression, affected clinicopathological factors in gastric cancer by different mechanisms. Thus, an immunological combination of HLA class I expression and Treg cell infiltration may more accurately predict postoperative outcome. Immunological balance needs to be restored after evaluation of each immunological deficit in gastric cancer.

  8. Physiologically based pharmacokinetic modeling: from regulatory science to regulatory policy.

    Science.gov (United States)

    Sinha, V; Zhao, P; Huang, S M; Zineh, I

    2014-05-01

    Assessment of controllable sources of intra- and interpatient variability in drug response is of critical importance in the regulatory evaluation of new drugs.(1) Although determinants of response variability would ideally be understood and accounted for before approval of a new pharmaceutical product, this is rarely the case for all; clinical trials in specific populations that definitively test optimal dosing in patient management strategies are not routinely performed prior to drug approval.

  9. The Political Economy of Regulatory Risk

    OpenAIRE

    Strausz, Roland

    2009-01-01

    I investigate the argument that, in a two–party system with different regulatory objectives, political uncertainty generates regulatory risk. I show that this risk has a fluctuation effect that hurts both parties and an output–expansion effect that benefits one party. Consequently, at least one party dislikes regulatory risk. Moreover, both political parties gain from eliminating regulatory risk when political divergence is small or the winning probability of the regulatory–risk–averse party ...

  10. 76 FR 64043 - Iowa Regulatory Program

    Science.gov (United States)

    2011-10-17

    ... Office of Surface Mining Reclamation and Enforcement 30 CFR Part 915 Iowa Regulatory Program AGENCY...), are announcing receipt of a proposed amendment to the Iowa regulatory program (Iowa program) under the... regulatory program by updating its adoption by reference of applicable portions of the Code of Federal...

  11. Department of Education Semiannual Regulatory Agenda

    Science.gov (United States)

    2010-12-20

    ... additional information regarding the planned action. In accordance with ED's Principles for Regulating listed... [The Regulatory Plan and Unified Agenda of Federal Regulatory and Deregulatory Actions... Subtitles A and B Unified Agenda of Federal Regulatory and Deregulatory Actions AGENCY: Office of the...

  12. 21 CFR 500.88 - Regulatory method.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Regulatory method. 500.88 Section 500.88 Food and... § 500.88 Regulatory method. (a) The sponsor shall submit for evaluation and validation a regulatory method developed to monitor compliance with FDA's operational definition of no residue. (b) The...

  13. 12 CFR 562.2 - Regulatory reports.

    Science.gov (United States)

    2010-01-01

    ... not limited to the minimum requirements under generally accepted accounting principles (GAAP) because... condition and operation of savings associations. The Report of Examination and the Thrift Financial Report (TFR) are examples of regulatory reports. Regulatory reports are regulatory documents, not accounting...

  14. Regulatory point of view of SAT application

    International Nuclear Information System (INIS)

    Juhasz, L.

    2002-01-01

    I present the regulatory system for monitoring operator training and check competency of operator personnel in Hungary and the effects of SAT to the regulatory framework/practice related to recruitment, training and authorisation of operating personnel. Also I introduce an application to manage the initial and refreshing training to regulatory bodies. (author)

  15. Regulatory aspects of NPP safety

    International Nuclear Information System (INIS)

    Kastchiev, G.

    1999-01-01

    Extensive review of the NPP Safety is presented including tasks of Ministry of Health, Ministry of Internal Affairs, Ministry of Environment and Waters, Ministry of Defense in the field of national system for monitoring the nuclear power. In the frame of national nuclear safety legislation Bulgaria is in the process of approximation of the national legislation to that of EC. Detailed analysis of the status of regulatory body, its functions, organisation structure, responsibilities and future tasks is included. Basis for establishing the system of regulatory inspections and safety enforcement as well as intensification of inspections is described. Assessment of safety modifications is concerned with complex program for reconstruction of Units 1-4 of Kozloduy NPP, as well as for modernisation of Units 5 and 6. Qualification and licensing of the NPP personnel, Year 2000 problem, priorities and the need of international assistance are mentioned

  16. [Regulatory requirements for topical preparations].

    Science.gov (United States)

    Wohlrab, J; Klauck, D; Savtcheva, E

    2014-03-01

    Professional use of topical treatment in dermatological practice requires not only knowledge about the pharmacological properties, efficacy, safety and pharmaceutical quality of a preparation, but also about its regulatory classification. The latter essentially determines the physician's prescription practice and therapeutic freedom. The regulatory framework with which one is confronted unfortunately lacks transparency. It regulates not only the prescribability and reimbursability of proprietary medicinal products and extemporaneous preparations, but also the obligation to give information as well as the details of liability of both the prescriber (physician) and the manufacturer (pharmaceutical company or pharmacist). The prescriber needs to be aware of to what extent the pharmacist has the possibility and even obligation to change the prescribed preparation. In some cases this can directly affect the therapeutic concept of the physician and even impair the effectiveness and safety of the chosen therapy.

  17. Nutrient profiling for regulatory purposes.

    Science.gov (United States)

    Rayner, Mike

    2017-08-01

    In this paper, I first provide definitions of nutrient profiling and of a nutrient profile model. I set out the purposes of nutrient profiling: both general and specific. I give two examples of nutrient profile models that have been developed for regulatory purposes by the Food Standards Agency (FSA) in the UK and the WHO for its European Region - the UK FSA/Ofcom and the WHO-Euro models - and compare the way the models are constructed and function, how they have been developed, the extent to which they have been tested and validated and their use in regulation. Finally I draw some conclusions about the future use of nutrient profiling for regulatory purposes. I argue that its full potential has yet to be realised and give some reasons why. I pose some urgent research questions with respect to nutrient profiling.

  18. Compliance. Regulatory policy P-211

    International Nuclear Information System (INIS)

    2001-05-01

    This regulatory policy describes the basic principles and directives for establishing and conducting the Canadian Nuclear Safety Commission (CNSC) Compliance Program. The program is aimed at securing compliance by regulated persons with regulatory requirements made under the Nuclear Safety and Control Act ('the Act'). The policy applies to persons who are regulated by the CNSC through the Act, regulations and licences, as well as by decisions and orders made under the Act. The policy applies to officers and employees of the CNSC, and its authorized representatives or agents, who are involved in developing and carrying out compliance activities. Compliance, in the context of this policy, means conformity by regulated persons with the legally binding requirements of the Act, and the CNSC regulations, licences, decisions, and orders made under the Act. Compliance activities are CNSC measures of promotion, verification and enforcement aimed at securing compliance by regulated person with the applicable legally binding requirements. (author)

  19. Compliance. Regulatory policy P-211

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2001-05-01

    This regulatory policy describes the basic principles and directives for establishing and conducting the Canadian Nuclear Safety Commission (CNSC) Compliance Program. The program is aimed at securing compliance by regulated persons with regulatory requirements made under the Nuclear Safety and Control Act ('the Act'). The policy applies to persons who are regulated by the CNSC through the Act, regulations and licences, as well as by decisions and orders made under the Act. The policy applies to officers and employees of the CNSC, and its authorized representatives or agents, who are involved in developing and carrying out compliance activities. Compliance, in the context of this policy, means conformity by regulated persons with the legally binding requirements of the Act, and the CNSC regulations, licences, decisions, and orders made under the Act. Compliance activities are CNSC measures of promotion, verification and enforcement aimed at securing compliance by regulated person with the applicable legally binding requirements. (author)

  20. 75 FR 21686 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of...

    Science.gov (United States)

    2010-04-26

    ... to pay arbitration awards to remain in the securities industry presents regulatory risks and is...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of Proposed Rule... Regulatory Authority, Inc. (``FINRA'') filed with the Securities and Exchange Commission (``SEC'' or...

  1. 75 FR 11166 - Joint Meeting of the Nuclear Regulatory Commission and the Federal Energy Regulatory Commission...

    Science.gov (United States)

    2010-03-10

    ... From the Federal Register Online via the Government Publishing Office ] DEPARTMENT OF ENERGY Federal Energy Regulatory Commission Joint Meeting of the Nuclear Regulatory Commission and the Federal Energy Regulatory Commission; Notice of Joint Meeting of the Nuclear Regulatory Commission and the...

  2. 78 FR 36011 - Region VII Regulatory Fairness Board; Federal Regulatory Enforcement Fairness Hearing

    Science.gov (United States)

    2013-06-14

    ... SMALL BUSINESS ADMINISTRATION Region VII Regulatory Fairness Board; Federal Regulatory Enforcement... Regional (Region VII) Small Business Regulatory Fairness Board. SUMMARY: The (SBA) Office of the National... the Region VII Regulatory Fairness Board must contact Jeanna Trenkamp by June 17, 2013 in writing, by...

  3. National legislative and regulatory activities

    International Nuclear Information System (INIS)

    2015-01-01

    This section treats of the following National legislative and regulatory activities: 1 - Canada: Liability and compensation; 2 - France: Liability and compensation; Nuclear safety and radiological protection; 3 - Greece: Organisation and structure; 4 - Hungary: General legislation; 5 - India: Liability and compensation; 6 - Japan: Liability and compensation; 7 - Korea: Liability and compensation; 8 - Lithuania: General legislation; Transport of radioactive material; 9 - Slovak Republic: International co-operation; Liability and compensation; 10 - Slovenia: General legislation; 11 - Switzerland: Liability and compensation; 12 - United States: Radioactive waste management

  4. Methodological developments vs. regulatory requirements.

    Science.gov (United States)

    Bauer, Peter

    2006-08-01

    This is a discussion of the following three papers appearing in this special issue on adaptive designs: 'FDA's critical path initiative: A perspective on contributions of biostatistics' by Robert T. O'Neill, 'A regulatory view on adaptive/flexible clinical trial design' by H. M. James Hung, Robert T. O'Neill, Sue-Jane Wang and John Lawrence; and 'Confirmatory clinical trials with an adaptive design' by Armin Koch.

  5. Technology competition and regulatory advantage

    OpenAIRE

    Boscheck, Ralf

    2010-01-01

    The importance of competition law as a policy lever to help the EU compete at the forefront of science and technology seems to have been overlooked by the Commission. As a consequence, the EU appears to be at a disadvantage to the USA in terms of the regulatory environment for intellectual property and licensing practices. This article examines these differences and explores the pros and cons of the European and American approaches to competition law, ultimately arguing in favour of regulator...

  6. The conduct of regulatory activities

    International Nuclear Information System (INIS)

    Wright, H.A.

    1975-01-01

    The main emphasis is placed on the legal responsibility of the utility in UK to build and operate its plant to avoid any nuclear hazard. The regulatory practices have endeavoured to inculcate a proper emphasis towards safety by the people who comprise the management of the utility, and to avoid any erosion of their legal responsibility as the best and possibly only practical means to achieve adequate safety standards. (orig./HP) [de

  7. Essays on Environmental Regulatory Policy

    OpenAIRE

    Dobson, Sarah

    2012-01-01

    Two common desires for individuals are to live in a society with a healthy and sustainable environment, and a growing and productive economy. Through environmental regulatory policy, governments pursue these objectives on behalf of their electorate. It can often be a difficult balancing act, however, as these objectives do not always fit well together. Industrial activities that drive and stimulate the economy often have negative and lasting impacts on the environment. In this dissertation,...

  8. 'Green' Preferences as Regulatory Policy

    OpenAIRE

    Brennan, Timothy

    2001-01-01

    We examine the suggestion that if consumers in sufficient numbers are willing to pay the premium to have power generated using low-emission technologies, tax or permit policies become less necessary or stringent. While there are implementation difficulties with this proposal, our purpose is more fundamental: can economics make sense of using preferences as a regulatory instrument? If “green” preferences are exogenously given, to what extent can or should they be regarded as a substitute for o...

  9. Principles of regulatory policy design

    OpenAIRE

    Sappington, David E.M.; DEC

    1994-01-01

    The author contrasts command-and-control regulation (tight control of water purification, for example) with more flexible forms, including incentive regulation (such as price cap regulation), potential regulation (providing for closer scrutiny if enough customers complain), and reactive rather than proactive policies (the firm proposing actions, the regulatory saying yes or no). He contrasts informing regulation (for example, requiring that consumers be informed about ingredients in a product...

  10. Regulatory change and monetary policy

    OpenAIRE

    Bank for International Settlements

    2015-01-01

    Report submitted by a Working Group established by the Committee on the Global Financial System and the Markets Committee. The Group was chaired by Ulrich Bindseil (European Central Bank) and William R Nelson (Federal Reserve Board). Financial regulation is evolving, as policymakers seek to strengthen the financial system in order to make it more robust and resilient. Changes in the regulatory environment are likely to have an impact on financial system structure and on the behaviour of finan...

  11. National legislative and regulatory activities

    International Nuclear Information System (INIS)

    Anon.

    2009-01-01

    This part gathers the national legislative and regulatory activities. The subjects tackled are as follow: radiological protection (Belgium), transport of radioactive materials (Belgium, France), general legislation (Brazil, Ireland, Republic of Moldova, Serbia, Turkey), third part liability (Japan), radioactive waste management (Korea, Romania, Slovenia, Usa), regime of radioactive materials (Romania), organisation and structure (Switzerland), regime of nuclear installations (Usa), regulations on nuclear trade (Usa). (N.C)

  12. Principles of good regulatory research

    International Nuclear Information System (INIS)

    Rogers, K.

    1991-01-01

    The Commissioner of the US Regulatory Commission addresses several important research-related subjects. The paper describes the Agency philosophy with respect to independence, openness, efficiency, clarity, and reliability; research philosophy with respect to the need for research, the need for quality, and the need for efficiency; research areas with respect to plant aging, human factors, severe accident analysis, advanced reactors, and radioactive waste management; and systems approach to reactor operations, training, licensing, and maintenance

  13. Estadios precoces de cancer oral: pronóstico en relación con gradación histológica, linfagiogénesis intratumoral y expresión de factor de crecimiento endotelial vascular Tipo-C (VEGF-C Early stage oral cancer: prognosis with regard to histological grading, intratumoral lymphangiogenesis, and the expression of vascular endothelial growth factor-C (VEGF-C

    Directory of Open Access Journals (Sweden)

    M.F. Muñoz-Guerra

    2006-02-01

    Full Text Available Objetivos. Los sistemas de gradación histológica se han usado clásicamente como factor pronóstico y marcadores de comportamiento clínico en el carcinoma epidermoide intra-oral (CEI. Sin embargo, su utilidad pronóstica permanece controvertida. Nuestro objetivo ha sido evaluar la presencia de linfangiogénesis intratumoral (LI, un nuevo hallazgo morfológico, en un análisis retrospectivo de muestras de tejido en parafina dentro de un grupo de estadios precoces de CEI, relacionándolo con clásicos sistemas de gradación histológica y teniendo en cuenta su importancia pronóstica. Asimismo, pretendemos determinar si la expresión del factor de crecimiento endotelial vascular -C (VEGF-C se correlaciona con la evolución de la enfermedad. Diseño. Realizamos un estudio retrospectivo basado en 96 casos de CEI. Todos los pacientes presentaban tumores intraorales T1-T2 y fueron tratados primariamente mediante resección local asociada con disección cervical electiva, la cual mostró ausencia de afectación ganglionar regional. En el grupo de 96 muestras analizamos la LI utilizando el marcador específico del endotelio linfático PA2.26. Adicionalmente, estudiamos la expresión del VEGF-C. Todos los casos fueron clasificados de acuerdo con los sistemas de gradación histológica descritos por Broders, Anneroth y Bryne. El estudio estadístico se fundamentó en el análisis univariante de supervivencia causa-específica y supervivencia libre de recidiva según el método de Kaplan-Meier. Resultados. El grupo de pacientes con ausencia de LI mostró mejor pronóstico en cuanto a supervivencia y periodo libre de enfermedad, aunque la diferencia no mostró valores estadísticamente significativos. El estudio no mostró una relación entre la expresión de VEGF-C y la presencia de LI. Sin embargo, no observamos recidivas entre el grupo con ausencia de expresión de VEGF-C. El análisis comparativo de los sistemas de gradación histológica mostró una

  14. The Political Economy of Regulatory Change

    DEFF Research Database (Denmark)

    Buch-Hansen, Hubert

    2012-01-01

    This article aims to explain the broader evolution of British merger control. To this end it outlines a novel critical political economy perspective on regulation and regulatory change which differs from established political economy approaches, such as the regulatory capitalism/state perspectives......, in three main ways: it places regulatory ideas at the heart of the analysis, it differentiates between different degrees of regulatory change, and it links regulatory change in delineated issue areas with changing power balances between fractions of capital and labor. The application of this perspective...

  15. 75 FR 36698 - Draft Regulatory Guide: Issuance, Availability

    Science.gov (United States)

    2010-06-28

    ... From the Federal Register Online via the Government Publishing Office NUCLEAR REGULATORY COMMISSION Draft Regulatory Guide: Issuance, Availability AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Draft Regulatory Guide, DG-1216, ``Plant-Specific Applicability of...

  16. 75 FR 3760 - Draft Regulatory Guide: Issuance, Availability

    Science.gov (United States)

    2010-01-22

    ... From the Federal Register Online via the Government Publishing Office NUCLEAR REGULATORY COMMISSION Draft Regulatory Guide: Issuance, Availability AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Draft Regulatory Guide, DG-8037, Information Relevant to Ensuring...

  17. 75 FR 16516 - Draft Regulatory Guide: Issuance, Availability

    Science.gov (United States)

    2010-04-01

    ... From the Federal Register Online via the Government Publishing Office NUCLEAR REGULATORY COMMISSION Draft Regulatory Guide: Issuance, Availability AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Draft Regulatory Guide, DG-2004, ``Emergency Planning for Research...

  18. 75 FR 1830 - Final Regulatory Guide: Issuance, Availability

    Science.gov (United States)

    2010-01-13

    ... From the Federal Register Online via the Government Publishing Office NUCLEAR REGULATORY COMMISSION Final Regulatory Guide: Issuance, Availability AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Regulatory Guide (RG) 5.71, ``Cyber Security Programs for Nuclear...

  19. 75 FR 13599 - Draft Regulatory Guide: Issuance, Availability

    Science.gov (United States)

    2010-03-22

    ... From the Federal Register Online via the Government Publishing Office NUCLEAR REGULATORY COMMISSION Draft Regulatory Guide: Issuance, Availability AGENCY: Nuclear Regulatory Commission. ACTION: Notice of issuance and availability of Draft Regulatory Guide, DG-8040, ``Health Physics Surveys During...

  20. 76 FR 24539 - Final Regulatory Guide: Issuance, Availability

    Science.gov (United States)

    2011-05-02

    ... From the Federal Register Online via the Government Publishing Office NUCLEAR REGULATORY COMMISSION Final Regulatory Guide: Issuance, Availability AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Regulatory Guide (RG) 3.67, ``Standard Format and Content for...

  1. 75 FR 18241 - Draft Regulatory Guide: Issuance, Availability

    Science.gov (United States)

    2010-04-09

    ... From the Federal Register Online via the Government Publishing Office NUCLEAR REGULATORY COMMISSION Draft Regulatory Guide: Issuance, Availability AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Draft Regulatory Guide, DG-8036, ``Personnel Monitoring Device...

  2. 75 FR 48382 - Draft Regulatory Guide: Issuance, Availability

    Science.gov (United States)

    2010-08-10

    ... From the Federal Register Online via the Government Publishing Office NUCLEAR REGULATORY COMMISSION Draft Regulatory Guide: Issuance, Availability AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Draft Regulatory Guide, DG-1228, ``Standard Format and Content of...

  3. 75 FR 20645 - Draft Regulatory Guide: Issuance, Availability

    Science.gov (United States)

    2010-04-20

    ... From the Federal Register Online via the Government Publishing Office ] NUCLEAR REGULATORY COMMISSION Draft Regulatory Guide: Issuance, Availability AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Draft Regulatory Guide, DG-4018. FOR FURTHER INFORMATION CONTACT...

  4. 75 FR 62893 - Draft Regulatory Guide: Issuance, Availability

    Science.gov (United States)

    2010-10-13

    ... From the Federal Register Online via the Government Publishing Office NUCLEAR REGULATORY COMMISSION Draft Regulatory Guide: Issuance, Availability AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Draft Regulatory Guide, DG-1196, ``Qualification for Cement...

  5. 75 FR 28073 - Draft Regulatory Guide: Issuance, Availability

    Science.gov (United States)

    2010-05-19

    ... From the Federal Register Online via the Government Publishing Office NUCLEAR REGULATORY COMMISSION Draft Regulatory Guide: Issuance, Availability AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Draft Regulatory Guide, DG-3039, ``Standard Format and Content for...

  6. 75 FR 48381 - Final Regulatory Guide: Issuance, Availability

    Science.gov (United States)

    2010-08-10

    ... From the Federal Register Online via the Government Publishing Office NUCLEAR REGULATORY COMMISSION Final Regulatory Guide: Issuance, Availability AGENCY: Nuclear Regulatory Commission. ACTION: Notice of issuance and availability of Regulatory Guide, RG 1.216, ``Containment Structural Integrity...

  7. 76 FR 2725 - Draft Regulatory Guide: Issuance, Availability

    Science.gov (United States)

    2011-01-14

    ... From the Federal Register Online via the Government Publishing Office NUCLEAR REGULATORY COMMISSION Draft Regulatory Guide: Issuance, Availability AGENCY: Nuclear Regulatory Commission. ACTION: Issuance, Availability of Draft Regulatory Guide (DG)-1245. FOR FURTHER INFORMATION CONTACT: Mark P. Orr, U...

  8. 76 FR 11288 - Draft Regulatory Guide: Issuance, Availability

    Science.gov (United States)

    2011-03-01

    ... From the Federal Register Online via the Government Publishing Office NUCLEAR REGULATORY COMMISSION Draft Regulatory Guide: Issuance, Availability AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Draft Regulatory Guide, DG-7008, ``Leakage Tests on Packages for...

  9. 75 FR 11574 - Draft Regulatory Guide: Issuance, Availability

    Science.gov (United States)

    2010-03-11

    ... From the Federal Register Online via the Government Publishing Office NUCLEAR REGULATORY COMMISSION Draft Regulatory Guide: Issuance, Availability AGENCY: Nuclear Regulatory Commission. ACTION: Notice of issuance and availability of draft regulatory guide, DG-1242, ``Service Level I, II, and III...

  10. 75 FR 53352 - Draft Regulatory Guide: Issuance, Availability

    Science.gov (United States)

    2010-08-31

    ... From the Federal Register Online via the Government Publishing Office NUCLEAR REGULATORY COMMISSION Draft Regulatory Guide: Issuance, Availability AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Draft Regulatory Guide, DG-1247, ``Design-Basis Hurricane and...

  11. 75 FR 5630 - Draft Regulatory Guide: Issuance, Availability

    Science.gov (United States)

    2010-02-03

    ... From the Federal Register Online via the Government Publishing Office NUCLEAR REGULATORY COMMISSION Draft Regulatory Guide: Issuance, Availability AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Draft Regulatory Guide, DG-4017. FOR FURTHER INFORMATION CONTACT...

  12. 76 FR 189 - Final Regulatory Guide: Issuance, Availability

    Science.gov (United States)

    2011-01-03

    ... From the Federal Register Online via the Government Publishing Office NUCLEAR REGULATORY COMMISSION Final Regulatory Guide: Issuance, Availability AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Regulatory Guide 3.71, Revision 2, ``Nuclear Criticality Safety...

  13. 75 FR 45166 - Draft Regulatory Guide: Issuance, Availability

    Science.gov (United States)

    2010-08-02

    ... From the Federal Register Online via the Government Publishing Office NUCLEAR REGULATORY COMMISSION Draft Regulatory Guide: Issuance, Availability AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Draft Regulatory Guide, DG-3030, ``Nuclear Criticality Safety...

  14. 75 FR 42170 - Final Regulatory Guide: Issuance, Availability

    Science.gov (United States)

    2010-07-20

    ... From the Federal Register Online via the Government Publishing Office NUCLEAR REGULATORY COMMISSION Final Regulatory Guide: Issuance, Availability AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Regulatory Guide, RG 8.40, ``Methods for Measuring Effective Dose...

  15. 75 FR 33853 - Draft Regulatory Guide: Issuance, Availability

    Science.gov (United States)

    2010-06-15

    ... From the Federal Register Online via the Government Publishing Office ] NUCLEAR REGULATORY COMMISSION Draft Regulatory Guide: Issuance, Availability AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Draft Regulatory Guide, DG-1240, ``Condition Monitoring Program...

  16. 75 FR 29785 - Draft Regulatory Guide: Issuance, Availability

    Science.gov (United States)

    2010-05-27

    ... From the Federal Register Online via the Government Publishing Office NUCLEAR REGULATORY COMMISSION Draft Regulatory Guide: Issuance, Availability AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Draft Regulatory Guide, DG-1248, ``Nuclear Power Plant Simulation...

  17. 76 FR 23845 - Draft Regulatory Guide: Issuance, Availability

    Science.gov (United States)

    2011-04-28

    ... From the Federal Register Online via the Government Publishing Office NUCLEAR REGULATORY COMMISSION Draft Regulatory Guide: Issuance, Availability AGENCY: Nuclear Regulatory Commission. ACTION: Notice of issuance and availability of Draft Regulatory Guide, DG-1197, ``Inservice Inspection of...

  18. 75 FR 58444 - Draft Regulatory Guide: Issuance, Availability

    Science.gov (United States)

    2010-09-24

    ... COMMISSION Draft Regulatory Guide: Issuance, Availability AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Draft Regulatory Guide, DG-1244, ``Availability of Electric Power.... The draft regulatory guide (DG), entitled, ``Availability of Electric Power Sources'' temporarily...

  19. 76 FR 5215 - Draft Regulatory Guide: Issuance, Availability

    Science.gov (United States)

    2011-01-28

    ... From the Federal Register Online via the Government Publishing Office NUCLEAR REGULATORY COMMISSION Draft Regulatory Guide: Issuance, Availability AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Draft Regulatory Guide, DG-7007, ``Administrative Guide for...

  20. 76 FR 59448 - Draft Regulatory Guide; Issuance, Availability

    Science.gov (United States)

    2011-09-26

    ... From the Federal Register Online via the Government Publishing Office NUCLEAR REGULATORY COMMISSION Draft Regulatory Guide; Issuance, Availability AGENCY: Nuclear Regulatory Commission. ACTION: Notice of issuance and availability of Draft Regulatory Guide, DG-8050, ``Applications of Bioassay for...

  1. 76 FR 10917 - Draft Regulatory Guide: Issuance, Availability

    Science.gov (United States)

    2011-02-28

    ... From the Federal Register Online via the Government Publishing Office NUCLEAR REGULATORY COMMISSION Draft Regulatory Guide: Issuance, Availability AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Draft Regulatory Guide, DG-1254, ``Qualification of Connection...

  2. 76 FR 6086 - Draft Regulatory Guide: Issuance, Availability

    Science.gov (United States)

    2011-02-03

    ... Draft Regulatory Guide: Issuance, Availability AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Availability of Draft Regulatory Guide. SUMMARY: The U.S. Nuclear Regulatory Commission (Commission or NRC) is...

  3. 75 FR 52996 - Draft Regulatory Guide: Issuance, Availability

    Science.gov (United States)

    2010-08-30

    ... From the Federal Register Online via the Government Publishing Office NUCLEAR REGULATORY COMMISSION Draft Regulatory Guide: Issuance, Availability AGENCY: Nuclear Regulatory Commission. ACTION: Notice of issuance and availability of Draft Regulatory Guide, DG-8035, ``Administrative Practices in...

  4. Organization of nuclear regulatory activities

    International Nuclear Information System (INIS)

    Blidaru, Valentin

    2008-01-01

    The paper presents the structure, missions and organizational aspects of the CNCAN, the National Commission for the control of nuclear activities in Romania. The paper addresses the following main issues: 1.General aspects; 2.Organizational structure of the NRA in Romania; 3.General description of the Division for Nuclear Safety Assessments; 4.Specific activities; 5.Regulatory approaches and practices. Under the title of 'General aspects' the following three basic statements are highlighted: 1.CNCAN is a governmental organization responsible for the development of the regulatory framework, the control of its implementation and the licensing of nuclear facilities; 2.CNCAN is the national authority competent in exercising the regulatory activity, authorization and control in the nuclear field provided by the law No. 111/ 1996 republished in 1998; 3.The Commission exercises its functions independently of the ministries and other authorities of the public control administration being subordinated to the Romanian Government. The organizational structure is as follows: - President, the Managerial Council and the Advisory Council coordinating the four General Divisions that are responsible for: - Nuclear Safety with Division of Nuclear Safety Assessment and Division of Nuclear Objectives Surveillance; - Radiological Safety with Division of Radiological Safety Assessment and Division of Operational Radiation Protection; - Surveillance of Environmental Radioactivity with Division of Assessment and Analysis and Division of National Network; - Development and Resource with the Division of Economy and Division of Human Resources. In addition under direct coordination of the President operate the Division of Radiation Protection, Transport and Radioactive Waste and the Division of International Cooperation and Communication. Specific activities are listed describing among others the issues of: - Safety of nuclear installation; - Evaluation relating to licensing of nuclear

  5. Regulatory pathways for vaccines for developing countries.

    Science.gov (United States)

    Milstien, Julie; Belgharbi, Lahouari

    2004-01-01

    Vaccines that are designed for use only in developing countries face regulatory hurdles that may restrict their use. There are two primary reasons for this: most regulatory authorities are set up to address regulation of products for use only within their jurisdictions and regulatory authorities in developing countries traditionally have been considered weak. Some options for regulatory pathways for such products have been identified: licensing in the country of manufacture, file review by the European Medicines Evaluation Agency on behalf of WHO, export to a country with a competent national regulatory authority (NRA) that could handle all regulatory functions for the developing country market, shared manufacturing and licensing in a developing country with competent manufacturing and regulatory capacity, and use of a contracted independent entity for global regulatory approval. These options have been evaluated on the basis of five criteria: assurance of all regulatory functions for the life of the product, appropriateness of epidemiological assessment, applicability to products no longer used in the domestic market of the manufacturing country, reduction of regulatory risk for the manufacturer, and existing rules and regulations for implementation. No one option satisfies all criteria. For all options, national infrastructures (including the underlying regulatory legislative framework, particularly to formulate and implement local evidence-based vaccine policy) must be developed. WHO has led work to develop this capacity with some success. The paper outlines additional areas of action required by the international community to assure development and use of vaccines needed for the developing world. PMID:15042235

  6. Defining Tobacco Regulatory Science Competencies.

    Science.gov (United States)

    Wipfli, Heather L; Berman, Micah; Hanson, Kacey; Kelder, Steven; Solis, Amy; Villanti, Andrea C; Ribeiro, Carla M P; Meissner, Helen I; Anderson, Roger

    2017-02-01

    In 2013, the National Institutes of Health and the Food and Drug Administration funded a network of 14 Tobacco Centers of Regulatory Science (TCORS) with a mission that included research and training. A cross-TCORS Panel was established to define tobacco regulatory science (TRS) competencies to help harmonize and guide their emerging educational programs. The purpose of this paper is to describe the Panel's work to develop core TRS domains and competencies. The Panel developed the list of domains and competencies using a semistructured Delphi method divided into four phases occurring between November 2013 and August 2015. The final proposed list included a total of 51 competencies across six core domains and 28 competencies across five specialized domains. There is a need for continued discussion to establish the utility of the proposed set of competencies for emerging TRS curricula and to identify the best strategies for incorporating these competencies into TRS training programs. Given the field's broad multidisciplinary nature, further experience is needed to refine the core domains that should be covered in TRS training programs versus knowledge obtained in more specialized programs. Regulatory science to inform the regulation of tobacco products is an emerging field. The paper provides an initial list of core and specialized domains and competencies to be used in developing curricula for new and emerging training programs aimed at preparing a new cohort of scientists to conduct critical TRS research. © The Author 2016. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  7. Wetlands: The changing regulatory landscape

    International Nuclear Information System (INIS)

    Glick, R.M.

    1993-01-01

    Protection of wetlands became a national issue in 1988 when President George Bush pledged no net loss of wetlands in the US under his open-quotes environmental presidency.close quotes As wetlands became a national issue, the job of protecting them became an obligation for many groups, including hydro-power developers. Now, when a site selected for development includes an area that may be classified as a wetland, the developer quickly discovers the importance of recognizing and protecting these natural habitats. Federal legislation severely limits development of wetland, and most states increase the restrictions with their own wetlands regulations. The difficulty of defining wetlands complicates federal and state enforcement. Land that appears to be dry may in fact be classified as a wetland. So, even if a site appears dry, potential hydro developers must confirm whether or not any jurisdictional wetlands are present. Regulated lands include much more than marshes and swamps. Further complicating the definition of wetlands, a recent court decision found that even artificially created wetlands, such as man-made ponds, may be subject to regulation. Hydro developers must be aware of current regulatory requirements before they consider development of any site that may contain wetlands. To be certain that a site is open-quotes buildableclose quotes from the standpoint of wetlands regulation, a developer must verify (with the help of state agencies) that the property does not contain any jurisdictional wetlands. If it does, the regulatory process before development becomes much more complicated. For the short term, uncertainty abounds and extreme caution is in order. Because the regulatory process has become so complex and an agreeable definition of wetlands so elusive, the trend among the Corps and collaborating agencies is to constrict nationwide permits in favor of narrowing the jurisdictional definition of wetlands

  8. Advances in Canadian regulatory practice

    International Nuclear Information System (INIS)

    Waddington, J.G.

    1993-03-01

    The new General Amendments to the Regulations, new recommendations on dose limits, developments in techniques and safety thinking, and aging of plant are all contributing to the need for a significant number of new regulatory document on a wide range of topics. this paper highlights a number of initiatives taken in response to these pressures, giving a brief background to the initiative and, where possible, outlining some of the ideas in the document licensing guides on new dose limits, dosimetry, safety analysis, reliability, fault tree analysis, reporting requirements, human factors, software, the ALARA principle, backfitting and the licensing process. (Author) 29 refs., fig., 4 tabs

  9. Regulatory guidance for license renewal

    International Nuclear Information System (INIS)

    Thoma, John A.

    1991-01-01

    The proposed 10 CFR Part 54 rule proceduralizes the process for license renewal by identifying both the administrative and technical requirements for a renewal application. To amplify and support this regulation, written guidance has been provided in the form of a draft Regulatory Guide (DG 1009) and a draft Standard Review Plan for License Renewal (NUREG 1299). This guidance is scheduled to be finalized in 1992. Similar guidance will be provided for the proposed revisions to 10 CFR Part 51 concerning the environmental aspects of license renewal. (author)

  10. Regulatory Issues Surrounding Merchant Interconnection

    International Nuclear Information System (INIS)

    Kuijlaars, Kees-Jan; Zwart, Gijsbert

    2003-11-01

    We discussed various issues concerning the regulatory perspective on private investment in interconnectors. One might claim that leaving investment in transmission infrastructure to competing market parties is more efficient than relying on regulated investment only (especially in the case of long (DC) lines connecting previously unconnected parts of the grids, so that externalities from e.g. loop flows do not play a significant role). We considered that some aspects of interconnection might reduce these market benefits. In particular, the large fixed costs of interconnection construction may lead to significant under investment (due to both first mover monopoly power and the fact that part of generation cost efficiencies realised by interconnection are not captured by the investor itself, and remain external to the investment decision). Second, merchant ownership restricts future opportunities for adaptation of regulation, as would be required e.g. for introduction of potentially more sophisticated methods of congestion management or market splitting. Some of the disadvantages of merchant investment may be mitigated however by a suitable regulatory framework, and we discussed some views in this direction. The issues we discussed are not intended to give a complete framework, and detailed regulation will certainly involve many more specific requirements. Areas we did not touch upon include e.g. the treatment of deep connection costs, rules for operation and maintenance of the line, and impact on availability of capacity on other interconnections

  11. Global Banking System Regulatory Environment

    Directory of Open Access Journals (Sweden)

    Oleh Mozhovyi

    2017-03-01

    Full Text Available The international and domestic experience shows that the main factors of financial destabilization during the financial crises are in the banking sector. The article reveals that the vulnerability of the financial system is connected with functions, deposit and credit transactions, risks distribution and ensuring liquidity; banks act as a major factor in stabilisation measures in the current context of globalization processes, since the economic stability of banking activities relates directly to all the entities and only stable banking system can withstand the crisis phenomena. Therefore, as a result of the analysis, it is proved that not only reduction of risks of banks is needed, but also introduction of the effective supervision system over implementation of the requirements and standards to prevent these risks. According to modern international approaches, banks use the so-called prudential supervision, which is based on the risk management assessment policy on the part of the Bank’s management, and regulatory bodies contribute to implementation of such policy. The authors have concluded that not only modern specificity of banks, but also the impact of supervision systems and regulation of modern trends in development of the banking should be analysed. Application of the general regulatory principles and banking risks methodology is required. The task of supervision is distribution of reliable risk management practices in the banking system, taking into account national peculiarities of development.

  12. Pollution prevention: A regulatory update

    International Nuclear Information System (INIS)

    Walzer, A.E.; Maynard, J.W.

    1993-01-01

    Pollution prevention is the emphasis of the 1990s environmental philosophy. This new environmental era was ushered in when President Bush signed the Pollution Prevention Act in October 1990. This law, with its accompanying philosophy, was in response to the realization that end-of-the-pipe treatment, which frequently changed the media in which a pollutant or waste was discharged, was inadequate to protect the environment and human health. Pollution prevention advocates source reduction, where material substitutions and engineering solutions are sought to reduce the volume and toxicity of waste and pollutants. This proactive approach reduces environmental impacts such as those of former waste sites which have produced environmental legacies that will cost billions of dollars and take decades to remediate. This paper describes pollution prevention philosophy and summarizes regulatory pollution prevention requirements. It describes current regulatory trends in the area of pollution prevention, including voluntary programs and enforcement actions. The Pollution Prevention Act of 1990 is described, and pollution prevention initiatives embodied in other laws, including the Clean Air Act, the Clean Water Act, the Emergency Planning and Community Right-To-Know Act, the Resource Conservation and Recovery Act, and the Toxic Substances Control Act, are discussed. A historical overview of waste minimization initiatives within the Department of Energy is given, and other pollution prevention initiatives that affect federal facilities, such as Executive Order 12780, which mandates recycling and the procurement of recycled materials, are also outlined

  13. Global Summit on Regulatory Science 2013.

    Science.gov (United States)

    Howard, Paul C; Tong, Weida; Weichold, Frank; Healy, Marion; Slikker, William

    2014-12-01

    Regulatory science has been defined as the science that is used to develop regulatory decisions by government bodies. Regulatory science encompasses many scientific disciplines that oversee many studies producing a wide array of data. These may include fundamental research into the cellular interaction or response to a particular chemical or substance, hazard-assessment and dose-response studies in animal species, neurophysiological or neurobehavioral studies, best practices for the generation and analysis of genomics data, bioinformatics approaches, and mathematical modeling of risk. The Global Summit on Regulatory Science is an international conference with a mission to explore emerging and innovative technologies, and provide a platform to enhance translation of basic science into regulatory applications. The Third Global Summit on Regulatory Science which focused on nanotechnology is discussed. Published by Elsevier Inc.

  14. A study of bacterial gene regulatory mechanisms

    DEFF Research Database (Denmark)

    Hansen, Sabine

    the different regulatory mechanisms affect system dynamics. We have designed a synthetic gene regulatory network (GRN) in bacterial cells that enables us to study the dynamics of GRNs. The results presented in this PhD thesis show that model equations based on the established mechanisms of action of each...... of a particular type of regulatory mechanism. The synthetic system presented in this thesis is, to our knowledge, the first of its kind to allow a direct comparison of the dynamic behaviors of gene regulatory networks that employ different mechanisms of regulation. In addition to studying the dynamic behavior...... switch off the expression of unfavorable proteins. This dynamic regulation requires a coordinated effort by a network of regulatory factors. The regulatory mechanisms employed by bacterial cell to regulate their protein expression have been extensively studied. However, little is known about how...

  15. Environmental regulatory update table, July 1991

    Energy Technology Data Exchange (ETDEWEB)

    Houlberg, L.M.; Hawkins, G.T.; Salk, M.S.

    1991-08-01

    This Environmental Regulatory Update Table (July 1991) provides information on regulatory initiatives of interest to DOE operations and contractor staff with environmental management responsibilities. The table is updated each month with information from the Federal Register and other sources, including direct contact with regulatory agencies. Each table entry provides a chronological record of the rulemaking process for that initiative with an abstract and a projection of further action.

  16. Environmental Regulatory Update Table, November 1991

    Energy Technology Data Exchange (ETDEWEB)

    Houlberg, L.M.; Hawkins, G.T.; Salk, M.S.

    1991-12-01

    The Environmental Regulatory Update Table provides information on regulatory initiatives of interest to DOE operations and contractor staff with environmental management responsibilities. The table is updated each month with information from the Federal Register and other sources, including direct contact with regulatory agencies. Each table entry provides a chronological record of the rulemaking process for that initiative with an abstract and a projection of further action.

  17. Environmental Regulatory Update Table, April 1989

    International Nuclear Information System (INIS)

    Houlberg, L.; Langston, M.E.; Nikbakht, A.; Salk, M.S.

    1989-05-01

    The Environmental Regulatory Update Table provides information on regulatory initiatives of interest to DOE operations and contractor staff with environmental management responsibilities. The table is updated each month with information from the Federal Register and other sources, including direct contact with regulatory agencies. Each table entry provides a chronological record of the rulemaking process for that initiative with an abstract and a projection of further action

  18. Environmental Regulatory Update Table, December 1991

    Energy Technology Data Exchange (ETDEWEB)

    Houlberg, L.M.; Hawkins, G.T.; Salk, M.S.

    1992-01-01

    The Environmental Regulatory Update Table provides information on regulatory initiatives of interest to DOE operations and contractor staff with environmental management responsibilities. The table is updated each month with information from the Federal Register and other sources, including direct contact with regulatory agencies. Each table entry provides a chronological record of the rulemaking process for that initiative with an abstract and a projection of further action.

  19. Environmental regulatory update table, March 1989

    International Nuclear Information System (INIS)

    Houlberg, L.; Langston, M.E.; Nikbakht, A.; Salk, M.S.

    1989-04-01

    The Environmental Regulatory Update Table provides information on regulatory initiatives of interest to DOE operations and contractor staff with environmental management responsibilities. The table is updated each month with information from the Federal Register and other sources, including direct contact with regulatory agencies. Each table entry provides a chronological record of the rulemaking process for that initiative with an abstract and a projection of further action

  20. Grand Gulf-prioritization of regulatory requirements

    International Nuclear Information System (INIS)

    Meisner, M.J.

    1993-01-01

    As cost pressures mount, Grand Gulf nuclear station (GGNS) is relying increasingly on various prioritization approaches to implement, modify, eliminate, or defer regulatory requirements. Regulatory requirements can be prioritized through the use of three measures: (1) safety (or risk) significance; (2) cost; and (3) public policy (or political) significance. This paper summarizes GGNS' efforts to implement solutions to regulatory issues using these three prioritization schemes to preserve a balance between cost and safety benefit

  1. Environmental regulatory update table, March 1989

    Energy Technology Data Exchange (ETDEWEB)

    Houlberg, L.; Langston, M.E.; Nikbakht, A.; Salk, M.S.

    1989-04-01

    The Environmental Regulatory Update Table provides information on regulatory initiatives of interest to DOE operations and contractor staff with environmental management responsibilities. The table is updated each month with information from the Federal Register and other sources, including direct contact with regulatory agencies. Each table entry provides a chronological record of the rulemaking process for that initiative with an abstract and a projection of further action.

  2. Environmental Regulatory Update Table, April 1989

    Energy Technology Data Exchange (ETDEWEB)

    Houlberg, L.; Langston, M.E.; Nikbakht, A.; Salk, M.S.

    1989-05-01

    The Environmental Regulatory Update Table provides information on regulatory initiatives of interest to DOE operations and contractor staff with environmental management responsibilities. The table is updated each month with information from the Federal Register and other sources, including direct contact with regulatory agencies. Each table entry provides a chronological record of the rulemaking process for that initiative with an abstract and a projection of further action.

  3. Environmental Regulatory Update Table, August 1991

    Energy Technology Data Exchange (ETDEWEB)

    Houlberg, L.M., Hawkins, G.T.; Salk, M.S.

    1991-09-01

    This Environmental Regulatory Update Table (August 1991) provides information on regulatory initiatives of interest to DOE operations and contractor staff with environmental management responsibilities. The table is updated each month with information from the Federal Register and other sources, including direct contact with regulatory agencies. Each table entry provides a chronological record of the rulemaking process for that initiative with an abstract and a projection of further action.

  4. Environmental Regulatory Update Table, September 1991

    Energy Technology Data Exchange (ETDEWEB)

    Houlberg, L.M.; Hawkins, G.T.; Salk, M.S.

    1991-10-01

    The Environmental Regulatory Update Table provides information on regulatory initiatives of interest to DOE operations and contractor staff with environmental management responsibilities. The table is updated each month with information from the Federal Register and other sources, including direct contact with regulatory agencies. Each table entry provides a chronological record of the rulemaking process for that initiative with an abstract and a projection of further action.

  5. Environmental Regulatory Update Table, October 1991

    Energy Technology Data Exchange (ETDEWEB)

    Houlberg, L.M.; Hawkins, G.T.; Salk, M.S.

    1991-11-01

    The Environmental Regulatory Update Table provides information on regulatory initiatives of interest to DOE operations and contractor staff with environmental management responsibilities. The table is updated each month with information from the Federal Register and other sources, including direct contact with regulatory agencies. Each table entry provides a chronological record of the rulemaking process for that initiative with an abstract and a projection of further action.

  6. Annual Report 2008. Nuclear Regulatory Authority

    International Nuclear Information System (INIS)

    2009-01-01

    The present Annual Report of Activities of the Nuclear Regulatory Authority (ARN), prepared regularly from the creation as independent institution, describes across four parts and seven annexes the activities developed by the organism during 2008. The main topic are: the organization and the activity of the ARN; the regulatory standards; the licensing and inspection of nuclear power plants and critical facilities; the emergency systems; the occupational surveillance; the environmental monitoring; improved organizational and budgetary developments. Also, this publication have annexes with the following content: regulatory documents; regulatory guides; measurement and evaluation of the drinking water of Ezeiza.

  7. Annual Report 2007. Nuclear Regulatory Authority

    International Nuclear Information System (INIS)

    2008-01-01

    The present Annual Report of Activities of the Nuclear Regulatory Authority (ARN), prepared regularly from the creation as independent institution, describes across tree parts and seven annexes the activities developed by the organism during 2007. The main topic are: the organization and the activity of the ARN; the regulatory standards; the licensing and inspection of nuclear power plants and critical facilities; the emergency systems; the occupational surveillance; the environmental monitoring; improved organizational. Also, this publication have annexes with the following content: regulatory documents; inspections to medical, industrial and training installations; regulatory guides; measurement and evaluation of the drinking water of Ezeiza.

  8. Annual Report 2009. Nuclear Regulatory Authority

    International Nuclear Information System (INIS)

    2010-01-01

    The present Annual Report of Activities of the Nuclear Regulatory Authority (ARN), prepared regularly from the creation as independent institution, describes across four parts and seven annexes the activities developed by the organism during 2009. The main topic are: the organization and the activity of the ARN; the regulatory standards; the licensing and inspection of nuclear power plants and critical facilities; the emergency systems; the environmental monitoring; the occupational surveillance; the training and the public information; improved organizational and budgetary developments. Also, this publication have annexes with the following content: regulatory documents; inspections to medical, industrial and training installations; regulatory guides; measurement and evaluation of the drinking water of Ezeiza.

  9. Federal Energy Regulatory Commission (FERC) Regions

    Data.gov (United States)

    Department of Homeland Security — Federal Energy Regulatory Commission (FERC) Regions. FERC is an independent agency that regulates the interstate transmission of electricity, natural gas, and oil....

  10. Regulatory Information by Topic: Emergency Management

    Science.gov (United States)

    Regulatory information about emergencies, including chemical accident prevention, risk management plans (RMPs), chemical reporting, community right to know, and oil spills and hazardous substances releases.

  11. National legislative and regulatory activities

    International Nuclear Information System (INIS)

    2016-01-01

    This section treats of the following National legislative and regulatory activities: 1 - Argentina: Organisation and structure; 2 - France: Radioactive waste management (Act No. 2016-1015 of 25 July 2016 specifying the procedures for creating a reversible deep geological repository for long-lived medium and high-level radioactive waste), Liability and compensation (Decree No. 2016-333 of 21 March 2016 implementing Article L. 597-28 of the French Environmental Code and relating to third party liability in the field of nuclear energy; Ministerial Order of 19 August 2016 listing the sites benefiting from a reduced amount of liability pursuant to decree No. 2016-333 of 21 March 2016 implementing Article L. 597-28 of the French Environmental Code and relating to third party liability in the field of nuclear energy), Nuclear facilities (Decree No. 2016-846 of 28 June 2016 related to the modification, final shutdown and decommissioning of basic nuclear installations, and to subcontracting); 3 - Germany: Nuclear trade - including non-proliferation (Amendments to the Foreign Trade Act and the Foreign Trade Ordinance (2015)), Radioactive waste management (Act on the Organisational Restructuring in the Field of Radioactive Waste Management (2016); Final report of the Commission to Review the Financing for the Phase-out of Nuclear Energy; Draft Bill of an Act on the Reorganisation of the Responsibility of Nuclear Waste Disposal (2016)); 4 - Lithuania: Nuclear safety and radiological protection (including nuclear emergency planning), Nuclear security (Physical security of sources of ionising radiation), Radioactive waste management, Licensing and regulatory infrastructure (Enforcement measures); 5 - Luxembourg: Radioactive waste management (Agreement between the Grand Duchy of Luxembourg and the Kingdom of Belgium on the Management and Final Disposal of the Radioactive Waste of the Grand Duchy of Luxembourg on the Territory of the Kingdom of Belgium, signed on 4 July 2016); 6

  12. Reduction of regulatory risk: a network economic approach

    OpenAIRE

    Knieps, Günter; Weiß, Hans-Jörg

    2007-01-01

    Several definitions of regulatory risk are known from the literature. From the perspective of regulatory reform it is important to differentiate between the impact of a given regulatory scheme on the firm's risk exposure and the risk arising from discretionary behavior of regulatory agencies. Whereas the conse-quences of effective regulation in principle are known and accepted, excessive regulatory discretion may cause a strong need for regulatory reform. Regulatory reform focussing on the re...

  13. Regulatory control of nuclear power plants

    International Nuclear Information System (INIS)

    2002-01-01

    The purpose of this book is to support IAEA training courses and workshops in the field of regulatory control of nuclear power plants as well as to support the regulatory bodies of Member States in their own training activities. The target group is the professional staff members of nuclear safety regulatory bodies supervising nuclear power plants and having duties and responsibilities in the following regulatory fields: regulatory framework; regulatory organization; regulatory guidance; licensing and licensing documents; assessment of safety; and regulatory inspection and enforcement. Important topics such as regulatory competence and quality of regulatory work as well as emergency preparedness and public communication are also covered. The book also presents the key issues of nuclear safety such as 'defence-in-depth' and safety culture and explains how these should be taken into account in regulatory work, e.g. during safety assessment and regulatory inspection. The book also reflects how nuclear safety has been developed during the years on the basis of operating experience feedback and results of safety research by giving topical examples. The examples cover development of operating procedures and accident management to cope with complicated incidents and severe accidents to stress the importance of regulatory role in nuclear safety research. The main target group is new staff members of regulatory bodies, but the book also offers good examples for more experienced inspectors to be used as comparison and discussion basis in internal workshops organized by the regulatory bodies for refreshing and continuing training. The book was originally compiled on the basis of presentations provided during the two regulatory control training courses in 1997 and 1998. The textbook was reviewed at the beginning of the years 2000 and 2002 by IAEA staff members and consistency with the latest revisions of safety standards have been ensured. The textbook was completed in the

  14. National legislative and regulatory activities

    International Nuclear Information System (INIS)

    2015-01-01

    This section treats of the following National legislative and regulatory activities: 1 - Australia: General legislation - Bill to amend the Australian Radiation Protection and Nuclear Safety Act 1998; 2 - France: General legislation - Law No. 2015-992 of 17 August 2015 on the energy transition for green growth; ASN Report on the state of nuclear safety and radiation protection in France in 2014; 3 - Germany: Radioactive waste management - First Ordinance to amend the 2005 Gorleben Development Freeze Ordinance (2015); 4 - Greece: Radioactive waste management - Joint Ministerial Decision establishing the national policy on the management of spent fuel and radioactive waste; 5 - Lithuania: Nuclear safety and radiological protection - Revised requirements for modifications, Plan for enhancement of nuclear safety, New requirements for the commissioning of nuclear power plants, Revised requirements regulating the provision of information on abnormal events; Radioactive waste management - Revised requirements for acceptance criteria for near surface repository; Nuclear security - Revised requirements for physical protection; 6 - Romania: Licensing and regulatory infrastructure - Government Decision No. 600/2014 for approval of National Nuclear Safety and Security; International co-operation - Government Decision No. 525/2014 for approval of the Co-operation Agreement on the radioactive waste management between the French National Radioactive Waste Management Agency (ANDRA) and Nuclear Agency and Radioactive Waste (ANDR) Strategy; Memorandum of Understanding for Co-operation and Exchange of Information in Nuclear Regulatory Matters between the National Commission for Nuclear Activities Control (CNCAN) of Romania and the President of National Atomic Energy Agency (PAA) of Poland; Government Decision No. 540/2015 for approval of the Agreement between the Government of Romania and the Government of the People's Republic of China regarding co-operation in the peaceful

  15. Regulatory aspects of sludge management

    International Nuclear Information System (INIS)

    Sharples, F.E.

    1992-01-01

    The paper presents an overview of radioactive waste land disposal restrictions by discussing the following topics: highlights of Resource Conservation and Recovery Act history; purposes of land disposal restrictions; regulatory definition of land disposal; US Environmental Protection Agency (EPA) implementation of land disposal restrictions; schedules for implementing land disposal restrictions; solvent and dioxin wastes; classification of liquid hazardous and radioactive wastes; generator and treatment, storage, and disposal responsibilities; variances and extensions; and options for mixed waste management. Land disposal restrictions take into account the long-term uncertainties associated with land disposal, the need to manage waste right the first time they are disposed, and the persistence toxicity, mobility, propensity to bioaccumulate, and volume. In the Department of Energy system land disposal restrictions affect mixed waste management and site remedial action programs

  16. Regulatory practices - United States example

    International Nuclear Information System (INIS)

    Shapar, M.

    1976-01-01

    In 1954, the Atomic Energy Act of 1946 was revised to do away with the federal state monopoly in this field and to enable private industry to develop nuclear power. This evolution led the federal authorities to give the Atomic Energy Commission the powers to control the design, licensing and operation of nuclear reactors. These powers were constantly strengthened and are now exercised by the Nuclear Regulatory Commission (NRC). Since its creation in 1975, the Commission has amended the regulations on licensing of nuclear reactors in the light of experience acquired so as to shorten the duration of this procedure. These amendments concern the standardization of nuclear power plants, limited work authorizations, the methods for issuing licenses. The objective of the Commission aim to make the licensing procedure for nuclear power plants simpler and more efficient and hence, less costly, while ensuring that a very high level for safety standards and environmental protection is maintained. (NEA) [fr

  17. National legislative and regulatory activities

    International Nuclear Information System (INIS)

    Anon.

    2011-01-01

    This chapter of Nuclear Law Bulletin gathers some documents about national legislative and regulatory activities: - Belgium: Amendment of the Act on classification and security clearances, certifications and security notifications; Czech Republic: Resolution of the government of the Czech Republic on the time schedule of preparatory works for enlarging the nuclear power plant Temelin; Finland: Temporary Amendment to the Nuclear Liability Act; Ireland: Merchant Shipping Act; Romania: Emergency Ordinance on the identification, designation and protection of critical infrastructures; Emergency Ordinance on the control regime of dual-use items; Amendment to the Act on the safe conduct of nuclear activities; Nuclear safety norms on design and construction of nuclear power plants and nuclear safety norms on siting of nuclear power plants; United Kingdom: Establishment of the Office for Nuclear Regulation; United States: Waste Confidence Decision and Rule Update; Response to recent events in Japan

  18. Intratumoral Th2 predisposition combines with an increased Th1 functional phenotype in clinical response to intravesical BCG in bladder cancer.

    Science.gov (United States)

    Pichler, Renate; Gruenbacher, Georg; Culig, Zoran; Brunner, Andrea; Fuchs, Dietmar; Fritz, Josef; Gander, Hubert; Rahm, Andrea; Thurnher, Martin

    2017-04-01

    Th1-type immunity is considered to be required for efficient response to BCG in bladder cancer, although Th2 predisposition of BCG responders has recently been reported. The aim was to evaluate the relationship of Th1 and Th2 components in 23 patients undergoing BCG treatment. Peripheral blood, serum and urine samples were prospectively collected at baseline, during and after BCG. Th1 (neopterin, tryptophan, kynurenine, kynurenine-to-tryptophan ratio (KTR), IL-12, IFN-γ, soluble TNF-R75 and IL-2Rα) and Th2 (IL-4, IL-10) biomarkers as well as CD4 expression in T helper (Th), effector and regulatory T cells were determined. Local immune cell subsets were measured on formalin-fixed, paraffin-embedded cancer tissue by immunohistochemistry to examine expression of transcription factors that control Th1 (T-bet) and Th2-type (GATA3) immunity. We confirmed a Th2 predisposition with a mean GATA3/T-bet ratio of 5.51. BCG responders showed significantly higher levels of urinary (p = 0.003) and serum neopterin (p = 0.012), kynurenine (p = 0.015), KTR (p = 0.005), IFN-γ (p = 0.005) and IL-12 (p = 0.003) during therapy, whereas levels of IL-10 decreased significantly (p Th1-type immune responses and thus contribute to the BCG success.

  19. 75 FR 59771 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving the...

    Science.gov (United States)

    2010-09-28

    ...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving the Proposed Rule.... I. Introduction On July 27, 2010, the Financial Industry Regulatory Authority, Inc. (``FINRA'') (f/k... pertinent distribution-related information from its members in a timely fashion to facilitate its Regulation...

  20. 78 FR 29190 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving the...

    Science.gov (United States)

    2013-05-17

    ... be identified as late for reporting and dissemination purposes and would not be considered ``last...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving the Proposed Rule..., 2013, Financial Industry Regulatory Authority, Inc. (``FINRA'') filed with the Securities and Exchange...

  1. 78 FR 76973 - Regulatory Capital Rules: Regulatory Capital, Implementation of Basel III, Capital Adequacy...

    Science.gov (United States)

    2013-12-20

    ... contains regulatory documents #0;having general applicability and legal effect, most of which are keyed #0...-AD 87 Regulatory Capital Rules: Regulatory Capital, Implementation of Basel III, Capital Adequacy, Transition Provisions, Prompt Corrective Action, Standardized Approach for Risk-Weighted Assets, Market...

  2. 75 FR 69508 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filings...

    Science.gov (United States)

    2010-11-12

    ... regulatory risk.\\7\\ \\7\\ See Notice, supra note 3, 75 FR at 47863. Because proposed FINRA Rule 4530 is based... persons that may pose a regulatory risk.\\33\\ \\29\\ See State Farm Letter. \\30\\ Id. \\31\\ See Amendment No. 1... members and associated persons that may pose a regulatory risk.\\81\\ \\80\\ See CAI Letter and FSI Letter...

  3. 75 FR 53998 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing...

    Science.gov (United States)

    2010-09-02

    ... characteristics and risks of security futures. \\6\\ 15 U.S.C. 78o-3(b)(6). B. Self-Regulatory Organization's...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing and Immediate Effectiveness of Proposed Rule Change To Amend the Security Futures Risk Disclosure Statement August 27, 2010...

  4. 75 FR 47863 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of...

    Science.gov (United States)

    2010-08-09

    ... identify and investigate firms, offices and associated persons that may pose a regulatory risk. Proposal... and associated persons that may pose a regulatory risk. Some of these commenters are also concerned... regulatory risk. \\38\\ Puplava. Additionally, in response to one commenter,\\39\\ FINRA wishes to clarify an...

  5. 76 FR 37384 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing...

    Science.gov (United States)

    2011-06-27

    ... COMMISSION Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing and... Recording and Reporting Requirements June 21, 2011. Pursuant to Section 19(b)(1) of the Securities Exchange..., Financial Industry Regulatory Authority, Inc. (``FINRA'') filed with the Securities and Exchange Commission...

  6. 75 FR 51124 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing...

    Science.gov (United States)

    2010-08-18

    ... COMMISSION Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing and... To Submit a Contrary Exercise Advice and the Time for a Final Exercise Decision in the Event of a..., Financial Industry Regulatory Authority, Inc. (``FINRA'') filed with the Securities and Exchange Commission...

  7. 75 FR 17806 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of...

    Science.gov (United States)

    2010-04-07

    ... commenter raised the following issues related to the proposed 30-second reporting requirement.\\22\\ First...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of Amendment No. 2... Financial Industry Regulatory Authority, Inc. (``FINRA'') filed with the Securities and Exchange Commission...

  8. 78 FR 72946 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of...

    Science.gov (United States)

    2013-12-04

    ...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of Amendment No. 1... August 23, 2013, the Financial Industry Regulatory Authority, Inc. (``FINRA'') filed with the Securities... unable to obtain such information, it has to resort to restricting all new issue allocations to such...

  9. 77 FR 47470 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of...

    Science.gov (United States)

    2012-08-08

    ...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Withdrawal of Proposed Rule Change To Adopt FINRA Rule 2231 (Customer Account Statements) in the Consolidated FINRA Rulebook August 2, 2012. On April 22, 2009, the Financial Industry Regulatory Authority, Inc. (``FINRA'') (f/k/a...

  10. 76 FR 9838 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of...

    Science.gov (United States)

    2011-02-22

    ... resolve promissory note cases. \\8\\ 15 U.S.C. 78o-3(b)(6). B. Self-Regulatory Organization's Statement on... COMMISSION Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of Proposed Rule Change Relating to Promissory Note Proceedings February 15, 2011. Pursuant to Section 19(b)(1...

  11. 76 FR 50796 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing...

    Science.gov (United States)

    2011-08-16

    ...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing and Immediate Effectiveness of Proposed Rule Change To Increase the Position Limit for Options on the Standard and Poor's... Financial Industry Regulatory Authority, Inc. (``FINRA'') filed with the Securities and Exchange Commission...

  12. Development of targeted therapy for ovarian cancer mediated by a plasmid expressing diphtheria toxin under the control of H19 regulatory sequences

    Directory of Open Access Journals (Sweden)

    Birman Tatiana

    2009-08-01

    Full Text Available Abstract Background Ovarian cancer ascites fluid (OCAF, contains malignant cells, is usually present in women with an advanced stage disease and currently has no effective therapy. Hence, we developed a new therapy strategy to target the expression of diphtheria toxin gene under the control of H19 regulatory sequences in ovarian tumor cells. H19 RNA is present at high levels in human cancer tissues (including ovarian cancer, while existing at a nearly undetectable level in the surrounding normal tissue. Methods H19 gene expression was tested in cells from OCAF by the in-situ hybridization technique (ISH using an H19 RNA probe. The therapeutic potential of the toxin vector DTA-H19 was tested in ovarian carcinoma cell lines and in a heterotopic animal model for ovarian cancer. Results H19 RNA was detected in 90% of patients with OCAF as determined by ISH. Intratumoral injection of DTA-H19 into ectopically developed tumors caused 40% inhibition of tumor growth. Conclusion These observations may be the first step towards a major breakthrough in the treatment of human OCAF, while the effect in solid tumors required further investigation. It should enable us to identify likely non-responders in advance, and to treat patients who are resistant to all known therapies, thereby avoiding treatment failure.

  13. USI A-43 regulatory analysis. Revision 1

    International Nuclear Information System (INIS)

    1985-10-01

    This report consists of: (1) the regulatory analysis for Unresolved Safety Issue (USI) A-43, ''Containment Emergency Sump Performance''; (2) the proposed resolution; (3) a summary of public comments received and action taken; (4) the Committee to Review Generic Requirements (CRGR) minutes related to this USI; and (5) appendices that summarize assumptions, calculational methods, consequence analyses, and cost estimates used in this regulatory analysis

  14. Environment, safety, and health regulatory implementation plan

    Energy Technology Data Exchange (ETDEWEB)

    1993-10-21

    To identify, document, and maintain the Uranium Mill Tailings Remedial Action (UMTRA) Project`s environment, safety, and health (ES&H) regulatory requirements, the US Department of Energy (DOE) UMTRA Project Office tasked the Technical Assistance Contractor (TAC) to develop a regulatory operating envelope for the UMTRA Project. The system selected for managing the UMTRA regulatory operating envelope data bass is based on the Integrated Project Control/Regulatory Compliance System (IPC/RCS) developed by WASTREN, Inc. (WASTREN, 1993). The IPC/RCS is a tool used for identifying regulatory and institutional requirements and indexing them to hardware, personnel, and program systems on a project. The IPC/RCS will be customized for the UMTRA Project surface remedial action and groundwater restoration programs. The purpose of this plan is to establish the process for implementing and maintaining the UMTRA Project`s regulatory operating envelope, which involves identifying all applicable regulatory and institutional requirements and determining compliance status. The plan describes how the Project will identify ES&H regulatory requirements, analyze applicability to the UMTRA Project, and evaluate UMTRA Project compliance status.

  15. Environment, safety, and health regulatory implementation plan

    International Nuclear Information System (INIS)

    1993-01-01

    To identify, document, and maintain the Uranium Mill Tailings Remedial Action (UMTRA) Project's environment, safety, and health (ES ampersand H) regulatory requirements, the US Department of Energy (DOE) UMTRA Project Office tasked the Technical Assistance Contractor (TAC) to develop a regulatory operating envelope for the UMTRA Project. The system selected for managing the UMTRA regulatory operating envelope data bass is based on the Integrated Project Control/Regulatory Compliance System (IPC/RCS) developed by WASTREN, Inc. (WASTREN, 1993). The IPC/RCS is a tool used for identifying regulatory and institutional requirements and indexing them to hardware, personnel, and program systems on a project. The IPC/RCS will be customized for the UMTRA Project surface remedial action and groundwater restoration programs. The purpose of this plan is to establish the process for implementing and maintaining the UMTRA Project's regulatory operating envelope, which involves identifying all applicable regulatory and institutional requirements and determining compliance status. The plan describes how the Project will identify ES ampersand H regulatory requirements, analyze applicability to the UMTRA Project, and evaluate UMTRA Project compliance status

  16. 77 FR 8072 - Semiannual Regulatory Flexibility Agenda

    Science.gov (United States)

    2012-02-13

    ... pledged; and certain other elements including a strategic analysis of the company's plans for maintaining... Expects Further Action........ 01/00/12 Regulatory Flexibility Analysis Required: Yes. Agency Contact... Action........ 12/00/11 Regulatory Flexibility Analysis Required: Yes. Agency Contact: Dena Milligan...

  17. Regulatory Circuits Linking Energy Status to Growth

    NARCIS (Netherlands)

    Jansen, W.M.

    2017-01-01

    Plant growth and development critically depend on carbon nutrient status. Over the past years several core regulatory systems that link plant carbon status to growth have emerged. The core regulatory systems studied include the trehalose 6-phosphate (T6P) signaling system and the Target of Rapamycin

  18. Regulatory and technical reports (abstract index journal)

    International Nuclear Information System (INIS)

    1994-06-01

    This compilation consists of bibliographic data and abstracts for the formal regulatory and technical reports issued by the US Nuclear Regulatory Commission (NRC) Staff and its contractors. It is NRC's intention to publish this compilation quarterly and to cumulate it annually

  19. 77 FR 26413 - Promoting International Regulatory Cooperation

    Science.gov (United States)

    2012-05-04

    ... growth, innovation, competitiveness, and job creation. In an increasingly global economy, international... Order 13609 of May 1, 2012 Promoting International Regulatory Cooperation By the authority vested in me... promote international regulatory cooperation, it is hereby ordered as follows: Section 1. Policy...

  20. Genomics in the land of regulatory science.

    Science.gov (United States)

    Tong, Weida; Ostroff, Stephen; Blais, Burton; Silva, Primal; Dubuc, Martine; Healy, Marion; Slikker, William

    2015-06-01

    Genomics science has played a major role in the generation of new knowledge in the basic research arena, and currently question arises as to its potential to support regulatory processes. However, the integration of genomics in the regulatory decision-making process requires rigorous assessment and would benefit from consensus amongst international partners and research communities. To that end, the Global Coalition for Regulatory Science Research (GCRSR) hosted the fourth Global Summit on Regulatory Science (GSRS2014) to discuss the role of genomics in regulatory decision making, with a specific emphasis on applications in food safety and medical product development. Challenges and issues were discussed in the context of developing an international consensus for objective criteria in the analysis, interpretation and reporting of genomics data with an emphasis on transparency, traceability and "fitness for purpose" for the intended application. It was recognized that there is a need for a global path in the establishment of a regulatory bioinformatics framework for the development of transparent, reliable, reproducible and auditable processes in the management of food and medical product safety risks. It was also recognized that training is an important mechanism in achieving internationally consistent outcomes. GSRS2014 provided an effective venue for regulators andresearchers to meet, discuss common issues, and develop collaborations to address the challenges posed by the application of genomics to regulatory science, with the ultimate goal of wisely integrating novel technical innovations into regulatory decision-making. Published by Elsevier Inc.

  1. Meditation and its regulatory role on sleep

    Directory of Open Access Journals (Sweden)

    Ravindra P. Nagendra

    2012-04-01

    Full Text Available Intense meditation practices help to achieve a harmony between body and mind. Meditation practices influence brain functions, induce various intrinsic neural plasticity events, modulate autonomic, metabolic, endocrine and immune functions and thus mediate global regulatory changes in various behavioural states including sleep. This brief review focuses on the effect of meditation as a self regulatory phenomenon on sleep.

  2. m-government legal and regulatory framework

    African Journals Online (AJOL)

    Wondwossen Mulugeta

    and researchers. CURRENT E-GOVERNMENT. REGULATORY ELEMENTS. In an attempt to regulate the e-Government and. ICT related initiatives the Ethiopian government has been engaged in producing some regulatory and legal documents. These legal document include: e-Signature law, e-Commerce law, data.

  3. 5 CFR 838.102 - Regulatory structure.

    Science.gov (United States)

    2010-01-01

    ... (CONTINUED) COURT ORDERS AFFECTING RETIREMENT BENEFITS Court Orders Generally Organization and Structure of Regulations on Court Orders § 838.102 Regulatory structure. (a) This part is organized as follows: (1) Subpart... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Regulatory structure. 838.102 Section 838...

  4. Adaptive Dynamics of Regulatory Networks: Size Matters

    Directory of Open Access Journals (Sweden)

    Martinetz Thomas

    2009-01-01

    Full Text Available To accomplish adaptability, all living organisms are constructed of regulatory networks on different levels which are capable to differentially respond to a variety of environmental inputs. Structure of regulatory networks determines their phenotypical plasticity, that is, the degree of detail and appropriateness of regulatory replies to environmental or developmental challenges. This regulatory network structure is encoded within the genotype. Our conceptual simulation study investigates how network structure constrains the evolution of networks and their adaptive abilities. The focus is on the structural parameter network size. We show that small regulatory networks adapt fast, but not as good as larger networks in the longer perspective. Selection leads to an optimal network size dependent on heterogeneity of the environment and time pressure of adaptation. Optimal mutation rates are higher for smaller networks. We put special emphasis on discussing our simulation results on the background of functional observations from experimental and evolutionary biology.

  5. Regulatory Competition in Global Financial Markets

    DEFF Research Database (Denmark)

    Ringe, Georg

    2015-01-01

    or operations of financial institutions to other jurisdictions. Where this happens, such arbitrage can trigger regulatory competition between jurisdictions that may respond to the relocation of financial services (or threats to relocate) by moderating regulatory standards. Both arbitrage and regulatory......The decades-long discussion on the merits of regulatory competition appears in a new light on the global financial market. There are a number of strategies that market participants use to avoid the reach of regulation, in particular by virtue of shifting trading abroad or else relocating activities...... competition are a reality in today’s global financial market, and the financial sector is different from their traditional fields of application: the ease of arbitrage, the fragility of banking and the risks involved are exceptional. Most importantly, regulatory arbitrage does not or only rarely occurs...

  6. Annual Report 2011. Nuclear Regulatory Authority

    International Nuclear Information System (INIS)

    2011-01-01

    The present Annual Report of Activities of the Nuclear Regulatory Authority (ARN), prepared regularly from the creation as independent institution, describes across six chapters and seven annexes the activities developed by the organism during 2011. The main topic are: institutional issues; regulatory guides and standards; argentinean nuclear regulatory system; quality assurance of the ARN; the institutional communications; the licensing and inspection of nuclear power plants and critical facilities; the emergency systems; the safeguards and the physical protection; the environmental control; the institutional relations; the training and the public information. Also, this publication have annexes with the following content: the regulatory framework; regulatory documents; inspections to medical, industrial and training installations; measurement and evaluation of the drinking water of Ezeiza; international expert's report on the application of the international standards of radiological protection of the public in the zone of the Ezeiza Atomic Center; ethical code

  7. Annual Report 2010. Nuclear Regulatory Authority

    International Nuclear Information System (INIS)

    2010-01-01

    The present Annual Report of Activities of the Nuclear Regulatory Authority (ARN), prepared regularly from the creation as independent institution, describes across six chapters and seven annexes the activities developed by the organism during 2010. The main topic are: institutional issues; regulatory guides and standards; argentinean nuclear regulatory system; quality assurance of the ARN; the institutional communications; the licensing and inspection of nuclear power plants and critical facilities; the emergency systems; the safeguards and the physical protection; the environmental control; the institutional relations; the training and the public information. Also, this publication have annexes with the following content: the regulatory framework; regulatory documents; inspections to medical, industrial and training installations; measurement and evaluation of the drinking water of Ezeiza; international expert's report on the application of the international standards of radiological protection of the public in the zone of the Ezeiza Atomic Center; ethical code

  8. National legislative and regulatory activities

    International Nuclear Information System (INIS)

    2013-01-01

    This section compiles the presentations of the following texts sorted by country. Armenia - Licensing and regulatory infrastructure: New design safety requirements adopted, New seismic hazard assessment guidelines adopted; France - Licensing and regulatory infrastructure: Decree No. 2012-1248 of 9 November 2012 authorising the ITER Organisation to create the 'ITER' basic nuclear installation in Saint-Paul-lez-Durance (Bouches-du-Rhone); - Nuclear security: Law No. 2012-1473 of 28 December 2012 authorizing the approval of the Amendment to the Convention on the Physical Protection of Nuclear Material; - Nuclear safety and radiological protection: Complementary safety assessments. Follow-up of the stress tests carried out on French nuclear power plants. Action Plan of the French Nuclear Safety Authority (ASN) - December 2012; - International cooperation: Decree No. 2012-1178 of 22 October 2012 publishing the Cooperation Agreement between the government of the French Republic and the government of the Republic of Tunisia for the development of peaceful uses of nuclear energy, signed in Tunis on 23 April 2009; Decree No. 2012-1180 of 22 October 2012 publishing the Cooperation Agreement between the government of the French Republic and the government of Mongolia in the field of nuclear energy (with annex), signed in Ulaanbaatar on 14 October 2010; Germany - General legislation: Bill to amend the Atomic Energy Act to expedite the retrieval of radioactive waste from and to decommission the Asse II Mine (2013); Act to amend the Act on Environmental Legal Remedies and other environmental provisions (2013); - Radiation protection: General administrative rules on Section 47 of the Radiation Protection Ordinance (2012); - Nuclear Safety: Safety requirements for nuclear power plants (2012); - Transport of radioactive material: International Transport of Dangerous Goods by Road (2010, 2012); - Regulations on nuclear trade (including non-proliferation): Export List (2013); Greece

  9. National legislative and regulatory activities

    International Nuclear Information System (INIS)

    Anon.

    2001-01-01

    These columns treat of the legislative and regulatory activities of different OECD countries: Australia (environment protection and biodiversity conservation act and regulations, 1999-2000); Bulgaria (basic standards for radiation protection, 2000); France (decree on the standard tax charged on polluting activities due from operators of installations classified for environmental protection purposes, 2000; amendment of the orders on the transport of dangerous goods by road and by rail, 2000); Georgia (law on nuclear and radiation safety, 1998); Germany (amendments to nuclear legislation implementing EURATOM directives, 2000; amendment to the nuclear third party liability provisions of the atomic energy act, 2001; amendment to the foreign trade ordinance, 2000; ordinance on the treatment of foodstuffs with radiation, 2000; general administrative regulations on radioactivity limits in food and feeds); Ireland (European communities regulations on foodstuffs treated with ionizing radiations, 2000); Japan (law for nuclear sitting area development, 2000; Republic of Korea (amendments to the act on compensation for nuclear damage, 2001); Latvia (act on radiation safety and nuclear safety, 2000); Lithuania (resolution approving the decommissioning program for Unit 1, Ignalina NPP, 2001); Luxembourg (grand-ducal regulations on the protection of the public against the risks resulting from ionizing radiation, 2000; grand-ducal regulations relating to foods and food ingredients treated with ionizing radiation, 2000); Mexico (norm regarding selection, qualification and training requirements for staff of a NPP, 2000; norm regarding solid residue as radioactive waste, 2000); Mongolia (law on nuclear weapons free status and its implementing resolution, 2000); Netherlands (amendment to the nuclear energy act, 2000); Norway (act on radiation and use of radiation, 2000); Pakistan (nuclear authority ordinance, 2001); Poland (atomic energy act, 2000); Spain (royal decree on activities

  10. 77 FR 34379 - Notice of Joint Meeting of the Nuclear Regulatory Commission and the Federal Energy Regulatory...

    Science.gov (United States)

    2012-06-11

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF ENERGY Federal Energy Regulatory Commission Notice of Joint Meeting of the Nuclear Regulatory Commission and the Federal Energy Regulatory Commission The Federal Energy Regulatory Commission (FERC) and the Nuclear Regulatory...

  11. Nuclear energy - some regulatory aspects

    International Nuclear Information System (INIS)

    Jennekens, Jon.

    1980-03-01

    The nuclear industry is often perceived by the public as being uniquely hazardous. As a consequence, the demands placed upon a nuclear regulatory agency invariably include sorting out the valid from the invalid. As the public becomes better informed, more time should become available for regulating the industry. The Canadian nuclear safety philosophy relies upon fundamental principle and basic criteria which licensees must show they are meeting at all stages in the development of a nuclear facility. In reactors, the concept of defence in depth involves the use of well-qualified personnel, compliance with national and international engineering codes and standards, the separation of process and safety systems, frequent testing of safety systems, redundancy in monitoring, control and initiation systems, multiple barriers against fission product release, and strict enforcement of compliance measurements. The Atomic Energy Control Board is writing a set of licensing guides to cover the whole nuclear fuel cycle; however, these will not lead to the impsition of a 'design by regulation' approach in Canada. (LL)

  12. Regulatory measures for traffic safety

    International Nuclear Information System (INIS)

    Veerapur, R.D.; Bharambe, S.D.; Patnaik, S.K.; Tandle, A.K.; Sonawane, K.A.; Kumar, Rajesh; Venkat Subramanian, K.

    2017-01-01

    Traffic safety is an issue related to occupational safety not restricted alone to the transportation but extends beyond. BARC has many facilities spread across large area in Mumbai and outside Mumbai. BARC deploys large number of buses, mini buses, jeeps and cars for commuting its employees to reach BARC and for commuting within BARC premises. Additionally, trucks, fire tenders, trailers etc. are also deployed for transportation of materials. No moving vehicle is ever free of the possibility of involvement in an accident. Vehicular accidents and the fatalities on road are the result of inter-play of a number of factors. The vehicle population has been steadily increasing with the pace picking up significantly in recent past. Increase in vehicle population in the face of limited road space used by a large variety of traffic has heightened the need and urgency for a well-thought-out road safety. Therefore, existence of regulatory authority to regulate traffic and vehicles to ensure safety of its employees and vehicles is very essential. BARC Traffic Safety Committee (BTSC), which is the regulating body for traffic safety is responsible for ensuring overall traffic safety. (author)

  13. Industry Presentation to Regulatory Workshop

    International Nuclear Information System (INIS)

    Treasure, Mark

    2012-01-01

    Mr. Mark Treasure from EDF NGL gave a presentation on industry perspectives on safety culture oversight. Mr. Treasure is the Nuclear Inspection and Oversight Manager within the Safety and Regulation Division. The presentation started with an explanation of the role of the nuclear inspection and oversight group (internal regulator), and their current approach to internal oversight of safety culture. A key element of the current internal regulatory oversight program is Management and Leadership Assessments. These are carried out by a team including management peers from other plants to enhance credibility. Findings can be linked to safety performance, and typically identify issues in areas such as accountability arrangements and strategic focus of the leadership team. Safety indicators have also been introduced to show trends in safety management and safety performance for each EDF UK nuclear power plant. A periodic nuclear safety culture survey is also carried out to identify focus areas and progress. The presentation included discussion on views of the role of the nuclear regulator. Important aspects were identified as: - Supporting the internal regulator by seeking to understand before taking enforcement action, maintaining an open dialogue and recognising that this area is complex and that there is rarely a 'silver bullet' solution. - Communication: being visible and actively discussing safety improvement, and use of language which emphasises nuclear safety rather than legal compliance. - Positive reinforcement to recognise efforts and encourage further improvement

  14. 76 FR 6085 - Draft Regulatory Guide: Issuance, Availability

    Science.gov (United States)

    2011-02-03

    ... 73 [NRC-2011-0014] RIN 3150-AI49 Draft Regulatory Guide: Issuance, Availability AGENCY: Nuclear Regulatory Commission. ACTION: Notice Availability of Draft Regulatory Guide. SUMMARY: The U.S. Nuclear...

  15. DMPD: Regulatory pathways in inflammation. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17967718 Regulatory pathways in inflammation. Mantovani A, Garlanda C, Locati M, Ro....html) (.csml) Show Regulatory pathways in inflammation. PubmedID 17967718 Title Regulatory pathways in infl

  16. Communication Regulatory Science: Mapping a New Field.

    Science.gov (United States)

    Noar, Seth M; Cappella, Joseph N; Price, Simani

    2017-12-13

    Communication regulatory science is an emerging field that uses validated techniques, tools, and models to inform regulatory actions that promote optimal communication outcomes and benefit the public. In the opening article to this special issue on communication and tobacco regulatory science, we 1) describe Food and Drug Administration (FDA) regulation of tobacco products in the US; 2) introduce communication regulatory science and provide examples in the tobacco regulatory science realm; and 3) describe the special issue process and final set of articles. Communication research on tobacco regulatory science is a burgeoning area of inquiry, and this work advances communication science, informs and potentially guides the FDA, and may help to withstand legal challenges brought by the tobacco industry. This research has the potential to have a major impact on the tobacco epidemic and population health by helping implement the most effective communications to prevent tobacco initiation and increase cessation. This special issue provides an example of 10 studies that exemplify tobacco regulatory science and demonstrate how the health communication field can affect regulation and benefit public health.

  17. Regulatory analysis technical evaluation handbook. Final report

    International Nuclear Information System (INIS)

    1997-01-01

    The purpose of this Handbook is to provide guidance to the regulatory analyst to promote preparation of quality regulatory analysis documents and to implement the policies of the Regulatory Analysis Guidelines of the US Nuclear Regulatory Commission (NUREG/BR-0058 Rev. 2). This Handbook expands upon policy concepts included in the NRC Guidelines and translates the six steps in preparing regulatory analyses into implementable methodologies for the analyst. It provides standardized methods of preparation and presentation of regulatory analyses, with the inclusion of input that will satisfy all backfit requirements and requirements of NRC's Committee to Review Generic Requirements. Information on the objectives of the safety goal evaluation process and potential data sources for preparing a safety goal evaluation is also included. Consistent application of the methods provided here will result in more directly comparable analyses, thus aiding decision-makers in evaluating and comparing various regulatory actions. The handbook is being issued in loose-leaf format to facilitate revisions. NRC intends to periodically revise the handbook as new and improved guidance, data, and methods become available

  18. Regulatory analysis technical evaluation handbook. Final report

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1997-01-01

    The purpose of this Handbook is to provide guidance to the regulatory analyst to promote preparation of quality regulatory analysis documents and to implement the policies of the Regulatory Analysis Guidelines of the US Nuclear Regulatory Commission (NUREG/BR-0058 Rev. 2). This Handbook expands upon policy concepts included in the NRC Guidelines and translates the six steps in preparing regulatory analyses into implementable methodologies for the analyst. It provides standardized methods of preparation and presentation of regulatory analyses, with the inclusion of input that will satisfy all backfit requirements and requirements of NRC`s Committee to Review Generic Requirements. Information on the objectives of the safety goal evaluation process and potential data sources for preparing a safety goal evaluation is also included. Consistent application of the methods provided here will result in more directly comparable analyses, thus aiding decision-makers in evaluating and comparing various regulatory actions. The handbook is being issued in loose-leaf format to facilitate revisions. NRC intends to periodically revise the handbook as new and improved guidance, data, and methods become available.

  19. Nuclear Regulatory Commission: more aggressive leadership needed

    International Nuclear Information System (INIS)

    Staats, E.B.

    1980-01-01

    The Energy Reorganization Act of 1974 which established the Nuclear Regulatory Commission required GAO to evaluate the Commission's performance by January 18, 1980. This report responds to that requirement. GAO concluded that, although improvements have been made, the Commission's nuclear regulatory performance can be characterized best as slow, indecisive, cautious - in a word, complacent. This has largely resulted from a lack of aggressive leadership as evidenced by the Commissioners' failure to establish regulatory goals, control policymaking, and most importantly, clearly define their roles in nuclear regulation

  20. Street-level Bureaucrats and Regulatory Deterrence

    DEFF Research Database (Denmark)

    Winter, Søren C.; J. May, Peter

    2015-01-01

    This chapter considers the role of street-level bureaucrats in regulatory deterrence. The empirical foci are the degrees and ways with which regulatory inspectors shape regulated entities’ perceptions that noncompliance will be detected. These are examined using data about the enforcement...... the difficulty of assessing the detection risk, regulated entities use various heuristics regarding competence of inspectors, fairness of inspection, and trust in others that affect their perceptions of the likelihood of violations being detected. These results underscore the importance of fair and competent...... inspection for improving compliance. More generally, the chapter demonstrates the roles street-level bureaucrats fulfill on the frontlines of regulatory enforcement....

  1. Regulatory governance of telecommunications liberalisation in Taiwan

    International Nuclear Information System (INIS)

    Cheng, Kuo-Tai; Hebenton, Bill

    2008-01-01

    This paper examines the changing role of government and market in regulating the telecommunications sector from since 1996 in Taiwan. It contextualises the theoretical aspects of regulatory governance for institutional design and practices, and reviews the concepts and mechanisms for appraising privatisation and regulatory systems. Using a conceptual framework for researching privatisation and regulation, it describes the process and issues pertinent to telecommunications liberalisation and privatisation in Taiwan, supported by a brief presentation of theoretical points of view as well as practitioners' views. The paper presents results concerning criteria for appraising privatisation and regulatory governance and considers policy lessons that can be learned from the experiences of the Taiwanese telecommunications sector's liberalisation. (author)

  2. REGULATORY T CELLS AND VASECTOMY

    Science.gov (United States)

    Rival, Claudia; Wheeler, Karen; Jeffrey, Sarah; Qiao, Hui; Luu, Brian; Tewalt, Eric F; Engelhard, Victor H; Tardif, Stephen; Hardy, Daniel; del Rio, Roxana; Teuscher, Cory; Tung, Kenneth

    2013-01-01

    CD4+CD25+ regulatory T cells (Tregs) strongly influence the early and late autoimmune responses to meiotic germ cell antigens (MGCA) and the gonadal immunopathology in vasectomized mice. This is supported by the published and recently acquired information presented here. Within 24 hours of unilateral vasectomy (uni-vx) the ipsilateral epididymis undergoes epithelial cell apoptosis followed by necrosis, severe inflammation, and granuloma formation. Unexpectedly, vasectomy alone induced MGCA-specific tolerance. In contrast, uni-vx plus simultaneous Treg depletion resulted in MGCA-specific autoimmune response and bilateral autoimmune orchitis. Both tolerance and autoimmunity were strictly linked to the early epididymal injury. We now discovered that testicular autoimmunity in uni-vx mice did not occur when Treg depletion was delayed by one week. Remarkably, this delayed Treg depletion also prevented tolerance induction. Therefore, tolerance depends on a rapid de novo Treg response to MGCA exposed after vasectomy. Moreover, tolerance was blunted in mice genetically deficient in PD-1 ligand, suggesting the involvement of induced Treg. We conclude that pre-existing natural Treg prevents post-vasectomy autoimmunity, whereas vasectomy-induced Treg maintains post-vasectomy tolerance. We further discovered that vasectomized mice were still resistant to autoimmune orchitis induction for at least 12–16 months; thus, tolerance is long-lasting. Although significant sperm autoantibodies of low titers became detectable in uni-vx mice at seven months, the antibody titers fluctuated over time, suggesting a dynamic “balance” between the autoimmune and tolerance states. Finally, we observed severe epididymal fibrosis and hypo-spermatogenesis at 12 months after uni-vx: findings of highly critical clinical significance. PMID:24080233

  3. Regulatory requirements for radiation protection

    International Nuclear Information System (INIS)

    Mason, E.A.; Cunningham, R.E.; Hard, J.E.; Mattson, R.J.; Smith, R.D.; Peterson, H.T. Jr.

    1977-01-01

    Regulatory requirements for radiation protection have evolved and matured over several decades. Due to the wide adoption of recommendations of the International Commission on Radiation Protection (ICRP), there exists international agreement on the principles to be followed for radiation protection. This foundation will be increasingly important due to the growing need for international agreements and standards for radiation protection and radioactive materials management. During the infancy of the commercial nuclear industry, primary reliance was placed on the protection of the individual, both in the work force and as a member of the public. With the growth of nuclear power in the 1960's and 1970's, environmental impact assessments and expert reviews of bio-effects data have focused attention on statistical risks to large population groups and the use of the collective dose commitment concept to estimate potential effects. The potential release of long-lived radionuclides from the nuclear fuel cycle requires further consideration of radionuclide accumulation in the biosphere and calls for controls conceived and implemented at the international level. The initial development efforts for addressing these concerns already have been instituted by the ICRP and the IAEA. However, formal international agreements and a unified set of international standards may be required to implement the recommendations of these groups. Further international efforts in the field of radiation protection are also called for in developing waste management practices and radioactive effluent control technology, in site selection for fuel reprocessing plants and waste dispersal facilities, and for ensuring safe transport of high-level wastes in various forms. Since the regulation of very low dose rates and doses will be involved, it will be useful to reexamine dose-effect relationships and societal goals for health protection. Improved criteria and methodologies for ''as low as readily

  4. Nicotine psychopharmacology: policy and regulatory.

    Science.gov (United States)

    Henningfield, Jack E; Zeller, Mitch

    2009-01-01

    Powerful nerve agent, poison, addictive drug, or wonder medicine of the future? Nicotine has had a long and storied history in pharmacology, physiology, public health and, more recently, in regulatory policy initiatives in the United States and internationally. Psychopharmacology research on nicotine and tobacco came to particular prominence in the latter third of the twentieth century with exploration addressing the role of nicotine in tobacco use, the potential categorization of nicotine as an addictive drug, the pharmacological basis for treatment of tobacco addiction, and the perspective of policy developers seeking to reduce the toll of tobacco use. In fact, the 2005 ratification of the World Health Organization's first global health treaty, the Framework Convention on Tobacco Control, provides further impetus for extending the science foundation for tobacco disease control and policy efforts. Implementation of the treaty's provisions will control tobacco use and reduce the 500 million premature deaths projected to occur in the first half of the twenty-first century from tobacco use. Psychopharmacological research on nicotine and tobacco was important in the rationale and development of the treaty. The public health relevance of psychopharmacology research continues to grow with the realization of the potential of nicotine and related drugs to treat or prevent a diverse range of disorders (e.g., Alzheimer's disease, attention deficit hyperactivity disorder, and pain). Although comprehensive review of the research and implications is beyond the scope of this article, the more modest goal of providing insight into the theoretical, clinical, and policy importance of key psychopharmacology research laboratories over the past few decades is attempted.

  5. A regulatory network for human adenocarcinoma

    African Journals Online (AJOL)

    AJL

    2012-03-13

    Table 3). Regulation network of TF-pathway. To further investigate the regulatory relationships between TFs and pathways, we mapped DEGs to pathways and got a regulation network between TFs and pathways (Figure 2).

  6. Nuclear safety regulatory review and research

    International Nuclear Information System (INIS)

    Queniart, D.

    1979-01-01

    The IPSN is thechnical body that supports the regulatory authorities for nuclear safety in France. This paper presents the connection between safety research and safety analysis, and the role of the IPSN in both fields. (author)

  7. 75 FR 79873 - Semiannual Regulatory Agenda

    Science.gov (United States)

    2010-12-20

    ... Act Subcontract Reporting Procedures 9000-AL63 494 FAR Case 2008-039, Reporting Executive Compensation... Analysis Required: Yes Agency Contact: Karlos Morgan, Procurement Analyst, General Services Administration... Regulatory Flexibility Analysis Required: Yes Agency Contact: Karlos Morgan, Procurement Analyst, General...

  8. Regulatory Hybridization in the Transnational Sphere

    DEFF Research Database (Denmark)

    Hybridization has become a defining feature of regulatory frameworks. The combined forces of globalization and privatization together with increased reliance on self-regulation have resulted in the emergence of a multitude of regulatory arrangements which combine elements from several legal orders....... This book offers a conceptual framework as well as numerous empirical explorations capable of increasing our understanding of regulatory hybridization. A number of central dichotomies are deconstructed: national vs. transnational law; international vs. transnational law; convergence vs. divergence; … read...... moresoft law vs. hard law; territorial vs. non-territorial, ‘top-down’ vs. ‘bottom-up’ globalization and national vs. global just as the implications of regulatory hybridization for the question of choice of court and conflict of laws are analyzed....

  9. 76 FR 40200 - Semiannual Regulatory Flexibility Agenda

    Science.gov (United States)

    2011-07-07

    ... Vol. 76 Thursday, No. 130 July 7, 2011 Part XXI Federal Reserve System Semiannual Regulatory Agenda #0;#0;Federal Register / Vol. 76 , No. 130 / Thursday, July 7, 2011 / Unified Agenda#0;#0; [[Page 40200

  10. Nuclear Regulatory Commission Issuances, December 1980

    International Nuclear Information System (INIS)

    1980-12-01

    Contents: Issuances of the Nuclear Regulatory Commission; Issuances of the Atomic Safety and Licensing Appeal Boards; Issuances of the Atomic Safety and Licensing Boards; and Issuances of the Directors Denial

  11. Systemic Risk and Optimal Regulatory Architecture

    NARCIS (Netherlands)

    Espinosa-Vega, M.A.; Kahn, C.; Matta, R.; Sole, J.

    2011-01-01

    Until the recent financial crisis, the safety and soundness of financial institutions was assessed from the perspective of the individual institution. The financial crisis highlighted the need to take systemic externalities seriously when rethinking prudential oversight and the regulatory

  12. BIOSENSORS FOR ENVIRONMENTAL MONITORING: A REGULATORY PERSPECTIVE

    Science.gov (United States)

    Biosensors show the potential to complement laboratory-based analytical methods for environmental applications. Although biosensors for potential environmental-monitoring applications have been reported for a wide range of environmental pollutants, from a regulatory perspective, ...

  13. Regulatory viewpoint on nuclear fuel quality assurance

    International Nuclear Information System (INIS)

    Tripp, L.E.

    1976-01-01

    Considerations of the importance of fuel quality and performance to nuclear safety, ''as low reasonably achievable'' release of radioactive materials in reactor effluents, and past fuel performance problems demonstrate the need for strong regulatory input, review and inspection of nuclear fuel quality assurance programs at all levels. Such a regulatory program is being applied in the United States of America by the US Nuclear Regulatory Commission. Quality assurance requirements are contained within government regulations. Guidance on acceptable methods of implementing portions of the quality assurance program is contained within Regulatory Guides and other NRC documents. Fuel supplier quality assurance program descriptions are reviewed as a part of the reactor licensing process. Inspections of reactor licensee control of their fuel vendors as well as direct inspections of fuel vendor quality assurance programs are conducted on a regularly scheduled basis. (author)

  14. Regulatory control of radiation sources in Slovakia

    International Nuclear Information System (INIS)

    Auxtova, L.

    2001-01-01

    In Slovakia, there are two regulatory authorities. Regulatory control of the utilization of nuclear energy, based on the Slovak National Council's law No. 130/1998 on the peaceful uses of nuclear energy, is exercised by the Nuclear Regulatory Authority of the Slovak Republic. The second regulatory authority - the Ministry of Health - is empowered by law No. 72/1994 on the protection of human health to license radiation sources and is responsible for radiation protection supervision (there are nearly 3000 establishments with sealed sources, radiation generators and unsealed sources in Slovakia). Pursuant to a new radiation protection regulation based on international standards, radiation sources are to be categorized in six classes according to the associated exposure and contamination hazards. A national strategy for improving the safety of radiation sources over their life-cycle and for the management of disused and orphan sources is being prepared for governmental approval. (author)

  15. Regulatory framework for nuclear power plant operation

    International Nuclear Information System (INIS)

    Perez Alcaniz, T.; Esteban Barriendos, M.

    1995-01-01

    As the framework of standards and requirements covering each phase of nuclear power plant project and operation developed, plant owners defined their licensing commitments (codes, rules and design requirements) during the project and construction phase before start-up and incorporated regulatory requirements imposed by the regulatory Body during the licensing process prior to operation. This produces a regulatory framework for operating a plant. It includes the Licensing Basis, which is the starting point for analyzing and incorporating new requirements, and for re-evaluation of existing ones. This presentation focuses on the problems of applying this regulatory framework to new operating activities, in particular to new projects, analyzing new requirements, and reconsidering existing ones. Clearly establishing a plant's licensing basis allows all organizations involved in plant operation to apply the requirements in a more rational way. (Author)

  16. 75 FR 79863 - Semiannual Regulatory Agenda

    Science.gov (United States)

    2010-12-20

    ... represent that it will make good faith efforts to award subcontracts to small businesses at the same... measurement of management and technical assistance projects conducted by Women's Business Center program... Part XVII Small Business Administration ###Semiannual Regulatory Agenda### [[Page 79864

  17. Mobile Source Emissions Regulatory Compliance Data Inventory

    Data.gov (United States)

    U.S. Environmental Protection Agency — The Mobile Source Emissions Regulatory Compliance Data Inventory data asset contains measured summary compliance information on light-duty, heavy-duty, and non-road...

  18. Regulatory issues in international maritime transport

    Science.gov (United States)

    2001-08-11

    This report focuses on regulations governing international liner and bulk shipping. The report discusses the web of regulatory measures that surround these two segments of the shipping industry, and which have a considerable impact on its performance...

  19. Modernizing the Regulatory System for Biotechnology Products

    Science.gov (United States)

    This Web page describes the continuing effort to modernize the federal regulatory system for biotechnology products as well as clarify various roles of EPA, FDA and USDA in evaluating new biotechnology products.

  20. Regulatory Competition in Global Financial Markets

    DEFF Research Database (Denmark)

    Ringe, Georg

    2016-01-01

    and the evaluation of their merits. I argue that regulatory competition has many advantages over alternative global approaches, notably international harmonization of regulation, by offering a dynamic process for the discovery of efficient regulatory standards. However, the risk is that countries lower......, such arbitrage can trigger regulatory competition between jurisdictions that may respond to the relocation of financial services (or threats to relocate) by moderating their regulatory standards. This study develops a framework for the assessment of both phenomena in the context of financial regulation...... their standards solely to attract business and thereby impose externalities on the worldwide financial market by undermining financial stability as a global public good. Policymakers worldwide are experimenting with remedies to respond to the phenomenon. I introduce the importance of an effective special...

  1. Annual Report 2013. Nuclear Regulatory Authority

    International Nuclear Information System (INIS)

    2010-01-01

    The present Annual Report of Activities of the Nuclear Regulatory Authority (ARN), prepared regularly from the creation as independent institution, describes across seven parts and eight annexes the activities developed by the organism during 2013. The main topic are: the organization and the activity of the ARN; the regulatory standards; the licensing and inspection of nuclear power plants and critical facilities; the emergency systems; the environmental monitoring; the occupational surveillance; the training and the public information; improved organizational and budgetary developments. Also, this publication has annexes with the following content: regulatory documents; inspections to medical; presentations of publications from ARN staff; measurement and evaluation of the drinking water of Ezeiza; international expert report on the implementation of international standards on radiation protection in the Ezeiza Atomic Center; Code of Ethics of the Nuclear Regulatory Authority.

  2. Nuclear Regulatory Commission Issuances, November 1980

    International Nuclear Information System (INIS)

    1980-11-01

    Contents: Issuances of the Nuclear Regulatory Commission; Issuances of the Atomic Safety and Licensing Appeal Boards; Issuances of the Atomic Safety and Licensing Boards; and Issuances of the Directors Denial

  3. Safety culture as a matter of regulatory control and regulatory effectiveness

    International Nuclear Information System (INIS)

    Camargo, C.T.M.; Furieri, E.B.; Arrieta, L.A.I.; Almeida, C.U.C.

    2002-01-01

    More than 15 years have passed since the term 'safety culture' was introduced by the International Nuclear Safety Advisory Group (INSAG), and although the concept now is widely accepted, practical applications and characteristics have been disseminated mainly for nuclear power plant operating organizations. There is still a lack of international guidance on the use of safety culture as a regulatory matter and on the application of the concept within regulatory organizations. This work explores the meaning of safety culture in two different fields: as an element of safety management systems it shall be a matter of regulatory control; as a complementary tool for quality management it should be used to enhance regulatory effectiveness. Brazilian recent experience on regulating nuclear power reactors provide some examples on how the concept of safety culture may influence regulatory strategies and regulatory management. (author)

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

    Directory of Open Access Journals (Sweden)

    José I. Lopez

    2016-04-01

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

  5. Measuring Regulatory Restrictions in Logistics Services

    OpenAIRE

    Claire HOLLWEG; Marn-Heong WONG

    2009-01-01

    This study measures the extent of restrictions on trade in logistics services in the ASEAN+6 economies by constructing a logistics regulatory restrictiveness index for each economy that quantifies the extent of government regulations faced by logistics service providers. This is the first study of its kind to construct a regulatory index of the entire logistics sector, which includes the main modes of international transport and customs restrictions. The indices show that large differences ex...

  6. Mission Risk Reduction Regulatory Change Management

    Science.gov (United States)

    Scroggins, Sharon

    2007-01-01

    NASA Headquarters Environmental Management Division supports NASA's mission to pioneer the future in space exploration, scientific discovery, and aeronautics research by integrating environmental considerations into programs and projects early-on, thereby proactively reducing NASA's exposure to institutional, programmatic and operational risk. As part of this effort, NASA established the Principal Center for Regulatory Risk Analysis and Communication (RRAC PC) as a resource for detecting, analyzing, and communicating environmental regulatory risks to the NASA stakeholder community. The RRAC PC focuses on detecting emerging environmental regulations and other operational change drivers that may pose risks to NASA programs and facilities, and effectively communicating the potential risks. For example, regulatory change may restrict how and where certain activities or operations may be conducted. Regulatory change can also directly affect the ability to use certain materials by mandating a production phase-out or restricting usage applications of certain materials. Regulatory change can result in significant adverse impacts to NASA programs and facilities due to NASA's stringent performance requirements for materials and components related to human-rated space vehicles. Even if a regulation does not directly affect NASA operations, U.S. and international regulations can pose program risks indirectly through requirements levied on manufacturers and vendors of components and materials. For example, manufacturers can change their formulations to comply with new regulatory requirements. Such changes can require time-consuming and costly requalification certification for use in human spaceflight programs. The RRAC PC has implemented a system for proactively managing regulatory change to minimize potential adverse impacts to NASA programs and facilities. This presentation highlights the process utilized by the RRACPC to communicate regulatory change and the associated

  7. A Regulatory RNA Inducing Transgenerationally Inherited Phenotypes

    DEFF Research Database (Denmark)

    Jensen, Lea Møller

    . The variation in Arabidopsis enables different regulatory networks and mechanisms to shape the phenotypic characteristics. The thesis describes the identification of regulatory RNA encoded by an enzyme encoding gene. The RNA regulates by inducing transgenerationally inherited phenotypes. The function of the RNA...... is dependent on the genetic background illustrating that polymorphisms are found in either interactors or target genes of the RNA. Furthermore, the RNA provides a mechanistic link between accumulation of glucosinolate and onset of flowering....

  8. IPTV Market Development and Regulatory Aspects

    DEFF Research Database (Denmark)

    Tadayoni, Reza; Sigurdsson, Halldór Matthias

    2006-01-01

    The aim of this paper is to analyse the development of IPTV technology / market and to discuss major regulatory parameters. A general overview of architectures and the technologies deployed for establishing IPTV services is given and the main stake holder identified, along with, the current service...... architecture, the available content in IPTV platforms, and the current business models. Furthermore the regulatory framework of the TV broadcast and IPTV in Europe is analysed....

  9. Diagnosis of the Brazilian Nuclear Regulatory body

    International Nuclear Information System (INIS)

    Santos Gomes, Rogerio dos; Magalhaes Ennes Ennes, Edson Carlos

    2008-01-01

    This work has the objective to present the diagnosis of the existing structure in the Brazilian Government to ensure the radioprotection and nuclear safety in the country, being compared the current situation with the conclusions presented in another studies, carried through in last 30 years, with special attention in the existence of the necessary available to support and independence of the national regulatory body for the development of the regulatory inspections activities in the radioprotection and nuclear safety. (author)

  10. Radioactive waste management regulatory framework in Mexico

    International Nuclear Information System (INIS)

    Barcenas, M.; Mejia, M.

    2001-01-01

    The purpose of this paper is to present an overview of the current regulatory framework concerning the radioactive waste management in Mexico. It is intended to show regulatory historical antecedents, the legal responsibilities assigned to institutions involved in the radioactive waste management, the sources of radioactive waste, and the development and preparation of national standards for fulfilling the legal framework for low level radioactive waste. It is at present the most important matter to be resolved. (author)

  11. ATMPs for Cancer Immunotherapy: A Regulatory Overview.

    Science.gov (United States)

    Galli, Maria Cristina

    2016-01-01

    This chapter discusses European regulatory requirements for development of advanced therapy medicinal products (ATMP) for cancer immunotherapy approaches, describing the framework for clinical trials and for marketing authorization.Regulatory critical issues and challenges for developing ATMP are also discussed, with focus on potency determination, long-term follow-up, comparability, and insertional mutagenesis issues. Some of the most critical features of GMP application to ATMP are also described.

  12. Advancing a Vision for Regulatory Science Training.

    Science.gov (United States)

    Adamo, Joan E; Wilhelm, Erin E; Steele, Scott J

    2015-10-01

    Regulatory science, a complex field which draws on science, law, and policy, is a growing discipline in medical-related applications. Competencies help define both a discipline and the criteria to measure high-quality learning experiences. This paper identifies competencies for regulatory science, how they were developed, and broader recommendations to enhance education and training in this burgeoning field, including a multifaceted training approach. © 2015 Wiley Periodicals, Inc.

  13. Regulatory policy and the energy sector

    Energy Technology Data Exchange (ETDEWEB)

    Gilland, T. (ed.)

    1993-01-01

    The Centre for the Study of Regulated Industries (CRI) provides a neutral debating forum for parties interested in regulatory matters. This document is composed of the proceedings of a seminar on Regulatory Policy and the Energy Sector held in London in November 1992. The papers cover issues such as the Electricity Supply Price Review, privatization of the United Kingdom coal industry and integrated energy policy, environmental regulation and incentives and the significance of European Commission policies on cross border competition. (UK)

  14. Development of multipurpose regulatory PSA model

    International Nuclear Information System (INIS)

    Lee, Chang Ju; Sung, Key Yong; Kim, Hho Jung; Yang, Joon Eon; Ha, Jae Joo

    2004-01-01

    Generally, risk information for nuclear facilities comes from the results of Probabilistic safety assessment (PSA). PSA is a systematic tool to ensure the safety of nuclear facilities, since it is based on thorough and consistent application of probability models. In particular, the PSA has been widely utilized for risk-informed regulation (RIR), including various licensee-initiated risk-informed applications (RIA). In any regulatory decision, the main goal is to make a sound safety decision based on technically defensible information. Also, due to the increased public requests for giving a safety guarantee, the regulator should provide the visible means of safety. The use of PSA by the regulator can give the answer on this problem. Therefore, in order to study the applicability of risk information for regulatory safety management, it is a demanding task to prepare a well-established regulatory PSA model and tool. In 2002, KINS and KAERI together made a research cooperation to form a working group to develop the regulatory PSA model - so-called MPAS model. The MPAS stands for multipurpose probabilistic analysis of safety. For instance, a role of the MPAS model is to give some risk insights in the preparation of various regulatory programs. Another role of this model is to provide an independent risk information to the regulator during regulatory decision-making, not depending on the licensee's information

  15. KWOC (Key-Word-Out-of-Context) Index of US Nuclear Regulatory Commission Regulatory Guide Series

    Energy Technology Data Exchange (ETDEWEB)

    Jennings, S.D.

    1990-04-01

    To meet the objectives of the program funded by the Department of Energy (DOE)-Nuclear Energy (NE) Technology Support Programs, the Performance Assurance Project Office (PAPO) administers a Performance Assurance Information Program that collects, compiles, and distributes program-related information, reports, and publications for the benefit of the DOE-NE program participants. THE KWOC Index of US Nuclear Regulatory Commission Regulatory Guide Series'' is prepared as an aid in searching for specific topics in the US Nuclear Regulatory Commission, Regulatory Guide Series.

  16. KWOC [Key-Word-Out-of-Context] Index of US Nuclear Regulatory Commission Regulatory Guide Series

    International Nuclear Information System (INIS)

    Jennings, S.D.

    1990-04-01

    To meet the objectives of the program funded by the Department of Energy (DOE)-Nuclear Energy (NE) Technology Support Programs, the Performance Assurance Project Office (PAPO) administers a Performance Assurance Information Program that collects, compiles, and distributes program-related information, reports, and publications for the benefit of the DOE-NE program participants. THE ''KWOC Index of US Nuclear Regulatory Commission Regulatory Guide Series'' is prepared as an aid in searching for specific topics in the US Nuclear Regulatory Commission, Regulatory Guide Series

  17. Nuclear transport - The regulatory dimension

    International Nuclear Information System (INIS)

    Green, L.

    2002-01-01

    is important that regulators and operators comprehend each others positions. There is a clear determination on industry and the key international organisations to maintain dialogue. Through the World Nuclear Transport Institute, industry has a dedicated channel through which it can develop consolidated positions on nuclear transport matters and represent industry's collective views in the key bodies where the regulatory regime is discussed. WNTI provides the nuclear transport industry, with the collective voice in the key intergovernmental agencies which are so important to it. (author)

  18. 76 FR 28102 - Notice of Issuance of Regulatory Guide

    Science.gov (United States)

    2011-05-13

    ..., Probabilistic Risk Assessment Branch, Division of Risk Analysis, Office of Nuclear Regulatory Research, U.S... results of risk analyses are used to help justify regulatory action. As such, the principles, process, and... NUCLEAR REGULATORY COMMISSION [NRC-2009-0385] Notice of Issuance of Regulatory Guide AGENCY...

  19. 12 CFR 567.2 - Minimum regulatory capital requirement.

    Science.gov (United States)

    2010-01-01

    ... 12 Banks and Banking 5 2010-01-01 2010-01-01 false Minimum regulatory capital requirement. 567.2... Regulatory Capital Requirements § 567.2 Minimum regulatory capital requirement. (a) To meet its regulatory capital requirement a savings association must satisfy each of the following capital standards: (1) Risk...

  20. 12 CFR 914.1 - Regulatory Report defined.

    Science.gov (United States)

    2010-01-01

    ... Bank. (b) Examples. Regulatory Report includes: (1) Call reports and reports of instrument-level risk... 12 Banks and Banking 7 2010-01-01 2010-01-01 false Regulatory Report defined. 914.1 Section 914.1... DATA AVAILABILITY AND REPORTING § 914.1 Regulatory Report defined. (a) Definition. Regulatory Report...

  1. 75 FR 36715 - Final Regulatory Guide: Issuance, Availability

    Science.gov (United States)

    2010-06-28

    ... From the Federal Register Online via the Government Publishing Office NUCLEAR REGULATORY COMMISSION Final Regulatory Guide: Issuance, Availability AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Regulatory Guide, RG 1.62. FOR FURTHER INFORMATION CONTACT: Karl J...

  2. 7 CFR 1700.32 - Program Accounting and Regulatory Analysis.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 11 2010-01-01 2010-01-01 false Program Accounting and Regulatory Analysis. 1700.32... Accounting and Regulatory Analysis. RUS, through Program Accounting and Regulatory Analysis, monitors and... Assistant Administrator, Program Accounting and Regulatory Analysis, directs and coordinates program...

  3. 76 FR 14108 - Notice of Issuance of Regulatory Guide

    Science.gov (United States)

    2011-03-15

    ... implementing specific parts of the agency's regulations, techniques that the staff uses in evaluating specific... ``Regulatory Guides'' at http://www.nrc.gov/reading-rm/doc-collections/ . The regulatory analysis may be found... COMMISSION Notice of Issuance of Regulatory Guide AGENCY: Nuclear Regulatory Commission. ACTION: Notice of...

  4. National legislative and regulatory activities

    International Nuclear Information System (INIS)

    2017-01-01

    This section treats of the following National legislative and regulatory activities: 1 - Algeria, Nuclear safety and radiological protection, Executive Decree No. 17-126 of 27 March 2017; 2 - Belgium, Liability and compensation, Law of 7 December 2016 modifying the law of 22 July 1985 on third party liability in the field of nuclear energy; 3 - Canada, Liability and compensation, Ratification by Canada of the Convention on Supplementary Compensation for Nuclear Damage; 4 - France, Radioactive waste management: Decree No. 2017-231 of 23 February 2017 implementing Article L. 542-1-2 of the French Environmental Code (Code de l'environnement) and setting out the provisions of the National Radioactive Material and Waste Management Plan; and Order of 23 February 2017 implementing Decree No. 2017-231 of 23 February 2017 implementing Article L. 542-1-2 of the French Environmental Code setting out the provisions of the National Radioactive Material and Waste Management Plan; Liability and compensation: Order of 10 November 2016 amending the Appendix to the Order of 19 August 2016, setting the list of reduced liability amount sites pursuant to Decree No. 2016-333 of 21 March 2016 implementing Article L. 597-28 of the Environmental Code and relating to third party liability in the nuclear energy field; International co-operation: Decree No. 2016-1225 of 16 September 2016 making public the Protocol to the Co-operation Agreement between the Government of the French Republic and the Government of the Hashemite Kingdom of Jordan for the Development of the Pacific Uses of Nuclear Energy, signed in Paris on 27 August 2008; 5 - Germany, Transport of radioactive materials: New Versions of Ordinances on the Transport of Dangerous Goods (2017); Radioactive Waste Management: Act on the Reorganisation of the Responsibility of Nuclear Waste Disposal (2017); 6 - Lithuania, Nuclear security: Cyber security; Nuclear installations: Free release criteria of buildings and site of nuclear

  5. 75 FR 8771 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving...

    Science.gov (United States)

    2010-02-25

    ... to furnish, upon the written request of the other member, a statement of its financial condition as...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving Proposed Rule Change To Adopt FINRA Rule 2261 (Disclosure of Financial Condition) in the Consolidated FINRA Rulebook...

  6. 75 FR 475 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of...

    Science.gov (United States)

    2010-01-05

    ... member, a statement of its financial condition as disclosed in its most recently prepared balance sheet...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of Proposed Rule Change To Adopt FINRA Rule 2261 (Disclosure of Financial Condition) in the Consolidated FINRA Rulebook...

  7. 78 FR 69732 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of...

    Science.gov (United States)

    2013-11-20

    ...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of a Proposed Rule Change To Amend FINRA Rule 8312 (FINRA BrokerCheck Disclosure) To Include Information About Members and Their Associated Persons of Any Registered National Securities Exchange That Uses the CRD System for...

  8. 76 FR 72736 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Granting...

    Science.gov (United States)

    2011-11-25

    ... two reporting formats simultaneously, but that if a firm has a system-related issue during the MPP... reporting of certain bonds with sinking funds, that ``FINRA is engaged in an ongoing review of issues raised...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Granting Approval of Proposed...

  9. 76 FR 63969 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of...

    Science.gov (United States)

    2011-10-14

    ...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of Amendment No. 1 to Proposed Rule Change To Adopt FINRA Rule 2231 (Customer Account Statements) in the Consolidated... Account Statements) in the Consolidated FINRA Rulebook (``Notice''). The Notice contained incorrect...

  10. 76 FR 21932 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Granting...

    Science.gov (United States)

    2011-04-19

    ... correct a statement therein, as follows: I. Introduction On February 4, 2011, the Financial Industry... COMMISSION Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Granting Approval of a Proposed Rule Change Relating to Promissory Note Proceedings; Correction April 13, 2011. Need...

  11. Safeguards inventory and process monitoring regulatory comparison

    Energy Technology Data Exchange (ETDEWEB)

    Cavaluzzi, Jack M. [Texas A & M Univ., College Station, TX (United States); Gibbs, Philip W. [Brookhaven National Lab. (BNL), Upton, NY (United States)

    2013-06-27

    Detecting the theft or diversion of the relatively small amount of fissile material needed to make a nuclear weapon given the normal operating capacity of many of today’s running nuclear production facilities is a difficult task. As throughput increases, the ability of the Material Control and Accountability (MC&A) Program to detect the material loss decreases because the statistical measurement uncertainty also increases. The challenge faced is the ability of current accounting, measurement, and material control programs to detect small yet significant losses under some regulatory approaches can decrease to the point where it is extremely low if not practically non-existent at normal operating capacities. Adding concern to this topic is that there are variations among regulatory bodies as far as what is considered a Significant Quantity (SQ). Some research suggests that thresholds should be lower than those found in any current regulation which if adopted would make meeting detection goals even more difficult. This paper reviews and compares the current regulatory requirements for the MA elements related to physical inventory, uncertainty of the Inventory Difference (ID), and Process Monitoring (PM) in the United States Department of Energy (DOE) and Nuclear Regulatory Commission (NRC), Rosatom of the Russian Federation and the Chinese Atomic Energy Agency (CAEA) of China. The comparison looks at how the regulatory requirements for the implementation of various MA elements perform across a range of operating capacities in example facilities.

  12. Use of risk information in regulatory reviews

    International Nuclear Information System (INIS)

    Sagar, B.; Benke, R.; Mohanty, S.

    2004-01-01

    The regulatory framework for licensing any high-level waste repository at Yucca Mountain in the United States, calls for appropriate use of risk information to ensure operational safety during the pre-closure period and long-term safety during the post-closure period. This paper focuses on the post-closure period. Regulations in the Code of Federal Regulations (CFR), Title 10, Part 63, apply to any repository at Yucca Mountain and envision use of probabilistic methods to develop quantitative risk information. Accumulated engineering and scientific experience at Yucca Mountain and analog sites and quantitative risk information from studies conducted by the implementer, regulator, and others are combined to formulate 'risk insights,' which are then used to plan and execute regulatory reviews. The U.S. Nuclear Regulatory Commission (NRC) and the Center for Nuclear Waste Regulatory Analyses (CNWRA) recently consolidated the knowledge gained during several g ears and developed such risk insights for the potential repository at Yucca Mountain. This paper discusses the types of risk information used to generate risk insights and how the risk insights will be used in regulatory reviews. A companion paper presents more details on sensitivity analysis methods used to generate risk information. (authors)

  13. Regulatory focus affects physician risk tolerance.

    Science.gov (United States)

    Veazie, Peter J; McIntosh, Scott; Chapman, Benjamin P; Dolan, James G

    2014-01-01

    Risk tolerance is a source of variation in physician decision-making. This variation, if independent of clinical concerns, can result in mistaken utilization of health services. To address such problems, it will be helpful to identify nonclinical factors of risk tolerance, particularly those amendable to intervention-regulatory focus theory suggests such a factor. This study tested whether regulatory focus affects risk tolerance among primary care physicians. Twenty-seven primary care physicians were assigned to promotion-focused or prevention-focused manipulations and compared on the Risk Taking Attitudes in Medical Decision Making scale using a randomization test. Results provide evidence that physicians assigned to the promotion-focus manipulation adopted an attitude of greater risk tolerance than the physicians assigned to the prevention-focused manipulation (p = 0.01). The Cohen's d statistic was conventionally large at 0.92. Results imply that situational regulatory focus in primary care physicians affects risk tolerance and may thereby be a nonclinical source of practice variation. Results also provide marginal evidence that chronic regulatory focus is associated with risk tolerance (p = 0.05), but the mechanism remains unclear. Research and intervention targeting physician risk tolerance may benefit by considering situational regulatory focus as an explanatory factor.

  14. Scientific underpinnings of biotechnology regulatory frameworks.

    Science.gov (United States)

    Gleim, Savannah; Smyth, Stuart J

    2018-05-25

    Part of what is presently missing at domestic regulatory levels (and that is important at the international level as well) is a detailed understanding of what the rules of, and for, regulation should be, who the actors, stakeholders and major decision makers are and finally, how to get agreement about the rules. Greater insights into the system of rules that underpin regulatory frameworks for agri-food and biotechnology products in genetically modified (GM) crop- adopting nations will provide value by clarifying the evidence used to commercialize these technologies. This article examines the public documents available from Canada, the United States, the European Union and the Organisation for Economic Cooperation and Development regarding the development of regulatory risk assessment frameworks for products of biotechnology to determine what science grounds these frameworks. The documentation used to provide the initial structure to the existing regulatory frameworks identifies the linkages, connections and relationships that exist between science, risk assessment and regulatory policy. The relationship between risk and regulation has never been more critical to the commercialization of innovative agricultural products. Documenting the role of science-based risk assessment in regulations and how this has changed over the 20 years of experience in regulating GM crops will identify changes in the risk/regulation relationship. Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved.

  15. Regulatory aspects of criticality control in Australia

    International Nuclear Information System (INIS)

    Zimin, Sergei

    2003-01-01

    With the creation of Australian Radiation Protection and Nuclear Safety Agency (ARPANSA) the Australian approach to criticality safety was revisited. Consistency with international best practices is required by the Act that created ARPANSA and this was applied to practices in criticality safety adopted in other countries. This required extensive regulatory efforts both in auditing the major Australian Nuclear Operator, Australian Nuclear Science and Technology Organisation (ANSTO), and assessing the existing in Australia criticality safety practices and implementing the required changes using the new legislative power of ARPANSA. The adopted regulatory approach is formulated through both the issued by ARPANSA licenses for nuclear installations (including reactors, fuel stores and radioactive waste stores) and the string of new regulatory documents, including the Regulatory Assessment Principles and the Regulatory Assessment Guidelines for criticality safety. The main features of the adopted regulation include the requirements of independent peer-review, ongoing refresher training coupled with annual accreditation and the reliance on the safe design rather than on an administrative control. (author)

  16. Phylogeny based discovery of regulatory elements

    Directory of Open Access Journals (Sweden)

    Cohen Barak A

    2006-05-01

    Full Text Available Abstract Background Algorithms that locate evolutionarily conserved sequences have become powerful tools for finding functional DNA elements, including transcription factor binding sites; however, most methods do not take advantage of an explicit model for the constrained evolution of functional DNA sequences. Results We developed a probabilistic framework that combines an HKY85 model, which assigns probabilities to different base substitutions between species, and weight matrix models of transcription factor binding sites, which describe the probabilities of observing particular nucleotides at specific positions in the binding site. The method incorporates the phylogenies of the species under consideration and takes into account the position specific variation of transcription factor binding sites. Using our framework we assessed the suitability of alignments of genomic sequences from commonly used species as substrates for comparative genomic approaches to regulatory motif finding. We then applied this technique to Saccharomyces cerevisiae and related species by examining all possible six base pair DNA sequences (hexamers and identifying sequences that are conserved in a significant number of promoters. By combining similar conserved hexamers we reconstructed known cis-regulatory motifs and made predictions of previously unidentified motifs. We tested one prediction experimentally, finding it to be a regulatory element involved in the transcriptional response to glucose. Conclusion The experimental validation of a regulatory element prediction missed by other large-scale motif finding studies demonstrates that our approach is a useful addition to the current suite of tools for finding regulatory motifs.

  17. Functional characterization of variations on regulatory motifs.

    Directory of Open Access Journals (Sweden)

    Michal Lapidot

    2008-03-01

    Full Text Available Transcription factors (TFs regulate gene expression through specific interactions with short promoter elements. The same regulatory protein may recognize a variety of related sequences. Moreover, once they are detected it is hard to predict whether highly similar sequence motifs will be recognized by the same TF and regulate similar gene expression patterns, or serve as binding sites for distinct regulatory factors. We developed computational measures to assess the functional implications of variations on regulatory motifs and to compare the functions of related sites. We have developed computational means for estimating the functional outcome of substituting a single position within a binding site and applied them to a collection of putative regulatory motifs. We predict the effects of nucleotide variations within motifs on gene expression patterns. In cases where such predictions could be compared to suitable published experimental evidence, we found very good agreement. We further accumulated statistics from multiple substitutions across various binding sites in an attempt to deduce general properties that characterize nucleotide substitutions that are more likely to alter expression. We found that substitutions involving Adenine are more likely to retain the expression pattern and that substitutions involving Guanine are more likely to alter expression compared to the rest of the substitutions. Our results should facilitate the prediction of the expression outcomes of binding site variations. One typical important implication is expected to be the ability to predict the phenotypic effect of variation in regulatory motifs in promoters.

  18. Regulatory principles governing Salmonella and Yersinia virulence

    Science.gov (United States)

    Erhardt, Marc; Dersch, Petra

    2015-01-01

    Enteric pathogens such as Salmonella and Yersinia evolved numerous strategies to survive and proliferate in different environmental reservoirs and mammalian hosts. Deciphering common and pathogen-specific principles for how these bacteria adjust and coordinate spatiotemporal expression of virulence determinants, stress adaptation, and metabolic functions is fundamental to understand microbial pathogenesis. In order to manage sudden environmental changes, attacks by the host immune systems and microbial competition, the pathogens employ a plethora of transcriptional and post-transcriptional control elements, including transcription factors, sensory and regulatory RNAs, RNAses, and proteases, to fine-tune and control complex gene regulatory networks. Many of the contributing global regulators and the molecular mechanisms of regulation are frequently conserved between Yersinia and Salmonella. However, the interplay, arrangement, and composition of the control elements vary between these closely related enteric pathogens, which generate phenotypic differences leading to distinct pathogenic properties. In this overview we present common and different regulatory networks used by Salmonella and Yersinia to coordinate the expression of crucial motility, cell adhesion and invasion determinants, immune defense strategies, and metabolic adaptation processes. We highlight evolutionary changes of the gene regulatory circuits that result in different properties of the regulatory elements and how this influences the overall outcome of the infection process. PMID:26441883

  19. Evolution of Cis-Regulatory Elements and Regulatory Networks in Duplicated Genes of Arabidopsis.

    Science.gov (United States)

    Arsovski, Andrej A; Pradinuk, Julian; Guo, Xu Qiu; Wang, Sishuo; Adams, Keith L

    2015-12-01

    Plant genomes contain large numbers of duplicated genes that contribute to the evolution of new functions. Following duplication, genes can exhibit divergence in their coding sequence and their expression patterns. Changes in the cis-regulatory element landscape can result in changes in gene expression patterns. High-throughput methods developed recently can identify potential cis-regulatory elements on a genome-wide scale. Here, we use a recent comprehensive data set of DNase I sequencing-identified cis-regulatory binding sites (footprints) at single-base-pair resolution to compare binding sites and network connectivity in duplicated gene pairs in Arabidopsis (Arabidopsis thaliana). We found that duplicated gene pairs vary greatly in their cis-regulatory element architecture, resulting in changes in regulatory network connectivity. Whole-genome duplicates (WGDs) have approximately twice as many footprints in their promoters left by potential regulatory proteins than do tandem duplicates (TDs). The WGDs have a greater average number of footprint differences between paralogs than TDs. The footprints, in turn, result in more regulatory network connections between WGDs and other genes, forming denser, more complex regulatory networks than shown by TDs. When comparing regulatory connections between duplicates, WGDs had more pairs in which the two genes are either partially or fully diverged in their network connections, but fewer genes with no network connections than the TDs. There is evidence of younger TDs and WGDs having fewer unique connections compared with older duplicates. This study provides insights into cis-regulatory element evolution and network divergence in duplicated genes. © 2015 American Society of Plant Biologists. All Rights Reserved.

  20. Nuclear Regulatory Commission Information Digest, 1991 edition

    International Nuclear Information System (INIS)

    Olive, K.L.

    1991-03-01

    The Nuclear Regulatory Commission Information Digest provides a summary of information about the US Nuclear Regulatory Commission (NRC), NRC's regulatory responsibilities, and the areas NRC licenses. This digest is a compilation of NRC-related data and is designed to provide a quick reference to major facts about the agency and the industry it regulates. In general, the data cover 1975 through 1990, with exceptions noted. For operating US commercial nuclear power reactors, information on generating capacity and average capacity factor is obtained from Monthly Operating Reports submitted to the NRC directly by the licensee. This information is reviewed for consistency only. No independent validation and/or verification is performed by the NRC. For detailed and complete information about tables and figures, refer to the source publications. This digest is published annually for the general use of the NRC staff and is available to the public. 30 figs., 12 tabs

  1. Current status of developmental neurotoxicity: regulatory view

    DEFF Research Database (Denmark)

    Hass, Ulla

    2003-01-01

    . Until recently, however, developmental neurotoxicity testing of industrial chemicals has not been a clear regulatory requirement in EU, probably due to the lack of an accepted OECD TG. The revised EU Technical Guidance Document for Risk Assessment (EU-TGD) has now included the OECD draft TG 426...... in the testing strategy for new and existing substances, and biocides. Hopefully, this will lead to an improved database for risk assessment of potential developmental neurotoxicants. However, the regulatory authorities and toxicologists will also be faced with the challenge that decisions have to be made......The need for developmental neurotoxicity testing has been recognized for decades and guidelines are available, as the USEPA guideline and the OECD draft TG 426. Regulatory testing of industrial chemicals for developmental neurotoxicity is required to some extent, especially for pesticides in the US...

  2. Structure and drafting of safeguards regulatory documents

    International Nuclear Information System (INIS)

    Cole, R.J.; Bennett, C.A.; Edelhertz, H.; Wood, M.T.; Brown, R.J.; Roberts, F.P.

    1977-09-01

    This study develops hypothesis about the relation between the structure and drafting of safeguards regulatory documents and the ability of document users to understand and implement them in a way that reflects the intent and requirements of the NRC. Four decisions are needed to improve communication: (1) Should improvement of safeguards regulatory documents as communication instruments be an explicit NRC program. (2) What specific methods of communication should be the focus of improvement efforts. (3) What actions to improve communications are feasible and desirable. (4) How should the NRC divide its available effort and resources among desirable actions in order to provide the most effective communication through regulatory documents. This volume contains: introduction, conceptual bases, legal requirements, targets, choice of documents, preparation of documents, readability, and further study of recommended changes in structure and drafting

  3. Current approaches to gene regulatory network modelling

    Directory of Open Access Journals (Sweden)

    Brazma Alvis

    2007-09-01

    Full Text Available Abstract Many different approaches have been developed to model and simulate gene regulatory networks. We proposed the following categories for gene regulatory network models: network parts lists, network topology models, network control logic models, and dynamic models. Here we will describe some examples for each of these categories. We will study the topology of gene regulatory networks in yeast in more detail, comparing a direct network derived from transcription factor binding data and an indirect network derived from genome-wide expression data in mutants. Regarding the network dynamics we briefly describe discrete and continuous approaches to network modelling, then describe a hybrid model called Finite State Linear Model and demonstrate that some simple network dynamics can be simulated in this model.

  4. CD4-regulatory cells in COPD patients

    DEFF Research Database (Denmark)

    Smyth, Lucy J C; Starkey, Cerys; Vestbo, Jørgen

    2007-01-01

    BACKGROUND: The numbers of airway CD8 and B lymphocytes are increased in COPD patients, suggesting an autoimmune process. CD4-regulatory T cells control autoimmunity but have not been studied in patients with COPD. OBJECTIVE: To compare T-regulatory cell numbers in the BAL from COPD patients......, smokers with normal lung function, and healthy nonsmokers (HNS). METHODS: BAL and peripheral blood mononuclear cell (PBMC) samples were obtained from 26 COPD patients, 19 smokers, and 8 HNS. Flow cytometry was performed for regulatory phenotypic markers. RESULTS: COPD patients had increased BAL CD8...... numbers compared to smokers and HNS. CD4 numbers were similar between groups. There was increased BAL CD4CD25(bright) expression in smokers (median 28.8%) and COPD patients (median 23.1%) compared to HNS (median 0%). Increased FoxP3 expression was confirmed in BAL CD4CD25(bright) cells. BAL CD4CD25 cells...

  5. Regulatory Activities for Licensee's Safety Culture

    International Nuclear Information System (INIS)

    Choi, Young Sung; Choi, Kwang Sik

    2008-01-01

    Weaknesses in safety culture have contributed to a number of incidents/accidents in the nuclear and other high hazard sectors worldwide in the past. These events have fostered an increasing awareness of the need for licensees to develop a strong safety culture to support successful and sustainable nuclear safety performance. Regulatory bodies are taking a growing interest in this issue, and several are actively working to develop and implement approaches to maintaining regulatory oversight of licensee safety culture. However, these approaches are not yet well-established, and it was considered prudent to share experiences and developing methodologies in order to disseminate good practices and avoid potential pitfalls. This paper presents the findings, conclusions and recommendations of international meetings and other countries' activities on safety culture and gives some suggestions for regulators to consider when planning regulatory oversight for licensee's safety culture

  6. Regulatory governance of telecommunications liberalisation in Taiwan

    Energy Technology Data Exchange (ETDEWEB)

    Cheng, Kuo-Tai [Department of Regional Studies in Humanity and Social Sciences, National Hsin-Chu University of Education, No. 521 Nan-Da Road, Hsin-Chu 300 (China); Hebenton, Bill [School of Law, University of Manchester, M13 9PP (United Kingdom)

    2008-12-15

    This paper examines the changing role of government and market in regulating the telecommunications sector from since 1996 in Taiwan. It contextualises the theoretical aspects of regulatory governance for institutional design and practices, and reviews the concepts and mechanisms for appraising privatisation and regulatory systems. Using a conceptual framework for researching privatisation and regulation, it describes the process and issues pertinent to telecommunications liberalisation and privatisation in Taiwan, supported by a brief presentation of theoretical points of view as well as practitioners' views. The paper presents results concerning criteria for appraising privatisation and regulatory governance and considers policy lessons that can be learned from the experiences of the Taiwanese telecommunications sector's liberalisation. (author)

  7. Targeting regulatory T cells in cancer.

    LENUS (Irish Health Repository)

    Byrne, William L

    2012-01-31

    Infiltration of tumors by regulatory T cells confers growth and metastatic advantages by inhibiting antitumor immunity and by production of receptor activator of NF-kappaB (RANK) ligand, which may directly stimulate metastatic propagation of RANK-expressing cancer cells. Modulation of regulatory T cells can enhance the efficacy of cancer immunotherapy. Strategies include depletion, interference with function, inhibition of tumoral migration, and exploitation of T-cell plasticity. Problems with these strategies include a lack of specificity, resulting in depletion of antitumor effector T cells or global interruption of regulatory T cells, which may predispose to autoimmune diseases. Emerging technologies, such as RNA interference and tetramer-based targeting, may have the potential to improve selectivity and efficacy.

  8. Nuclear Regulatory Commission Information Digest 1992 edition

    International Nuclear Information System (INIS)

    Olive, K.

    1992-03-01

    The Nuclear Regulatory Commission Information Digest provides a summary of information about the US Nuclear Regulatory Commission (NRC), NRC's regulatory responsibilities, the activities NRC licenses, and general information on domestic and worldwide nuclear energy. This digest is a compilation of nuclear- and NRC-related data and is designed to provide a quick reference to major facts about the agency and industry it regulates. In general, the data cover 1975 through 1991, with exceptions noted. Information on generating capacity and average capacity factor for operating US commercial nuclear power reactors is obtained from monthly operating reports that are submitted directly to the NRC by the licensee. This information is reviewed by the NRC for consistency only and no independent validation and/or verification is performed

  9. Transcription regulatory networks analysis using CAGE

    KAUST Repository

    Tegnér, Jesper N.

    2009-10-01

    Mapping out cellular networks in general and transcriptional networks in particular has proved to be a bottle-neck hampering our understanding of biological processes. Integrative approaches fusing computational and experimental technologies for decoding transcriptional networks at a high level of resolution is therefore of uttermost importance. Yet, this is challenging since the control of gene expression in eukaryotes is a complex multi-level process influenced by several epigenetic factors and the fine interplay between regulatory proteins and the promoter structure governing the combinatorial regulation of gene expression. In this chapter we review how the CAGE data can be integrated with other measurements such as expression, physical interactions and computational prediction of regulatory motifs, which together can provide a genome-wide picture of eukaryotic transcriptional regulatory networks at a new level of resolution. © 2010 by Pan Stanford Publishing Pte. Ltd. All rights reserved.

  10. Statistical significance of cis-regulatory modules

    Directory of Open Access Journals (Sweden)

    Smith Andrew D

    2007-01-01

    Full Text Available Abstract Background It is becoming increasingly important for researchers to be able to scan through large genomic regions for transcription factor binding sites or clusters of binding sites forming cis-regulatory modules. Correspondingly, there has been a push to develop algorithms for the rapid detection and assessment of cis-regulatory modules. While various algorithms for this purpose have been introduced, most are not well suited for rapid, genome scale scanning. Results We introduce methods designed for the detection and statistical evaluation of cis-regulatory modules, modeled as either clusters of individual binding sites or as combinations of sites with constrained organization. In order to determine the statistical significance of module sites, we first need a method to determine the statistical significance of single transcription factor binding site matches. We introduce a straightforward method of estimating the statistical significance of single site matches using a database of known promoters to produce data structures that can be used to estimate p-values for binding site matches. We next introduce a technique to calculate the statistical significance of the arrangement of binding sites within a module using a max-gap model. If the module scanned for has defined organizational parameters, the probability of the module is corrected to account for organizational constraints. The statistical significance of single site matches and the architecture of sites within the module can be combined to provide an overall estimation of statistical significance of cis-regulatory module sites. Conclusion The methods introduced in this paper allow for the detection and statistical evaluation of single transcription factor binding sites and cis-regulatory modules. The features described are implemented in the Search Tool for Occurrences of Regulatory Motifs (STORM and MODSTORM software.

  11. Regulatory and technical reports compilation for 1980

    International Nuclear Information System (INIS)

    Oliu, W.E.; McKenzi, L.

    1981-04-01

    This compilation lists formal regulatory and technical reports and conference proceedings issued in 1980 by the US Nuclear Regulatory Commission. The compilation is divided into four major sections. The first major section consists of a sequential listing of all NRC reports in report-number order. The second major section of this compilation consists of a key-word index to report titles. The third major section contains an alphabetically arranged listing of contractor report numbers cross-referenced to their corresponding NRC report numbers. Finally, the fourth section is an errata supplement

  12. REDfly: a Regulatory Element Database for Drosophila.

    Science.gov (United States)

    Gallo, Steven M; Li, Long; Hu, Zihua; Halfon, Marc S

    2006-02-01

    Bioinformatics studies of transcriptional regulation in the metazoa are significantly hindered by the absence of readily available data on large numbers of transcriptional cis-regulatory modules (CRMs). Even the richly annotated Drosophila melanogaster genome lacks extensive CRM information. We therefore present here a database of Drosophila CRMs curated from the literature complete with both DNA sequence and a searchable description of the gene expression pattern regulated by each CRM. This resource should greatly facilitate the development of computational approaches to CRM discovery as well as bioinformatics analyses of regulatory sequence properties and evolution.

  13. Dietary Supplements: Regulatory Challenges and Research Resources.

    Science.gov (United States)

    Dwyer, Johanna T; Coates, Paul M; Smith, Michael J

    2018-01-04

    Many of the scientific and regulatory challenges that exist in research on the safety, quality and efficacy of dietary supplements are common to all countries as the marketplace for them becomes increasingly global. This article summarizes some of the challenges in supplement science and provides a case study of research at the Office of Dietary Supplements at the National Institutes of Health, USA, along with some resources it has developed that are available to all scientists. It includes examples of some of the regulatory challenges faced and some resources for those who wish to learn more about them.

  14. Safety culture from a regulatory perspective

    International Nuclear Information System (INIS)

    Dahlgren, K.

    1996-01-01

    The Swedish Nuclear Power Inspectorate, SKI, has in its regulatory approach to the area of management and organization focussed on the process of continuous improvement and have in collaboration with Battelle Human Affairs Research Center, Seattle, developed a conceptual model of the important characteristics of a continuous improvement organization and how to assess it. In this work SKI has also recognized the importance of the regulatory goals and strategies adopted by SKI for promoting an improvement process on the part of the utilities, which will be further discussed below. 15 refs

  15. Regulatory Competition in Global Financial Markets

    DEFF Research Database (Denmark)

    Ringe, Georg

    2015-01-01

    competition are a reality in today’s global financial market, and the financial sector is different from their traditional fields of application: the ease of arbitrage, the fragility of banking and the risks involved are exceptional. Most importantly, regulatory arbitrage does not or only rarely occurs......The decades-long discussion on the merits of regulatory competition appears in a new light on the global financial market. There are a number of strategies that market participants use to avoid the reach of regulation, in particular by virtue of shifting trading abroad or else relocating activities...

  16. Regulatory affairs for biomaterials and medical devices

    CERN Document Server

    Amato, Stephen F; Amato, B

    2015-01-01

    All biomaterials and medical devices are subject to a long list of regulatory practises and policies which must be adhered to in order to receive clearance. This book provides readers with information on the systems in place in the USA and the rest of the world. Chapters focus on a series of procedures and policies including topics such as commercialization, clinical development, general good practise manufacturing and post market surveillance.Addresses global regulations and regulatory issues surrounding biomaterials and medical devicesEspecially useful for smaller co

  17. Excessive crying in infants with regulatory disorders.

    Science.gov (United States)

    Maldonado-Duran, M; Sauceda-Garcia, J M

    1996-01-01

    The authors point out a correlation between regulatory disorders in infants and the problem of excessive crying. The literature describes other behavioral problems involving excessive crying in very young children, but with little emphasis on this association. The recognition and diagnosis of regulatory disorders in infants who cry excessively can help practitioners design appropriate treatment interventions. Understanding these conditions can also help parents tailor their caretaking style, so that they provide appropriate soothing and stimulation to their child. In so doing, they will be better able to develop and preserve a satisfactory parent-child relationship, as well as to maintain their own sense of competence and self-esteem as parents.

  18. Needs of research for regulatory purposes

    International Nuclear Information System (INIS)

    Wanner, H.

    2010-01-01

    Hans Wanner, Swiss Federal Nuclear Safety Inspectorate (ENSI), presented a general overview of regulatory research at the international level based on a preliminary input from international colleagues and observed that the question of active involvement of nuclear regulatory and supervisory bodies in R and D projects has become a topic of increasing interest in recent years even if the way in which research is included in regulatory activities varies from country to country. The range spans from countries with no regulatory R and D activities to countries with extensive activities that are often carried out by independent research organisations acting on behalf of the regulatory body. In a few countries, the regulator and implementer have their research carried out by the same research institutes. As an example H. Wanner explained the organisation of R and D work in Switzerland. He presented the potential merits of R and D work carried out by the regulator and introduced a number of questions that would gain from being addressed at an international level. He stressed that the R and D work performed by the implementer must be comprehensive and there should be, in principle, no need for complementary work by the regulatory body. Nevertheless, R and D work of the regulator has still several merits. It improves the regulator's necessary competence to review the safety case allowing it to rely on the scientific community. It provides the regulator's independence, allowing a different view on the safety case from the implementer's view. By bringing to the fore the scientific and technical ability of the regulator, R and D work by the regulator provides additional confidence to the stakeholders in the credibility of the regulator. There may exist further motivations for the regulator to carry out its own R and D projects, among which is the verification of key safety issues or the investigation of topics not addressed by the implementer, i.e., to fill scientific gaps. The

  19. Biosimilars: State of Clinical and Regulatory Science.

    Science.gov (United States)

    Klein, Agnes Victoria; Wang, Jian; Feagan, Brian G; Omoto, Mark

    2017-01-01

    On May 12, 2017, various issues and challenges associated with biologics were discussed during a session of the annual joint conference of Canadian Society for Pharmaceutical Sciences and Canadian Chapter of Controlled Release Society at Hyatt Regency Hotel, Montréal, QC, Canada.  An update on the Canadian regulatory guidelines for biosimilars was given, followed by viewpoints expressed by regulatory, academic and industry scientists.  Topics of discussion included: reference biologic drug, clinical considerations, immunogenicity, extrapolation and clarification of terminology, product monograph, international collaboration, switching and interchangeability, naming conventions, clinical and non-clinical evaluation, authorization of indications, statistical equivalence, the nor-switch study and biologics marketplace.

  20. Views from the japanese regulatory authority

    International Nuclear Information System (INIS)

    Aoyama, S.

    2004-01-01

    The legislation system for regulation of radioisotope in Japan was established in 1957. The system has been revised gradually since its establishment. Major amendments of the law were made in 1988 on the basis of ICRP Publication 26 and in 2000 on the basis of Publication 60. Main principles provided in the publication have been already introduced into the law. However, some concepts proposed in the recommendations are still under discussion. The current status of implementation of the ICRP recommendations in the Japanese regulatory system is summarised. Views from the regulatory authority of Japan on the points to be improved in the current system of radiological protection are presented. (author)

  1. Regulatory and technical reports (abstract index journal)

    International Nuclear Information System (INIS)

    1994-03-01

    This compilation consists of bibliographic data and abstracts for the formal regulatory and technical reports issued by the US Nuclear Regulatory Commission staff and its contractors. There are four types of reports included: staff reports, conference reports, contractor reports, and international agreement reports. In addition to the main citations with abstracts, the following are also included: Secondary report number index; Personal author index; Subject index; NRC originating organization indices for staff reports and international agreement reports; NRC contract sponsor index; Contractor index; International organization index; and Licensed facility index

  2. Regulatory issues in accreditation of toxicology laboratories.

    Science.gov (United States)

    Bissell, Michael G

    2012-09-01

    Clinical toxicology laboratories and forensic toxicology laboratories operate in a highly regulated environment. This article outlines major US legal/regulatory issues and requirements relevant to accreditation of toxicology laboratories (state and local regulations are not covered in any depth). The most fundamental regulatory distinction involves the purposes for which the laboratory operates: clinical versus nonclinical. The applicable regulations and the requirements and options for operations depend most basically on this consideration, with clinical toxicology laboratories being directly subject to federal law including mandated options for accreditation and forensic toxicology laboratories being subject to degrees of voluntary or state government–required accreditation.

  3. Categorization and selection of regulatory approaches for nuclear power plants

    International Nuclear Information System (INIS)

    Sugaya, Junko; Harayama, Yuko

    2009-01-01

    Several new regulatory approaches have been introduced to Japanese nuclear safety regulations, in which a prescriptive and deterministic approach had traditionally predominated. However, the options of regulatory approaches that can possibly be applied to nuclear safety regulations as well as the methodology for selecting the options are not systematically defined. In this study, various regulatory approaches for nuclear power plants are categorized as prescriptive or nonprescriptive, outcome-based or process-based, and deterministic or risk-informed. 18 options of regulatory approaches are conceptually developed and the conditions for selecting the appropriate regulatory approaches are identified. Current issues on nuclear regulations regarding responsibilities, transparency, consensus standards and regulatory inspections are examined from the viewpoints of regulatory approaches to verify usefulness of the categorization and selection concept of regulatory approaches. Finally, some of the challenges at the transitional phase of regulatory approaches are discussed. (author)

  4. Regulatory Control of Radiation Sources. Safety Guide (Arabic Edition)

    International Nuclear Information System (INIS)

    2012-01-01

    This Safety Guide is intended to assist States in implementing the requirements established in Safety Standards Series No. GS-R-1, Legal and Governmental Infrastructure for Nuclear, Radiation, Radioactive Waste and Transport Safety, for a national regulatory infrastructure to regulate any practice involving radiation sources in medicine, industry, research, agriculture and education. The Safety Guide provides advice on the legislative basis for establishing regulatory bodies, including the effective independence of the regulatory body. It also provides guidance on implementing the functions and activities of regulatory bodies: the development of regulations and guides on radiation safety; implementation of a system for notification and authorization; carrying out regulatory inspections; taking necessary enforcement actions; and investigating accidents and circumstances potentially giving rise to accidents. The various aspects relating to the regulatory control of consumer products are explained, including justification, optimization of exposure, safety assessment and authorization. Guidance is also provided on the organization and staffing of regulatory bodies. Contents: 1. Introduction; 2. Legal framework for a regulatory infrastructure; 3. Principal functions and activities of the regulatory body; 4. Regulatory control of the supply of consumer products; 5. Functions of the regulatory body shared with other governmental agencies; 6. Organization and staffing of the regulatory body; 7. Documentation of the functions and activities of the regulatory body; 8. Support services; 9. Quality management for the regulatory system.

  5. Analysis of safety-related regulatory actions by Japan's pharmaceutical regulatory agency.

    Science.gov (United States)

    Ishiguro, Chieko; Misu, Takashi; Iwasa, Eiko; Izawa, Tadashi

    2017-11-01

    To evaluate the safety-related regulatory actions implemented by Japan's Pharmaceuticals and Medical Devices Agency (PMDA) in 2012. We analyzed serious safety issues appended to drug package inserts (PIs) in Japan in 2012. The issues were characterized according to drug class, adverse event, years since drug approval, initiator of regulatory actions, revised section of PI, and evidence source. We also quantified the durations from signal detection to tentative decision and from tentative decision to regulatory action. We identified 144 serious safety issues during the study period, and the majority of evidence originated from spontaneous reports (83.5%). The PMDA initiated regulatory actions for half of all safety issues, and the median duration from drug approval to regulatory action was 8 years (interquartile range [IQR], 3-26.5 years). The median duration was 49 days (IQR, 0-362 days) from signal detection to tentative decision and 84 days (IQR, 63-136 days) from tentative decision to regulatory action. Several safety issues involving older drugs and multiple products had protracted decision-making durations. Most safety issues led to prompt regulatory actions predominantly based on spontaneous reports. Some safety issues that were not easily detected by the spontaneous reporting system were identified years after approval. In addition, several safety issues required assessments of multiple drug products, which prolonged the decision-making process. Copyright © 2017 John Wiley & Sons, Ltd.

  6. Department of Commerce Semiannual Regulatory Agenda

    Science.gov (United States)

    2010-04-26

    ... Counsel for Regulation, Office of the Assistant General Counsel for Legislation and Regulation, U.S... the significance and timing of some regulatory actions under consideration by the Councils at the time... CBTPA), and title XXXI of the Trade Act of 2002 (the Andean Trade Promotion and Drug Eradication Act or...

  7. Structure and drafting of safeguards regulatory documents

    International Nuclear Information System (INIS)

    Cole, R.J.; Bennett, C.A.; Edelhertz, H.; Wood, M.T.; Brown, R.J.; Roberts, F.P.

    1977-09-01

    Improving communication of NRU's requirements is the subject of this study. This summary is organized in terms of four decisions on whether safeguards regulatory documents as communication instruments should be an explicit NRC program, what communication methods should be focused on, what actions are feasible and desirable, and how should the NRC divide its effort and resources among desirable actions

  8. 47 CFR 69.727 - Regulatory relief.

    Science.gov (United States)

    2010-10-01

    ... customer. (b) Phase II relief. Upon satisfaction of the Phase II triggers specified in §§ 69.709(c) or 69... Pricing Flexibility § 69.727 Regulatory relief. (a) Phase I relief. Upon satisfaction of the Phase I... section 272 of the Communications Act of 1934, as amended, or § 64.1903 of this chapter, the price cap LEC...

  9. Regulatory capital requirements and bail in mechanisms

    NARCIS (Netherlands)

    Joosen, B.P.M.; Haentjens, M.; Wessels, B.

    2015-01-01

    With the introduction of the Capital Requirements Regulation (CRR) in the European Union, the qualitative requirements for bank regulatory capital have changed. These changes aim at implementing in Europe the Basel III principles for better bank capital that is able to absorb losses of banks,

  10. 76 FR 33181 - Regulatory Review Schedule

    Science.gov (United States)

    2011-06-08

    ...'s regulatory review process establishes a detailed tribal consultation schedule with a description... 66 Casino 1, 2, 3, 4, 5 Southwest. Hotel, Albuquerque, NM. July 28-29, 2011 NIGC Consultation-- DOI..., 3, 4, 5 Southwest. Casino, Scottsdale, AZ. Sept. 7-8, 2011 NIGC Consultation--United Radisson Hotel...

  11. Nuclear Regulatory Infrastructure in the Philippines

    International Nuclear Information System (INIS)

    Leonin, Teofilo V. Jr.

    2015-01-01

    Regulating the use of radioactive materials in the Philippines involves the adherence to legislation, regulations, standards and regulatory guides. It is based on a detailed review and assessment of the radiation safety program of owners and users of these materials and associated equipment against safety requirements and on additional verification of the operating practices and procedures. Republic Acts 5207 and 2067, both as amended, are implemented through the regulations which are titled Code of PNRI Regulations or CPRs are developed and issued together with supporting regulatory guides, Bulletins and other documents detailing the safety requirements. These issuance adhere to internationally accepted requirements on radiation protection, and nuclear safety and security, as well as safeguards. Design documents and technical Specifications of important radioactive materials, equipment and components are required to be submitted and reviewed by the PNRI before the issuance of an authorization in the form of a license Verification of adherence to regulations and safety requirements are periodically checked through the implementation of an inspection and enforcement program. The ISO certified regulatory management system of PNRI is documented in a QMS manual that provides guidance on all work processes. It involves systematic planning and evaluation of activities, multiple means of getting feedback on the work processes, and continuous efforts to improve its effectiveness. Efforts are implemented in order to strengthen the transparency openness, independence, technical competence and effectiveness of the regulatory body. (author)

  12. 77 FR 8028 - Semiannual Regulatory Agenda

    Science.gov (United States)

    2012-02-13

    ... Compensation and First- Tier Subcontract Awards. 485 FAR Case 2011-004, 9000-AL88 Socioeconomic Program Parity... Analysis Required: Yes. Agency Contact: Karlos Morgan, Procurement Analyst, DOD/GSA/NASA (FAR), 1275 First... Regulatory Flexibility Analysis Required: Yes. Agency Contact: William Clark, Procurement Analyst, DOD/GSA...

  13. Regulatory Challenges for Cartilage Repair Technologies.

    Science.gov (United States)

    McGowan, Kevin B; Stiegman, Glenn

    2013-01-01

    In the United States, few Food and Drug Administration (FDA)-approved options exist for the treatment of focal cartilage and osteochondral lesions. Developers of products for cartilage repair face many challenges to obtain marketing approval from the FDA. The objective of this review is to discuss the necessary steps for FDA application and approval for a new cartilage repair product. FDA Guidance Documents, FDA Panel Meetings, scientific organization recommendations, and clinicaltrials.gov were reviewed to demonstrate the current thinking of FDA and the scientific community on the regulatory process for cartilage repair therapies. Cartilage repair therapies can receive market approval from FDA as medical devices, drugs, or biologics, and the specific classification of product can affect the nonclinical, clinical, and regulatory strategy to bring the product to market. Recent FDA guidance gives an outline of the required elements to bring a cartilage repair product to market, although these standards are often very general. As a result, companies have to carefully craft their study patient population, comparator group, and clinical endpoint to best showcase their product's attributes. In addition, regulatory strategy and manufacturing process validation need to be considered early in the clinical study process to allow for timely product approval following the completion of clinical study. Although the path to regulatory approval for a cartilage repair therapy is challenging and time-consuming, proper clinical trial planning and attention to the details can eventually save companies time and money by bringing a product to the market in the most expeditious process possible.

  14. Genomic regulatory landscapes and chromosomal rearrangements

    DEFF Research Database (Denmark)

    Ladegaard, Elisabete L Engenheiro

    2008-01-01

    and mental retardation-AUTS2), where the breakpoints in all cases mutated the known disease-causing protein-coding genes. In two rearrangements with breakpoints within putative regulatory landscapes of genes where human phenotypes are unknown (HMX2/HMX3 and FOXP1), the functional characterization of CNEs...

  15. 76 FR 41411 - West Virginia Regulatory Program

    Science.gov (United States)

    2011-07-14

    ... Office of Surface Mining Reclamation and Enforcement 30 CFR Part 948 West Virginia Regulatory Program AGENCY: Office of Surface Mining Reclamation and Enforcement (OSM), Interior. ACTION: Interim rule; effective date. SUMMARY: On June 29, 2011, OSM published an interim rule approving a program amendment...

  16. 77 FR 58975 - Pennsylvania Regulatory Program

    Science.gov (United States)

    2012-09-25

    ... Office of Surface Mining Reclamation and Enforcement 30 CFR Part 938 Pennsylvania Regulatory Program AGENCY: Office of Surface Mining Reclamation and Enforcement (OSM), Interior. ] ACTION: Proposed rule... Citizens Coal Council and the Environmental Integrity Project. We are also notifying the public of the date...

  17. Deferred Tax Assests and Bank Regulatory Capital

    NARCIS (Netherlands)

    Gallemore, J.

    2012-01-01

    Abstract: In this study, I examine three issues: (1) whether the probability of bank failure is increasing in the proportion of regulatory capital composed of deferred tax assets (DTA), (2) whether market participants incorporate the increased failure risk associated with the DTA component of

  18. Regulatory Promotion of Emergent CCS Technology

    Energy Technology Data Exchange (ETDEWEB)

    Davies, Lincoln; Uchitel, Kirsten; Johnson, David

    2014-01-01

    Despite the growing inevitability of climate change and the attendant need for mitigation strategies, carbon capture and sequestration (CCS) has yet to gain much traction in the United States. Recent regulatory proposals by the U.S. Environmental Protection Agency (EPA), limited in scope to new-build power plants, represent the only significant policy initiative intended to mandate diffusion of CCS technology. Phase I of this Project assessed barriers to CCS deployment as prioritized by the CCS community. That research concluded that there were four primary barriers: (1) cost, (2) lack of a carbon price, (3) liability, and (4) lack of a comprehensive regulatory regime. Phase II of this Project, as presented in this Report, assesses potential regulatory models for CCS and examines where those models address the hurdles to diffusing CCS technology identified in Phase I. It concludes (1) that a CCS-specific but flexible standard, such as a technology performance standard or a very particular type of market-based regulation, likely will promote CCS diffusion, and (2) that these policies cannot work alone, but rather, should be combined with other measures, such as liability limits and a comprehensive CCS regulatory regime.

  19. Independent regulatory authorities in European electricity markets

    International Nuclear Information System (INIS)

    Larsen, Anders; Pedersen, Lene Holm; Sorensen, Eva Moll; Olsen, Ole Jess

    2006-01-01

    Liberalisation of the electricity market has taken place in most European countries within the last decade. It is considered a precondition of successful liberalisation to establish so-called independent regulatory authorities. In this article, we compare the status and practice of them in 16 European countries, and discuss the relationship between the organisation of the regulation and the market outcome

  20. Regulatory Capital: Why Is It Different?

    NARCIS (Netherlands)

    Schoenmaker, D.

    2015-01-01

    The global financial crisis has highlighted that deviations between the accounting and regulatory concepts of equity capital have gone too far. Accounting standards have been going too far in the application of fair value accounting. If there are no markets during times of crises, it does not make