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Sample records for international neuroblastoma risk

  1. Neuroblastoma survivors are at increased risk for second malignancies: A report from the International Neuroblastoma Risk Group Project.

    Science.gov (United States)

    Applebaum, Mark A; Vaksman, Zalman; Lee, Sang Mee; Hungate, Eric A; Henderson, Tara O; London, Wendy B; Pinto, Navin; Volchenboum, Samuel L; Park, Julie R; Naranjo, Arlene; Hero, Barbara; Pearson, Andrew D; Stranger, Barbara E; Cohn, Susan L; Diskin, Sharon J

    2017-02-01

    The incidence of second malignant neoplasm (SMN) within the first ten years of diagnosis in high-risk neuroblastoma patients treated with modern, intensive therapy is unknown. Further, the underlying germline genetics that contribute to SMN in these survivors are not known. The International Neuroblastoma Risk Group (INRG) database of patients diagnosed from 1990 to 2010 was analysed. SMN risk was accessed by cumulative incidence, standardised incidence ratios (SIRs) and absolute excess risk. A candidate gene-based association study evaluated genetic susceptibility to SMN in neuroblastoma survivors. Of the 5987 patients in the INRG database with SMN data enrolled in a clinical trial, 43 (0.72%) developed a SMN. The 10-year cumulative incidence of SMN for high-risk patients was 1.8% (95% confidence interval [CI] 1.0-2.6%) compared with 0.38% (95% CI: 0.22-0.94%) for low-risk patients (P = 0.01). High-risk patients had an almost 18-fold higher incidence of SMN compared to age- and sex-matched controls (SIR = 17.5 (95% CI: 11.4-25.3), absolute excess risk = 27.6). For patients treated on high- and intermediate-risk clinical trials, the SIR of acute myelogenous leukaemia was 106.8 (95% CI: 28.7-273.4) and 127.7 (95%CI: 25.7-373.3), respectively. Variants implicating DNA repair genes XRCC3 (rs861539: P = 0.006; odds ratio: 2.04, 95%CI: 1.19-3.46) and MSH2 (rs17036651: P = 0.009; odds ratio: 0.26, 95% CI: 0.08-0.81) were associated with SMN. The intensive multi-modality treatment strategy currently used to treat high-risk neuroblastoma is associated with a significantly increased risk of secondary acute myelogenous leukaemia. Defining the interactions of treatment exposures and genetic factors that promote the development of SMN is critical for optimising survivorship care. Copyright © 2016 Elsevier Ltd. All rights reserved.

  2. Influence of image-defined risk factors on the outcome of patients with localised neuroblastoma. A report from the LNESG1 study of the European International Society of Paediatric Oncology Neuroblastoma Group.

    Science.gov (United States)

    Monclair, Tom; Mosseri, Véronique; Cecchetto, Giovanni; De Bernardi, Bruno; Michon, Jean; Holmes, Keith

    2015-09-01

    The European multicenter study LNESG1 was designed to evaluate the safety and efficacy of surgical treatment alone in patients with localised neuroblastoma. In a retrospective, observational study we examined the impact of image-defined risk factors (IDRF) on operative complications and survival (EFS and OS). 534 patients with localised, non-MYCN amplified neuroblastoma were recruited between 1995 and 1999. Group 1 consisted of 291 patients without IDRF (Stage L1 in the International Neuroblastoma Risk Group (INRG) staging system), all treated with primary surgery. Group 2: 118 patients with IDRF (INRG Stage L2), also treated with primary surgery. Group 3: 125 patients in whom primary surgery was not attempted, 106 receiving neo-adjuvant chemotherapy. In L1 patients (Group 1) 5-year EFS was 92% and OS 98%. In L2 patients (Group 2 and 3) EFS was 79% and OS 89%. The differences in both EFS and OS were significant. EFS and OS in Group 2 (86% and 95%) were significantly better than 73% and 83% in Group 3. In INSS stage 1, 2 and 3, EFS were respectively 94%, 81% and 76%. Except between stage 2 and 3 the differences were significant. OS were respectively 99%, 93% and 83%, all significantly different. The 17% operative complication rate in L2 patients was significantly higher than 5% in L1 patients. In localised neuroblastoma, IDRF at diagnosis are associated with worse survival rates and higher rates of operative complications. The impact of IDRF should become an integrated part of therapy planning. © 2015 Wiley Periodicals, Inc.

  3. Advances in Risk Classification and Treatment Strategies for Neuroblastoma

    Science.gov (United States)

    Pinto, Navin R.; Applebaum, Mark A.; Volchenboum, Samuel L.; Matthay, Katherine K.; London, Wendy B.; Ambros, Peter F.; Nakagawara, Akira; Berthold, Frank; Schleiermacher, Gudrun; Park, Julie R.; Valteau-Couanet, Dominique; Pearson, Andrew D.J.

    2015-01-01

    Risk-based treatment approaches for neuroblastoma have been ongoing for decades. However, the criteria used to define risk in various institutional and cooperative groups were disparate, limiting the ability to compare clinical trial results. To mitigate this problem and enhance collaborative research, homogenous pretreatment patient cohorts have been defined by the International Neuroblastoma Risk Group classification system. During the past 30 years, increasingly intensive, multimodality approaches have been developed to treat patients who are classified as high risk, whereas patients with low- or intermediate-risk neuroblastoma have received reduced therapy. This treatment approach has resulted in improved outcome, although survival for high-risk patients remains poor, emphasizing the need for more effective treatments. Increased knowledge regarding the biology and genetic basis of neuroblastoma has led to the discovery of druggable targets and promising, new therapeutic approaches. Collaborative efforts of institutions and international cooperative groups have led to advances in our understanding of neuroblastoma biology, refinements in risk classification, and stratified treatment strategies, resulting in improved outcome. International collaboration will be even more critical when evaluating therapies designed to treat small cohorts of patients with rare actionable mutations. PMID:26304901

  4. Results of a Quality Assurance Review of External Beam Radiation Therapy in the International Society of Paediatric Oncology (Europe) Neuroblastoma Group's High-risk Neuroblastoma Trial: A SIOPEN Study

    International Nuclear Information System (INIS)

    Gaze, Mark N.; Boterberg, Tom; Dieckmann, Karin; Hörmann, Marcus; Gains, Jennifer E.; Sullivan, Kevin P.; Ladenstein, Ruth

    2013-01-01

    Purpose: Radiation therapy is important for local control in neuroblastoma. This study reviewed the compliance of plans with the radiation therapy guidelines of the International Society of Paediatric Oncology (Europe) Neuroblastoma Group (SIOPEN) High-Risk Trial protocol. Methods and Materials: The SIOPEN trial central electronic database has sections to record diagnostic imaging and radiation therapy planning data. Individual centers may upload data remotely, but not all centers involved in the trial chose to use this system. A quality scoring system was devised based on how well the radiation therapy plan matched the protocol guidelines, to what extent deviations were justified, and whether adverse effects may result. Central review of radiation therapy planning was undertaken retrospectively in 100 patients for whom complete diagnostic and treatment sets were available. Data were reviewed and compared against protocol guidelines by an international team of radiation oncologists and radiologists. For each patient in the sample, the central review team assigned a quality assurance score. Results: It was found that in 48% of patients there was full compliance with protocol requirements. In 29%, there were deviations for justifiable reasons with no likely long-term adverse effects resulting. In 5%, deviations had occurred for justifiable reasons, but that might result in adverse effects. In 1%, there was a deviation with no discernible justification, which would not lead to long-term adverse events. In 17%, unjustified deviations were noted, with a risk of an adverse outcome resulting. Conclusions: Owing to concern over the proportion of patients in whom unjustified deviations were observed, a protocol amendment has been issued. This offers the opportunity for central review of radiation therapy plans before the start of treatment and the treating clinician a chance to modify plans.

  5. Results of a quality assurance review of external beam radiation therapy in the International Society of Paediatric Oncology (Europe) Neuroblastoma Group's High-risk Neuroblastoma Trial: a SIOPEN study.

    Science.gov (United States)

    Gaze, Mark N; Boterberg, Tom; Dieckmann, Karin; Hörmann, Marcus; Gains, Jennifer E; Sullivan, Kevin P; Ladenstein, Ruth

    2013-01-01

    Radiation therapy is important for local control in neuroblastoma. This study reviewed the compliance of plans with the radiation therapy guidelines of the International Society of Paediatric Oncology (Europe) Neuroblastoma Group (SIOPEN) High-Risk Trial protocol. The SIOPEN trial central electronic database has sections to record diagnostic imaging and radiation therapy planning data. Individual centers may upload data remotely, but not all centers involved in the trial chose to use this system. A quality scoring system was devised based on how well the radiation therapy plan matched the protocol guidelines, to what extent deviations were justified, and whether adverse effects may result. Central review of radiation therapy planning was undertaken retrospectively in 100 patients for whom complete diagnostic and treatment sets were available. Data were reviewed and compared against protocol guidelines by an international team of radiation oncologists and radiologists. For each patient in the sample, the central review team assigned a quality assurance score. It was found that in 48% of patients there was full compliance with protocol requirements. In 29%, there were deviations for justifiable reasons with no likely long-term adverse effects resulting. In 5%, deviations had occurred for justifiable reasons, but that might result in adverse effects. In 1%, there was a deviation with no discernible justification, which would not lead to long-term adverse events. In 17%, unjustified deviations were noted, with a risk of an adverse outcome resulting. Owing to concern over the proportion of patients in whom unjustified deviations were observed, a protocol amendment has been issued. This offers the opportunity for central review of radiation therapy plans before the start of treatment and the treating clinician a chance to modify plans. Copyright © 2013 Elsevier Inc. All rights reserved.

  6. Results of a Quality Assurance Review of External Beam Radiation Therapy in the International Society of Paediatric Oncology (Europe) Neuroblastoma Group's High-risk Neuroblastoma Trial: A SIOPEN Study

    Energy Technology Data Exchange (ETDEWEB)

    Gaze, Mark N., E-mail: mark.gaze@uclh.nhs.uk [Department of Oncology, University College London Hospitals NHS Foundation Trust, London (United Kingdom); Boterberg, Tom [Department of Radiation Oncology, Ghent University Hospital, Ghent (Belgium); Dieckmann, Karin; Hoermann, Marcus [General Hospital Vienna, Medical University Vienna (Austria); Gains, Jennifer E.; Sullivan, Kevin P. [Department of Oncology, University College London Hospitals NHS Foundation Trust, London (United Kingdom); Ladenstein, Ruth [Children' s Cancer Research Institute, St. Anna Children' s Hospital, Vienna (Austria)

    2013-01-01

    Purpose: Radiation therapy is important for local control in neuroblastoma. This study reviewed the compliance of plans with the radiation therapy guidelines of the International Society of Paediatric Oncology (Europe) Neuroblastoma Group (SIOPEN) High-Risk Trial protocol. Methods and Materials: The SIOPEN trial central electronic database has sections to record diagnostic imaging and radiation therapy planning data. Individual centers may upload data remotely, but not all centers involved in the trial chose to use this system. A quality scoring system was devised based on how well the radiation therapy plan matched the protocol guidelines, to what extent deviations were justified, and whether adverse effects may result. Central review of radiation therapy planning was undertaken retrospectively in 100 patients for whom complete diagnostic and treatment sets were available. Data were reviewed and compared against protocol guidelines by an international team of radiation oncologists and radiologists. For each patient in the sample, the central review team assigned a quality assurance score. Results: It was found that in 48% of patients there was full compliance with protocol requirements. In 29%, there were deviations for justifiable reasons with no likely long-term adverse effects resulting. In 5%, deviations had occurred for justifiable reasons, but that might result in adverse effects. In 1%, there was a deviation with no discernible justification, which would not lead to long-term adverse events. In 17%, unjustified deviations were noted, with a risk of an adverse outcome resulting. Conclusions: Owing to concern over the proportion of patients in whom unjustified deviations were observed, a protocol amendment has been issued. This offers the opportunity for central review of radiation therapy plans before the start of treatment and the treating clinician a chance to modify plans.

  7. Development of an electronic database for quality assurance of radiotherapy in the International Society of Paediatric Oncology (Europe) high risk neuroblastoma study

    International Nuclear Information System (INIS)

    Gaze, Mark N.; Boterberg, Tom; Dieckmann, Karin; Habrand, Jean-Louis; Helfre, Sylvie; Peylan-Ramu, Nili; Chrzanowska, Elzbieta Korab; Schreier, Guenter; Ladenstein, Ruth

    2010-01-01

    Quality assurance of radiotherapy is an important determinant of outcome in some cancers. SIOPEN-R-NET developed a computerised remote data entry system for recording imaging and treatment parameters for its multimodality high risk neuroblastoma study. This will enable investigation of the relationship between radiotherapy quality and local control.

  8. Transcriptional Profiling Reveals a Common Metabolic Program in High-Risk Human Neuroblastoma and Mouse Neuroblastoma Sphere-Forming Cells

    Directory of Open Access Journals (Sweden)

    Mengling Liu

    2016-10-01

    Full Text Available High-risk neuroblastoma remains one of the deadliest childhood cancers. Identification of metabolic pathways that drive or maintain high-risk neuroblastoma may open new avenues of therapeutic interventions. Here, we report the isolation and propagation of neuroblastoma sphere-forming cells with self-renewal and differentiation potential from tumors of the TH-MYCN mouse, an animal model of high-risk neuroblastoma with MYCN amplification. Transcriptional profiling reveals that mouse neuroblastoma sphere-forming cells acquire a metabolic program characterized by transcriptional activation of the cholesterol and serine-glycine synthesis pathways, primarily as a result of increased expression of sterol regulatory element binding factors and Atf4, respectively. This metabolic reprogramming is recapitulated in high-risk human neuroblastomas and is prognostic for poor clinical outcome. Genetic and pharmacological inhibition of the metabolic program markedly decreases the growth and tumorigenicity of both mouse neuroblastoma sphere-forming cells and human neuroblastoma cell lines. These findings suggest a therapeutic strategy for targeting the metabolic program of high-risk neuroblastoma.

  9. Telomerase activation by genomic rearrangements in high-risk neuroblastoma

    Science.gov (United States)

    Peifer, Martin; Hertwig, Falk; Roels, Frederik; Dreidax, Daniel; Gartlgruber, Moritz; Menon, Roopika; Krämer, Andrea; Roncaioli, Justin L.; Sand, Frederik; Heuckmann, Johannes M.; Ikram, Fakhera; Schmidt, Rene; Ackermann, Sandra; Engesser, Anne; Kahlert, Yvonne; Vogel, Wenzel; Altmüller, Janine; Nürnberg, Peter; Thierry-Mieg, Jean; Thierry-Mieg, Danielle; Mariappan, Aruljothi; Heynck, Stefanie; Mariotti, Erika; Henrich, Kai-Oliver; Glöckner, Christian; Bosco, Graziella; Leuschner, Ivo; Schweiger, Michal R.; Savelyeva, Larissa; Watkins, Simon C.; Shao, Chunxuan; Bell, Emma; Höfer, Thomas; Achter, Viktor; Lang, Ulrich; Theissen, Jessica; Volland, Ruth; Saadati, Maral; Eggert, Angelika; de Wilde, Bram; Berthold, Frank; Peng, Zhiyu; Zhao, Chen; Shi, Leming; Ortmann, Monika; Büttner, Reinhard; Perner, Sven; Hero, Barbara; Schramm, Alexander; Schulte, Johannes H.; Herrmann, Carl; O’Sullivan, Roderick J.; Westermann, Frank; Thomas, Roman K.; Fischer, Matthias

    2016-01-01

    Neuroblastoma is a malignant paediatric tumour of the sympathetic nervous system1. Roughly half of these tumours regress spontaneously or are cured by limited therapy. By contrast, high-risk neuroblastomas have an unfavourable clinical course despite intensive multimodal treatment, and their molecular basis has remained largely elusive2–4. Here we have performed whole-genome sequencing of 56 neuroblastomas (high-risk, n = 39; low-risk, n = 17) and discovered recurrent genomic rearrangements affecting a chromosomal region at 5p15.33 proximal of the telomerase reverse transcriptase gene (TERT). These rearrangements occurred only in high-risk neuroblastomas (12/39, 31%) in a mutually exclusive fashion with MYCN amplifications and ATRX mutations, which are known genetic events in this tumour type1,2,5. In an extended case series (n = 217), TERT rearrangements defined a subgroup of high-risk tumours with particularly poor outcome. Despite a large structural diversity of these rearrangements, they all induced massive transcriptional upregulation of TERT. In the remaining high-risk tumours, TERT expression was also elevated in MYCN-amplified tumours, whereas alternative lengthening of telomeres was present in neuroblastomas without TERT or MYCN alterations, suggesting that telomere lengthening represents a central mechanism defining this subtype. The 5p15.33 rearrangements juxtapose the TERT coding sequence to strong enhancer elements, resulting in massive chromatin remodelling and DNA methylation of the affected region. Supporting a functional role of TERT, neuroblastoma cell lines bearing rearrangements or amplified MYCN exhibited both upregulated TERT expression and enzymatic telomerase activity. In summary, our findings show that remodelling of the genomic context abrogates transcriptional silencing of TERT in high-risk neuroblastoma and places telomerase activation in the centre of transformation in a large fraction of these tumours. PMID:26466568

  10. Neuroblastoma

    International Nuclear Information System (INIS)

    Hall-Craggs, M.A.; Finn, J.P.; Dicks-Mireaux, C.; Kiely, E.M.; Pritchard, J.

    1989-01-01

    Twenty-one children with neuroblastoma (mean age, 36.7 months) were examined with high-field strength (1.5 T) MR imaging to define how accurately disease could be documented and to establish optimum sequences. Twenty-eight studies were obtained with T1- and T2-weighted spin-echo and short inversion-recovery (STIR) sequences. Thirteen children underwent surgery, 16 CT. MR imaging exactly predicted tumor extent and involvement of adjacent organs, vessels, and the spine in all patients undergoing surgery. STIR images defined tumor margins and node involvement most clearly. Following chemotherapy, MR imaging could not differentiate active tumor from maturing ganglioneuroma or residual hyperplasia. MR imaging was superior to CT in assessing intraabdominal, marrow, and spinal disease

  11. Neuroblastoma

    International Nuclear Information System (INIS)

    Thomas, P.R.M.

    1987-01-01

    Neuroblastoma is a complex disease with prognosis varying not only with stage, but also with age, site, and histology. Dissemination is the main problem. For stage I tumors, complete surgical excision alone is likely to be curative. For stage II tumors, postoperative irradiation is not clearly established, but it should be considered for patients over 1 year of age with incompletely resected tumors or positive lymph nodes. For stage III tumors, radiation therapy is indicated, with possible second-look surgery after treatment. Adjuvant chemotherapy is being tested. The prognosis is uncertain and may depend partly on the lymph node status. For stage IV tumors, chemotherapy is preferred. Remissions are usually obtained, although cure is very unlikely, except in infants. Radiation has a definite palliative role. For stage IV-S tumors, a conservative approach is preferred, with active treatment being reserved for complications of tumor bulk or obvious progression. New approaches include the use of total-body irradiation with chemotherapy, with or without transplantation, in stage IV patients in an attempt to maintain remissions. Tumor market such as N-myc help to define the indications for aggressive therapy. Once it is possible to maintain complete remissions, a dramatic improvement in the overall prognosis is likely

  12. Dinutuximab in the Treatment of High-Risk Neuroblastoma in Children

    Directory of Open Access Journals (Sweden)

    Hazal Gur

    2017-06-01

    Full Text Available Neuroblastoma is the most common extracranial tumor derived from neural crest cells in childhood, and treatment of high-risk neuroblastoma is a difficulty in oncology field. The discovery of new treatment strategies to treat pediatric patients with high-risk neuroblastoma is important. Dinutuximab (ch14.18; Unituxin, a chimeric human-mouse monoclonal antibody, is approved by Food and Drug Administration in 2015 to be used specifically in the treatment of high-risk neuroblastoma. It binds the disialoganglioside (GD2 antigen on the surface of neuroblastoma cells and induces lysis of GD2-expressed neuroblastoma cells via antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. To enhance its activity, it is used with a combination of granulocyte-macrophage colony-stimulating factor, interleukin 2, and 13- cis -retinoic acid. In this review, we discuss the use of dinutuximab in the treatment of high-risk neuroblastoma.

  13. The genetic landscape of high-risk neuroblastoma.

    Science.gov (United States)

    Pugh, Trevor J; Morozova, Olena; Attiyeh, Edward F; Asgharzadeh, Shahab; Wei, Jun S; Auclair, Daniel; Carter, Scott L; Cibulskis, Kristian; Hanna, Megan; Kiezun, Adam; Kim, Jaegil; Lawrence, Michael S; Lichenstein, Lee; McKenna, Aaron; Pedamallu, Chandra Sekhar; Ramos, Alex H; Shefler, Erica; Sivachenko, Andrey; Sougnez, Carrie; Stewart, Chip; Ally, Adrian; Birol, Inanc; Chiu, Readman; Corbett, Richard D; Hirst, Martin; Jackman, Shaun D; Kamoh, Baljit; Khodabakshi, Alireza Hadj; Krzywinski, Martin; Lo, Allan; Moore, Richard A; Mungall, Karen L; Qian, Jenny; Tam, Angela; Thiessen, Nina; Zhao, Yongjun; Cole, Kristina A; Diamond, Maura; Diskin, Sharon J; Mosse, Yael P; Wood, Andrew C; Ji, Lingyun; Sposto, Richard; Badgett, Thomas; London, Wendy B; Moyer, Yvonne; Gastier-Foster, Julie M; Smith, Malcolm A; Guidry Auvil, Jaime M; Gerhard, Daniela S; Hogarty, Michael D; Jones, Steven J M; Lander, Eric S; Gabriel, Stacey B; Getz, Gad; Seeger, Robert C; Khan, Javed; Marra, Marco A; Meyerson, Matthew; Maris, John M

    2013-03-01

    Neuroblastoma is a malignancy of the developing sympathetic nervous system that often presents with widespread metastatic disease, resulting in survival rates of less than 50%. To determine the spectrum of somatic mutation in high-risk neuroblastoma, we studied 240 affected individuals (cases) using a combination of whole-exome, genome and transcriptome sequencing as part of the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative. Here we report a low median exonic mutation frequency of 0.60 per Mb (0.48 nonsilent) and notably few recurrently mutated genes in these tumors. Genes with significant somatic mutation frequencies included ALK (9.2% of cases), PTPN11 (2.9%), ATRX (2.5%, and an additional 7.1% had focal deletions), MYCN (1.7%, causing a recurrent p.Pro44Leu alteration) and NRAS (0.83%). Rare, potentially pathogenic germline variants were significantly enriched in ALK, CHEK2, PINK1 and BARD1. The relative paucity of recurrent somatic mutations in neuroblastoma challenges current therapeutic strategies that rely on frequently altered oncogenic drivers.

  14. The genetic landscape of high-risk neuroblastoma

    Science.gov (United States)

    Pugh, Trevor J.; Morozova, Olena; Attiyeh, Edward F.; Asgharzadeh, Shahab; Wei, Jun S.; Auclair, Daniel; Carter, Scott L.; Cibulskis, Kristian; Hanna, Megan; Kiezun, Adam; Kim, Jaegil; Lawrence, Michael S.; Lichenstein, Lee; McKenna, Aaron; Pedamallu, Chandra Sekhar; Ramos, Alex H.; Shefler, Erica; Sivachenko, Andrey; Sougnez, Carrie; Stewart, Chip; Ally, Adrian; Birol, Inanc; Chiu, Readman; Corbett, Richard D.; Hirst, Martin; Jackman, Shaun D.; Kamoh, Baljit; Khodabakshi, Alireza Hadj; Krzywinski, Martin; Lo, Allan; Moore, Richard A.; Mungall, Karen L.; Qian, Jenny; Tam, Angela; Thiessen, Nina; Zhao, Yongjun; Cole, Kristina A.; Diamond, Maura; Diskin, Sharon J.; Mosse, Yael P.; Wood, Andrew C.; Ji, Lingyun; Sposto, Richard; Badgett, Thomas; London, Wendy B.; Moyer, Yvonne; Gastier-Foster, Julie M.; Smith, Malcolm A.; Auvil, Jaime M. Guidry; Gerhard, Daniela S.; Hogarty, Michael D.; Jones, Steven J. M.; Lander, Eric S.; Gabriel, Stacey B.; Getz, Gad; Seeger, Robert C.; Khan, Javed; Marra, Marco A.; Meyerson, Matthew; Maris, John M.

    2013-01-01

    Neuroblastoma is a malignancy of the developing sympathetic nervous system that often presents with widespread metastatic disease, resulting in survival rates of less than 50%1. To determine the spectrum of somatic mutation in high-risk neuroblastoma, we studied 240 cases using a combination of whole exome, genome and transcriptome sequencing as part of the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative. Here we report a low median exonic mutation frequency of 0.60 per megabase (0.48 non-silent), and remarkably few recurrently mutated genes in these tumors. Genes with significant somatic mutation frequencies included ALK (9.2% of cases), PTPN11 (2.9%), ATRX (2.5%, an additional 7.1% had focal deletions), MYCN (1.7%, a recurrent p.Pro44Leu alteration), and NRAS (0.83%). Rare, potentially pathogenic germline variants were significantly enriched in ALK, CHEK2, PINK1, and BARD1. The relative paucity of recurrent somatic mutations in neuroblastoma challenges current therapeutic strategies reliant upon frequently altered oncogenic drivers. PMID:23334666

  15. Proton Radiotherapy for High-Risk Pediatric Neuroblastoma: Early Outcomes and Dose Comparison

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    Hattangadi, Jona A. [Harvard Radiation Oncology Program, Boston, MA (United States); Rombi, Barbara [Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA (United States); Provincial Agency for Proton Therapy, Trento (Italy); Yock, Torunn I.; Broussard, George [Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA (United States); Friedmann, Alison M.; Huang, Mary [Department of Pediatric Hematology-Oncology, Massachusetts General Hospital, Boston, MA (United States); Chen, Yen-Lin E.; Lu, Hsiao-Ming; Kooy, Hanne [Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA (United States); MacDonald, Shannon M., E-mail: smacdonald@partners.org [Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA (United States)

    2012-07-01

    Purpose: To report the early outcomes for children with high-risk neuroblastoma treated with proton radiotherapy (RT) and to compare the dose distributions for intensity-modulated photon RT (IMRT), three-dimensional conformal proton RT (3D-CPT), and intensity-modulated proton RT to the postoperative tumor bed. Methods and Materials: All patients with high-risk (International Neuroblastoma Staging System Stage III or IV) neuroblastoma treated between 2005 and 2010 at our institution were included. All patients received induction chemotherapy, surgical resection of residual disease, high-dose chemotherapy with stem cell rescue, and adjuvant 3D-CPT to the primary tumor sites. The patients were followed with clinical examinations, imaging, and laboratory testing every 6 months to monitor disease control and side effects. IMRT, 3D-CPT, and intensity-modulated proton RT plans were generated and compared for a representative case of adjuvant RT to the primary tumor bed followed by a boost. Results: Nine patients were treated with 3D-CPT. The median age at diagnosis was 2 years (range 10 months to 4 years), and all patients had Stage IV disease. All patients had unfavorable histologic characteristics (poorly differentiated histologic features in 8, N-Myc amplification in 6, and 1p/11q chromosomal abnormalities in 4). The median tumor size at diagnosis was 11.4 cm (range 7-16) in maximal dimension. At a median follow-up of 38 months (range 11-70), there were no local failures. Four patients developed distant failure, and, of these, two died of disease. Acute side effects included Grade 1 skin erythema in 5 patients and Grade 2 anorexia in 2 patients. Although comparable target coverage was achieved with all three modalities, proton therapy achieved substantial normal tissue sparing compared with IMRT. Intensity-modulated proton RT allowed additional sparing of the kidneys, lungs, and heart. Conclusions: Preliminary outcomes reveal excellent local control with proton therapy

  16. Recommendations for the standardization of bone marrow disease assessment and reporting in children with neuroblastoma on behalf of the International Neuroblastoma Response Criteria Bone Marrow Working Group.

    Science.gov (United States)

    Burchill, Susan A; Beiske, Klaus; Shimada, Hiroyuki; Ambros, Peter F; Seeger, Robert; Tytgat, Godelieve A M; Brock, Penelope R; Haber, Michelle; Park, Julie R; Berthold, Frank

    2017-04-01

    The current study was conducted to expedite international standardized reporting of bone marrow disease in children with neuroblastoma and to improve equivalence of care. A multidisciplinary International Neuroblastoma Response Criteria Bone Marrow Working Group was convened by the US National Cancer Institute in January 2012 with representation from Europe, North America, and Australia. Practical transferable recommendations to standardize the reporting of bone marrow disease were developed. To the authors' knowledge, the current study is the first to comprehensively present consensus criteria for the collection, analysis, and reporting of the percentage area of bone marrow parenchyma occupied by tumor cells in trephine-biopsies. The quantitative analysis of neuroblastoma content in bone marrow aspirates by immunocytology and reverse transcriptase-quantitative polymerase chain reaction are revised. The inclusion of paired-like homeobox 2b (PHOX2B) for immunohistochemistry and reverse transcriptase-quantitative polymerase chain reaction is recommended. Recommendations for recording bone marrow response are provided. The authors endorse the quantitative assessment of neuroblastoma cell content in bilateral core needle biopsies-trephines and aspirates in all children with neuroblastoma, with the exception of infants, in whom the evaluation of aspirates alone is advised. It is interesting to note that 5% disease is accepted as an internationally achievable level for disease assessment. The quantitative assessment of neuroblastoma cells is recommended to provide data from which evidence-based numerical criteria for the reporting of bone marrow response can be realized. This is particularly important in the minimal disease setting and when neuroblastoma detection in bone marrow is intermittent, where clinical impact has yet to be validated. The wide adoption of these harmonized criteria will enhance the ability to compare outcomes from different trials and facilitate

  17. The genetic landscape of high-risk neuroblastoma | Office of Cancer Genomics

    Science.gov (United States)

    Abstract: Neuroblastoma is a malignancy of the developing sympathetic nervous system that often presents with widespread metastatic disease, resulting in survival rates of less than 50%. To determine the spectrum of somatic mutation in high-risk neuroblastoma, we studied 240 affected individuals (cases) using a combination of whole-exome, genome and transcriptome sequencing as part of the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative.

  18. Neuroblastoma in children

    International Nuclear Information System (INIS)

    Hoermann, M.

    2008-01-01

    Neuroblastomas have a very heterogenic clinical presentation, ranging from relatively benign forms with the potential of spontaneous regression, to foudroyant malignant forms. Over half of neuroblastomas must be classified as high-risk tumors with a markedly high rate of recurrence. Despite multidisciplinary therapeutic approaches, the survival rate of children with this type of tumor is still below 40%. An ever-growing amount of data from international studies dating from the early 1970s onwards, points to the necessity of re-evaluating the medical approach in establishing the diagnosis and staging, understanding tumor biology and pathology, as well as therapy planning. (orig.) [de

  19. A multidisciplinary team care approach improves outcomes in high-risk pediatric neuroblastoma patients.

    Science.gov (United States)

    Chang, Hsiu-Hao; Liu, Yen-Lin; Lu, Meng-Yao; Jou, Shiann-Tarng; Yang, Yung-Li; Lin, Dong-Tsamn; Lin, Kai-Hsin; Tzen, Kai-Yuan; Yen, Ruoh-Fang; Lu, Ching-Chu; Liu, Chia-Ju; Peng, Steven Shinn-Forng; Jeng, Yung-Ming; Huang, Shiu-Feng; Lee, Hsinyu; Juan, Hsueh-Fen; Huang, Min-Chuan; Liao, Yung-Feng; Lee, Ya-Ling; Hsu, Wen-Ming

    2017-01-17

    We assessed the impact of a multidisciplinary team care program on treatment outcomes in neuroblastoma patients. Newly diagnosed neuroblastoma patients received treatment under the Taiwan Pediatric Oncology Group (TPOG) N2002 protocol at the National Taiwan University Hospital beginning in 2002. A multidisciplinary team care approach that included nurse-led case management for patients treated under this protocol began in January 2010. Fifty-eight neuroblastoma patients, including 29 treated between 2002 and 2009 (Group 1) and 29 treated between 2010 and 2014 (Group 2), were enrolled in the study. The 5-year overall survival (OS) and event-free survival (EFS) rates for all 58 patients were 59% and 54.7%, respectively. Group 2 patients, who were treated after implementation of the multidisciplinary team care program, had better 3-year EFS (P = 0.046), but not OS (P = 0.16), rates than Group 1 patients. In a multivariate analysis, implementation of the multidisciplinary team approach was the only significant independent prognostic factor for neuroblastoma patients. In further subgroup analyses, the multidisciplinary team approach improved EFS, but not OS, in patients with stage 4 disease, those in the high-risk group, and those with non-MYCN amplified tumors. These data indicate a multidisciplinary team care approach improved survival outcomes in high-risk neuroblastoma patients. However, further investigation will be required to evaluate the long-term effects of this approach over longer follow-up periods.

  20. Endoscopic internal biliary drainage in a child with malignant obstructive jaundice caused by neuroblastoma

    International Nuclear Information System (INIS)

    Okada, Tadao; Yoshida, Hideo; Matsunaga, Tadashi; Kouchi, Katunori; Ohtsuka, Yasuhiro; Ohnuma, Naomi; Tsuyuguchi, Toshio; Yamaguchi, Taketo; Saisho, Hiromitsu

    2003-01-01

    We describe a 13-year-old girl who underwent insertion of a Flexima biliary stent for obstructive jaundice due to compression of the extrahepatic bile duct by an enlarged lymph node secondary to neuroblastoma. This novel endoscopic internal biliary drainage procedure was safe and effective even for a child, and improved her quality of life. We further review other treatment options available for malignant obstructive jaundice in children. (orig.)

  1. Endoscopic internal biliary drainage in a child with malignant obstructive jaundice caused by neuroblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Okada, Tadao; Yoshida, Hideo; Matsunaga, Tadashi; Kouchi, Katunori; Ohtsuka, Yasuhiro; Ohnuma, Naomi [Department of Paediatric Surgery, Chiba University, School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8677 (Japan); Tsuyuguchi, Toshio; Yamaguchi, Taketo; Saisho, Hiromitsu [First Department of Internal Medicine, Chiba University School of Medicine, Chiba (Japan)

    2003-02-01

    We describe a 13-year-old girl who underwent insertion of a Flexima biliary stent for obstructive jaundice due to compression of the extrahepatic bile duct by an enlarged lymph node secondary to neuroblastoma. This novel endoscopic internal biliary drainage procedure was safe and effective even for a child, and improved her quality of life. We further review other treatment options available for malignant obstructive jaundice in children. (orig.)

  2. Validation of Postinduction Curie Scores in High-Risk Neuroblastoma: A Children's Oncology Group and SIOPEN Group Report on SIOPEN/HR-NBL1.

    Science.gov (United States)

    Yanik, Gregory A; Parisi, Marguerite T; Naranjo, Arlene; Nadel, Helen; Gelfand, Michael J; Park, Julie R; Ladenstein, Ruth L; Poetschger, Ulrike; Boubaker, Ariane; Valteau-Couanet, Dominique; Lambert, Bieke; Castellani, Maria-Rita; Bar-Sever, Zvi; Oudoux, Aurore; Kaminska, Anna; Kreissman, Susan G; Shulkin, Barry L; Matthay, Katherine K

    2018-03-01

    A semiquantitative 123 I-metaiodobenzylguanidine ( 123 I-MIBG) scoring method (the Curie score, or CS) was previously examined in the Children's Oncology Group (COG) high-risk neuroblastoma trial, COG A3973, with a postinduction CS of more than 2 being associated with poor event-free survival (EFS). The validation of the CS in an independent dataset, International Society of Paediatric Oncology European Neuroblastoma/High-Risk Neuroblastoma 1 (SIOPEN/HR-NBL1), is now reported. Methods: A retrospective analysis of 123 I-MIBG scans obtained from patients who had been prospectively enrolled in SIOPEN/HR-NBL1 was performed. All patients exhibited 123 I-MIBG-avid, International Neuroblastoma Staging System stage 4 neuroblastoma. 123 I-MIBG scans were evaluated at 2 time points, diagnosis ( n = 345) and postinduction ( n = 330), before consolidation myeloablative therapy. Scans of 10 anatomic regions were evaluated, with each region being scored 0-3 on the basis of disease extent and a cumulative CS generated. Cut points for outcome analysis were identified by Youden methodology. CSs from patients enrolled in COG A3973 were used for comparison. Results: The optimal cut point for CS at diagnosis was 12 in SIOPEN/HR-NBL1, with a significant outcome difference by CS noted (5-y EFS, 43.0% ± 5.7% [CS ≤ 12] vs. 21.4% ± 3.6% [CS > 12], P 2], P < 0.0001). The postinduction CS maintained independent statistical significance in Cox models when adjusted for the covariates of age and MYCN gene copy number. Conclusion: The prognostic significance of postinduction CSs has now been validated in an independent cohort of patients (SIOPEN/HR-NBL1), with a postinduction CS of more than 2 being associated with an inferior outcome in 2 independent large, cooperative group trials. © 2018 by the Society of Nuclear Medicine and Molecular Imaging.

  3. Retinoic acid postconsolidation therapy for high-risk neuroblastoma patients treated with autologous haematopoietic stem cell transplantation.

    Science.gov (United States)

    Peinemann, Frank; van Dalen, Elvira C; Enk, Heike; Berthold, Frank

    2017-08-25

    Neuroblastoma is a rare malignant disease and mainly affects infants and very young children. The tumours mainly develop in the adrenal medullary tissue, with an abdominal mass as the most common presentation. About 50% of patients have metastatic disease at diagnosis. The high-risk group is characterised by metastasis and other features that increase the risk of an adverse outcome. High-risk patients have a five-year event-free survival of less than 50%. Retinoic acid has been shown to inhibit growth of human neuroblastoma cells and has been considered as a potential candidate for improving the outcome of patients with high-risk neuroblastoma. This review is an update of a previously published Cochrane Review. To evaluate the efficacy and safety of additional retinoic acid as part of a postconsolidation therapy after high-dose chemotherapy (HDCT) followed by autologous haematopoietic stem cell transplantation (HSCT), compared to placebo retinoic acid or to no additional retinoic acid in people with high-risk neuroblastoma (as defined by the International Neuroblastoma Risk Group (INRG) classification system). We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library (2016, Issue 11), MEDLINE in PubMed (1946 to 24 November 2016), and Embase in Ovid (1947 to 24 November 2016). Further searches included trial registries (on 22 December 2016), conference proceedings (on 23 March 2017) and reference lists of recent reviews and relevant studies. We did not apply limits by publication year or languages. Randomised controlled trials (RCTs) evaluating additional retinoic acid after HDCT followed by HSCT for people with high-risk neuroblastoma compared to placebo retinoic acid or to no additional retinoic acid. Primary outcomes were overall survival and treatment-related mortality. Secondary outcomes were progression-free survival, event-free survival, early toxicity, late toxicity, and health-related quality of life. We used standard

  4. Radiation Therapy to the Primary and Postinduction Chemotherapy MIBG-Avid Sites in High-Risk Neuroblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Mazloom, Ali; Louis, Chrystal U.; Nuchtern, Jed; Kim, Eugene; Russell, Heidi; Allen-Rhoades, Wendy; Krance, Robert; Paulino, Arnold C., E-mail: apaulino@mdanderson.org

    2014-11-15

    Purpose: Although it is generally accepted that consolidation therapy for neuroblastoma includes irradiation of the primary site and any remaining metaiodobenzylguanidine (MIBG)-avid metastatic sites, limited information has been published regarding the efficacy of this approach. Methods and Materials: Thirty patients with high-risk neuroblastoma were treated at 1 radiation therapy (RT) department after receiving 5 cycles of induction chemotherapy and resection. All patients had at least a partial response after induction therapy, based upon international neuroblastoma response criteria. The primary sites were treated with 24 to 30 Gy whereas the MIBG-avid metastatic sites were treated with 24 Gy. RT was followed by high-dose chemotherapy with autologous stem cell rescue and 6 months of cis-retinoic acid. Results: The 5-year progression-free survival (PFS) and overall survival (OS) rates were 48% and 59%, respectively. The 5-year locoregional control at the primary site was 84%. There were no differences in locoregional control according to degree of primary surgical resection. The 5-year local control rate for metastatic sites was 74%. The 5-year PFS rates for patients with 0, 1, 2, and >3 postinduction MIBG sites were 66%, 57%, 20%, and 0% (P<.0001), respectively, whereas 5-year OS rates were 80%, 57%, 50%, and 0%, respectively (P<.0001). Conclusions: RT to the primary site and postinduction MIBG-positive metastatic sites was associated with 84% and 74% local control, respectively. The number of MIBG-avid sites present after induction chemotherapy and surgery was predictive of progression-free and overall survival.

  5. Internalization of a polysialic acid-binding Escherichia coli bacteriophage into eukaryotic neuroblastoma cells.

    Science.gov (United States)

    Lehti, Timo A; Pajunen, Maria I; Skog, Maria S; Finne, Jukka

    2017-12-04

    Eukaryotic organisms are continuously exposed to bacteriophages, which are efficient gene transfer agents in bacteria. However, bacteriophages are considered not to pass the eukaryotic cell membrane and enter nonphagocytic cells. Here we report the binding and penetration of Escherichia coli PK1A2 bacteriophage into live eukaryotic neuroblastoma cells in vitro. The phage interacts with cell surface polysialic acid, which shares structural similarity with the bacterial phage receptor. Using fluorescence and electron microscopy, we show that phages are internalized via the endolysosomal route and persist inside the human cells up to one day without affecting cell viability. Phage capsid integrity is lost in lysosomes, and the phage DNA is eventually degraded. We did not detect the entry of phage DNA into the nucleus; however, we speculate that this might occur as a rare event, and propose that this potential mechanism could explain prokaryote-eukaryote gene flow.

  6. Physician Perspectives on Palliative Care for Children With Neuroblastoma: An International Context.

    Science.gov (United States)

    Balkin, Emily M; Thompson, Daria; Colson, K Ellicott; Lam, Catherine G; Matthay, Katherine K

    2016-05-01

    Studies have shown that children with cancer globally lack access to palliative care. Little is known regarding physicians' perceptions of palliative care, treatment access, and self-reported competence in providing palliative care. Members of the Global Neuroblastoma Network (online tumor board) were surveyed. Eighty-three respondents met inclusion criteria; 53 (64%) completed the survey. Most respondents trained in high-income countries (HIC) but practice in low- and middle-income countries (LMIC), and care for more than five patients with neuroblastoma annually. WHO Essential Medicines in palliative care varied in availability, with incomplete access across LMIC centers. Nonpharmacologic therapies were inconsistently available. Contrary to international definitions, 17% of respondents inappropriately considered palliative care as that initiated only after curative therapy is stopped. Mean physician competence composite score (Likert scale 1-5, 5 = very competent) in providing symptomatic relief and palliative care across phases of care was 2.93 (95% CI 2.71-3.22). Physicians reported significantly greater competence in symptom management during cure-directed therapy than during end-of-life (P = 0.02) or when patients are actively dying (P = 0.007). Practicing in HIC, prior palliative care training, having access to radiotherapy, and not having to turn patients away due to bed shortages were significantly predictive of perceived competence in providing palliative care at end of life. An international sample identified gaps in treatment and palliative care service availability, in understanding the definition of palliative care, and in self-reported competence in providing palliative care. Increased perceived competence was associated with training, which supports the need for increased palliative care education and advocacy, especially in LMIC. © 2016 Wiley Periodicals, Inc.

  7. Likelihood of Bone Recurrence in Prior Sites of Metastasis in Patients With High-Risk Neuroblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Polishchuk, Alexei L. [Department of Radiation Oncology, University of California at San Francisco School of Medicine and UCSF Benioff Children' s Hospital, San Francisco, California (United States); Li, Richard [Division of Radiation Oncology, Dana Farber/Boston Children' s Cancer and Blood Disorders Center, Brigham and Women' s Hospital, Harvard Medical School, Boston, Massachusetts (United States); Hill-Kayser, Christine [Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania (United States); Little, Anthony [Division of Oncology, Children' s Hospital of Philadelphia, Philadelphia, Pennsylvania (United States); Hawkins, Randall A. [Department of Radiology, University of California at San Francisco School of Medicine and UCSF Benioff Children' s Hospital, San Francisco, California (United States); Hamilton, Jeffrey; Lau, Michael [Department of Radiation Oncology, University of California at San Francisco School of Medicine and UCSF Benioff Children' s Hospital, San Francisco, California (United States); Tran, Hung Chi [Division of Hematology/Oncology, Children' s Hospital of Los Angeles, Los Angeles, California (United States); Strahlendorf, Caron [Division of Hematology and Oncology, Department of Pediatrics, The University of British Columbia, Vancouver, British Columbia (Canada); Lemons, Richard S. [Division of Pediatric Hematology/Oncology, University of Utah School of Medicine, Salt Lake City, Utah (United States); Weinberg, Vivian [Department of Radiation Oncology, University of California at San Francisco School of Medicine and UCSF Benioff Children' s Hospital, San Francisco, California (United States); Matthay, Katherine K.; DuBois, Steven G. [Department of Pediatrics, University of California at San Francisco School of Medicine and UCSF Benioff Children' s Hospital, San Francisco, California (United States); and others

    2014-07-15

    Purpose/Objectives: Despite recent improvements in outcomes, 40% of children with high-risk neuroblastoma will experience relapse, facing a guarded prognosis for long-term cure. Whether recurrences are at new sites or sites of original disease may guide decision making during initial therapy. Methods and Materials: Eligible patients were retrospectively identified from institutional databases at first metastatic relapse of high-risk neuroblastoma. Included patients had disease involving metaiodobenzylguanidine (MIBG)-avid metastatic sites at diagnosis and first relapse, achieved a complete or partial response with no more than one residual MIBG-avid site before first relapse, and received no total body irradiation or therapy with {sup 131}I-MIBG before first relapse. Anatomically defined metastatic sites were tracked from diagnosis through first relapse to determine tendency of disease to recur at previously involved versus uninvolved sites and to assess whether this pattern was influenced by site irradiation. Results: Of 159 MIBG-avid metastatic sites identified among 43 patients at first relapse, 131 (82.4%) overlapped anatomically with the set of 525 sites present at diagnosis. This distribution was similar for bone sites, but patterns of relapse were more varied for the smaller subset of soft tissue metastases. Among all metastatic sites at diagnosis in our subsequently relapsed patient cohort, only 3 of 19 irradiated sites (15.8%) recurred as compared with 128 of 506 (25.3%) unirradiated sites. Conclusions: Metastatic bone relapse in neuroblastoma usually occurs at anatomic sites of previous disease. Metastatic sites identified at diagnosis that did not receive radiation during frontline therapy appeared to have a higher risk of involvement at first relapse relative to previously irradiated metastatic sites. These observations support the current paradigm of irradiating metastases that persist after induction chemotherapy in high-risk patients. Furthermore

  8. Local Control With 21-Gy Radiation Therapy for High-Risk Neuroblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Casey, Dana L. [Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York (United States); Kushner, Brian H.; Cheung, Nai-Kong V.; Modak, Shakeel [Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York (United States); LaQuaglia, Michael P. [Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York (United States); Wolden, Suzanne L., E-mail: woldens@mskcc.org [Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York (United States)

    2016-10-01

    Purpose: To evaluate local control after 21-Gy radiation therapy (RT) to the primary site in patients with high-risk neuroblastoma. Methods and Materials: After receiving dose-intensive chemotherapy and gross total resection (GTR), 246 patients (aged 1.2-17.9 years, median 4.0 years) with high-risk neuroblastoma underwent RT to the primary site at Memorial Sloan Kettering from 2000 to 2014. Radiation therapy consisted of 21 Gy in twice-daily fractions of 1.5 Gy each. Local failure (LF) was correlated with biologic prognostic factors and clinical findings at the time of diagnosis and start of RT. Results: Median follow-up of surviving patients was 6.4 years. Cumulative incidence of LF was 7.1% at 2 years after RT and 9.8% at 5 years after RT. The isolated LF rate was 3.0%. Eighty-six percent of all local failures were within the RT field. Local control was worse in patients who required more than 1 surgical resection to achieve GTR (22.4% vs 8.3%, P=.01). There was also a trend toward inferior local control with MYCN-amplified tumors or serum lactate dehydrogenase ≥1500 U/L (P=.09 and P=.06, respectively). Conclusion: After intensive chemotherapy and maximal surgical debulking, hyperfractionated RT with 21 Gy in high-risk neuroblastoma results in excellent local control. Given the young patient age, concern for late effects, and local control >90%, dose reduction may be appropriate for patients without MYCN amplification who achieve GTR.

  9. Local Control With 21-Gy Radiation Therapy for High-Risk Neuroblastoma

    International Nuclear Information System (INIS)

    Casey, Dana L.; Kushner, Brian H.; Cheung, Nai-Kong V.; Modak, Shakeel; LaQuaglia, Michael P.; Wolden, Suzanne L.

    2016-01-01

    Purpose: To evaluate local control after 21-Gy radiation therapy (RT) to the primary site in patients with high-risk neuroblastoma. Methods and Materials: After receiving dose-intensive chemotherapy and gross total resection (GTR), 246 patients (aged 1.2-17.9 years, median 4.0 years) with high-risk neuroblastoma underwent RT to the primary site at Memorial Sloan Kettering from 2000 to 2014. Radiation therapy consisted of 21 Gy in twice-daily fractions of 1.5 Gy each. Local failure (LF) was correlated with biologic prognostic factors and clinical findings at the time of diagnosis and start of RT. Results: Median follow-up of surviving patients was 6.4 years. Cumulative incidence of LF was 7.1% at 2 years after RT and 9.8% at 5 years after RT. The isolated LF rate was 3.0%. Eighty-six percent of all local failures were within the RT field. Local control was worse in patients who required more than 1 surgical resection to achieve GTR (22.4% vs 8.3%, P=.01). There was also a trend toward inferior local control with MYCN-amplified tumors or serum lactate dehydrogenase ≥1500 U/L (P=.09 and P=.06, respectively). Conclusion: After intensive chemotherapy and maximal surgical debulking, hyperfractionated RT with 21 Gy in high-risk neuroblastoma results in excellent local control. Given the young patient age, concern for late effects, and local control >90%, dose reduction may be appropriate for patients without MYCN amplification who achieve GTR.

  10. Distinct evolutionary mechanisms for genomic imbalances in high-risk and low-risk neuroblastomas

    Directory of Open Access Journals (Sweden)

    Gisselsson David

    2007-09-01

    Full Text Available Abstract Background Neuroblastoma (NB is the most common extracranial solid tumour of childhood. Several genomic imbalances correlate to prognosis in NB, with structural rearrangements, including gene amplification, in a near-diploid setting typically signifying high-risk tumours and numerical changes in a near-triploid setting signifying low-risk tumours. Little is known about the temporal sequence in which these imbalances occur during the carcinogenic process. Methods We have reconstructed the appearance of cytogenetic imbalances in 270 NBs by first grouping tumours and imbalances through principal component analysis and then using the number of imbalances in each tumour as an indicator of evolutionary progression. Results Tumours clustered in four sub-groups, dominated respectively by (1 gene amplification in double minute chromosomes and few other aberrations, (2 gene amplification and loss of 1p sequences, (3 loss of 1p and other structural aberrations including gain of 17q, and (4 whole-chromosome gains and losses. Temporal analysis showed that the structural changes in groups 1–3 were acquired in a step-wise fashion, with loss of 1p sequences and the emergence of double minute chromosomes as the earliest cytogenetic events. In contrast, the gains and losses of whole chromosomes in group 4 occurred through multiple simultaneous events leading to a near-triploid chromosome number. Conclusion The finding of different temporal patterns for the acquisition of genomic imbalances in high-risk and low-risk NBs lends strong support to the hypothesis that these tumours are biologically diverse entities, evolving through distinct genetic mechanisms.

  11. A single center clinical analysis of children with high-risk neuroblastoma.

    Science.gov (United States)

    Tian, Xiangdong; Cao, Yanna; Wang, Jingfu; Yan, Jie; Tian, Yao; Li, Zhongyuan; Wang, Huijuan; Duan, Xiaofeng; Jin, Yan; Zhao, Qiang

    2017-05-02

    The current multidisciplinary treatment for patients with high-risk neuroblastoma (NB) is the common census. However, protocols and opinions are different in different regions and institutions. We aimed to assess the protocol formulated by Chinese Children's Cancer Group study in 2009, and the impact of surgery extent was highlightly evaluated. This study enrolled patients with high-risk neuroblastoma between 2009 and 2014 in Department of Pediatric Oncology of Tianjin Medical University Cancer Institute and Hospital. The clinical characteristics of patients were illustrated and surgery extent was evaluated by the impact on survival rate. The 3-year overall survival (OS) and progression-free survival (PFS) were 56.2% and 50.5%, respectively. LDH (Pneuroblastoma patients in short time. This study showed no substantial survival benefit in patients with high-risk NB undergoing gross total tumor resection. Multidisciplinary intensive treatment was essential, especially for patients received subtotal tumor resection. Longer term follow-up is needed to survey complications in surviving patients who received intensive chemotherapy and radiotherapy.

  12. Panobinostat synergistically enhances the cytotoxic effects of cisplatin, doxorubicin or etoposide on high-risk neuroblastoma cells.

    Directory of Open Access Journals (Sweden)

    Guan Wang

    Full Text Available High-risk neuroblastoma remains a therapeutic challenge with a long-term survival rate of less than 40%. Therefore, new agents are urgently needed to overcome chemotherapy resistance so as to improve the treatment outcome of this deadly disease. Histone deacetylase (HDAC inhibitors (HDACIs represent a novel class of anticancer drugs. Recent studies demonstrated that HDACIs can down-regulate the CHK1 pathway by which cancer cells can develop resistance to conventional chemotherapy drugs. This prompted our hypothesis that combining HDACIs with DNA damaging chemotherapeutic drugs for treating neuroblastoma would result in enhanced anti-tumor activities of these drugs. Treatment of high-risk neuroblastoma cell lines with a novel pan-HDACI, panobinostat (LBH589, resulted in dose-dependent growth arrest and apoptosis in 4 high-risk neuroblastoma cell lines. Further, the combination of panobinostat with cisplatin, doxorubicin, or etoposide resulted in highly synergistic antitumor interactions in the high-risk neuroblastoma cell lines, independent of the sequence of drug administration. This was accompanied by cooperative induction of apoptosis. Furthermore, panobinostat treatment resulted in substantial down-regulation of CHK1 and its downstream pathway and abrogation of the G2 cell cycle checkpoint. Synergistic antitumor interactions were also observed when the DNA damaging agents were combined with a CHK1-specific inhibitor, LY2603618. Contrary to panobinostat treatment, LY2603618 treatments neither resulted in abrogation of the G2 cell cycle checkpoint nor enhanced cisplatin, doxorubicin, or etoposide-induced apoptosis in the high-risk neuroblastoma cells. Surprisingly, LY2603618 treatments caused substantial down-regulation of total CDK1. Despite this discrepancy between panobinostat and LY2603618, our results indicate that suppression of the CHK1 pathway by panobinostat is at least partially responsible for the synergistic antitumor interactions

  13. Neuroblastoma Treatment

    Science.gov (United States)

    ... adrenal glands. Signs and symptoms of neuroblastoma include bone pain and a lump in the abdomen, neck, ... options for neuroblastoma are also affected by tumor biology, which includes: The patterns of the tumor cells. ...

  14. Neuroblastoma and MYCN

    Science.gov (United States)

    Huang, Miller; Weiss, William A.

    2013-01-01

    Neuroblastoma, the most common extracranial solid tumor of childhood, is thought to originate from undifferentiated neural crest cells. Amplification of the MYC family member, MYCN, is found in ∼25% of cases and correlates with high-risk disease and poor prognosis. Currently, amplification of MYCN remains the best-characterized genetic marker of risk in neuroblastoma. This article reviews roles for MYCN in neuroblastoma and highlights recent identification of other driver mutations. Strategies to target MYCN at the level of protein stability and transcription are also reviewed. PMID:24086065

  15. {sup 18}F-DOPA PET/CT for assessment of response to induction chemotherapy in a child with high-risk neuroblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Piccardo, Arnoldo [Galliera Hospital, Nuclear Medicine Unit, Genoa (Italy); E.O. Ospedali Galliera, Department of Nuclear Medicine, Genoa (Italy); Lopci, Egesta [Humanitas Clinical and Research Center, Nuclear Medicine Department, Rozzano, MI (Italy); Foppiani, Luca [Galliera Hospital, Internal Medicine and Endocrinology, Genoa (Italy); Morana, Giovanni [G. Gaslini Children' s Hospital, Department of Pathology and Radiology, Genoa (Italy); Conte, Massimo [G. Gaslini Children' s Hospital, Department of Hematology-Oncology, Genoa (Italy)

    2014-03-15

    Functional imaging plays a crucial role in the assessment of neuroblastoma. The evaluation of response to induction chemotherapy is a cornerstone in scheduling proper treatment management in patients affected by high-risk neuroblastoma. {sup 123}I-metaiodobenzylguanidine has been recognized as the radiopharmaceutical of choice in neuroblastoma assessment. To date, the clinical role of PET/CT in pediatric malignancy is not well established.{sup 18}F-DOPA-PET/CT has been recently used in neuroblastoma, and compared with {sup 123}I-MIBG-scan. Scant new data are available about the role of this tool in the evaluation of treatment response after induction chemotherapy. We investigate the role of {sup 18}F-DOPA-PET/CT in characterizing the response to induction chemotherapy in a child affected by high-risk-neuroblastoma, in whom the rare association of {sup 123}I-MIBG-negative primary tumor and MIBG-positive bone marrow metastases was observed. (orig.)

  16. Identification of GPC2 as an Oncoprotein and Candidate Immunotherapeutic Target in High-Risk Neuroblastoma.

    Science.gov (United States)

    Bosse, Kristopher R; Raman, Pichai; Zhu, Zhongyu; Lane, Maria; Martinez, Daniel; Heitzeneder, Sabine; Rathi, Komal S; Kendsersky, Nathan M; Randall, Michael; Donovan, Laura; Morrissy, Sorana; Sussman, Robyn T; Zhelev, Doncho V; Feng, Yang; Wang, Yanping; Hwang, Jennifer; Lopez, Gonzalo; Harenza, Jo Lynne; Wei, Jun S; Pawel, Bruce; Bhatti, Tricia; Santi, Mariarita; Ganguly, Arupa; Khan, Javed; Marra, Marco A; Taylor, Michael D; Dimitrov, Dimiter S; Mackall, Crystal L; Maris, John M

    2017-09-11

    We developed an RNA-sequencing-based pipeline to discover differentially expressed cell-surface molecules in neuroblastoma that meet criteria for optimal immunotherapeutic target safety and efficacy. Here, we show that GPC2 is a strong candidate immunotherapeutic target in this childhood cancer. We demonstrate high GPC2 expression in neuroblastoma due to MYCN transcriptional activation and/or somatic gain of the GPC2 locus. We confirm GPC2 to be highly expressed on most neuroblastomas, but not detectable at appreciable levels in normal childhood tissues. In addition, we demonstrate that GPC2 is required for neuroblastoma proliferation. Finally, we develop a GPC2-directed antibody-drug conjugate that is potently cytotoxic to GPC2-expressing neuroblastoma cells. Collectively, these findings validate GPC2 as a non-mutated neuroblastoma oncoprotein and candidate immunotherapeutic target. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. {sup 123}I-mIBG scintigraphy in neuroblastoma: development of a SIOPEN semi-quantitative reporting,method by an international panel

    Energy Technology Data Exchange (ETDEWEB)

    Lewington, V. [King' s College, London (United Kingdom); Lambert, B. [Ghent University, Radiology and Nuclear Medicine, Ghent (Belgium); Poetschger, U. [Children' s Cancer Research Institute, Department for Studies and Statistics on Integrated Research and Projects (S2IRP), Vienna (Austria); Sever, Z. Bar [Schneider Children' s Medical Centre of Israel, Petach-Tikva (Israel); Giammarile, F. [CHLS, Pierre-Benite (France); McEwan, A.J.B. [Cross Cancer Institute, Edmonton (Canada); Castellani, Rita [Fondazione IRCCS Istituto Nazionale dei Tumori, Nuclear Medicine, Milan (Italy); Lynch, T. [Northern Ireland Cancer Centre, Belfast (United Kingdom); Shulkin, B. [St Jude' s Children' s Research Hospital, Memphis (United States); Drobics, M. [Information Management and eHealth, AIT Austrian Institute of Technology GmbH Safety and Security Department, Vienna (Austria); Staudenherz, A. [AKH, Vienna (Austria); Ladenstein, R. [Children' s Cancer Research Institute, Department for Studies and Statistics on Integrated Research and Projects (S2IRP), Vienna (Austria); St. Anna Children' s Hospital and Medical University, Vienna (Austria)

    2017-02-15

    A robust method is required to standardise objective reporting of diagnostic {sup 123}I-mIBG images in neuroblastoma. Prerequisites for an appropriate system are low inter- and intra-observer error and reproducibility across a broad disease spectrum. We present a new reporting method, developed and tested for SIOPEN by an international expert panel. Patterns of abnormal skeletal {sup 123}I-mIBG uptake were defined and assigned numerical scores [0-6] based on disease extent within 12 body segments. Uptake intensity was excluded from the analysis. Data sets from 82 patients were scored independently by six experienced specialists as unblinded pairs (pre- and post-induction chemotherapy) and in random order as a blinded study. Response was defined as ≥50 % reduction in post induction score compared with baseline. In total, 1968 image sets were reviewed individually. Response rates of 88 % and 82 % were recorded for patients with baseline skeletal scores ≤23 and 24-48 respectively, compared with 44 % response in patients with skeletal scores >48 (p = 0.02). Reducing the number of segments or extension scale had a small but statistically negative impact upon the number of responses detected. Intraclass correlation coefficients [ICCs] calculated for the unblinded and blinded study were 0.95 at diagnosis and 0.98 and 0.99 post-induction chemotherapy, respectively. The SIOPEN mIBG score method is reproducible across the full spectrum of disease in high risk neuroblastoma. Numerical assessment of skeletal disease extent avoids subjective evaluation of uptake intensity. This robust approach provides a reliable means with which to examine the role of 123I mIBG scintigraphy as a prognostic indicator in neuroblastoma. (orig.)

  18. 123I-mIBG scintigraphy in neuroblastoma: development of a SIOPEN semi-quantitative reporting,method by an international panel

    International Nuclear Information System (INIS)

    Lewington, V.; Lambert, B.; Poetschger, U.; Sever, Z. Bar; Giammarile, F.; McEwan, A.J.B.; Castellani, Rita; Lynch, T.; Shulkin, B.; Drobics, M.; Staudenherz, A.; Ladenstein, R.

    2017-01-01

    A robust method is required to standardise objective reporting of diagnostic 123 I-mIBG images in neuroblastoma. Prerequisites for an appropriate system are low inter- and intra-observer error and reproducibility across a broad disease spectrum. We present a new reporting method, developed and tested for SIOPEN by an international expert panel. Patterns of abnormal skeletal 123 I-mIBG uptake were defined and assigned numerical scores [0-6] based on disease extent within 12 body segments. Uptake intensity was excluded from the analysis. Data sets from 82 patients were scored independently by six experienced specialists as unblinded pairs (pre- and post-induction chemotherapy) and in random order as a blinded study. Response was defined as ≥50 % reduction in post induction score compared with baseline. In total, 1968 image sets were reviewed individually. Response rates of 88 % and 82 % were recorded for patients with baseline skeletal scores ≤23 and 24-48 respectively, compared with 44 % response in patients with skeletal scores >48 (p = 0.02). Reducing the number of segments or extension scale had a small but statistically negative impact upon the number of responses detected. Intraclass correlation coefficients [ICCs] calculated for the unblinded and blinded study were 0.95 at diagnosis and 0.98 and 0.99 post-induction chemotherapy, respectively. The SIOPEN mIBG score method is reproducible across the full spectrum of disease in high risk neuroblastoma. Numerical assessment of skeletal disease extent avoids subjective evaluation of uptake intensity. This robust approach provides a reliable means with which to examine the role of 123I mIBG scintigraphy as a prognostic indicator in neuroblastoma. (orig.)

  19. Patterns of Relapse in High-Risk Neuroblastoma Patients Treated With and Without Total Body Irradiation

    International Nuclear Information System (INIS)

    Li, Richard; Polishchuk, Alexei; DuBois, Steven; Hawkins, Randall; Lee, Stephanie W.; Bagatell, Rochelle; Shusterman, Suzanne; Hill-Kayser, Christine; Al-Sayegh, Hasan; Diller, Lisa; Haas-Kogan, Daphne A.; Matthay, Katherine K.; London, Wendy B.

    2017-01-01

    Purpose: External beam radiation therapy to initial sites of disease may influence relapse patterns in high-risk neuroblastoma. However, the effect of systemic irradiation by use of total body irradiation (TBI) on anatomic patterns of relapse has not previously been investigated. Methods and Materials: We retrospectively analyzed patients receiving definitive treatment of high-risk neuroblastoma with subsequent relapse in bony metastatic sites, with a date of relapse between January 1, 1997, and December 31, 2012. Anatomic sites of disease, defined by metaiodobenzylguanidine (MIBG) avidity, were compared at diagnosis and at first relapse. The Fisher exact test was performed to compare relapse in initially involved sites between patients treated with and without TBI. Results: Seventy-four patients with a median age at diagnosis of 3.5 years (range, 0.3-15.3 years) had relapse in 227 sites of MIBG-avid metastatic disease, with a median time to relapse of 1.8 years. Of the 227 sites of first relapse, 154 sites (68%) were involved at diagnosis. When we compared relapse patterns in patients treated with and without TBI, 12 of 23 patients (52%) treated with TBI had relapse in ≥1 previously MIBG-avid site of disease whereas 40 of 51 patients (78%) treated without TBI had relapse in ≥1 previously MIBG-avid site of disease (P=.03). Conclusions: Patients treated with systemic irradiation in the form of TBI were significantly less likely to have relapse in prior sites of disease. These findings support further investigation into the role of radiopharmaceutical therapies in curative multimodality therapy.

  20. Patterns of Relapse in High-Risk Neuroblastoma Patients Treated With and Without Total Body Irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Li, Richard [Harvard Medical School, Boston, Massachusetts (United States); Brigham and Women' s Hospital, Boston, Massachusetts (United States); Polishchuk, Alexei [School of Medicine, University of California San Francisco, San Francisco, California (United States); DuBois, Steven [Harvard Medical School, Boston, Massachusetts (United States); Dana-Farber/Boston Children' s Cancer and Blood Disorders Center, Boston, Massachusetts (United States); Hawkins, Randall [School of Medicine, University of California San Francisco, San Francisco, California (United States); Lee, Stephanie W. [Brigham and Women' s Hospital, Boston, Massachusetts (United States); Bagatell, Rochelle [Children' s Hospital of Philadelphia, Philadelphia, Pennsylvania (United States); Shusterman, Suzanne [Harvard Medical School, Boston, Massachusetts (United States); Dana-Farber/Boston Children' s Cancer and Blood Disorders Center, Boston, Massachusetts (United States); Hill-Kayser, Christine [Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Al-Sayegh, Hasan [Brigham and Women' s Hospital, Boston, Massachusetts (United States); Dana-Farber/Boston Children' s Cancer and Blood Disorders Center, Boston, Massachusetts (United States); Diller, Lisa [Harvard Medical School, Boston, Massachusetts (United States); Dana-Farber/Boston Children' s Cancer and Blood Disorders Center, Boston, Massachusetts (United States); Haas-Kogan, Daphne A. [Harvard Medical School, Boston, Massachusetts (United States); Brigham and Women' s Hospital, Boston, Massachusetts (United States); Dana-Farber/Boston Children' s Cancer and Blood Disorders Center, Boston, Massachusetts (United States); Matthay, Katherine K. [School of Medicine, University of California San Francisco, San Francisco, California (United States); London, Wendy B. [Harvard Medical School, Boston, Massachusetts (United States); Dana-Farber/Boston Children' s Cancer and Blood Disorders Center, Boston, Massachusetts (United States); and others

    2017-02-01

    Purpose: External beam radiation therapy to initial sites of disease may influence relapse patterns in high-risk neuroblastoma. However, the effect of systemic irradiation by use of total body irradiation (TBI) on anatomic patterns of relapse has not previously been investigated. Methods and Materials: We retrospectively analyzed patients receiving definitive treatment of high-risk neuroblastoma with subsequent relapse in bony metastatic sites, with a date of relapse between January 1, 1997, and December 31, 2012. Anatomic sites of disease, defined by metaiodobenzylguanidine (MIBG) avidity, were compared at diagnosis and at first relapse. The Fisher exact test was performed to compare relapse in initially involved sites between patients treated with and without TBI. Results: Seventy-four patients with a median age at diagnosis of 3.5 years (range, 0.3-15.3 years) had relapse in 227 sites of MIBG-avid metastatic disease, with a median time to relapse of 1.8 years. Of the 227 sites of first relapse, 154 sites (68%) were involved at diagnosis. When we compared relapse patterns in patients treated with and without TBI, 12 of 23 patients (52%) treated with TBI had relapse in ≥1 previously MIBG-avid site of disease whereas 40 of 51 patients (78%) treated without TBI had relapse in ≥1 previously MIBG-avid site of disease (P=.03). Conclusions: Patients treated with systemic irradiation in the form of TBI were significantly less likely to have relapse in prior sites of disease. These findings support further investigation into the role of radiopharmaceutical therapies in curative multimodality therapy.

  1. Cross-cohort analysis identifies a TEAD4 ↔ MYCN positive-feedback loop as the core regulatory element of high-risk neuroblastoma. | Office of Cancer Genomics

    Science.gov (United States)

    High-risk neuroblastomas show a paucity of recurrent somatic mutations at diagnosis. As a result, the molecular basis for this aggressive phenotype remains elusive. Recent progress in regulatory network analysis helped us elucidate disease-driving mechanisms downstream of genomic alterations, including recurrent chromosomal alterations. Our analysis identified three molecular subtypes of high-risk neuroblastomas, consistent with chromosomal alterations, and identified subtype-specific master regulator (MR) proteins that were conserved across independent cohorts.

  2. RFC-1 80G>A polymorphism in case-mother/control-mother dyads is associated with risk of nephroblastoma and neuroblastoma.

    Science.gov (United States)

    Montalvão-de-Azevedo, Rafaela; Vasconcelos, Gisele M; Vargas, Fernando R; Thuler, Luiz Claudio; Pombo-de-Oliveira, Maria S; de Camargo, Beatriz

    2015-02-01

    Embryonic tumors are associated with an interruption during normal organ development; they may be related to disturbances in the folate pathway involved in DNA synthesis, methylation, and repair. Prenatal supplementation with folic acid is associated with a decreased risk of neuroblastoma, brain tumors, retinoblastoma, and nephroblastoma. The aim of this study was to investigate the association between MTHFR rs1801133 (C677T) and RFC-1 rs1051266 (G80A) genotypes with the risk of developing nephroblastoma and neuroblastoma. Case-mother/control-mother dyad study. Samples from Brazilian children with nephroblastoma (n=80), neuroblastoma (n=66), healthy controls (n=453), and their mothers (case n=93; control n=75) were analyzed. Genomic DNA was isolated from peripheral blood cells and/or buccal cells and genotyped to identify MTHFR C677T and RFC-1 G80A polymorphisms. Differences in genotype distribution between patients and controls were tested by multiple logistic regression analysis. Risk for nephroblastoma and neuroblastoma was two- to fourfold increased among children with RFC-1 polymorphisms. An increased four- to eightfold risk for neuroblastoma and nephroblastoma was seen when the child and maternal genotypes were combined. Our results suggest that mother and child RFC-1 G80A genotypes play a role on the risk of neuroblastoma and nephroblastoma since this polymorphism may impair the intracellular levels of folate, through carrying fewer folate molecules to the cell interior, and thus, the intracellular concentration is not enough to maintain regular DNA synthesis and methylation pathways.

  3. Reactivating TP53 signaling by the novel MDM2 inhibitor DS-3032b as a therapeutic option for high-risk neuroblastoma

    Science.gov (United States)

    Arnhold, Viktor; Schmelz, Karin; Proba, Jutta; Winkler, Annika; Wünschel, Jasmin; Toedling, Joern; Deubzer, Hedwig E.; Künkele, Annette; Eggert, Angelika; Schulte, Johannes H.; Hundsdoerfer, Patrick

    2018-01-01

    Fewer than 50% of patients with high-risk neuroblastoma survive five years after diagnosis with current treatment protocols. Molecular targeted therapies are expected to improve survival. Although MDM2 has been validated as a promising target in preclinical models, no MDM2 inhibitors have yet entered clinical trials for neuroblastoma patients. Toxic side effects, poor bioavailability and low efficacy of the available MDM2 inhibitors that have entered phase I/II trials drive the development of novel MDM2 inhibitors with an improved risk-benefit profile. We investigated the effect of the novel MDM2 small molecular inhibitor, DS-3032b, on viability, proliferation, senescence, migration, cell cycle arrest and apoptosis in a panel of six neuroblastoma cell lines with different TP53 and MYCN genetic backgrounds, and assessed efficacy in a murine subcutaneous model for high-risk neuroblastoma. Re-analysis of existing expression data from 476 primary neuroblastomas showed that high-level MDM2 expression correlated with poor patient survival. DS-3032b treatment enhanced TP53 target gene expression and induced G1 cell cycle arrest, senescence and apoptosis. CRISPR-mediated MDM2 knockout in neuroblastoma cells mimicked DS-3032b treatment. TP53 signaling was selectively activated by DS-3032b in neuroblastoma cells with wildtype TP53, regardless of the presence of MYCN amplification, but was significantly reduced by TP53 mutations or expression of a dominant-negative TP53 mutant. Oral DS-3032b administration inhibited xenograft tumor growth and prolonged mouse survival. Our in vitro and in vivo data demonstrate that DS-3032b reactivates TP53 signaling even in the presence of MYCN amplification in neuroblastoma cells, to reduce proliferative capacity and cause cytotoxicity. PMID:29416773

  4. Neuroblastoma | Office of Cancer Genomics

    Science.gov (United States)

    The TARGET Neuroblastoma projects elucidate comprehensive molecular characterization to determine the genetic changes that drive the initiation and progression of high-risk or hard-to-treat childhood cancers. Neuroblastoma (NBL) is a cancer that arises in immature nerve cells of the sympathetic nervous system, primarily affecting infants and children.

  5. Assessment of organ dose reduction and secondary cancer risk associated with the use of proton beam therapy and intensity modulated radiation therapy in treatment of neuroblastomas

    International Nuclear Information System (INIS)

    Fuji, Hiroshi; Harada, Hideyuki; Asakura, Hirofumi; Nishimura, Tetsuo; Schneider, Uwe; Ishida, Yuji; Konno, Masahiro; Yamashita, Haruo; Kase, Yuki; Murayama, Shigeyuki; Onoe, Tsuyoshi; Ogawa, Hirofumi

    2013-01-01

    To compare proton beam therapy (PBT) and intensity-modulated radiation therapy (IMRT) with conformal radiation therapy (CRT) in terms of their organ doses and ability to cause secondary cancer in normal organs. Five patients (median age, 4 years; range, 2–11 years) who underwent PBT for retroperitoneal neuroblastoma were selected for treatment planning simulation. Four patients had stage 4 tumors and one had stage 2A tumor, according to the International Neuroblastoma Staging System. Two patients received 36 Gy, two received 21.6 Gy, and one received 41.4 Gy of radiation. The volume structures of these patients were used for simulations of CRT and IMRT treatment. Dose–volume analyses of liver, stomach, colon, small intestine, pancreas, and bone were performed for the simulations. Secondary cancer risks in these organs were calculated using the organ equivalent dose (OED) model, which took into account the rates of cell killing, repopulation, and the neutron dose from the treatment machine. In all evaluated organs, the mean dose in PBT was 20–80% of that in CRT. IMRT also showed lower mean doses than CRT for two organs (20% and 65%), but higher mean doses for the other four organs (110–120%). The risk of secondary cancer in PBT was 24–83% of that in CRT for five organs, but 121% of that in CRT for pancreas. The risk of secondary cancer in IMRT was equal to or higher than CRT for four organs (range 100–124%). Low radiation doses in normal organs are more frequently observed in PBT than in IMRT. Assessments of secondary cancer risk showed that PBT reduces the risk of secondary cancer in most organs, whereas IMRT is associated with a higher risk than CRT

  6. Neuroblastoma: morphological pattern, molecular genetic features, and prognostic factors

    Directory of Open Access Journals (Sweden)

    A. M. Stroganova

    2016-01-01

    Full Text Available Neuroblastoma, the most common extracranial tumor of childhood, arises from the developing neurons of the sympathetic nervous system (neural cress stem cells and has various biological and clinical characteristics. The mean age at disease onset is 18 months. Neuroblastoma has a number of unique characteristics: a capacity for spontaneous regression in babies younger than 12 months even in the presence of distant metastases, for differentiation (maturation into ganglioneuroma in infants after the first year of life, and for swift aggressive development and rapid metastasis. There are 2 clinical classifications of neuroblastoma: the International neuroblastoma staging system that is based on surgical results and the International Neuroblastoma Risk Group Staging System. One of the fundamentally important problems for the clinical picture of neuroblastoma is difficulties making its prognosis. Along with clinical parameters (a patient’s age, tumor extent and site, some histological, molecular biochemical (ploidy and genetic (chromosomal aberrations, MYCN gene status, deletion of the locus 1p36 and 11q, the longer arm of chromosome 17, etc. characteristics of tumor cells are of considerable promise. MYCN gene amplification is observed in 20–30 % of primary neuroblastomas and it is one of the major indicators of disease aggressiveness, early chemotherapy resistance, and a poor prognosis. There are 2 types of MYCN gene amplification: extrachromosomal (double acentric chromosomes and intrachromosomal (homogenically painted regions. Examination of double acentric chromosomes revealed an interesting fact that it may be eliminated (removed from the nucleus through the formation of micronuclei. MYCN oncogene amplification is accompanied frequently by 1p36 locus deletion and longer 17q arm and less frequently by 11q23 deletion; these are poor prognostic factors for the disease. The paper considers in detail the specific, unique characteristics of the

  7. Combinations of genetic data in a study of neuroblastoma risk genotypes

    DEFF Research Database (Denmark)

    Capasso, Mario; Calabrese, Francesco Maria; Iolascon, Achille

    2014-01-01

    Analysis of combinations of genetic changes that occur exclusively in patients may be a supplementary strategy to the single-locus strategy used in many genetic studies. The genotypes of 16 SNPs within susceptibility loci for neuroblastoma (NB) were analyzed in a previous study. In the present...

  8. High-dose I-131 MIBG treatment for young children with high-risk neuroblastoma, and its practical problem. From the experience of the youngest case in Japan

    International Nuclear Information System (INIS)

    Araki, Raita; Nishimura, Ryosei; Mase, Shintaro

    2012-01-01

    High-dose I-131 MIBG (metaiodobenzylguanidine) therapy combined with auto- or allo-hematopoietic stem cell transplantation is becoming a potential treatment for patients with high-risk neuroblastoma worldwide. However, only older children, who can perform personal care, had been given high-dose I-131 MIBG treatment to avoid the needless radiation exposure to caregivers and medical staff in Japan. In this case report, we have used the high dose MIBG therapy followed by autologous PBSCT (peripheral blood stem cell transplantation) for a 1-year-old boy with a newly diagnosed high-risk neuroblastoma with MYCN amplifications. The total radiation exposure to all parties involved was very limited, even in the youngest case in Japan, probably due to adequate preparations. This encouraging experience may remove the age limit for high-dose I-131 MIBG treatment for the patients with high-risk neuroblastoma in Japan. (author)

  9. Batrachotoxin modifies the gating kinetics of sodium channels in internally perfused neuroblastoma cells.

    Science.gov (United States)

    Huang, L Y; Moran, N; Ehrenstein, G

    1982-01-01

    We have studied the effects of batrachotoxin (BTX) on sodium channels in hybrid mouse neuroblastoma cells NG108-15 by using the suction pipet voltage clamp method. BTX-modified sodium channels activate with first-order kinetics and, over most of the potential range, activate more slowly than normal sodium channels. The peak conductance-voltage curve and the time constant of activation-versus-voltage curve for BTX-modified sodium channels are shifted about 50 mV in the hyperpolarizing direction compared to the corresponding curves for normal sodium channels. There is no change in the slope of the conductance-voltage curve. These results suggest that BTX slows down one of the steps leading to channel opening, which consequently becomes rate-limiting. In addition, BTX eliminates both fast and slow inactivation. PMID:6281796

  10. Genetics Home Reference: neuroblastoma

    Science.gov (United States)

    ... Share: Email Facebook Twitter Home Health Conditions Neuroblastoma Neuroblastoma Printable PDF Open All Close All Enable Javascript to view the expand/collapse boxes. Description Neuroblastoma is a type of cancer that most often ...

  11. RGS2 modulates the activity and internalization of dopamine D2 receptors in neuroblastoma N2A cells.

    Science.gov (United States)

    Luessen, Deborah J; Hinshaw, Tyler P; Sun, Haiguo; Howlett, Allyn C; Marrs, Glen; McCool, Brian A; Chen, Rong

    2016-11-01

    Dysregulated expression and function of dopamine D2 receptors (D2Rs) are implicated in drug addiction, Parkinson's disease and schizophrenia. In the current study, we examined whether D2Rs are modulated by regulator of G protein signaling 2 (RGS2), a member of the RGS family that regulates G protein signaling via acceleration of GTPase activity. Using neuroblastoma 2a (N2A) cells, we found that RGS2 was immunoprecipitated by aluminum fluoride-activated Gαi2 proteins. RGS2 siRNA knockdown enhanced membrane [(35)S] GTPγS binding to activated Gαi/o proteins, augmented inhibition of cAMP accumulation and increased ERK phosphorylation in the presence of a D2/D3R agonist quinpirole when compared to scrambled siRNA treatment. These data suggest that RGS2 is a negative modulator of D2R-mediated Gαi/o signaling. Moreover, RGS2 knockdown slightly increased constitutive D2R internalization and markedly abolished quinpirole-induced D2R internalization assessed by immunocytochemistry. RGS2 knockdown did not compromise agonist-induced β-arrestin membrane recruitment; however, it prevents β-arrestin dissociation from the membrane after prolonged quinpirole treatment during which time β-arrestin moved away from the membrane in control cells. Additionally, confocal microscopy analysis of β-arrestin post-endocytic fate revealed that quinpirole treatment caused β-arrestin to translocate to the early and the recycling endosome in a time-dependent manner in control cells whereas translocation of β-arrestin to these endosomes did not occur in RGS2 knockdown cells. The impaired β-arrestin translocation likely contributed to the abolishment of quinpirole-stimulated D2R internalization in RGS2 knockdown cells. Thus, RGS2 is integral for β-arrestin-mediated D2R internalization. The current study revealed a novel regulation of D2R signaling and internalization by RGS2 proteins. Copyright © 2016 Elsevier Ltd. All rights reserved.

  12. Neuroblastoma : Crossing borders in targeted therapy

    NARCIS (Netherlands)

    Bate-Eya, L.T.

    2017-01-01

    Neuroblastoma is the most commonly diagnosed childhood cancer and accounts for about 15% of all pediatric malignancies deaths. Thus far, the treatment options of neuroblastoma is limited with only a 30-40% long term survival rate in high-risk patients. In this thesis, we describe the isolation and

  13. Vascular endothelial growth factor (VEGF-C - a potent risk factor in children diagnosed with stadium 4 neuroblastoma.

    Directory of Open Access Journals (Sweden)

    Bogdan Miskowiak

    2009-01-01

    Full Text Available To evaluate the immunohistochemical expression of VEGF-C, CD34 and VEGFR-2 in cancer tissue of children diagnosed with stadium 4 neuroblastoma (NB and correlate their presence with the survival rate of children diagnosed with that stage of the disease. Eighteen children assigned to stadium 4 composed the study group. Fourteen patients (allocated to stadium 3 formed a control group. VEGF-C, CD34 and VEGFR-2 expressions were evaluated by immunohistochemical assay. Consecutive slides incubated with anti-CD34 and anti-VEGFR-2 antibodies revealed that the two markers were colocalized within endothelial layer of the blood vessels. On the other hand, VEGF-C was expressed exclusively in tumour cells. As demonstrated by Fisher's exact test, the risk of NB treatment failure (progression or relapse as well as tumour related death, when all the patients were considered, was found to be significant in VEGF-C positive patients. VEGF-C expression in NB constitutes a potent risk factor and may direct future anti-angiogenic treatment strategy. The proximity of VEGF-C and CD34/VEGFR-2 of NB could be the equivalent of a potentially interesting VEGF-C fashion involving a tumour cell invasion into the blood vessels in an early phase of metastases promoting.

  14. INTERNAL AUDIT AND RISK MANAGEMENT

    Directory of Open Access Journals (Sweden)

    Elena RUSE

    2014-04-01

    Full Text Available The existence of risk in economic activity can not be denied. In fact, the risk is a concept which exists in every activity, the term of risk being identified with uncertainty, respectively the (unchance to produce an undesirable event. Internal audit and risk management aim at the same goal, namely the control of risks. Internal Audit performs several roles in risk management plan. The objectives of the internal audit function varies from company to company, but in all economic entities internal audit department aims to improve performance management, enterprise performance and thus improve the internal control system. This paper aims to demonstrate, among other things, that any event that may result in failure is unquestionably classified as risk.

  15. Olfactory neuroblastoma

    International Nuclear Information System (INIS)

    Rashid, D.; Ahmed, B.; Malik, S.M.; Khan, M.

    2000-01-01

    Olfactory neuroblastoma/esthesioneuroblastoma in a rare malignant tumour of the olfactory neuroepithelium. This is a report of 5 cases managed over the last 10 years at Combined Military Hospital, Rawalpindi. Age of the patients at presentation ranged from 27 to 70 years. The main symptoms were unilateral nasal obstruction and intermittent epistaxis. The mean duration of symptoms at presentation was 11 months. Two patients were staged as B and 3 as C at presentation. The stage of the disease correlated with the duration of symptoms. All the cases were diagnosed on histopathology. Three were offered combination of surgery and radiotherapy. One patient received only surgical treatment and one patient received radiotherapy and chemotherapy. Combination of surgery and radiotherapy showed best results. (author)

  16. Advances in the translational genomics of neuroblastoma

    Science.gov (United States)

    Bosse, Kristopher R.; Maris, John M.

    2015-01-01

    Neuroblastoma is an embryonal malignancy that commonly affects young children and is remarkably heterogenous in its malignant potential. Recently, the genetic basis of neuroblastoma has come into focus, which has catalyzed not only a more comprehensive understanding of neuroblastoma tumorigenesis, but has also revealed novel oncogenic vulnerabilities that are being leveraged therapeutically. Neuroblastoma is a model pediatric solid tumor in its use of recurrent genomic alterations, such as high-level MYCN amplification, for risk stratification. Given the relative paucity of recurrent activating somatic point mutations or gene fusions in primary neuroblastoma tumors studied at initial diagnosis, innovative treatment approaches beyond small molecules targeting mutated or dysregulated kinases will be required moving forward to achieve noticeable improvements in overall patient survival. However, the clonally acquired, oncogenic aberrations in relapsed neuroblastomas are currently being defined and may offer an opportunity to improve patient outcomes with molecularly targeted therapy directed towards aberrantly regulated pathways in relapsed disease. This review will summarize the current state of knowledge of neuroblastoma genetics and genomics, highlighting the improved prognostication and potential therapeutic opportunities that have arisen from recent advances in understanding germline predisposition, recurrent segmental chromosomal alterations, somatic point mutations and translocations, and clonal evolution in relapsed neuroblastoma. PMID:26539795

  17. Estimated Internal and External Radiation Exposure of Caregivers of Patients With Pediatric Neuroblastoma Undergoing 131I Metaiodobenzylguanidine Therapy: A Prospective Pilot Study.

    Science.gov (United States)

    Han, Sangwon; Yoo, Seon Hee; Koh, Kyung-Nam; Lee, Jong Jin

    2017-04-01

    Current recommendations suggest that family members should participate in the care of children receiving in-hospital I metaiodobenzylguanidine (MIBG) therapy for neuroblastoma. The present study aimed to measure the external radiation exposure and estimate the internal radiation exposure of caregivers during the hospital stay for I MIBG therapy. Caregivers received radiation safety instructions and a potassium iodide solution for thyroid blockade before patient admission. External radiation exposure was determined using a personal pocket dosimeter. Serial 24-hour urine samples were collected from caregivers during the hospital stay. Estimated internal radiation exposure was calculated based on the urine activity. Twelve cases (mean age, 6.2 ± 3.5 years; range, 2-13 years) were enrolled. The mean administered activity was 233.3 ± 74.9 (range, 150.0-350.0) mCi. The mean external radiation dose was 5.8 ± 7.2 (range, 0.8-19.9) mSv. Caregivers of children older than 4 years had significantly less external radiation exposure than those of children younger than 4 years (1.9 ± 1.0 vs 16.4 ± 5.0 mSv; P = 0.012). The mean estimated internal radiation dose was 11.3 ± 10.2 (range, 1.0-29.8) μSv. Caregivers receive both external and internal radiation exposure while providing in-hospital care to children receiving I MIBG therapy for neuroblastoma. However, the internal radiation exposure was negligible compared with the external radiation exposure.

  18. Overview and recent advances in the treatment of neuroblastoma.

    Science.gov (United States)

    Whittle, Sarah B; Smith, Valeria; Doherty, Erin; Zhao, Sibo; McCarty, Scott; Zage, Peter E

    2017-04-01

    Children with neuroblastoma have widely divergent outcomes, ranging from cure in >90% of patients with low risk disease to neuroblastoma, allowing for more accurate risk stratification and treatment reduction in many cases, although newer treatment strategies for children with high-risk and relapsed neuroblastoma are needed to improve outcomes. Areas covered: Neuroblastoma epidemiology, diagnosis, risk stratification, and recent advances in treatment of both newly diagnosed and relapsed neuroblastoma. Expert commentary: The identification of newer tumor targets and of novel cell-mediated immunotherapy agents may lead to novel therapeutic approaches, and clinical trials for regimens designed to target individual genetic aberrations in tumors are underway. A combination of therapeutic modalities will likely be required to improve survival and cure rates for patients with high-risk neuroblastoma.

  19. Cell Proliferation in Neuroblastoma

    Science.gov (United States)

    Stafman, Laura L.; Beierle, Elizabeth A.

    2016-01-01

    Neuroblastoma, the most common extracranial solid tumor of childhood, continues to carry a dismal prognosis for children diagnosed with advanced stage or relapsed disease. This review focuses upon factors responsible for cell proliferation in neuroblastoma including transcription factors, kinases, and regulators of the cell cycle. Novel therapeutic strategies directed toward these targets in neuroblastoma are discussed. PMID:26771642

  20. Accelerating drug development for neuroblastoma - New Drug Development Strategy: an Innovative Therapies for Children with Cancer, European Network for Cancer Research in Children and Adolescents and International Society of Paediatric Oncology Europe Neuroblastoma project.

    Science.gov (United States)

    Moreno, Lucas; Caron, Hubert; Geoerger, Birgit; Eggert, Angelika; Schleiermacher, Gudrun; Brock, Penelope; Valteau-Couanet, Dominique; Chesler, Louis; Schulte, Johannes H; De Preter, Katleen; Molenaar, Jan; Schramm, Alexander; Eilers, Martin; Van Maerken, Tom; Johnsen, John Inge; Garrett, Michelle; George, Sally L; Tweddle, Deborah A; Kogner, Per; Berthold, Frank; Koster, Jan; Barone, Giuseppe; Tucker, Elizabeth R; Marshall, Lynley; Herold, Ralf; Sterba, Jaroslav; Norga, Koen; Vassal, Gilles; Pearson, Andrew Dj

    2017-08-01

    Neuroblastoma, the commonest paediatric extra-cranial tumour, remains a leading cause of death from cancer in children. There is an urgent need to develop new drugs to improve cure rates and reduce long-term toxicity and to incorporate molecularly targeted therapies into treatment. Many potential drugs are becoming available, but have to be prioritised for clinical trials due to the relatively small numbers of patients. Areas covered: The current drug development model has been slow, associated with significant attrition, and few new drugs have been developed for neuroblastoma. The Neuroblastoma New Drug Development Strategy (NDDS) has: 1) established a group with expertise in drug development; 2) prioritised targets and drugs according to tumour biology (target expression, dependency, pre-clinical data; potential combinations; biomarkers), identifying as priority targets ALK, MEK, CDK4/6, MDM2, MYCN (druggable by BET bromodomain, aurora kinase, mTORC1/2) BIRC5 and checkpoint kinase 1; 3) promoted clinical trials with target-prioritised drugs. Drugs showing activity can be rapidly transitioned via parallel randomised trials into front-line studies. Expert opinion: The Neuroblastoma NDDS is based on the premise that optimal drug development is reliant on knowledge of tumour biology and prioritisation. This approach will accelerate neuroblastoma drug development and other poor prognosis childhood malignancies.

  1. Favorable Local Control From Consolidative Radiation Therapy in High-Risk Neuroblastoma Despite Gross Residual Disease, Positive Margins, or Nodal Involvement.

    Science.gov (United States)

    Ferris, Matthew J; Danish, Hasan; Switchenko, Jeffrey M; Deng, Claudia; George, Bradley A; Goldsmith, Kelly C; Wasilewski, Karen J; Cash, W Thomas; Khan, Mohammad K; Eaton, Bree R; Esiashvili, Natia

    2017-03-15

    To report the influence of radiation therapy (RT) dose and surgical pathology variables on disease control and overall survival (OS) in patients treated for high-risk neuroblastoma at a single institution. We conducted a retrospective study of 67 high-risk neuroblastoma patients who received RT as part of definitive management from January 2003 until May 2014. At a median follow-up of 4.5 years, 26 patients (38.8%) failed distantly; 4 of these patients also failed locally. One patient progressed locally without distant failure. Local control was 92.5%, and total disease control was 59.5%. No benefit was demonstrated for RT doses over 21.6 Gy with respect to local relapse-free survival (P=.55), disease-free survival (P=.22), or OS (P=.72). With respect to local relapse-free survival, disease-free survival, and OS, no disadvantage was seen for positive lymph nodes on surgical pathology, positive surgical margins, or gross residual disease. Of the patients with gross residual disease, 75% (6 of 8) went on to have no evidence of disease at time of last follow-up, and the 2 patients who failed did so distantly. Patients with high-risk neuroblastoma in this series maintained excellent local control, with no benefit demonstrated for radiation doses over 21.6 Gy, and no disadvantage demonstrated for gross residual disease after surgery, positive surgical margins, or pathologic lymph node positivity. Though the limitations of a retrospective review for an uncommon disease must be kept in mind, with small numbers in some of the subgroups, it seems that dose escalation should be considered only in exceptional circumstances. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Favorable Local Control From Consolidative Radiation Therapy in High-Risk Neuroblastoma Despite Gross Residual Disease, Positive Margins, or Nodal Involvement

    Energy Technology Data Exchange (ETDEWEB)

    Ferris, Matthew J., E-mail: mjferri@emory.edu [Department of Radiation Oncology, Emory University, Atlanta, Georgia (United States); Winship Cancer Institute, Emory University, Atlanta, Georgia (United States); Danish, Hasan [Department of Radiation Oncology, Emory University, Atlanta, Georgia (United States); Winship Cancer Institute, Emory University, Atlanta, Georgia (United States); Switchenko, Jeffrey M. [Winship Cancer Institute, Emory University, Atlanta, Georgia (United States); Department of Biostatistics and Bioinformatics, Emory University, Atlanta, Georgia (United States); Deng, Claudia [Department of Radiation Oncology, Emory University, Atlanta, Georgia (United States); Winship Cancer Institute, Emory University, Atlanta, Georgia (United States); George, Bradley A.; Goldsmith, Kelly C.; Wasilewski, Karen J.; Cash, W. Thomas [Aflac Cancer and Blood Disorders Center, Children' s Healthcare of Atlanta, Atlanta, Georgia (United States); Khan, Mohammad K.; Eaton, Bree R.; Esiashvili, Natia [Department of Radiation Oncology, Emory University, Atlanta, Georgia (United States); Winship Cancer Institute, Emory University, Atlanta, Georgia (United States)

    2017-03-15

    Purpose: To report the influence of radiation therapy (RT) dose and surgical pathology variables on disease control and overall survival (OS) in patients treated for high-risk neuroblastoma at a single institution. Methods and Materials: We conducted a retrospective study of 67 high-risk neuroblastoma patients who received RT as part of definitive management from January 2003 until May 2014. Results: At a median follow-up of 4.5 years, 26 patients (38.8%) failed distantly; 4 of these patients also failed locally. One patient progressed locally without distant failure. Local control was 92.5%, and total disease control was 59.5%. No benefit was demonstrated for RT doses over 21.6 Gy with respect to local relapse–free survival (P=.55), disease-free survival (P=.22), or OS (P=.72). With respect to local relapse–free survival, disease-free survival, and OS, no disadvantage was seen for positive lymph nodes on surgical pathology, positive surgical margins, or gross residual disease. Of the patients with gross residual disease, 75% (6 of 8) went on to have no evidence of disease at time of last follow-up, and the 2 patients who failed did so distantly. Conclusions: Patients with high-risk neuroblastoma in this series maintained excellent local control, with no benefit demonstrated for radiation doses over 21.6 Gy, and no disadvantage demonstrated for gross residual disease after surgery, positive surgical margins, or pathologic lymph node positivity. Though the limitations of a retrospective review for an uncommon disease must be kept in mind, with small numbers in some of the subgroups, it seems that dose escalation should be considered only in exceptional circumstances.

  3. Individualized risk assessment in neuroblastoma. Does the tumoral metabolic activity on {sup 123}I-MIBG SPECT predict the outcome?

    Energy Technology Data Exchange (ETDEWEB)

    Rogasch, Julian M.M.; Furth, Christian; Wedel, Florian; Brenner, Winfried; Amthauer, Holger; Schatka, Imke [Charite - Universitaetsmedizin Berlin, Department of Nuclear Medicine, Berlin (Germany); Hundsdoerfer, Patrick [Charite - Universitaetsmedizin Berlin, Department of Pediatric Oncology/Hematology, Berlin (Germany); Berlin Institute of Health (BIH), Berlin (Germany); Hofheinz, Frank [Helmholtz Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, PET Center, Dresden (Germany); Krueger, Paul-Christian [University Medicine Greifswald, Institute for Diagnostic Radiology and Neuroradiology, Greifswald (Germany); Lode, Holger [University Medicine Greifswald, Department of Pediatric Oncology and Hematology, Greifswald (Germany); Eggert, Angelika [Charite - Universitaetsmedizin Berlin, Department of Pediatric Oncology/Hematology, Berlin (Germany)

    2017-12-15

    Risk-adapted treatment in children with neuroblastoma (NB) is based on clinical and genetic factors. This study evaluated the metabolic tumour volume (MTV) and its asphericity (ASP) in pretherapeutic {sup 123}I-MIBG SPECT for individualized image-based prediction of outcome. This retrospective study included 23 children (11 girls, 12 boys; median age 1.8 years, range 0.3-6.8 years) with newly diagnosed NB consecutively examined with pretherapeutic {sup 123}I-MIBG SPECT. Primary tumour MTV and ASP were defined using semiautomatic thresholds. Cox regression analysis, receiver operating characteristic analysis (cut-off determination) and Kaplan-Meier analysis with the log-rank test for event-free survival (EFS) were performed for ASP, MTV, laboratory parameters (including urinary homovanillic acid-to-creatinine ratio, HVA/C), and clinical (age, stage) and genetic factors. Predictive accuracy of the optimal multifactorial model was determined in terms of Harrell's C and likelihood ratio χ {sup 2}. Median follow-up was 36 months (range 7-107 months; eight patients showed disease progression/relapse, four patients died). The only significant predictors of EFS in the univariate Cox regression analysis were ASP (p = 0.029; hazard ratio, HR, 1.032 for a one unit increase), MTV (p = 0.038; HR 1.012) and MYCN amplification status (p = 0.047; HR 4.67). The mean EFS in patients with high ASP (>32.0%) and low ASP were 21 and 88 months, respectively (p = 0.013), and in those with high MTV (>46.7 ml) and low MTV were 22 and 87 months, respectively (p = 0.023). A combined risk model of either high ASP and high HVA/C or high MTV and high HVA/C best predicted EFS. In this exploratory study, pretherapeutic image-derived and laboratory markers of tumoral metabolic activity in NB (ASP, MTV, urinary HVA/C) allowed the identification of children with a high and low risk of progression/relapse under current therapy. (orig.)

  4. International Conference on Risk Analysis

    CERN Document Server

    Oliveira, Teresa; Rigas, Alexandros; Gulati, Sneh

    2015-01-01

    This book covers the latest results in the field of risk analysis. Presented topics include probabilistic models in cancer research, models and methods in longevity, epidemiology of cancer risk, engineering reliability and economical risk problems. The contributions of this volume originate from the 5th International Conference on Risk Analysis (ICRA 5). The conference brought together researchers and practitioners working in the field of risk analysis in order to present new theoretical and computational methods with applications in biology, environmental sciences, public health, economics and finance.

  5. Risk assessment in international operations

    International Nuclear Information System (INIS)

    Stricklin, Daniela L.

    2008-01-01

    During international peace-keeping missions, a diverse number of non-battle hazards may be encountered, which range from heavily polluted areas, endemic disease, toxic industrial materials, local violence, traffic, and even psychological factors. Hence, elevated risk levels from a variety of sources are encountered during deployments. With the emphasis within the Swedish military moving from national defense towards prioritization of international missions in atypical environments, the risk of health consequences, including long term health effects, has received greater consideration. The Swedish military is interested in designing an optimal approach for assessment of health threats during deployments. The Medical Intelligence group at FOI CBRN Security and Defence in Umea has, on request from and in collaboration with the Swedish Armed Forces, reviewed a variety of international health threat and risk assessment models for military operations. Application of risk assessment methods used in different phases of military operations will be reviewed. An overview of different international approaches used in operational risk management (ORM) will be presented as well as a discussion of the specific needs and constraints for health risk assessment in military operations. This work highlights the specific challenges of risk assessment that are unique to the deployment setting such as the assessment of exposures to a variety of diverse hazards concurrently

  6. Neuroblastoma: A neurochemical approach

    International Nuclear Information System (INIS)

    Schor, N.F.

    1991-01-01

    Neuroblastoma is among the most common malignancies of childhood. Despite greatly improved therapy for some pediatric tumors, the prognosis for children with metastatic neuroblastoma has not changed significantly in the past 10 years. With conventional chemotherapy, radiation therapy, and surgery, children with metastatic neuroblastoma have a 20% long-term survival rate. The authors describe here approaches to neuroblastoma that target its neuronal characteristics. On the one hand, the neurotransmitter receptors on the surface of the neuroblastoma cells and, on the other hand, specific isozymes that distinguish neuroblastoma cells from their normal counterparts are the focus of these experimental therapies. In the former case, specificity for tumor cells is effected by (1) selective protection of normal neuronal elements from toxicity, or (2) selective potentiation of toxicity for neural tumor cells. It is hoped that these strategies will be generalizable to other neural crest-derived tumors. 32 references

  7. Olfactory Neuroblastoma: Diagnostic Difficulty

    Directory of Open Access Journals (Sweden)

    Vidya MN,

    2011-01-01

    Full Text Available Olfactory neuroblastoma is an uncommon malignant tumor of sinonasal tract arising from the olfactory neuro epithelium. The olfactory neuroblastomas presenting with divergent histomorphologies like, epithelial appearance of cells, lacking a neuro fibrillary background and absence of rosettes are difficult to diagnose. Such cases require immunohistochemistry to establish the diagnosis. We describe the clinical features, pathological and immunohistochemical findings of grade IV Olfactory neuroblastoma in a 57 year old man

  8. Antitumor Effect of Burchellin Derivatives Against Neuroblastoma.

    Science.gov (United States)

    Kurita, Masahiro; Takada, Tomomi; Wakabayashi, Noriko; Asami, Satoru; Ono, Shinichi; Uchiyama, Taketo; Suzuki, Takashi

    2018-02-01

    Neuroblastoma is one of the most commonly encountered malignant solid tumors in the pediatric age group. We examined the antitumor effects of five burchellin derivatives against human neuroblastoma cell lines. We evaluated cytotoxicity by the MTT assay for four human neuroblastoma and two normal cell lines. We also performed analysis of the apoptotic induction effect by flow cytometry, and examined the expression levels of apoptosis- and cell growth-related proteins by western blot analysis. We found that one of the burchellin derivatives (compound 4 ) exerted cytotoxicity against the neuroblastoma cell lines. Compound 4 induced caspase-dependent apoptosis via a mitochondrial pathway. The apoptosis mechanisms induced by compound 4 involved caspase-3, -7 and -9 activation and poly (ADP-ribose) polymerase cleavage. In addition, compound 4 induced cell death through inhibition of the cell growth pathway (via extracellular signal-regulated kinase 1 and 2, AKT8 virus oncogene cellular homolog, and signal transducer and activator of transcription 3). Compound 4 exerted cellular cytotoxicity against neuroblastoma cells via induction of caspase-dependent apoptosis, and may offer promise for further development as a useful drug for the treatment of advanced neuroblastoma. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  9. Clinical experience with radiation enhancement by hyperbaric oxygen in children with recurrent neuroblastoma stage IV

    NARCIS (Netherlands)

    Voûte, P. A.; van der Kleij, A. J.; de Kraker, J.; Hoefnagel, C. A.; Tiel-van Buul, M. M.; van Gennip, H.

    1995-01-01

    The high risk group of patients with neuroblastoma are children over 1 year with stage IV disease. Most series report a maximum of 20% survival at 5 years. For recurrent neuroblastoma stage IV, cure rates are not reported in the literature, but they are nil. Any treatment for recurrent neuroblastoma

  10. International ROR: risk, opportunity, reward

    International Nuclear Information System (INIS)

    Krentz, D.; Gair, J.

    1996-01-01

    Norcen Energy Resources Limited's pursuit of international oil and gas opportunities since the late 1980s were outlined. By 1994 Norcen had exploration and production concessions in 12 countries stretching from Algeria, Russia, Argentina, Indonesia to offshore Australia. The company had seen its share of risks, opportunities and rewards. Since 1994 international efforts of the Company have been focused on lower risk opportunities with exploration upside in defined core areas of South America, particularly in Venezuela, a country with conventional, heavy and ultra-heavy oil resources exceeding that of Saudi Arabia. These, and other similar foreign investments in the formerly closed national oil industries of South America have been greatly facilitated by the political liberalization, economic reforms and stabilization that have taken place there over the past ten years. The story of Norcen's successful bidding on the Oritupano-Leona production block in 1993 and Delta Centro exploration block in 1996 was the subject of this presentation

  11. Neuroblastoma treatment in the post-genomic era.

    Science.gov (United States)

    Esposito, Maria Rosaria; Aveic, Sanja; Seydel, Anke; Tonini, Gian Paolo

    2017-02-08

    Neuroblastoma is an embryonic malignancy of early childhood originating from neural crest cells and showing heterogeneous biological, morphological, genetic and clinical characteristics. The correct stratification of neuroblastoma patients within risk groups (low, intermediate, high and ultra-high) is critical for the adequate treatment of the patients.High-throughput technologies in the Omics disciplines are leading to significant insights into the molecular pathogenesis of neuroblastoma. Nonetheless, further study of Omics data is necessary to better characterise neuroblastoma tumour biology. In the present review, we report an update of compounds that are used in preclinical tests and/or in Phase I-II trials for neuroblastoma. Furthermore, we recapitulate a number of compounds targeting proteins associated to neuroblastoma: MYCN (direct and indirect inhibitors) and downstream targets, Trk, ALK and its downstream signalling pathways. In particular, for the latter, given the frequency of ALK gene deregulation in neuroblastoma patients, we discuss on second-generation ALK inhibitors in preclinical or clinical phases developed for the treatment of neuroblastoma patients resistant to crizotinib.We summarise how Omics drive clinical trials for neuroblastoma treatment and how much the research of biological targets is useful for personalised medicine. Finally, we give an overview of the most recent druggable targets selected by Omics investigation and discuss how the Omics results can provide us additional advantages for overcoming tumour drug resistance.

  12. Neuroblastoma na Criança: Relato de Caso/Neuroblastoma in Children: Case Report

    Directory of Open Access Journals (Sweden)

    Maysa Carla Mendonça Tame

    2013-03-01

    biological characteristic feature. The clinical presentation is extremely variable, reflecting the possible locations of the primary tumor within the sympathetic nervous system. The most common symptoms include abdominal pain and distention, localized bone pain, systemic symptoms (anorexia, malaise, fever, diarrhea. Is a rare tumor, with an incidence of 10 cases per million children between zero and four years old. Case Report: We report the case of a patient, now four years and eight months, with Neuroblastoma, primary adrenal tumor left adrenal, metastatic to bone marrow bilateral and multiple bones, which started neoadjuvant chemotherapy, immediately after diagnosis, with further evaluation for surgery, adjuvant chemotherapy and radiotherapy, and autologous bone marrow. The treatment is based on stratification of risk group and may involve: chemotherapy, radiation, surgery to remove the tumor and autologous bone marrow. The prognosis is related to the child's age at diagnosis, certain histologic features, staging and tumor genetic alterations. Discussion: Following the protocol, the tumor was staged at level 4, according to the International Neuroblastoma Staging System (INSS and proposed a treatment with multimodality, including an intensive chemotherapy with a combination of agents, followed by surgical resection, high doses of chemotherapy and radiotherapy for subsequent autologous bone marrow transplantation. This treatment was initiated by the patient on 24/08/2011, and is scheduled for a duration of at least one year.

  13. Drugs Approved for Neuroblastoma

    Science.gov (United States)

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for neuroblastoma. The list includes generic names and brand names. The drug names link to NCI's Cancer Drug Information summaries.

  14. Negotiated risks. International talks on hazardous issues

    International Nuclear Information System (INIS)

    Avenhaus, Rudolf; Sjoestedt, Gunnar

    2009-01-01

    This book fills a major gap in the risk literature, as it brings together two research strands: risks, to which IIASA's research programs have contributed significantly over the years, culminating in the Risk and Vulnerability Program, and international negotiations, on which there is an abundance of published work, much of it resulting from the work of IIASA's Processes of International Negotiations Program. Throughout the book, it is pointed out that there are actor-driven risks, namely those posed by international negotiations themselves, and issue-driven risks which are caused by large-scale human activities. In fact, negotiated risks deal with some of the most serious risks facing humanity: climate change, nuclear activities, and weapons of mass destruction. The book contains both scientific analyses on the nature of internationally negotiated risks and analyses of concrete risks, both of which are of immense practical relevance in the larger context of international negotiations. (orig.)

  15. Intravenous immunoglobulin with prednisone and risk-adapted chemotherapy for children with opsoclonus myoclonus ataxia syndrome associated with neuroblastoma (ANBL00P3): a randomised, open-label, phase 3 trial.

    Science.gov (United States)

    de Alarcon, Pedro A; Matthay, Katherine K; London, Wendy B; Naranjo, Arlene; Tenney, Sheena C; Panzer, Jessica A; Hogarty, Michael D; Park, Julie R; Maris, John M; Cohn, Susan L

    2018-01-01

    No previous clinical trial has been conducted for patients with neuroblastoma associated opsoclonus myoclonus ataxia syndrome (OMA), and current treatment is based on case reports. To evaluate the OMA response to prednisone and risk-adapted chemotherapy and determine if the addition of intravenous gammaglobulin (IVIG) further improves response, the Children's Oncology Group designed a randomized therapeutic trial. Eligible subjects were randomized to receive twelve cycles of IVIG (IVIG+) or no IVIG (NO-IVIG) in addition to prednisone and neuroblastoma risk-adapted chemotherapy. All low-risk patients were treated with cyclophosphamide. The severity of OMA symptoms was evaluated at 2, 6, and 12 months using a scale developed by Mitchell and Pike and baseline versus best response scores were compared. A single patient who did not undergo neurologic assessment was excluded from OMA response analysis. This study is registered with Clinical Trials.gov (identifier NCT00033293). Of the 53 patients enrolled in the study, 62% (33/53) were female. There were 44 low-risk, 7 intermediate-risk, and 2 high-risk neuroblastoma patients. Twenty-six subjects were randomized to receive IVIG+ and 27 were randomized to NO-IVIG. The neuroblastoma 3-year event-free survival (95% confidence interval (CI)) was 94.1% (87.3%, 100%) and overall survival was 98.0% (94.1%, 100%). Significantly higher rates of OMA response were observed in patients randomized to IVIG+ compared to NO-IVIG [21/26=80.8% for IVIG+; 11/27=40.7% for NO-IVIG (odds ratio=6.1; 95% CI: (1.5, 25.9), p=0.0029)]. For the majority of patients, the IVIG+ OMA regimen combined with cytoxan or other risk-based chemotherapy was well tolerated, although there was one toxic death in a high-risk subject. This is the only randomized prospective therapeutic clinical trial in children with neuroblastoma-associated OMA. The addition of IVIG to prednisone and risk-adapted chemotherapy significantly improves OMA response rate. IVIG

  16. Director, Risk Management and Internal Audit | IDRC - International ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Directs the establishment of the Internal Audit plans and priorities and performs risk-based Internal Audits designed to provide objective assurance and advice to the ... Establishes internal quality assessment processes and as directed by the Finance and Audit Committee ensures that external quality assessments are ...

  17. Long term outcome of high-risk neuroblastoma patients after immunotherapy with antibody ch14.18 or oral metronomic chemotherapy

    Directory of Open Access Journals (Sweden)

    Schrappe Martin

    2011-01-01

    Full Text Available Abstract Background The treatment of high-risk neuroblastoma patients consists of multimodal induction therapy to achieve remission followed by consolidation therapy to prevent relapses. However, the type of consolidation therapy is still discussed controversial. We applied metronomic chemotherapy in the prospective NB90 trial and monoclonal anti-GD2-antibody (MAB ch14.18 in the NB97 trial. Here, we present the long term outcome data of the patient cohort. Methods A total of 334 stage 4 neuroblastoma patients one year or older were included. All patients successfully completed the induction therapy. In the NB90 trial, 99 patients received at least one cycle of the oral maintenance chemotherapy (NB90 MT, 12 alternating cycles of oral melphalan/etoposide and vincristine/cyclophosphamide. In the NB97 trial, 166 patients commenced the MAB ch14.18 consolidation therapy (six cycles over 12 months. Patients who received no maintenance therapy according to the NB90 protocol or by refusal in NB97 (n = 69 served as controls. Results The median observation time was 11.11 years. The nine-year event-free survival rates were 41 ± 4%, 31 ± 5%, and 32 ± 6% for MAB ch14.18, NB90 MT, and no consolidation, respectively (p = 0.098. In contrast to earlier reports, MAB ch14.18 treatment improved the long-term outcome compared to no additional therapy (p = 0.038. The overall survival was better in the MAB ch14.18-treated group (9-y-OS 46 ± 4% compared to NB90 MT (34 ± 5%, p = 0.026 and to no consolidation (35 ± 6%, p = 0.019. Multivariable Cox regression analysis revealed ch14.18 consolidation to improve outcome compared to no consolidation, however, no difference between NB90 MT and MAB ch14.18-treated patients was found. Conclusions Follow-up analysis of the patient cohort indicated that immunotherapy with MAB ch14.18 may prevent late relapses. Finally, metronomic oral maintenance chemotherapy also appeared effective.

  18. Long term outcome of high-risk neuroblastoma patients after immunotherapy with antibody ch14.18 or oral metronomic chemotherapy

    International Nuclear Information System (INIS)

    Simon, Thorsten; Hero, Barbara; Faldum, Andreas; Handgretinger, Rupert; Schrappe, Martin; Klingebiel, Thomas; Berthold, Frank

    2011-01-01

    The treatment of high-risk neuroblastoma patients consists of multimodal induction therapy to achieve remission followed by consolidation therapy to prevent relapses. However, the type of consolidation therapy is still discussed controversial. We applied metronomic chemotherapy in the prospective NB90 trial and monoclonal anti-GD2-antibody (MAB) ch14.18 in the NB97 trial. Here, we present the long term outcome data of the patient cohort. A total of 334 stage 4 neuroblastoma patients one year or older were included. All patients successfully completed the induction therapy. In the NB90 trial, 99 patients received at least one cycle of the oral maintenance chemotherapy (NB90 MT, 12 alternating cycles of oral melphalan/etoposide and vincristine/cyclophosphamide). In the NB97 trial, 166 patients commenced the MAB ch14.18 consolidation therapy (six cycles over 12 months). Patients who received no maintenance therapy according to the NB90 protocol or by refusal in NB97 (n = 69) served as controls. The median observation time was 11.11 years. The nine-year event-free survival rates were 41 ± 4%, 31 ± 5%, and 32 ± 6% for MAB ch14.18, NB90 MT, and no consolidation, respectively (p = 0.098). In contrast to earlier reports, MAB ch14.18 treatment improved the long-term outcome compared to no additional therapy (p = 0.038). The overall survival was better in the MAB ch14.18-treated group (9-y-OS 46 ± 4%) compared to NB90 MT (34 ± 5%, p = 0.026) and to no consolidation (35 ± 6%, p = 0.019). Multivariable Cox regression analysis revealed ch14.18 consolidation to improve outcome compared to no consolidation, however, no difference between NB90 MT and MAB ch14.18-treated patients was found. Follow-up analysis of the patient cohort indicated that immunotherapy with MAB ch14.18 may prevent late relapses. Finally, metronomic oral maintenance chemotherapy also appeared effective

  19. Expression of FOXP3, CD14, and ARG1 in Neuroblastoma Tumor Tissue from High-Risk Patients Predicts Event-Free and Overall Survival

    Directory of Open Access Journals (Sweden)

    Sara Stigliani

    2015-01-01

    Full Text Available The prognosis of children with metastatic neuroblastoma (NB > 18 months at diagnosis is dismal. Since the immune status of the tumor microenvironment could play a role in the history of disease, we evaluated the expression of CD45, CD14, ARG1, CD163, CD4, FOXP3, Perforin-1 (PRF1, Granzyme B (GRMB, and IL-10 mRNAs in primary tumors at diagnosis from children with metastatic NB and tested whether the transcript levels are significantly associated to event-free and overall survival (EFS and OS, resp.. Children with high expression of CD14, ARG1 and FOXP3 mRNA in their primary tumors had significantly better EFS. Elevated expression of CD14, and FOXP3 mRNA was significantly associated to better OS. CD14 mRNA expression levels significantly correlated to all markers, with the exception of CD4. Strong positive correlations were found between PRF1 and CD163, as well as between PFR1 and FOXP3. It is worth noting that the combination of high levels of CD14, FOXP3, and ARG1 mRNAs identified a small group of patients with excellent EFS and OS, whereas low levels of CD14 were sufficient to identify patients with dismal survival. Thus, the immune status of the primary tumors of high-risk NB patients may influence the natural history of this pediatric cancer.

  20. Imaging of abdominal neuroblastoma in children

    International Nuclear Information System (INIS)

    Hugosson, C.; Nyman, R.; Jorulf, H.; McDonald, P.; Rifai, A.; Jacobsson, B.; Kofide, A.

    1999-01-01

    Purpose: The aims of the study were: (1) to assess the efficacy of different imaging methods for use prior to treatment; (2) to compare the surgico-histopathologically-based International Neuroblastoma Staging System (INSS) staging with the imaging results; and (3) to suggest a localisation scheme for abdominal neuroblastoma. Material and Methods: Thirty-one children with an abdominal neuroblastoma (median age 2 years), underwent abdominal US, CT of chest and abdomen, MR imaging of abdomen and spine, chest radiography, skeletal survey, radionuclide bone scintigraphy, MIBG scintigraphy, and bone marrow biopsy. Results: In the evaluation of local disease, CT and MR were superior to US. There was no significant difference between CT and MR in assessment of the location or size of the tumour. Evaluation of invasive growth and lymphadenopathy was uncertain irrespective of imaging modality. Intraspinal extension was more distinctly demonstrated with MR. Tissue characterization with CT and MR did not contribute in the assessment of the tumours. Contrast enhancement at CT and MR examinations both improved demarcation between tumour and kidney, and was a necessity for evaluation of vessel encasement with CT. The local disease was best assessed by either CT or MR, while metastatic disease was best revealed by CT, MR, scintigraphy or bone marrow biopsy. Conclusion: Imaging may be a valuable basis for clinical assessment and pretreatment staging of abdominal neuroblastoma. (orig.)

  1. Effect of Auger electrons internalized as Indium-111 labelled N-MYC phosphorothionate antisense oligonucleotide (In-111-N-MYC-AS) on human neuroblastoma cells: In vitro and in vivo studies

    International Nuclear Information System (INIS)

    Watanabe, N.; Tanada, S.; Sasaki, Y.

    2005-01-01

    Full text: Auger electrons which enter into cells cause biological effects with high-LET short range radiation on the neighborhood. The purpose of this study was to investigate the internalization of In-111-N-myc-AS and suppression of N-MYC in human neuroblastoma cells. Fifteen-mer AS, which was complementary to the region of the mRNA of N-myc beginning with ATG start codon, was derivatized with SCN-Bn-EDTA and labeled with In-111. In-111-N-myc-AS (1.33MBq/nmol) was prepared as naked form and encapsulated in cationic multilamellar liposome (CML). The internalization of In-111-N-myc-AS with or without CML into human neuroblastoma SK-N-DZ cells was determined both in vitro (cell culture) and in vivo (tumor bearing nude mice) studies by Southern blot analysis. Quantity of N-MYC in the tumor cells was also measured by Western blot analysis. In in vitro system 0.69-02pmol of In-111-N-myc-AS (80pmol) with CML was internalized in the cells (5x106) by 12h at 4 deg. C, which increased to 8.05?0.43pmol at 37 deg. C. The internalized naked In-111-N-myc-AS was 0.58?0.01pmol and 0.92?0.03pmol at 4 and 37 0 C, respectively. In vivo study revealed the internalization of In-111-N-myc-AS (8nmol) with CML in tumor cells (5x106) as 6.44?0.71pmol, while none (0pmol) of naked In-111-N-myc-AS was internalized. The effect of Auger electrons was shown by a decrease of N-MYC of the tumor cells by 20.6?2.49% in vitro and 12.9?1.17% in vivo in the case of In-111-N-myc-AS with CML, whereas unlabeled AS with CML or In-111-phosphorothioate sense oligonucleotide did not decrease the quantity of N-MYC of the tumor cells in vitro or in vivo. In conclusion, In-111-N-myc-AS with CML could be internalized into human neuroblastoma cells and suppress the activity of N-myc gene, which may prove useful for targeted Auger electrons radiotherapy. (author)

  2. Effect of Auger electrons internalized as Indium-111-labeled N-MYC phosphorothioate antisense oligonucleotide (In-111-N-MYC-AS) on human neuroblastoma cells: In-vitro and in-vivo studies

    International Nuclear Information System (INIS)

    Watanabe, Naoyuki; Tanada, Shuju; Sasaki, Yasuhito

    2004-01-01

    Full text: Auger electrons, which enter into cells, cause biological effects with high-LET short-range radiation on the neighborhood. The purpose of this study is to investigate the internalization of In-111-N-myc-AS and suppression of NMYC in human neuroblastoma cells. Fifteen-mer AS, which was complementary to the region of the mRNA of N-myc beginning with ATG start codon, was derivated with SCN-Bn-EDTA and labeled with In-111. In-111-Nmyc-AS (1.33MBq/nmol) was prepared as naked form and encapsulated in cationic multilamellar liposome (CML). The internalization of In-111-N-myc-AS with or without CML into human neuroblastoma SK-N-DZ cells was determined both in vitro (cell culture) and in vivo (tumor bearing nude mice) studies by Southern blot analysis. Quantity of N-MYC in the tumor cells was also measured by Western blot analysis. In in-vitro system 0.69∫0.02pmol of In-111-N-myc-AS (80pmol) with CML was internalized in the cells (5x106) by 12h at 4 deg. C, which increased to 8.05±0.43pmol at 37 deg. C. The internalized naked In-111-N-myc-AS was 0.58±0.01pmol and 0.92±0.03pmol at 4 and 37 deg. C, respectively. In-vivo study revealed the internalization of In-111-N-myc-AS (8nmol) with CML in tumor cells (5x106) as 6.44±0.71pmol, while none (0pmol) of naked In-111-Nmyc-AS was internalized. The effect of Auger electrons was shown by a decrease of N-MYC of the tumor cells by 20.6±2.49% in- vitro and 12.9±1.17% in vivo in the case of In-111-N-myc-AS with CML, whereas unlabeled AS with CML or In-111-phosphorothioate sense oligonucleotide did not decrease the quantity of N-MYC of the tumor cells in- vitro or in- vivo. In-111-N-myc-AS with CML could be internalized into human neuroblastoma cells and suppress the activity of N-myc gene, which may prove useful for targeted Auger electrons radiotherapy. (author)

  3. Immune response to racotumomab in a child with relapsed neuroblastoma

    Directory of Open Access Journals (Sweden)

    CLAUDIA VANESA SAMPOR

    2012-12-01

    Full Text Available Immunotherapy targeting ganglioside antigens is a powerful tool for the treatment of high risk neuroblastoma. However, only treatment with anti-GD2 antibodies has been used in clinical practice and other options may be pursued. We report the use of racotumomab, an anti-idiotype vaccine against N-glycolyl neuraminic acid (NeuGc- containing gangliosides, eliciting an immune response in a child with relapsed neuroblastoma expressing the NeuGcGM3 ganglioside.

  4. Reversible LSD1 inhibition with HCI-2509 induces the p53 gene expression signature and disrupts the MYCN signature in high-risk neuroblastoma cells.

    Science.gov (United States)

    Gupta, Sumati; Doyle, Kelly; Mosbruger, Timothy L; Butterfield, Andrew; Weston, Alexis; Ast, Allison; Kaadige, Mohan; Verma, Anupam; Sharma, Sunil

    2018-02-09

    Lysine-Specific Demethylase 1 (LSD1) over-expression correlates with poorly differentiated neuroblastoma and predicts poor outcome despite multimodal therapy. We have studied the efficacy of reversible and specific LSD1 inhibition with HCI-2509 in neuroblastoma cell lines and particularly the effect of HCI-2509 on the transcriptomic profile in MYCN amplified NGP cells. Cell survival assays show that HCI-2509 is cytotoxic to poorly differentiated neuroblastoma cell lines in low micromole or lower doses. Transcriptional profiling of NGP cells treated with HCI-2509 shows a significant effect on p53, cell cycle, MYCN and hypoxia pathway gene sets. HCI-2509 results in increased histone methyl marks and p53 levels along with cell cycle arrest in the G2/M phase and inhibition of colony formation of NGP cells. Our findings indicate that LSD1 inhibition with HCI-2509 has a multi-target effect in neuroblastoma cell lines, mediated in part via p53. MYCN-amplified neuroblastoma cells have a targeted benefit as HCI-2509 downregulates the MYCN upregulated gene set.

  5. Locoregional Tumor Progression After Radiation Therapy Influences Overall Survival in Pediatric Patients With Neuroblastoma

    International Nuclear Information System (INIS)

    Pai Panandiker, Atmaram S.; McGregor, Lisa; Krasin, Matthew J.; Wu Shengjie; Xiong Xiaoping; Merchant, Thomas E.

    2010-01-01

    Purpose: There is renewed attention to primary site irradiation and local control for patients with high-risk neuroblastoma (NB). We conducted a retrospective review to identify factors that might predict for locoregional tumor control and its impact on overall survival. Methods and Materials: Between July 2000 through August 2006, a total of 44 pediatric patients with NB received radiation therapy (RT) with curative intent using computed tomography (CT)-based treatment planning. The median age was 3.4 years and the median cumulative dose was 23.4 Gy. Overall survival and locoregional tumor control were measured from the start of RT to the date of death or event as determined by CT/magnetic resonance imaging/meta-iodobenzylguanidine. The influence of age at irradiation, gender, race, cumulative radiation dose, International Neuroblastoma Staging System stage, treatment protocol and resection status was determined with respect to locoregional tumor control. Results: With a median follow-up of 34 months ± 21 months, locoregional tumor progression was observed in 11 (25%) and was evenly divided between primary site and adjacent nodal/visceral site failure. The influence of locoregional control reached borderline statistical significance (p = 0.06). Age (p = 0.5), dose (p = 0.6), resection status (p = 0.7), and International Neuroblastoma Staging System stage (p = 0.08) did not influence overall survival. Conclusions: Overall survival in high-risk neuroblastoma is influenced by locoregional tumor control. Despite CT-based planning, progression in adjacent nodal/visceral sites appears to be common; this requires further investigation regarding target volume definitions, dose, and the effects of systemic therapy.

  6. Internal audit risk management in metropolitan municipalities

    Directory of Open Access Journals (Sweden)

    Christo Ackermann

    2016-07-01

    Full Text Available Internal audit functions (IAFs of organisations are regarded as crucial components of the combined assurance model, alongside the audit committee, management and external auditors. The combined assurance model aims at having integrated and aligned assurance in organisations with the overall aim of maximising risk and governance oversight and control efficiencies. In this regard, internal audit plays a crucial role, insofar as it consists of experts in risk, governance and control consultancy who provide assurance to senior management and the audit committee. Audit committees are dependent on internal audit for information and their effectiveness revolves around a strong and well-resourced internal audit function which is able to aid audit committees to meet their oversight responsibilities. There is thus a growing demand for managing risk through the process of risk management and internal audit is in a perfect position to assist with the improvement of such processes. If internal auditors wish to continue being an important aspect of the combined assurance model, they need to address the critical area, amongst others, of risk management as part of their work. If not, it follows that the board, audit committees and other levels of management will remain uninformed on the status of these matters which, in turn, will negatively impact the ability of these stakeholders to discharge their responsibilities. This study therefore focuses on analysing the functioning of IAFs, with specific reference to their risk management mandate. The study followed a mixed method approach to describe internal audits risk management functioning in the big eight metropolitan municipalities in South Africa. The results show that internal audit provide a broad scope of risk management work which assist senior management in the discharge of their responsibilities. However, in the public eye, internal audits risk management functioning is scant

  7. Increasing the clinical efficacy of NK and antibody-mediated cancer immunotherapy: potential predictors of successful clinical outcome observed in high-risk neuroblastoma

    Directory of Open Access Journals (Sweden)

    Tony A. Koehn

    2012-05-01

    Full Text Available Disease recurrence is frequent in high-risk neuroblastoma (NBL patients even after multimodality aggressive treatment [a combination of chemotherapy, surgical resection, local radiation therapy, autologous stem cell transplantation (ASCT and cis-retinoic acid (CRA]. Recent clinical studies have explored the use of monoclonal antibodies (mAbs that bind to disialoganglioside (GD2, highly expressed in NBL, as a means to enable immune effector cells to destroy NBL cells via antibody-dependent cell-mediated cytotoxicity (ADCC. Preclinical data indicate that ADCC can be more effective when appropriate effector cells are activated by cytokines. Clinical studies have pursued this by administering anti-GD2 mAb in combination with ADCC-enhancing cytokines (IL2 and GM-CSF, a regimen that has demonstrated improved cancer-free survival. More recently, early clinical studies have used a fusion protein that consists of the anti-GD2 mAb directly linked to IL2, and antitumor responses were seen in the Phase II setting. Analyses of genes that code for receptors that influence ADCC activity and Natural Killer (NK cell function [Fc Receptor (FcR, Killer Immunoglublin-like Receptor (KIR, and KIR-ligand (KIR-L] suggest patients with antitumor activity are more likely to have certain genotype profiles. Further analyses will need to be conducted to determine whether these genotypes can be used as predictive markers for favorable therapeutic outcome, thus potentially increasing the efficacy of mAb-mediated NK cell-based cancer immunotherapy.

  8. Mechanisms of neuroblastoma regression

    Science.gov (United States)

    Brodeur, Garrett M.; Bagatell, Rochelle

    2014-01-01

    Recent genomic and biological studies of neuroblastoma have shed light on the dramatic heterogeneity in the clinical behaviour of this disease, which spans from spontaneous regression or differentiation in some patients, to relentless disease progression in others, despite intensive multimodality therapy. This evidence also suggests several possible mechanisms to explain the phenomena of spontaneous regression in neuroblastomas, including neurotrophin deprivation, humoral or cellular immunity, loss of telomerase activity and alterations in epigenetic regulation. A better understanding of the mechanisms of spontaneous regression might help to identify optimal therapeutic approaches for patients with these tumours. Currently, the most druggable mechanism is the delayed activation of developmentally programmed cell death regulated by the tropomyosin receptor kinase A pathway. Indeed, targeted therapy aimed at inhibiting neurotrophin receptors might be used in lieu of conventional chemotherapy or radiation in infants with biologically favourable tumours that require treatment. Alternative approaches consist of breaking immune tolerance to tumour antigens or activating neurotrophin receptor pathways to induce neuronal differentiation. These approaches are likely to be most effective against biologically favourable tumours, but they might also provide insights into treatment of biologically unfavourable tumours. We describe the different mechanisms of spontaneous neuroblastoma regression and the consequent therapeutic approaches. PMID:25331179

  9. MEIS homeobox genes in neuroblastoma

    NARCIS (Netherlands)

    Geerts, Dirk; Revet, Ingrid; Jorritsma, Gerda; Schilderink, Nathalie; Versteeg, Rogier

    2005-01-01

    The common pediatric tumor neuroblastoma originates from primitive neural crest-derived precursor cells of the peripheral nervous system. Neuroblastoma especially affects very young children, and can already be present at birth. Its early onset and cellular origin predict the involvement of

  10. Study of International Standards of Risk Management

    Directory of Open Access Journals (Sweden)

    Dykan Volodymyr L.

    2014-01-01

    Full Text Available The goal of the article lies in the study of existing international standards of risk management, an important factor of improvement of risk management in domestic corporations and enterprises and development of recommendations on application of international standards in Ukraine, in particular, within the framework of building corporate systems of risk management. The conducted study shows that approaches on organisation of the process of risk management, used in standards of risk management, are of general character and differ with the degree of detailing. Their undoubted value in development of risk management in Ukraine is identification of a general direction of building corporate systems of risk management in practice. The said approaches at the national and corporate levels of standardisation in Ukraine within the framework of building corporate systems of risk management would allow improvement of risk management in corporations and enterprises. The prospect of further studies of domestic specialists in the field of risk management is development of the domestic standard of risk management with consideration of modern domestic specific features of development of risk management in Ukraine and leading foreign experience.

  11. Binimetinib inhibits MEK and is effective against neuroblastoma tumor cells with low NF1 expression.

    Science.gov (United States)

    Woodfield, Sarah E; Zhang, Linna; Scorsone, Kathleen A; Liu, Yin; Zage, Peter E

    2016-03-01

    Novel therapies are needed for children with high-risk and relapsed neuroblastoma. We hypothesized that MAPK/ERK kinase (MEK) inhibition with the novel MEK1/2 inhibitor binimetinib would be effective in neuroblastoma preclinical models. Levels of total and phosphorylated MEK and extracellular signal-regulated kinase (ERK) were examined in primary neuroblastoma tumor samples and in neuroblastoma cell lines by Western blot. A panel of established neuroblastoma tumor cell lines was treated with increasing concentrations of binimetinib, and their viability was determined using MTT assays. Western blot analyses were performed to examine changes in total and phosphorylated MEK and ERK and to measure apoptosis in neuroblastoma tumor cells after binimetinib treatment. NF1 protein levels in neuroblastoma cell lines were determined using Western blot assays. Gene expression of NF1 and MEK1 was examined in relationship to neuroblastoma patient outcomes. Both primary neuroblastoma tumor samples and cell lines showed detectable levels of total and phosphorylated MEK and ERK. IC50 values for cells sensitive to binimetinib ranged from 8 nM to 1.16 μM, while resistant cells did not demonstrate any significant reduction in cell viability with doses exceeding 15 μM. Sensitive cells showed higher endogenous expression of phosphorylated MEK and ERK. Gene expression of NF1, but not MEK1, correlated with patient outcomes in neuroblastoma, and NF1 protein expression also correlated with responses to binimetinib. Neuroblastoma tumor cells show a range of sensitivities to the novel MEK inhibitor binimetinib. In response to binimetinib, sensitive cells demonstrated complete loss of phosphorylated ERK, while resistant cells demonstrated either incomplete loss of ERK phosphorylation or minimal effects on MEK phosphorylation, suggesting alternative mechanisms of resistance. NF1 protein expression correlated with responses to binimetinib, supporting the use of NF1 as a biomarker to identify

  12. Evaluation of Genetic Predisposition for MYCN-Amplified Neuroblastoma.

    Science.gov (United States)

    Hungate, Eric A; Applebaum, Mark A; Skol, Andrew D; Vaksman, Zalman; Diamond, Maura; McDaniel, Lee; Volchenboum, Samuel L; Stranger, Barbara E; Maris, John M; Diskin, Sharon J; Onel, Kenan; Cohn, Susan L

    2017-10-01

    To investigate genetic predispositions for MYCN-amplified neuroblastoma, we performed a meta-analysis of three genome-wide association studies totaling 615 MYCN-amplified high-risk neuroblastoma cases and 1869 MYCN-nonamplified non-high-risk neuroblastoma cases as controls using a fixed-effects model with inverse variance weighting. All statistical tests were two-sided. We identified a novel locus at 3p21.31 indexed by the single nucleotide polymorphism (SNP) rs80059929 (odds ratio [OR] = 2.95, 95% confidence interval [CI] = 2.17 to 4.02, Pmeta = 6.47 × 10-12) associated with MYCN-amplified neuroblastoma, which was replicated in 127 MYCN-amplified cases and 254 non-high-risk controls (OR = 2.30, 95% CI = 1.12 to 4.69, Preplication = .02). To confirm this signal is exclusive to MYCN-amplified tumors, we performed a second meta-analysis comparing 728 MYCN-nonamplified high-risk patients to identical controls. rs80059929 was not statistically significant in MYCN-nonamplified high-risk patients (OR = 1.24, 95% CI = 0.90 to 1.71, Pmeta = .19). SNP rs80059929 is within intron 16 in the KIF15 gene. Additionally, the previously reported LMO1 neuroblastoma risk locus was statistically significant only in patients with MYCN-nonamplified high-risk tumors (OR = 0.63, 95% CI = 0.53 to 0.75, Pmeta = 1.51 × 10-8; Pmeta = .95). Our results indicate that common genetic variation predisposes to different neuroblastoma genotypes, including the likelihood of somatic MYCN-amplification. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  13. Enterprise risk management in international construction operations

    CERN Document Server

    Zhao, Xianbo; Low, Sui Pheng

    2015-01-01

    This book provides readers an understanding of the implementation of Enterprise Risk Management (ERM) for international construction operations. In an extended case study, it primarily focuses on Chinese construction firms (CCFs) based in Singapore. In this regard, the book explains the differences and similarities between Risk Management (RM), Project Risk Management (PRM) and ERM in the construction industry, and examines their linkages for international construction operations in a broader context. The explanation elaborates on how companies may adopt and implement RM, PRM and ERM as appropriate in their various operations, both in their home market as well as in overseas host markets. The book also reviews the whole spectrum of work relating to organizational behavior (OB) as one of the key underpinnings for companies to evaluate and implement ERM. It will benefit practitioners from the industry as well as academics interested in the implementation of ERM practices in international construction operat...

  14. Acute Complications After High-Dose Chemotherapy and Stem-Cell Rescue in Pediatric Patients With High-Risk Neuroblastoma Treated in Countries With Different Resources

    Directory of Open Access Journals (Sweden)

    Mahmoud M. Elzembely

    2018-03-01

    Full Text Available Purpose: High-dose chemotherapy with autologous stem-cell rescue (SCR is a key component of high-risk neuroblastoma (HRNB therapy. Carboplatin, etoposide, and melphalan (CEM or busulfan and melphalan (Bu/Mel are the most evaluated, effective high-dose chemotherapy for HRNB on the basis of results from major cooperative group studies. Toxicity profiles vary between these regimens, and practice variation exists regarding the preferred high-dose therapy (HDT. We sought to evaluate the safety of HDT and autologous SCR for HRNB in a resource-limited country (Egypt compared with the resource-rich United States. Patients and Methods: We performed a retrospective comparative review of single CEM-based HDT/SCR outcomes through day 100 for HRNB at the Fred Hutchinson Cancer Research Center (FH in the United States (2005 to 2015 versus Bu/Mel-based HDT at El-Sheikh Zayed Specialized Hospital (SZ in Egypt (2009 to 2015. Results: Forty-four patients at FH and 77 patients at SZ were reviewed. Pretransplant hepatic comorbidities were significantly higher at SZ (29 of 77 v nine of 44; P = .05, with 19 of 77 patients at SZ having hepatitis infection. Engraftment was delayed after SZ-Bu/Mel therapy compared with FH-CEM therapy for neutrophils (median 12 days v 10 days, respectively; P < .001 and platelets (median 20 days v 18 days, respectively; P < .001. Sinusoidal obstruction syndrome occurred later, after SZ-Bu/Mel therapy (median 19 days v 7 days; P = .033, and four of eight cases were fatal (six of eight patients had underlying hepatitis infection, whereas three of three cases after FH-CEM therapy were moderately severe. Resource utilization associated with the number of days with fever, antibiotic use, and the number of transfusions administered was significantly higher after FH-CEM therapy than after SZ-Bu/Mel therapy. Conclusion: Use of autologous stem-cell transplantation is feasible in the context of a resource-limited country.

  15. Research Award: Risk Management and Internal Audit

    International Development Research Centre (IDRC) Digital Library (Canada)

    Corey Piccioni

    2013-08-07

    Aug 7, 2013 ... manage research; and. • idenfying competencies, key success factors or performance indicators most crical to research instuons. In addion to their research project, the RMIA Research Awardee will be involved in a range of acvies to contribute to the ongoing program of risk management and internal audit ...

  16. Cell Survival Signaling in Neuroblastoma

    Science.gov (United States)

    Megison, Michael L.; Gillory, Lauren A.; Beierle, Elizabeth A.

    2013-01-01

    Neuroblastoma is the most common extracranial solid tumor of childhood and is responsible for over 15% of pediatric cancer deaths. Neuroblastoma tumorigenesis and malignant transformation is driven by overexpression and dominance of cell survival pathways and a lack of normal cellular senescence or apoptosis. Therefore, manipulation of cell survival pathways may decrease the malignant potential of these tumors and provide avenues for the development of novel therapeutics. This review focuses on several facets of cell survival pathways including protein kinases (PI3K, AKT, ALK, and FAK), transcription factors (NF-κB, MYCN and p53), and growth factors (IGF, EGF, PDGF, and VEGF). Modulation of each of these factors decreases the growth or otherwise hinders the malignant potential of neuroblastoma, and many therapeutics targeting these pathways are already in the clinical trial phase of development. Continued research and discovery of effective modulators of these pathways will revolutionize the treatment of neuroblastoma. PMID:22934706

  17. Therapeutic Innovations for Targeting Childhood Neuroblastoma: Implications of the Neurokinin-1 Receptor System.

    Science.gov (United States)

    Berger, Michael; VON Schweinitz, Dietrich

    2017-11-01

    Neuroblastoma is the most common solid extracranial malignant tumor in children. Despite recent advances in the treatment of this heterogenous tumor with surgery and chemotherapy, the prognosis in advanced stages remains poor. Interestingly, neuroblastoma is one of the few solid tumors, to date, in which an effect for targeted immunotherapy has been proven in controlled clinical trials, giving hope for further advances in the treatment of this and other tumors by targeted therapy. A large array of novel therapeutic options for targeted therapy of neuroblastoma is on the horizon. To this repεrtoirε, the neurokinin-1 receptor (NK1R) system was recently added. The present article explores the most recent developments in targeting neuroblastoma cells via the NK1R and how this new knowledge could be helpful to create new anticancer therapies agains neuroblastoma and other cancers. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  18. Immunosuppressive microenvironment in neuroblastoma

    Directory of Open Access Journals (Sweden)

    Vito ePistoia

    2013-06-01

    Full Text Available According to the cancer immunoediting model, the interplay between tumor cells and the host immune system is crucial for the control of tumor growth. NB is a pediatric tumor that presents with metastatic disease at diagnosis in about 50% of the cases, the majority of which have poor prognosis. In this Review article, immune escape pathways adopted by human neuroblastoma (NB cells are reviewed. These include intrinsic defects of tumor cells such impaired expression of the HLA class I related antigen processing machinery and functional alterations of the tumor microenvironment induced by NB cell-derived immunosuppressive molecules as MICA and HLA-G. Finally, examples of therapeutic interventions targeting the tumor microenvironment are discussed to emphasize the concept that successful cancer treatment may be achieved using this strategy.

  19. A case of neonatal neuroblastoma

    International Nuclear Information System (INIS)

    Nounaka, Osamu; Gotoh, Toshiaki; Takahashi, Kazuaki; Koyanagi, Tomohiko; Kakizaki, Hidehiro; Nakanishi, Shoichiro.

    1987-01-01

    A two-day-old male infant was referred to us for probable neuroblastoma, because of upper abdominal mass and positive urinary vanillylmandelic acid (VMA). Primary site of neuroblastoma was not found, but clinically IV-S stage neuroblastoma was strongly suspected, so 131 I-metaiodobenzylguanidine (MIBG) scan was performed. RI accumulation was found near the left adrenal region. Thus laparotomy was performed and left adrenal was resected. Liver biopsy was also performed. Microscopically multiple in situ foci of neuroblastoma cells were found in the left adrenal and tumor involvement was also seen in the liver. Skin and bone marrow metastasis were ruled out. Minimal chemotherapy was intended but abandoned soon because of possible spontaneous regression of stage IV-S neuroblastoma. Thereafter liver has been getting smaller and the patient has been doing well. Urinary VMA and homovanillic acid (HVA) per creatinine, which were used for follow-up, have also normalized after 3 months. Treatment of stage IV-S neuroblastoma and early diagnosis by 131 I-MIBG scan were reviewed. (author)

  20. Adolescent Neuroblastoma of Lower Limb

    Directory of Open Access Journals (Sweden)

    Rajeshwari K

    2013-04-01

    Full Text Available Neuroblastoma is an embryonic tumour of neural crest origin, commonly seen in children with upper abdomen involvement. Rarely neuroblastomas present in adolescents and adults involving lower limb. Histopathologically neuroblastoma of lower limb can be confused with other small round cell tumour especially with Ewing's sarcoma and rhabdomyosarcoma. A 16 year old male presented with 15x11cm swelling, pain and multiple discharging sinuses of right leg since 4 months. Routine haematological and biochemical analysis were within normal limits. Radiology of right leg showed large soft tissue swelling encompassing the pathological fracture of tibia and bowing of fibula. Fine needle aspiration of the swelling revealed malignant small round cell tumour. Histopathology revealed poorly differentiated neuroblastoma of lower limb. The immunohistochemistry of Synaptophysin and Chromogranin were positive and CD 99 was negative. Neuroblastoma diagnosed at unusual site with uncommon age has poor prognosis. Hence, one must keep in mind the differential diagnosis of neuroblastoma as one of the differential diagnosis in evaluating the soft tissue tumours of lower limb.

  1. Foreign Exchange Risk in International Transactions

    Directory of Open Access Journals (Sweden)

    Florentina-Olivia Balu

    2007-03-01

    Full Text Available Every international business is affected by the ever-changing value of the currencies implied in contracts. While many of us consider this unpredictability a nuisance, the volatility of currencies around the world can mean the difference between success and failure for many exporters/importers. Exchange rates between one currency and another can change dramatically in a short period of time, leaving the unprepared business exposed to potentially crippling losses. The efficient management of this risk is essential for the survival of a company and any business that is exposed to such a risk should ensure that it is fully prepared to manage it. Old standbys and recent breakthroughs in the area of financial risk management can remove much of the risk from currency rate movements. The range of such products is huge, with increasingly sophisticated techniques constantly being added. Among the most modern methods for managing exchange risk there are four major classes of derivative products like: forwards, futures, options, and swaps. Beyond the four main types of risk management instruments, there are a number of other products including "swaptions" (options on swaps; avenging options; yield curve swaps; futures on spreads; and options on portfolios. Sophisticated mathematical tools and high-speed computers are needed to calculate the price of these instruments and to determine their overall effect on the company. In this article we will focus on forward and futures contracts for managing foreign exchange risk. A forward is a contract to buy or sell currency at an agreed upon exchange rate at a specific date in the future. Futures are similar to forwards except that they're traded on exchanges which specify settlement dates. Also we make some recommendations related to the foreign exchange risk-management practices that are useful for companies involved in international trade and for financial institutions interested in providing hedging products to

  2. Foreign Exchange Risk in International Transactions

    Directory of Open Access Journals (Sweden)

    Florentina-Olivia Balu

    2007-03-01

    In this article we will focus on forward and futures contracts for managing foreign exchange risk. A forward is a contract to buy or sell currency at an agreed upon exchange rate at a specific date in the future. Futures are similar to forwards except that they’re traded on exchanges which specify settlement dates. Also we make some recommendations related to the foreign exchange risk-management practices that are useful for companies involved in international trade and for financial institutions interested in providing hedging products to these companies.

  3. Heparin-binding epidermal growth factor-like growth factor promotes neuroblastoma differentiation.

    Science.gov (United States)

    Gaviglio, Angela L; Knelson, Erik H; Blobe, Gerard C

    2017-05-01

    High-risk neuroblastoma is characterized by undifferentiated neuroblasts and low schwannian stroma content. The tumor stroma contributes to the suppression of tumor growth by releasing soluble factors that promote neuroblast differentiation. Here we identify heparin-binding epidermal growth factor-like growth factor (HBEGF) as a potent prodifferentiating factor in neuroblastoma. HBEGF mRNA expression is decreased in human neuroblastoma tumors compared with benign tumors, with loss correlating with decreased survival. HBEGF protein is expressed only in stromal compartments of human neuroblastoma specimens, with tissue from high-stage disease containing very little stroma or HBEGF expression. In 3 human neuroblastoma cell lines (SK-N-AS, SK-N-BE2, and SH-SY5Y), soluble HBEGF is sufficient to promote neuroblast differentiation and decrease proliferation. Heparan sulfate proteoglycans and heparin derivatives further enhance HBEGF-induced differentiation by forming a complex with the epidermal growth factor receptor, leading to activation of the ERK1/2 and STAT3 pathways and up-regulation of the inhibitor of DNA binding transcription factor. These data support a role for loss of HBEGF in the neuroblastoma tumor microenvironment in neuroblastoma pathogenesis.-Gaviglio, A. L., Knelson, E. H., Blobe, G. C. Heparin-binding epidermal growth factor-like growth factor promotes neuroblastoma differentiation. © FASEB.

  4. Epigenetic regulation of neuroblastoma development.

    Science.gov (United States)

    Durinck, Kaat; Speleman, Frank

    2018-01-19

    In recent years, technological advances have enabled a detailed landscaping of the epigenome and the mechanisms of epigenetic regulation that drive normal cell function, development and cancer. Rather than merely a structural entity to support genome compaction, we now look at chromatin as a very dynamic and essential constellation that is actively participating in the tight orchestration of transcriptional regulation as well as DNA replication and repair. The unique feature of chromatin flexibility enabling fast switches towards more or less restricted epigenetic cellular states is, not surprisingly, intimately connected to cancer development and treatment resistance, and the central role of epigenetic alterations in cancer is illustrated by the finding that up to 50% of all mutations across cancer entities affect proteins controlling the chromatin status. We summarize recent insights into epigenetic rewiring underlying neuroblastoma (NB) tumor formation ranging from changes in DNA methylation patterns and mutations in epigenetic regulators to global effects on transcriptional regulatory circuits that involve key players in NB oncogenesis. Insights into the disruption of the homeostatic epigenetic balance contributing to developmental arrest of sympathetic progenitor cells and subsequent NB oncogenesis are rapidly growing and will be exploited towards the development of novel therapeutic strategies to increase current survival rates of patients with high-risk NB.

  5. The Trend of International Risk Diversification

    Directory of Open Access Journals (Sweden)

    Oana Mionel

    2013-10-01

    Full Text Available The goal of this paper is to analyze the international diversification of risk through portfolio diversification based on investments abroad, particularly by investing in currencies of emerging countries. The starting point of the analysis is the work of Harry Markowitz, Portfolio selection, a reference work for the global financial environment in which the author states that a portfolio is efficient if it provides the highest possible expected return for a given level of risk and the lowest possible level of risk for any expected rate of earnings. The information used for this study comes from numerous sources and of great importance to international financial markets. The results based on the used data and information provide a comprehensive scan of how Federal Reserve proposed a clustered index of currencies, the current trend of exchange, the emerging BRIC countries scenario for 2050 and sources of the volatile emerging markets. Thus, following the completion of this work, we consider it necessary to pay attention to the course of emerging markets whose economic development and openness plays a significant role in their penetration of international investors’ investment plan.

  6. Cytokines Synergize to Combat Metastatic Neuroblastoma | Center for Cancer Research

    Science.gov (United States)

    Neuroblastoma is the most common extracranial solid tumor in children, and clinical outcomes of patients with this disease are quite variable. Prognosis is particularly poor for patients with high-risk tumors (classification based on patients’ age, extent of disease spread, and other biological features).

  7. Neuroblastoma and Its Zebrafish Model.

    Science.gov (United States)

    Zhu, Shizhen; Thomas Look, A

    2016-01-01

    Neuroblastoma, an important developmental tumor arising in the peripheral sympathetic nervous system (PSNS), accounts for approximately 10 % of all cancer-related deaths in children. Recent genomic analyses have identified a spectrum of genetic alterations in this tumor. Amplification of the MYCN oncogene is found in 20 % of cases and is often accompanied by mutational activation of the ALK (anaplastic lymphoma kinase) gene, suggesting their cooperation in tumor initiation and spread. Understanding how complex genetic changes function together in oncogenesis has been a continuing and daunting task in cancer research. This challenge was addressed in neuroblastoma by generating a transgenic zebrafish model that overexpresses human MYCN and activated ALK in the PSNS, leading to tumors that closely resemble human neuroblastoma and new opportunities to probe the mechanisms that underlie the pathogenesis of this tumor. For example, coexpression of activated ALK with MYCN in this model triples the penetrance of neuroblastoma and markedly accelerates tumor onset, demonstrating the interaction of these modified genes in tumor development. Further, MYCN overexpression induces adrenal sympathetic neuroblast hyperplasia, blocks chromaffin cell differentiation, and ultimately triggers a developmentally-timed apoptotic response in the hyperplastic sympathoadrenal cells. In the context of MYCN overexpression, activated ALK provides prosurvival signals that block this apoptotic response, allowing continued expansion and oncogenic transformation of hyperplastic neuroblasts, thus promoting progression to neuroblastoma. This application of the zebrafish model illustrates its value in rational assessment of the multigenic changes that define neuroblastoma pathogenesis and points the way to future studies to identify novel targets for therapeutic intervention.

  8. Targeted BIRC5 silencing using YM155 causes cell death in neuroblastoma cells with low ABCB1 expression

    NARCIS (Netherlands)

    Lamers, Fieke; Schild, Linda; Koster, Jan; Versteeg, Rogier; Caron, Huib N.; Molenaar, Jan J.

    2012-01-01

    The BIRC5 (Survivin) gene is located at chromosome 17q in the region that is frequently gained in high risk neuroblastoma. BIRC5 is strongly over expressed in neuroblastoma tumour samples, which correlates to a poor prognosis. We recently validated BIRC5 as a potential therapeutic target by showing

  9. Injury Risk in International Rugby Union

    Science.gov (United States)

    Moore, Isabel S.; Ranson, Craig; Mathema, Prabhat

    2015-01-01

    Background: Within international Rugby Union, only injury rates during the Rugby World Cup have been reported. Therefore, injury rates and types during other international tournaments are unknown. Purpose: To assess the 3-year incidence, severity, nature, and causes of match and training injuries sustained during different international tournaments played by the Welsh national Rugby Union team. Study Design: Descriptive epidemiology study. Methods: Injury data for all players (n = 78) selected for 1 national Rugby Union team over a 3-year period were analyzed using the international consensus statement methods. Player height (cm) and mass (kg) were recorded. Tournaments were grouped for comparisons as: autumn tournaments (2012 and 2013), Rugby World Cup (RWC; 2011), Six Nations (2012, 2013, and 2014), and summer tournaments (2012, 2013, and 2014). Injury incidence (injuries/1000 hours), prevalence (% of players unavailable), and severity (days lost) were calculated for each tournament. Injury location, type, and cause of match and training injuries were analyzed. Results: Match injury incidence was highest during autumn tournaments (262.5/1000 match-hours) and lowest during the RWC (178.6/1000 match-hours). Summer tournaments had the highest training incidence (5.5 injuries/1000 training-hours). Mild injuries were most likely during the RWC (risk ratio [RR], 2.02; 95% CI, 1.26-3.24), while severe injuries were most likely during autumn tournaments (RR, 3.27; 95% CI, 1.70-6.29). Quadriceps hematomas (18.8/1000 match-hours; 95% CI, 11.3-31.1) and concussions (13.8/1000 match-hours; 95% CI, 7.6-24.8) were the most common match injuries, with shoulder dislocations being the most severe (111 mean days lost per injury). Conclusion: Injury rates were considerably higher than those previously reported for multiple teams during RWC tournaments. Further investigation of injury rates and risk factors is recommended to accurately gauge their impact within international Rugby

  10. Biosocial risks of food: international aspects

    Directory of Open Access Journals (Sweden)

    Paolo Corvo

    2017-01-01

    Full Text Available Food consumption is influenced by a series of issues that affect both individuals, and people and cultures of the different parts of the world. It studies biosocial risks that have dramatic implications: obesity, anorexia and bulimia; malnutrition and hunger, involving more than 800 million people; the waste food, a real paradox of the global world; the land grabbing. These are very different problems because of causes and dynamics, but all of them require a profound change to be affected: a greater awareness of eating behaviour, an educational action on food topics, an intervention of regulatory institutions, local and international, which guarantees a fair market for products and food sovereignty.

  11. [International adoption: children's health risk evolution].

    Science.gov (United States)

    Dartiguenave, C

    2012-05-01

    The socioeconomic and sanitary conditions in many countries make it necessary to weigh as precisely as possible the uncertainties which might affect the health of internationally adopted children, which is one of the key drivers to adoption decision. Indeed, health troubles are more and more frequent among children proposed by countries, at a time when there are fewer children to be adopted. Hence the institutions and the actors in the field of international adoption are compelled to frequently update their professional practices, so as to cope both with the declining offer for adoptable children and with the increasing pressure from the birth countries of children to make host countries adopt children with high age or with special needs. It also requires from the administrations the will to provide better initial information and to implement the demand for an agreement. Meanwhile, in spite of those growing constraints, adopting families have been more and more risk adverse during the latest decades, this being a common trend in our developed countries.

  12. Graphene Oxide Nanoribbons Induce Autophagic Vacuoles in Neuroblastoma Cell Lines

    Directory of Open Access Journals (Sweden)

    Emanuela Mari

    2016-11-01

    Full Text Available Since graphene nanoparticles are attracting increasing interest in relation to medical applications, it is important to understand their potential effects on humans. In the present study, we prepared graphene oxide (GO nanoribbons by oxidative unzipping of single-wall carbon nanotubes (SWCNTs and analyzed their toxicity in two human neuroblastoma cell lines. Neuroblastoma is the most common solid neoplasia in children. The hallmark of these tumors is the high number of different clinical variables, ranging from highly metastatic, rapid progression and resistance to therapy to spontaneous regression or change into benign ganglioneuromas. Patients with neuroblastoma are grouped into different risk groups that are characterized by different prognosis and different clinical behavior. Relapse and mortality in high risk patients is very high in spite of new advances in chemotherapy. Cell lines, obtained from neuroblastomas have different genotypic and phenotypic features. The cell lines SK-N-BE(2 and SH-SY5Y have different genetic mutations and tumorigenicity. Cells were exposed to low doses of GO for different times in order to investigate whether GO was a good vehicle for biological molecules delivering individualized therapy. Cytotoxicity in both cell lines was studied by measuring cellular oxidative stress (ROS, mitochondria membrane potential, expression of lysosomial proteins and cell growth. GO uptake and cytoplasmic distribution of particles were studied by Transmission Electron Microscopy (TEM for up to 72 h. The results show that GO at low concentrations increased ROS production and induced autophagy in both neuroblastoma cell lines within a few hours of exposure, events that, however, are not followed by growth arrest or death. For this reason, we suggest that the GO nanoparticle can be used for therapeutic delivery to the brain tissue with minimal effects on healthy cells.

  13. Radiation doses and risks from internal emitters

    International Nuclear Information System (INIS)

    Harrison, John; Day, Philip

    2008-01-01

    This review updates material prepared for the UK Government Committee Examining Radiation Risks from Internal Emitters (CERRIE) and also refers to the new recommendations of the International Commission on Radiological Protection (ICRP) and other recent developments. Two conclusions from CERRIE were that ICRP should clarify and elaborate its advice on the use of its dose quantities, equivalent and effective dose, and that more attention should be paid to uncertainties in dose and risk estimates and their implications. The new ICRP recommendations provide explanations of the calculation and intended purpose of the protection quantities, but further advice on their use would be helpful. The new recommendations refer to the importance of understanding uncertainties in estimates of dose and risk, although methods for doing this are not suggested. Dose coefficients (Sv per Bq intake) for the inhalation or ingestion of radionuclides are published as reference values without uncertainty. The primary purpose of equivalent and effective dose is to enable the summation of doses from different radionuclides and from external sources for comparison with dose limits, constraints and reference levels that relate to stochastic risks of whole-body radiation exposure. Doses are calculated using defined biokinetic and dosimetric models, including reference anatomical data for the organs and tissues of the human body. Radiation weighting factors are used to adjust for the different effectiveness of different radiation types, per unit absorbed dose (Gy), in causing stochastic effects at low doses and dose rates. Tissue weighting factors are used to take account of the contribution of individual organs and tissues to overall detriment from cancer and hereditary effects, providing a simple set of rounded values chosen on the basis of age- and sex-averaged values of relative detriment. While the definition of absorbed dose has the scientific rigour required of a basic physical quantity

  14. Validation of the mIBG skeletal SIOPEN scoring method in two independent high-risk neuroblastoma populations: the SIOPEN/HR-NBL1 and COG-A3973 trials.

    Science.gov (United States)

    Ladenstein, Ruth; Lambert, Bieke; Pötschger, Ulrike; Castellani, Maria-Rita; Lewington, Valerie; Bar-Sever, Zvi; Oudoux, Aurore; Śliwińska, Anna; Taborska, Katerina; Biassoni, Lorenzo; Yanik, Gregory A; Naranjo, Arlene; Parisi, Marguerite T; Shulkin, Barry L; Nadel, Helen; Gelfand, Michael J; Matthay, Katherine K; Park, Julie R; Kreissman, Susan G; Valteau-Couanet, Dominique; Boubaker, Ariane

    2018-02-01

    Validation of the prognostic value of the SIOPEN mIBG skeletal scoring system in two independent stage 4, mIBG avid, high-risk neuroblastoma populations. The semi-quantitative SIOPEN score evaluates skeletal meta-iodobenzylguanidine (mIBG) uptake on a 0-6 scale in 12 anatomical regions. Evaluable mIBG scans from 216 COG-A3973 and 341 SIOPEN/HR-NBL1 trial patients were reviewed pre- and post-induction chemotherapy. The prognostic value of skeletal scores for 5-year event free survival (5 yr.-EFS) was tested in the source and validation cohorts. At diagnosis, both cohorts showed a gradual non-linear increase in risk with cumulative scores. Several approaches were explored to test the relationship between score and EFS. Ultimately, a cutoff score of ≤3 was the most useful predictor across trials. A SIOPEN score ≤ 3 pre-induction was found in 15% SIOPEN patients and in 22% of COG patients and increased post-induction to 60% in SIOPEN patients and to 73% in COG patients. Baseline 5 yr.-EFS rates in the SIOPEN/HR-NBL1 cohort for scores ≤3 were 47% ± 7% versus 26% ± 3% for higher scores at diagnosis (p  3 after induction have very poor outcomes and should be considered for alternative therapeutic strategies.

  15. LMO1 Synergizes with MYCN to Promote Neuroblastoma Initiation and Metastasis.

    Science.gov (United States)

    Zhu, Shizhen; Zhang, Xiaoling; Weichert-Leahey, Nina; Dong, Zhiwei; Zhang, Cheng; Lopez, Gonzalo; Tao, Ting; He, Shuning; Wood, Andrew C; Oldridge, Derek; Ung, Choong Yong; van Ree, Janine H; Khan, Amish; Salazar, Brittany M; Lummertz da Rocha, Edroaldo; Zimmerman, Mark W; Guo, Feng; Cao, Hong; Hou, Xiaonan; Weroha, S John; Perez-Atayde, Antonio R; Neuberg, Donna S; Meves, Alexander; McNiven, Mark A; van Deursen, Jan M; Li, Hu; Maris, John M; Look, A Thomas

    2017-09-11

    A genome-wide association study identified LMO1, which encodes an LIM-domain-only transcriptional cofactor, as a neuroblastoma susceptibility gene that functions as an oncogene in high-risk neuroblastoma. Here we show that dβh promoter-mediated expression of LMO1 in zebrafish synergizes with MYCN to increase the proliferation of hyperplastic sympathoadrenal precursor cells, leading to a reduced latency and increased penetrance of neuroblastomagenesis. The transgenic expression of LMO1 also promoted hematogenous dissemination and distant metastasis, which was linked to neuroblastoma cell invasion and migration, and elevated expression levels of genes affecting tumor cell-extracellular matrix interaction, including loxl3, itga2b, itga3, and itga5. Our results provide in vivo validation of LMO1 as an important oncogene that promotes neuroblastoma initiation, progression, and widespread metastatic dissemination. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. OPERATIONAL RISK IN INTERNATIONAL BUSINESS: TAXONOMY AND ASSESSMENT METHODS

    Directory of Open Access Journals (Sweden)

    Marinoiu Ana Maria

    2009-05-01

    Full Text Available The paper aims at presenting the classifications and the assessment methods for operational risk according to international regulations (ie. Basel 2, in the context of its importance as a managerial tool for international business. Considering the growin

  17. Protein tyrosine phosphatase receptor delta acts as a neuroblastoma tumor suppressor by destabilizing the aurora kinase a oncogene

    LENUS (Irish Health Repository)

    Meehan, Maria

    2012-02-05

    Abstract Background Protein tyrosine phosphatase receptor delta (PTPRD) is a member of a large family of protein tyrosine phosphatases which negatively regulate tyrosine phosphorylation. Neuroblastoma is a major childhood cancer arising from precursor cells of the sympathetic nervous system which is known to acquire deletions and alterations in the expression patterns of PTPRD, indicating a potential tumor suppressor function for this gene. The molecular mechanism, however, by which PTPRD renders a tumor suppressor effect in neuroblastoma is unknown. Results As a molecular mechanism, we demonstrate that PTPRD interacts with aurora kinase A (AURKA), an oncogenic protein that is over-expressed in multiple forms of cancer, including neuroblastoma. Ectopic up-regulation of PTPRD in neuroblastoma dephosphorylates tyrosine residues in AURKA resulting in a destabilization of this protein culminating in interfering with one of AURKA\\'s primary functions in neuroblastoma, the stabilization of MYCN protein, the gene of which is amplified in approximately 25 to 30% of high risk neuroblastoma. Conclusions PTPRD has a tumor suppressor function in neuroblastoma through AURKA dephosphorylation and destabilization and a downstream destabilization of MYCN protein, representing a novel mechanism for the function of PTPRD in neuroblastoma.

  18. Congenital neuroblastoma with placental involvement

    OpenAIRE

    Kume, Ayako; Morikawa, Teppei; Ogawa, Makiko; Yamashita, Aki; Yamaguchi, Shunichi; Fukayama, Masashi

    2014-01-01

    We describe an extremely rare case of congenital neuroblastoma with placental involvement. A fetus with a left abdominal mass detected during ultrasonography at 23 weeks’ gestation developed hydrops fetalis by 26 weeks’ gestation. The mother developed hypertension at 26 5/7 weeks’ gestation. Based on a clinical diagnosis of pregnancy-induced hypertension, labor was induced at 26 6/7 weeks. However, intrauterine fetal death was diagnosed during delivery. Postmortern examination revealed a soli...

  19. Intrarenal neuroblastoma mimics Wilms' tumor

    International Nuclear Information System (INIS)

    Muniz, Maria T. Cartaxo; Soares, Andrezza B.; Freitas, Elizabete M.; Araujo, Marcela; Pureza, Leda M.M.; Morais, Adriana; Antunes, Consuelo; Salles, Terezinha de J. Marques; Borges, Josenilda C.; Morais, Vera L.L. de; Romualdo Filho, Jose; Magalhaes, Mario H.

    2005-01-01

    This work reports the case history of a child with intrarenal neuroblastoma, initially diagnosed as Wilms' tumor. The patient, a one year and three months old girl, presented a hard abdominal mass on the left flank that extended to the meso gastric region, plus fever and paleness. The ultrasound of the entire abdomen revealed an intrarenal mass. Biopsy with fine needle in many points of the tumor revealed Wilms' tumor. The scarcely of the material, however, made immunohistoquemistry impossible at that moment. Because of the child's severe condition the SIOP protocol was started. As no clinical response was observed, an exploratory laparotomy was indicated with partial resection of the tumor and bone marrow aspiration (MO). The histopathologic study revealed a malignant neoplasia of small cells, poorly differentiated. IHQ was negative for WT-1 and positive for NB-84, synaptofisin, cromogranine. N-myc amplification was observed by molecular biology. The bone marrow aspiration identified metastatic small round cells infiltration. Intrarenal neuroblastoma is a rare entity that clinically and radiographically resembles Wilms' tumor. The objective of this case report is to show the importance of immunohistochemical and molecular analysis in the diagnosis of intrarenal neuroblastoma. (author)

  20. Comparisons on International Approaches of Business and Project Risk Management

    OpenAIRE

    Nadia Carmen ENE

    2005-01-01

    In this article we intend to present a comparative approach between three recognized international methodologies for risk management: RISKMAN, Project Management Institute Methodology-PMBoK and Project Risk Analysis and Management Guide (produced by Association for Project Management).

  1. The role of internal audit in companies' risk management

    Directory of Open Access Journals (Sweden)

    Vlaović-Begović Sanja

    2012-01-01

    Full Text Available The internal audit area of application differs according to management needs and demands, as well as the structure and the size of a company. Besides examination of bookkeeping information, law synchronization check, criminal action and mistakes discoveries, internal audit is more and more directed towards risk management process in order to respond to the demands of uncertain business and to secure adequate business decisions making for management. This paper examines the role of internal audit in companies' risk management that is represented in examination and evaluation of risk management processes, with the aim of decreasing risk to an acceptable level for a company. Besides that, internal audit can support the management in configuration and establishing more efficient, improved risk management process. In order to ensure independence and objectiveness of internal audit operation, activities and responsibilities of management and internal audit are clearly defined.

  2. Risk management and internal audit: Evidence from Greece

    Directory of Open Access Journals (Sweden)

    George Drogalas

    2017-07-01

    Full Text Available Risk management is ranked by financial executives as one of their most important objectives. For this reason, a wide range of literature on risk management has been developed. Within this fluid business environment, internal audit plays a key role in monitoring a company’s risk profile and identifying areas for improving risk management processes. The purpose of this study is to provide a comprehensive overview of the factors that impact on risk management regarding internal audit function. Empirical evidence was collected by means of a mailed survey. Regression analysis is used in order to illustrate the information gathered. Consistent with theory and our expectations, the results indicate that internal audit, internal auditor and added value of internal audit are statistically significantly associated with risk management.

  3. HOW INTERNAL RISK - BASED AUDIT APPRAISES THE EVALUATION OF RISKS MANAGEMENT

    Directory of Open Access Journals (Sweden)

    N. Dorosh

    2017-09-01

    Full Text Available The article deals with the nature and function of the internal risk-based audit process approach to create patterns of risks and methods of evaluation. Deals with the relationship between the level of maturity of the risk of the company and the method of risk-based internal audit. it was emphasized that internal auditing provides an independent and objective opinion to an organization’s management as to whether its risks are being managed to acceptable levels.

  4. Research Award: Risk Management and Internal Audit (RMIA)

    International Development Research Centre (IDRC) Digital Library (Canada)

    KKearney

    2011-09-12

    Sep 12, 2011 ... advisory role to various work assignments. Applicants should have a professional interest in internal audit and risk management. Knowledge of project management principles, enterprise risk management practices, and internal audit standards would be an asset. Your past study and research interests will ...

  5. Neuroblastoma in children: Update on clinicopathologic and genetic prognostic factors.

    Science.gov (United States)

    Ahmed, Atif A; Zhang, Lei; Reddivalla, Naresh; Hetherington, Maxine

    2017-04-01

    Neuroblastoma is the most common extracranial solid tumor in childhood accounting for 8-10% of all childhood malignancies. The tumor is characterized by a spectrum of histopathologic features and a heterogeneous clinical phenotype. Modern multimodality therapy results in variable clinical response ranging from cure in localized tumors to limited response in aggressive metastatic disease. Accurate clinical staging and risk assessment based on clinical, surgical, biologic and pathologic criteria are of pivotal importance in assigning prognosis and planning effective treatment approaches. Numerous studies have analyzed the presence of several clinicopathologic and biologic factors in association with the patient's prognosis and outcome. Although patient's age, tumor stage, histopathologic classification, and MYCN amplification are the most commonly validated prognostic markers, several new gene mutations have been identified in sporadic and familial neuroblastoma cases that show association with an adverse outcome. Novel molecular studies have also added data on chromosomal segmental aberrations in MYCN nonamplified tumors. In this review, we provide an updated summary of the clinical, serologic and genetic prognostic indicators in neuroblastoma including classic factors that have consistently played a role in risk stratification of patients as well as newly discovered biomarkers that may show a potential significance in patients' management.

  6. Financial Globalization, International Business Cycles, and Consumption Risk Sharing

    OpenAIRE

    Michael J. Artis; Mathias Hoffmann

    2007-01-01

    In spite of two decades of financial globalization, consumption-based indicators do not seem to signal more international risk sharing. We argue that consumption risk sharing among industrialised countries has actually increased - in particular since the 1990s - but that standard consumption-based measures of risk sharing - such as the volatility of consumption conditional on output or international consumption correlations - have beennunable to detect this increase. The reason is that consum...

  7. Risk Based Internal Auditing dan Implementasinya pada PT IBF

    Directory of Open Access Journals (Sweden)

    Choirul Anwar

    2009-09-01

    Full Text Available Risks deal with uncertainties. The bigger the uncertainties faced by firms, the larger opportunity and impact of the risks in future. Whether firms succeed in managing risks it depends a lot on the effectivity of internal control. PT Indonesia Buffon Film (PT IBF is one of many firms trying to optimalize its Internal Audit Department.The main problem in this company is managing the company to survive with accumulated losses over 90% of share capital in the period of 2007 to 2008. This research aims to describe the relationship between internal control and purpose of Internal Audit Department of PT IBF. The main focus is the management crisis happening due to weak leadership within the company. This in turn weakens internal control. Management is suggested to prioritize risks that contribute to the main risk, especially internal factors that can be controlled by management. PT IBF has deployed an implementation of the Australian/New Zealand Standard in Risk Management (AZ/NZS 4360 that helps the main purpose of the Risk Based Internal Auditing. Overall, PT IBF has done well to recognize that there are possible risks in their business operations. However, there are also gaps that must be analyzed and followed up further by management.

  8. Assessing the risk of work-related international travel.

    Science.gov (United States)

    Druckman, Myles; Harber, Philip; Liu, Yihang; Quigley, Robert L

    2014-11-01

    To identify factors affecting the likelihood of requiring medical services during international business trips. Data from more than 800,000 international trips and medical assistance cases provided to 48 multinational corporations in 2009. Travel destination countries were grouped into four a priori risk-related categories. Travel to "low" medical risk countries in aggregate accounted for more hospitalizations and medical evacuations than travel to "high" medical risk countries. Nevertheless, the risk per trip was much higher for travel to higher medical risk countries. Corporations with employees on international travel should allocate sufficient resources to manage and ideally prevent medical issues during business travel. Travel medicine must focus on more than infectious diseases, and programs are necessary for both high- and low-risk regions. Improved understanding of travel-related needs determines resource allocation and risk mitigation efforts.

  9. Intestinal Lymphangiectasia Secondary to Neuroblastoma

    Directory of Open Access Journals (Sweden)

    RM Reifen

    1994-01-01

    Full Text Available An eight month-old infant presented with a 10-day history of vomiting and diarrhea, and a one-week history of swelling of the lower extremities. Laboratory evaluations revealed hypoproteinemia and lymphocytopenia due to protein-losing enteropathy. Peroral small bowel biopsy showed intestinal lymphangiectasia. Subsequent onset of unexplained ecchymosis and obstructive jaundice resulted in additional studies which revealed an omental neuroblastoma as the underlying etiology of the infant’s symptoms. This report emphasizes the importance of considering secondary, obstructive causes for lymphangiectasia and protein-losing enteropathy.

  10. MIBG-treatment in neuroblastoma

    International Nuclear Information System (INIS)

    Treuner, J.; Gerein, V.; Klingebiel, T.; Schwabe, D.; Feine, U; Happ, J.; Niethammer, D.; Maul, F.; Dopfer, R.; Kornhuber, B.; Berthold, F.; Jurgens, H.; Hor, G.

    1988-01-01

    This paper reports the results of 27 children with neuroblastoma treated with 131 I-Metaiodobenzylguanidine (MIBG). They were either refractory to conventional therapy or experienced relapse after initially successful treatment. 7 children revealed stage IV and 20 stage III at the beginning of MIBG-treatment. MIBG was administered by infusion lasting from 30 min to 30 hrs. In most children the dose was split into two portions each infused over a period of 4 hrs with a 24 hrs interval between. Courses were repeated up to 6 times and maximum activity given to one patient cumulatively was 38,221 MBq. 24 patients were valuable for analysis of results

  11. Risk management and audit | IDRC - International Development ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    We recognize these risks and work to manage them effectively with the support of our knowledgeable staff on the ground. We manage risk: strategically, with a sound governance and accountability structure;; programmatically, with a well defined strategic and program framework and sound management processes; and ...

  12. Disseminated peripheral neuroblastoma in a Rhodesian Ridgeback dog.

    Science.gov (United States)

    Cook, R W; Abraham, L A; McCowan, C I

    2017-04-01

    A 4-year-old neutered male Rhodesian Ridgeback dog with right-sided Horner's syndrome, bilateral laryngeal paralysis, neck pain and bilateral hindlimb ataxia was euthanased following deterioration of its neurological status. Necropsy examination revealed an off-white retropharyngeal neoplastic mass (100 × 30 × 30 mm) attached to the base of the skull on the right side and macroscopic nodular metastases in the spleen and three vertebral bodies (C6, C7 and T6), including a nodule attached to the dura at C7. Histological evidence of neuroblastic tumour was detected in these macroscopic lesions, a regional lymph node, bone marrow of a femur and all 15 vertebral bodies (C1-T8) examined, including the three with macroscopic metastases, and in the lumens of small blood vessels in the lungs and liver. Ganglion cell differentiation was detected only in the primary retropharyngeal mass, one splenic nodule and the C7 dural nodule. Neoplastic cells were immunoreactive to neurofilament protein (ganglion cells only), vimentin and synaptophysin, and were negative for S100 protein, GFAP, CD3 and Pax5. The diagnosis was disseminated peripheral neuroblastoma, differentiating subtype (International Neuroblastoma Pathology Classification), with likely primary involvement of the right cranial cervical ganglion. This appears to be the first report of neuroblastoma in a dog with widespread occult haematogenous metastasis to bone marrow. © 2017 Australian Veterinary Association.

  13. Internal controls and credit risk relationship among banks in Europe

    Directory of Open Access Journals (Sweden)

    Ellis Kofi Akwaa-Sekyi

    2017-01-01

    Full Text Available Purpose: The study purport to investigate the effectiveness of internal control mechanisms, investigate whether evidence of agency problem is found among banks in Europe and determine how internal controls affect credit risk. Design/methodology/approach: Panel data from 91 banks from 23 European Union countries were studied from 2008-2014. Hausman’s specification test suggest the use of fixed effects estimation technique of GLS. Quantitatively modelled data on 15 variables covering elements of internal controls, objectives of internal controls, agency problem, bank and country specific variables were used. Findings: There is still high credit risk in spite of measures being implemented by the European Central Bank. Banks have individual entity factors that increase or decrease credit risk. The study finds effective internal control systems because objectives of internal controls are achieved and significantly determine credit risk. Agency problem is confirmed due to significant positive relation with credit risk. There is significant effect of internal controls on credit risk with specific variables as risk assessment, return on average risk weighted assets, institutional ownership, bank size, inflation, interest rate and GDP. Research limitations/implications: Missing data prevented the use of strongly balanced panel. The lack of flexibility with using quantitative approach did not allow further scrutiny of the nature of variables. However, statistical tests were acceptable for the model used. The study has implications for management and owners of banks to be warry of agency problem because that provides incentive for reckless high risk transactions that may benefit the agent than the principal. Management must engage in actions that profile the company better and enhances value maximization. Rising default risk has tendency to impair corporate image leading to loss of reputational capital. Originality/value: The study provides the use of

  14. NORM and the Risk of Internal Contamination

    International Nuclear Information System (INIS)

    Syaifudin, Mukh; Iin Kurnia; Yanti Lusiyanti; Siti Nurhayati; Iwiq Indrawati

    2003-01-01

    The earth and its atmosphere contain various natural radioactive materials known as NORM (naturally occurring radioactive materials) as sources of external and internal radiation exposures to human. The main radionuclides of NORM are uranium and thorium chairs and their progenies. In this paper, it will be discussed briefly about effects of internal contamination these elements which could enter into the body through inhalation and ingestion as well as absorption on the skin. The distribution, excretion and decontamination methods of the radionuclide incorporated in the body are also discussed. (author)

  15. Expression of Truncated Neurokinin-1 Receptor in Childhood Neuroblastoma is Independent of Tumor Biology and Stage.

    Science.gov (United States)

    Pohl, Alexandra; Kappler, Roland; Mühling, Jakob; VON Schweinitz, Dietrich; Berger, Michael

    2017-11-01

    Neuroblastoma is an embryonal malignancy arising from the aberrant growth of neural crest progenitor cells of the sympathetic nervous system. The tachykinin receptor 1 (TACR1) - substance P complex is associated with tumoral angiogenesis and cell proliferation in a variety of cancer types. Inhibition of TACR1 was recently described to impede growth of NB cell lines. However, the relevance of TACR1 in clinical settings is unknown. We investigated gene expression levels of full-length and truncated TACR1 in 59 neuroblastomas and correlated these data with the patients' clinical parameters such as outcome, metastasis, International Neuroblastoma Staging System (INSS) status, MYCN proto-oncogene, bHLH transcription factor (MYCN) status, gender and age. Our results indicated that TACR1 is ubiquitously expressed in neuroblastoma but expression levels are independent of clinical parameters. Our data suggest that TACR1 might serve as a potent anticancer target in a large variety of patients with neuroblastoma, independent of tumor biology and clinical stage. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  16. International Adoption: Benefits, Risks, and Vulnerabilities

    Science.gov (United States)

    Rochat, Tamsen; Richter, Linda

    2007-01-01

    International adoption is on the rise in the United States and is not without controversy. Reasons for the increase include higher rates of infertility in couples who have delayed parenthood; increased numbers of children who are relinquished, abandoned, or orphaned around the world; and the influence of third party agencies. Internationally…

  17. Nuclear medicine and multimodality imaging of pediatric neuroblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Mueller, Wolfgang Peter; Pfluger, Thomas [Ludwig-Maximilians-University of Munich, Department of Nuclear Medicine, Munich (Germany); Coppenrath, Eva [Ludwig-Maximilians-University of Munich, Department of Radiology, Munich (Germany)

    2013-04-15

    Neuroblastoma is an embryonic tumor of the peripheral sympathetic nervous system and is metastatic or high risk for relapse in nearly 50% of cases. Therefore, exact staging with radiological and nuclear medicine imaging methods is crucial for defining the adequate therapeutic choice. Tumor cells express the norepinephrine transporter, which makes metaiodobenzylguanidine (MIBG), an analogue of norepinephrine, an ideal tumor specific agent for imaging. MIBG imaging has several disadvantages, such as limited spatial resolution, limited sensitivity in small lesions and the need for two or even more acquisition sessions. Most of these limitations can be overcome with positron emission tomography (PET) using [F-18]2-fluoro-2-deoxyglucose [FDG]. Furthermore, new tracers, such as fluorodopa or somatostatin receptor agonists, have been tested for imaging neuroblastoma recently. However, MIBG scintigraphy and PET alone are not sufficient for operative or biopsy planning. In this regard, a combination with morphological imaging is indispensable. This article will discuss strategies for primary and follow-up diagnosis in neuroblastoma using different nuclear medicine and radiological imaging methods as well as multimodality imaging. (orig.)

  18. Targeting neuroblastoma stem cells with retinoic acid and proteasome inhibitor.

    Directory of Open Access Journals (Sweden)

    Barbara Hämmerle

    Full Text Available Neuroblastma cell lines contain a side-population of cells which express stemness markers. These stem-like cells may represent the potential underlying mechanism for resistance to conventional therapy and recurrence of neuroblastoma in patients.To develop novel strategies for targeting the side-population of neurobastomas, we analyzed the effects of 13-cis-retinoic acid (RA combined with the proteasome inhibitor MG132. The short-term action of the treatment was compared with effects after a 5-day recovery period during which both chemicals were withdrawn. RA induced growth arrest and differentiation of SH-SY5Y and SK-N-BE(2 neuroblastoma cell lines. Inhibition of the proteasome caused apoptosis in both cell lines, thus, revealing the critical role of this pathway in the regulated degradation of proteins involved in neuroblastoma proliferation and survival. The combination of RA with MG132 induced apoptosis in a dose-dependent manner, in addition to promoting G2/M arrest in treated cultures. Interestingly, expression of stem cell markers such as Nestin, Sox2, and Oct4 were reduced after the recovery period of combined treatment as compared with untreated cells or treated cells with either compound alone. Consistent with this, neurosphere formation was significantly impaired by the combined treatment of RA and MG132.Given that stem-like cells are associated with resistant to conventional therapy and are thought to be responsible for relapse, our results suggest that dual therapy of RA and proteasome inhibitor might be beneficial for targeting the side-population of cells associated residual disease in high-risk neuroblastoma.

  19. [International trends in laboral risk legislation].

    Science.gov (United States)

    García-Vigil, José Luis

    2010-01-01

    It had been established that labor damage are: laboral injuries, professional diseases and others diseases related with laboral conditions. All of them are referred to as diseases or damages suffered as a consequence of a laboral relations. It is implicated that the damage occurs in the place or during a laboral scheduled time with a causal direct relation. There is a trend in the Spanish laboral legislation, which is controversial in laboral medicine, because it includes a Law for the Prevention of Laboral Risks that consider also to the chronic diseases as a cause no traumatic of a laboral risk to conditioned a damage during the laboral journey.

  20. Comparison of Clinico-Radiological Features between Congenital Cystic Neuroblastoma and Neonatal Adrenal Hemorrhagic Pseudocyst

    Energy Technology Data Exchange (ETDEWEB)

    Eo, Hong; Kim, Ji Hye; Jang, Kyung Mi; Yoo, So Young [Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of); Lim, Gye Yeon [St. Mary' s Hospital Catholic University, Seoul (Korea, Republic of); Kim, Myung Joon [Severance Hospital Yonsei University, Seoul (Korea, Republic of); Kim, Ok Hwa [Ajou University Hospital, Suwon (Korea, Republic of)

    2011-02-15

    To evaluate the radiological and clinical findings of congenital cystic neuroblastomas as compared with those of the cystic presentation of neonatal adrenal hemorrhage. We analyzed the US (n = 52), CT (n = 24), and MR (n = 4) images as well as the medical records of 28 patients harboring congenital cystic neuroblastomas (n = 16) and neonatal adrenal hemorrhagic pseudocysts (n = 14). The history of prenatal detection, location, size, presence of outer wall enhancement, internal septations, solid portion, calcification, turbidity, vascular flow on a Doppler examination, and evolution patterns were compared in two groups of cystic lesions, by Fischer's exact test. All (100%) neuroblastomas and three (21%) of the 14 hemorrhagic pseudocysts were detected prenatally. Both groups of cystic lesions occurred more frequently on the right side; 11 of 16 (69%) for neuroblastomas and 11 of 14 (79%) for hemorrhagic pseudocysts. The size, presence of solid portion, septum, enhancement, and turbidity did not differ significantly (p > 0.05) between the two groups of cystic lesions. However, tiny calcifications (n = 3) and vascular flow on color Doppler US (n = 3) were noted in only neuroblastomas. The cystic neuroblastomas became complex solid and cystic masses, and did not disappear for up to 90 days in the three following cases, whereas 11 of the 14 (79%) hemorrhagic pseudocysts disappeared completely and the three remaining (27%) evolved to calcifications only. Although the imaging findings of two groups of cystic lesions were similar, prenatal detection, the presence of calcification on initial images, vascularity on color Doppler US, and evolution to a more complex mass may all favor neuroblastomas

  1. Comparison of Clinico-Radiological Features between Congenital Cystic Neuroblastoma and Neonatal Adrenal Hemorrhagic Pseudocyst

    International Nuclear Information System (INIS)

    Eo, Hong; Kim, Ji Hye; Jang, Kyung Mi; Yoo, So Young; Lim, Gye Yeon; Kim, Myung Joon; Kim, Ok Hwa

    2011-01-01

    To evaluate the radiological and clinical findings of congenital cystic neuroblastomas as compared with those of the cystic presentation of neonatal adrenal hemorrhage. We analyzed the US (n = 52), CT (n = 24), and MR (n = 4) images as well as the medical records of 28 patients harboring congenital cystic neuroblastomas (n = 16) and neonatal adrenal hemorrhagic pseudocysts (n = 14). The history of prenatal detection, location, size, presence of outer wall enhancement, internal septations, solid portion, calcification, turbidity, vascular flow on a Doppler examination, and evolution patterns were compared in two groups of cystic lesions, by Fischer's exact test. All (100%) neuroblastomas and three (21%) of the 14 hemorrhagic pseudocysts were detected prenatally. Both groups of cystic lesions occurred more frequently on the right side; 11 of 16 (69%) for neuroblastomas and 11 of 14 (79%) for hemorrhagic pseudocysts. The size, presence of solid portion, septum, enhancement, and turbidity did not differ significantly (p > 0.05) between the two groups of cystic lesions. However, tiny calcifications (n = 3) and vascular flow on color Doppler US (n = 3) were noted in only neuroblastomas. The cystic neuroblastomas became complex solid and cystic masses, and did not disappear for up to 90 days in the three following cases, whereas 11 of the 14 (79%) hemorrhagic pseudocysts disappeared completely and the three remaining (27%) evolved to calcifications only. Although the imaging findings of two groups of cystic lesions were similar, prenatal detection, the presence of calcification on initial images, vascularity on color Doppler US, and evolution to a more complex mass may all favor neuroblastomas

  2. Harmonization of international risk assessment protocol

    International Nuclear Information System (INIS)

    Toyofuku, Hajime . E-mail toyofuku@nihs.go.jp

    2006-01-01

    For over centuries developments in food production and new food safety management systems in most developed countries have been perceived by many to be efficient in the prevention of food-borne disease. Nevertheless a number of problems remain dominant, one of these being the high level of food-borne microbiological disease which seems, for some pathogens, to have increased over the last decades. The development of an interdisciplinary approach with direct interaction between surveillance and risk analysis systems is described as a potential basis for improved prevention of food-borne disease. Quantitative microbiological risk assessment is a relatively new scientific approach, able to link data from food within the entire food chain and the various data on human disease to provide a clear estimation of risk. Today food safety is one of the WHOs top eleven priorities; the Organization calls for more systematic and aggressive steps to be taken to reduce significantly the risk of microbiological food-borne diseases. Dealing with this challenge is one of the major challenges for the 21st century in regard to food safety, implying a significant re-direction of food microbiology efforts in many parts of the world

  3. Reduce Fraud Risk in Your District with Stronger Internal Controls

    Science.gov (United States)

    Okrzesik, Daryl J.; Nuehring, Bert G.

    2011-01-01

    Internal accounts offer schools a faster, more convenient way to handle the income and expenses that result from student fees, school clubs and organizations, field trips, fund-raising, and similar activities. But this convenience also incurs the added risk of fraud. Fortunately, there are proven ways to strengthen internal controls and reduce…

  4. Prevalence of Internalized Homophobia and HIV Associated Risks ...

    African Journals Online (AJOL)

    Prevalence of Internalized Homophobia and HIV Associated Risks among Men who have Sex with Men in Nigeria. ... With homosexual/gay men as reference, respondents who self-identified as bisexual were two times more likely [AOR 2.1; 95 CI: 1.6 – 2.9, p<0.001] to report internalized homophobia. Those who were HIV ...

  5. International Risk-Sharing: Macroeconomic and Financial Aspects

    NARCIS (Netherlands)

    Hadzi-Vaskov, M.

    2008-01-01

    International risk-sharing is one of the most important benefits from the process of international financial integration, which gained in speed, scope, and geographical coverage during the past decades. As long as different national economies are not perfectly correlated, there are possibilities for

  6. Infectious disease risk and international tourism demand.

    Science.gov (United States)

    Rosselló, Jaume; Santana-Gallego, Maria; Awan, Waqas

    2017-05-01

     For some countries, favourable climatic conditions for tourism are often associated with favourable conditions for infectious diseases, with the ensuing development constraints on the tourist sectors of impoverished countries where tourism's economic contribution has a high potential. This paper evaluates the economic implications of eradication of Malaria, Dengue, Yellow Fever and Ebola on the affected destination countries focusing on the tourist expenditures.  A gravity model for international tourism flows is used to provide an estimation of the impact of each travel-related disease on international tourist arrivals. Next the potential eradication of these diseases in the affected countries is simulated and the impact on tourism expenditures is estimated.  The results show that, in the case of Malaria, Dengue, Yellow Fever and Ebola, the eradication of these diseases in the affected countries would result in an increase of around 10 million of tourist worldwide and a rise in the tourism expenditure of 12 billion dollars.  By analysing the economic benefits of the eradication of Dengue, Ebola, Malaria, and Yellow Fever for the tourist sector-a strategic economic sector for many of the countries where these TRD are present-this paper explores a new aspect of the quantification of health policies which should be taken into consideration in future international health assessment programmes. It is important to note that the analysis is only made of the direct impact of the diseases' eradication and consequently the potential multiplicative effects of a growth in the GDP, in terms of tourism attractiveness, are not evaluated. Consequently, the economic results can be considered to be skeleton ones. © The Author 2017. Published by Oxford University Press in association with The London School of Hygiene and Tropical Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

  7. MYCN and HDAC5 transcriptionally repress CD9 to trigger invasion and metastasis in neuroblastoma

    Science.gov (United States)

    Fabian, Johannes; Opitz, Desirée; Althoff, Kristina; Lodrini, Marco; Hero, Barbara; Volland, Ruth; Beckers, Anneleen; de Preter, Katleen; Decock, Anneleen; Patil, Nitin; Abba, Mohammed; Kopp-Schneider, Annette; Astrahantseff, Kathy; Wünschel, Jasmin; Pfeil, Sebastian; Ercu, Maria; Künkele, Annette; Hu, Jamie; Thole, Theresa; Schweizer, Leonille; Mechtersheimer, Gunhild; Carter, Daniel; Cheung, Belamy B.; Popanda, Odilia; von Deimling, Andreas; Koster, Jan; Versteeg, Rogier; Schwab, Manfred; Marshall, Glenn M.; Speleman, Frank; Erb, Ulrike; Zoeller, Margot; Allgayer, Heike; Simon, Thorsten; Fischer, Matthias; Kulozik, Andreas E.; Eggert, Angelika; Witt, Olaf; Schulte, Johannes H.; Deubzer, Hedwig E.

    2016-01-01

    The systemic and resistant nature of metastatic neuroblastoma renders it largely incurable with current multimodal treatment. Clinical progression stems mainly from the increasing burden of metastatic colonization. Therapeutically inhibiting the migration-invasion-metastasis cascade would be of great benefit, but the mechanisms driving this cycle are as yet poorly understood. In-depth transcriptome analyses and ChIP-qPCR identified the cell surface glycoprotein, CD9, as a major downstream player and direct target of the recently described GRHL1 tumor suppressor. CD9 is known to block or facilitate cancer cell motility and metastasis dependent upon entity. High-level CD9 expression in primary neuroblastomas correlated with patient survival and established markers for favorable disease. Low-level CD9 expression was an independent risk factor for adverse outcome. MYCN and HDAC5 colocalized to the CD9 promoter and repressed transcription. CD9 expression diminished with progressive tumor development in the TH-MYCN transgenic mouse model for neuroblastoma, and CD9 expression in neuroblastic tumors was far below that in ganglia from wildtype mice. Primary neuroblastomas lacking MYCN amplifications displayed differential CD9 promoter methylation in methyl-CpG-binding domain sequencing analyses, and high-level methylation was associated with advanced stage disease, supporting epigenetic regulation. Inducing CD9 expression in a SH-EP cell model inhibited migration and invasion in Boyden chamber assays. Enforced CD9 expression in neuroblastoma cells transplanted onto chicken chorioallantoic membranes strongly reduced metastasis to embryonic bone marrow. Combined treatment of neuroblastoma cells with HDAC/DNA methyltransferase inhibitors synergistically induced CD9 expression despite hypoxic, metabolic or cytotoxic stress. Our results show CD9 is a critical and indirectly druggable suppressor of the invasion-metastasis cycle in neuroblastoma. PMID:27572323

  8. Improved therapy for neuroblastoma using a combination approach: superior efficacy with vismodegib and topotecan

    Science.gov (United States)

    Chaturvedi, Nagendra K.; McGuire, Timothy R.; Coulter, Don W.; Shukla, Ashima; McIntyre, Erin M.; Sharp, John Graham; Joshi, Shantaram S.

    2016-01-01

    Aberrant activation/expression of pathways/molecules including NF-kB, mTOR, hedgehog and polo-like-kinase-1 (PLK1) are correlated with poor-prognosis neuroblastoma. Therefore, to identify a most efficacious treatment for neuroblastoma, we investigated the efficacy of NF-kB/mTOR dual-inhibitor 13-197, hedgehog inhibitor vismodegib and PLK1 inhibitor BI2536 alone or combined with topotecan against high-risk neuroblastoma. The in vitro efficacy of the inhibitors alone or combined with topotecan on cell growth/apoptosis and molecular mechanism(s) were investigated. Results showed that as single agents 13-197, BI2536 and vismodegib significantly decreased neuroblastoma cell growth and induced apoptosis by targeting associated pathways/molecules. In combination with topotecan, 13-197 did not show significant additive/synergistic effects against neuroblastoma. However, BI2536 or vismodegib further significantly decreased neuroblastoma cell growth/survival. These results clearly showed that vismodegib combination with topotecan was synergistic and more efficacious compared with BI2536 in combination. Together, in vitro data demonstrated that vismodegib was most efficacious in potentiating topotecan-induced antineuroblastoma effects. Therefore, we tested the combined efficacy of vismodegib and topotecan against neuroblastoma in vivo using NSG mice. This resulted in significantly (p<0.001) reduced tumor growth and increased survival of mice. Together, the combination of vismodegib and topotecan showed a significant enhanced antineuroblastoma efficacy by targeting associated pathways/molecules which warrants further preclinical evaluation for translation to the clinic. PMID:26934655

  9. Localized but unresectable neuroblastoma: treatment and outcome of 145 cases. Italian Cooperative Group for Neuroblastoma.

    Science.gov (United States)

    Garaventa, A; De Bernardi, B; Pianca, C; Donfrancesco, A; Cordero di Montezemolo, L; Di Tullio, M T; Bagnulo, S; Mancini, A; Carli, M; Pession, A; Arrighini, A; Di Cataldo, A; Tamaro, P; Iasonni, V; Taccone, A; Rogers, D; Boni, L

    1993-09-01

    To define factors that influence outcome in children with localized but unresectable neuroblastoma by retrospective investigation of response to therapy and outcome in 21 Italian institutions. Of 145 assessable children diagnosed between 1979 and 1990, 77 were treated between 1979 and 1984 with three consecutive standard-dose (SD) protocols, and 68 between 1985 and 1990 with a high-dose (HD) protocol. All protocols included chemotherapy, followed by resection of primary tumor if feasible. If at least partial resection was achieved, consolidation therapy followed, except that from 1985 onward, patients considered disease-free following surgery received no further treatment. Ninety-four of 145 patients (65%) achieved a complete response (CR) or partial response (PR) with chemotherapy and 75 (52%) subsequently underwent complete resection of the primary tumor. Eighty-one patients are alive (73 without disease, eight with disease), 63 have died, and one is lost to follow-up. The 5-year overall survival (OS) rate is 55% and progression-free survival (PFS) rate 50%. Both OS and PFS correlated with response to chemotherapy, removal of primary tumor, HD therapy, and serum lactate dehydrogenase (LDH) levels. Infants (< 1 year), independent of primary tumor site, and children aged 1 to 15 years with a nonabdominal primary tumor, did better compared with children aged 1 to 15 years with an abdominal primary tumor (PFS, 72% and 64% v 30%; P < .001 and < .01, respectively). Outcome of this last group improved with the HD protocol (PFS, 40% v 23%; P = .01). In children with unresectable neuroblastoma, risk categories can be defined by age and primary tumor site. HD chemotherapy should be investigated for the poor-risk category age 1 to 15 years with an abdominal primary tumor.

  10. Narcolepsy/Cataplexy and Occult Neuroblastoma

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2013-11-01

    Full Text Available Investigators at the University of Chicago and Northwestern University, Chicago, IL; University Hospital Southampton, UK; and Kiev Paediatric Hospital, Ukraine, report three children with narcolepsy and cataplexy subsequently diagnosed with neuroblastoma.

  11. Biosocial risks of food: international aspects

    OpenAIRE

    Paolo Corvo

    2017-01-01

    Food consumption is influenced by a series of issues that affect both individuals, and people and cultures of the different parts of the world. It studies biosocial risks that have dramatic implications: obesity, anorexia and bulimia; malnutrition and hunger, involving more than 800 million people; the waste food, a real paradox of the global world; the land grabbing. These are very different problems because of causes and dynamics, but all of them require a profound change to be affected: a great...

  12. Neuroblastoma

    Science.gov (United States)

    ... the eyes Profuse sweating Rapid heart rate ( tachycardia ) Brain and nervous system problems may include: Inability to empty the bladder Loss of movement ( paralysis ) of the hips, legs, or feet (lower extremities) ...

  13. Neuroblastoma

    Science.gov (United States)

    ... the cancer has spread to the bones or bone marrow) weakness, numbness, inability to move a body part, or difficulty walking (if the cancer presses on the spinal cord) drooping eyelid, unequal pupils, sweating, and red ...

  14. Increase of sodium current after pyrethroid insecticides in mouse neuroblastoma cells

    NARCIS (Netherlands)

    Ruigt, G.S.F.; Neyt, H.C.; Zalm, J.M. van der; Bercken, J. van der

    1987-01-01

    The effects of 4 different pyrethroid insecticides on sodium channel gating in internally perfused, cultured mouse neuroblastoma cells (N1E-115) were studied using the suction pipette, voltage clamp technique. Pyrethroids increased the amplitude of the sodium current, sometimes by more than 200%.

  15. Orbital Metastasis Is Associated With Decreased Survival in Stage M Neuroblastoma.

    Science.gov (United States)

    Harreld, Julie H; Bratton, Emily M; Federico, Sara M; Li, Xingyu; Grover, William; Li, Yimei; Kerr, Natalie C; Wilson, Matthew W; Hoehn, Mary E

    2016-04-01

    Approximately 30% of patients with metastatic (stage M) neuroblastoma present with periorbital ecchymosis from orbital osseous disease. Though locoregional disease is staged by imaging, the prognostic significance of metastatic site in stage M disease is unknown. We hypothesize that, compared to nonorbital metastasis, orbital metastasis is associated with decreased survival in patients with stage M neuroblastoma, and that periorbital ecchymosis reflects location and extent of orbital disease. Medical records and imaging from 222 patients with stage M neuroblastoma seen at St. Jude Children's Research Hospital between January 1995 and May 2009 were reviewed. Thirty-seven patients were ecchymosis (log-rank test). Associations of periorbital ecchymosis with orbital metastasis location/extent were explored (Fisher's exact test, t-test). In patients ≥18 months of age, only orbital metastasis was associated with decreased 5YS (P = 0.0323) and OS (P = 0.0288). In patients ecchymosis was associated with higher number of involved orbital bones (P = 0.0135), but not location or survival. In patients ≥ 18 months of age with stage M neuroblastoma, orbital metastatic disease is associated with decreased 5YS and OS. In future clinical trials, orbital disease may be useful as an imaging-based risk factor for substratification of stage M neuroblastoma. © 2015 Wiley Periodicals, Inc.

  16. Cholinergic regulation of VIP gene expression in human neuroblastoma cells

    DEFF Research Database (Denmark)

    Kristensen, Bo; Georg, Birgitte; Fahrenkrug, Jan

    1997-01-01

    Vasoactive intestinal polypeptide, muscarinic receptor, neuroblastoma cell, mRNA, gene expression, peptide processing......Vasoactive intestinal polypeptide, muscarinic receptor, neuroblastoma cell, mRNA, gene expression, peptide processing...

  17. Development and Internal Validation of the Abdominoplasty Risk Calculator.

    Science.gov (United States)

    Vu, Michael M; Ellis, Marco F; Blough, Jordan T; Gutowski, Karol A; Kim, John Y S

    2018-01-01

    Risk calculators are an emerging tool that provide granular, individualized risk estimation. Presently, there is a paucity of risk calculators specific to plastic surgery. Abdominoplasty is a popular plastic surgery procedure associated with moderate risks of complications, such as surgical-site infection and dehiscence, and would benefit from the ability to provide patients with accurate, personalized risk assessment. Abdominoplasties from the National Surgical Quality Improvement Program 2005 to 2014 database were identified by Current Procedural Terminology code. Relevant perioperative variables included age, body mass index, sex, smoking history, diabetes, American Society of Anesthesiologists class, pulmonary comorbidities, hypertension, bleeding disorders, and operative duration. Multiple logistic regressions were used to generate 30-day risk models for medical complications, surgical-site infection, wound dehiscence, and reoperation. Internal validation of model performance was conducted using C-statistics, Hosmer-Lemeshow tests, and Brier scores. Among the 2499 cases identified, complication rates were as follows: medical complications, 3.8 percent; superficial surgical-site infection, 2.4 percent; deep or organ-space surgical-site infection, 1.6 percent; wound dehiscence, 1.0 percent; and reoperation, 2.0 percent. Risk prediction models were constructed and all demonstrated good predictive performance, with mean predicted risks closely matching observed complication rates. The distributions of predicted risk were wide and contained outliers with very high risk. A user-friendly, open-access online interface for these models is published at AbdominoplastyRisk.org. The authors developed an internally valid risk calculator for which individual patient characteristics can be input to predict 30-day complications after abdominoplasty. Given that estimated risk can vary widely, individualized risk assessment is a way to enhance shared decision-making between

  18. Preclinical Therapeutic Synergy of MEK1/2 and CDK4/6 Inhibition in Neuroblastoma.

    Science.gov (United States)

    Hart, Lori S; Rader, JulieAnn; Raman, Pichai; Batra, Vandana; Russell, Mike R; Tsang, Matthew; Gagliardi, Maria; Chen, Lucy; Martinez, Daniel; Li, Yimei; Wood, Andrew; Kim, Sunkyu; Parasuraman, Sudha; Delach, Scott; Cole, Kristina A; Krupa, Shiva; Boehm, Markus; Peters, Malte; Caponigro, Giordano; Maris, John M

    2017-04-01

    Purpose: Neuroblastoma is treated with aggressive multimodal therapy, yet more than 50% of patients experience relapse. We recently showed that relapsed neuroblastomas frequently harbor mutations leading to hyperactivated ERK signaling and sensitivity to MEK inhibition therapy. Here we sought to define a synergistic therapeutic partner to potentiate MEK inhibition. Experimental Design: We first surveyed 22 genetically annotated human neuroblastoma-derived cell lines (from 20 unique patients) for sensitivity to the MEK inhibitor binimetinib. After noting an inverse correlation with sensitivity to ribociclib (CDK4/6 inhibitor), we studied the combinatorial effect of these two agents using proliferation assays, cell-cycle analysis, Ki67 immunostaining, time-lapse microscopy, and xenograft studies. Results: Sensitivity to binimetinib and ribociclib was inversely related ( r = -0.58, P = 0.009). MYCN amplification status and expression were associated with ribociclib sensitivity and binimetinib resistance, whereas increased MAPK signaling was the main determinant of binimetinib sensitivity and ribociclib resistance. Treatment with both compounds resulted in synergistic or additive cellular growth inhibition in all lines tested and significant inhibition of tumor growth in three of four xenograft models of neuroblastoma. The augmented growth inhibition was attributed to diminished cell-cycle progression that was reversible upon removal of drugs. Conclusions: Here we demonstrate that combined binimetinib and ribociclib treatment shows therapeutic synergy across a broad panel of high-risk neuroblastoma preclinical models. These data support testing this combination therapy in relapsed high-risk neuroblastoma patients, with focus on cases with hyperactivated RAS-MAPK signaling. Clin Cancer Res; 23(7); 1785-96. ©2016 AACR . ©2016 American Association for Cancer Research.

  19. Age dependence of tumor genetics in unfavorable neuroblastoma: arrayCGH profiles of 34 consecutive cases, using a Swedish 25-year neuroblastoma cohort for validation

    International Nuclear Information System (INIS)

    Cetinkaya, Cihan; Martinsson, Tommy; Sandgren, Johanna; Träger, Catarina; Kogner, Per; Dumanski, Jan; Díaz de Ståhl, Teresita; Hedborg, Fredrik

    2013-01-01

    Aggressive neuroblastoma remains a significant cause of childhood cancer death despite current intensive multimodal treatment protocols. The purpose of the present work was to characterize the genetic and clinical diversity of such tumors by high resolution arrayCGH profiling. Based on a 32K BAC whole-genome tiling path array and using 50-250K Affymetrix SNP array platforms for verification, DNA copy number profiles were generated for 34 consecutive high-risk or lethal outcome neuroblastomas. In addition, age and MYCN amplification (MNA) status were retrieved for 112 unfavorable neuroblastomas of the Swedish Childhood Cancer Registry, representing a 25-year neuroblastoma cohort of Sweden, here used for validation of the findings. Statistical tests used were: Fisher’s exact test, Bayes moderated t-test, independent samples t-test, and correlation analysis. MNA or segmental 11q loss (11q-) was found in 28/34 tumors. With two exceptions, these aberrations were mutually exclusive. Children with MNA tumors were diagnosed at significantly younger ages than those with 11q- tumors (mean: 27.4 vs. 69.5 months; p=0.008; n=14/12), and MNA tumors had significantly fewer segmental chromosomal aberrations (mean: 5.5 vs. 12.0; p<0.001). Furthermore, in the 11q- tumor group a positive correlation was seen between the number of segmental aberrations and the age at diagnosis (Pearson Correlation 0.606; p=0.037). Among nonMNA/non11q- tumors (n=6), one tumor displayed amplicons on 11q and 12q and three others bore evidence of progression from low-risk tumors due to retrospective evidence of disease six years before diagnosis, or due to tumor profiles with high proportions of numerical chromosomal aberrations. An early age at diagnosis of MNA neuroblastomas was verified by registry data, with an average of 29.2 months for 43 cases that were not included in the present study. MNA and segmental 11q loss define two major genetic variants of unfavorable neuroblastoma with apparent

  20. Anti-GD2 mAb and Vorinostat synergize in the treatment of neuroblastoma

    NARCIS (Netherlands)

    Kroesen, M.; Bull, C.; Gielen, P.R.; Brok, I.C.; Armandari, I.; Wassink, M.; Looman, M.W.G.; Boon, L.; Brok, M.H.M.G.M. den; Hoogerbrugge, P.M.; Adema, G.J.

    2016-01-01

    Neuroblastoma (NBL) is a childhood malignancy of the sympathetic nervous system. For high-risk NBL patients, the mortality rate is still over 50%, despite intensive multimodal treatment. Anti-GD2 monoclonal antibody (mAB) in combination with systemic cytokine immunotherapy has shown clinical

  1. Internal dosimetry hazard and risk assessments: methods and applications

    Energy Technology Data Exchange (ETDEWEB)

    Roberts, G.A. [RWE NUKEM Limited, Didcot (United Kingdom)

    2006-07-01

    Routine internal dose exposures are typically (in the UK nuclear industry) less than external dose exposures: however, the costs of internal dosimetry monitoring programmes can be significantly greater than those for external dosimetry. For this reason decisions on when to apply routine monitoring programmes, and the nature of these programmes, can be more critical than for external dosimetry programmes. This paper describes various methods for performing hazard and risk assessments which are being developed by RWE NUKEM Limited Approved Dosimetry Services to provide an indication when routine internal dosimetry monitoring should be considered. (author)

  2. Internal dosimetry hazard and risk assessments: methods and applications

    International Nuclear Information System (INIS)

    Roberts, G.A.

    2006-01-01

    Routine internal dose exposures are typically (in the UK nuclear industry) less than external dose exposures: however, the costs of internal dosimetry monitoring programmes can be significantly greater than those for external dosimetry. For this reason decisions on when to apply routine monitoring programmes, and the nature of these programmes, can be more critical than for external dosimetry programmes. This paper describes various methods for performing hazard and risk assessments which are being developed by RWE NUKEM Limited Approved Dosimetry Services to provide an indication when routine internal dosimetry monitoring should be considered. (author)

  3. Risk and Real Estate Investment: An International Perspective

    OpenAIRE

    Tom G. Geurts; Austin J. Jaffe

    1996-01-01

    The literature regarding portfolio analysis for institutional real estate investors has until now largely been concerned with benefits associated with naive diversification strategies. In this paper, we discuss the prospects that institutional characteristics suggest for risk reduction in internationally diversified portfolios. The risk/return relationship of each country is affected by its own unique institutional environment and therefore there are potential benefits for investors. We argue...

  4. INTERNAL GOVERNANCE AND ROLE OF INTERNAL AUDIT IN FINANCIAL INSTITUTIONS. CASE STUDY: RISK BASED PLANNING

    Directory of Open Access Journals (Sweden)

    Andrei Florin

    2015-07-01

    Full Text Available The global financial crisis from 2008 was considered a trigger to reshape the financial systems and to enhance the risk management practices. Considering the developments and new guidelines that are now used it can be observed a “positive” effect of the crisis, in particular to strengthen the risk management culture and governance in all aspects. Comparing to 2008 year, the improvements that have been made to the risk management systems can be easily observed in the financial institutions. For the scope of the article, the subject of this review will be focused on the internal audit function. The main aspect is to capture the new practices that are now used in order to contribute to a performing internal governance system. A case study will be presented in order to better understand how the internal audit function is designed and acting as a “line” of defence in the internal governance system. Also, it is in the scope of the article to issue some recommendations for future developments of the audit function in order to better manage its mission and the objectives. A risk based model used in the planning activities is presented. The financial institutions improved significantly their internal governance system. The internal audit function is now better integrated in the internal structures and clear lines of communication were settled. As the conclusion of the article is illustrating, the internal governance was frequently not sufficiently developed causing a failure in the risk management systems from the systemically financial institutions. The content of the article has practical applicability, as the results and the recommendations could be used in the design of an audit function within a financial institution.

  5. The ALK inhibitor PF-06463922 is effective as a single agent in neuroblastoma driven by expression of ALK and MYCN

    Directory of Open Access Journals (Sweden)

    J. Guan

    2016-09-01

    Full Text Available The first-in-class inhibitor of ALK, c-MET and ROS1, crizotinib (Xalkori, has shown remarkable clinical efficacy in treatment of ALK-positive non-small cell lung cancer. However, in neuroblastoma, activating mutations in the ALK kinase domain are typically refractory to crizotinib treatment, highlighting the need for more potent inhibitors. The next-generation ALK inhibitor PF-06463922 is predicted to exhibit increased affinity for ALK mutants prevalent in neuroblastoma. We examined PF-06463922 activity in ALK-driven neuroblastoma models in vitro and in vivo. In vitro kinase assays and cell-based experiments examining ALK mutations of increasing potency show that PF-06463922 is an effective inhibitor of ALK with greater activity towards ALK neuroblastoma mutants. In contrast to crizotinib, single agent administration of PF-06463922 caused dramatic tumor inhibition in both subcutaneous and orthotopic xenografts as well as a mouse model of high-risk neuroblastoma driven by Th-ALKF1174L/MYCN. Taken together, our results suggest PF-06463922 is a potent inhibitor of crizotinib-resistant ALK mutations, and highlights an important new treatment option for neuroblastoma patients.

  6. Neuroblastoma management in Chinese children.

    Science.gov (United States)

    Li, Kai; Dong, Kuiran; Gao, Jiechun; Yao, Wei; Xiao, Xianmin; Zheng, Shan

    2012-04-01

    This study assesses the clinical features of neuroblastoma and survival. Data for 98 patients between January 2000 and December 2006 at Children's Hospital of Fudan University, Shanghai, China, were retrospectively analyzed. Diagnostic methods included imaging, 24-hr urine catecholamines, bone marrow biopsies, and histopathology analyses. Treatment followed the modified Japanese Study Group Protocol. Clinical characteristics, treatment, and outcome were depicted, and difficulties encountered were analyzed. The median age of patients was 48 months. There were 3, 13, 31, 49, and 2 patients in stages 1, 2, 3, 4, and 4s disease, respectively. Positive urinary vanillylmandelic acid (VMA) prevalence was low in localized disease (51.1%) and high in disseminated disease (70.6%, p = .03). Gross total resection rate was 60.8%. The five-year overall survival (OS) rate was 80% for stages 1 and 2, 48.3% for stage 3, and 20% for stage 4. The five-year OS rates significantly decreased in children older than 18 months (p indigence were the main causes for poorer outcome in late stages.

  7. Senior Audit and Risk Management Officer | IDRC - International ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Primary Duties or Responsibilities Internal Audit Engagements Planning the Audit Engagement Assists the Chief Audit Executive (CAE) to communicate and launch the audit with management; Learns about the audit entity to ensure it is well understood and that its risks have been comprehensively assessed; Formulates ...

  8. Research Award: Risk Management and Internal Audit (RMIA ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Jean-Claude Dumais

    2012-09-12

    Sep 12, 2012 ... management, internal control, and governance processes. RMIA encourages research proposals from applicants interested in a range of topics that may include: • examining current risk, control or governance issues facing organizations in developing countries;. • studying how financial and administrative ...

  9. Corporate Governance and Bank Insolvency Risk : International Evidence

    NARCIS (Netherlands)

    Anginer, D.; Demirguc-Kunt, Asli; Huizinga, H.P.; Ma, K.

    2014-01-01

    This paper finds that shareholder-friendly corporate governance is positively associated with bank insolvency risk, as proxied by the Z-score and the Merton’s distance to default measure, for an international sample of banks over the 2004-2008 period. Banks are special in that ‘good’ corporate

  10. Corporate Governance and Bank Insolvency Risk : International Evidence

    NARCIS (Netherlands)

    Anginer, D.; Demirguc-Kunt, A.; Huizinga, H.P.; Ma, K.

    This paper finds that shareholder-friendly corporate governance is positively associated with bank insolvency risk, as proxied by the Z-score and the Merton’s distance to default measure, for an international sample of banks over the 2004-2008 period. Banks are special in that ‘good’ corporate

  11. Codon 201Gly Polymorphic Type of the DCC Gene is Related to Disseminated Neuroblastoma

    Directory of Open Access Journals (Sweden)

    Xiao-Tang Kong

    2001-01-01

    Full Text Available The deleted in colorectal carcinoma (DCC gene is a potential tumor- suppressor gene on chromosome 18821.3. The relatively high frequency of loss of heterozygosity (LOH and loss of expression of this gene in neuroblastoma, especially in the advanced stages, imply the possibility of involvement of the DCC gene in progression of neuroblastoma. However, only few typical mutations have been identified in this gene, indicating that other possible mechanisms for the inactivation of this gene may exist. A polymorphic change (Arg to Gly at DCC codon 201 is related to advanced colorectal carcinoma and increases in the tumors with absent DCC protein expression. In order to understand whether this change is associated with the development or progression of neuroblastoma, we investigated codon 201 polymorphism of the DCC gene in 102 primary neuroblastomas by polymerase chain reaction single-strand conformation polymorphism. We found no missense or nonsense mutations, but a polymorphic change from CGA (Arg to GGA (Gly at codon 201 resulting in three types of polymorphism: codon 201Gly type, codon 201Arg/Gly type, and codon 201Arg type. The codon 201Gly type occurred more frequently in disseminated (stages IV and IVs neuroblastomas (72% than in localized (stages I, II, and III tumors (48% (P=.035, and normal controls (38% (P=.024. In addition, the codon 201Gly type was significantly more common in tumors found clinically (65% than in those found by mass screening (35% (P=.002. The results suggested that the codon 201Gly type of the DCC gene might be associated with a higher risk of disseminating neuroblastoma.

  12. Identifying and managing risk in international construction projects

    Directory of Open Access Journals (Sweden)

    Sachin Kerur

    2012-04-01

    Full Text Available Over the last decade, major construction projects have increasingly arisen in countries or regions that lack specialist, expert construction contractors, suppliers and consultants. Steps are being taken by governments in the Middle East, Eastern Europe, China, India and developing markets to address national infrastructure deficits, and by so doing, are creating new regions of booming construction demand. When coupled with anaemic growth in developed markets such as the United Kingdom, the USA and Western Europe, foreign markets present attractive opportunities to the global construction industry. However, foreign markets are littered with the cautionary tales of international contractors and consultants that have failed to grasp the intricacies and risks of operating in a new environment and have failed to capitalise on the opportunities available. By identifying the classes of risks, and undertaking detailed analysis, ranking and mitigation of relevant jurisdictional risks, participants in international construction projects will increase the likelihood of project success and commercial longevity in the new jurisdiction. Risk identification and assessment is not a science but an art, and while there are many potential approaches to the issue, we propose that our strategies for identifying, assessing, ranking and mitigating jurisdictional risks offer new international players a good chance of commercial success.

  13. Validation Techniques of the Intern Models for Credit Risk

    Directory of Open Access Journals (Sweden)

    Nicolae Dardac

    2006-09-01

    Provided the development of complex methodologies of risk measurement and management, on a large scale, by credit institutions, simple and static rules of the first accord have become less and less relevant during the last years. And so, the need of setting up a own funds adequacy framework which is much more risk sensitive and provides incentives to credit institutions on what concerns the improvement of risk measurement and management systems was met by approval of the Basel II Accord, which will, therefore, lead to the strengthening of financial stability. The revisal of the Accord was mainly focused on the increase of risk analysis and internal measurement and the changes made to their estimation allow banks to create their own methodological framework to calculate capital requirements (also considering each credit institution’ risk appetite.

  14. Bilateral cystic neuroblastoma: imaging features and differential diagnoses

    International Nuclear Information System (INIS)

    Cassady, C.; Winters, W.D.

    1997-01-01

    Neuroblastoma is one of the most common malignant tumors of childhood, with 40 % arising in the adrenal glands. Bilateral adrenal involvement from synchronous development or metastatic spread of the tumor is seen in less than 10 % of children with neuroblastoma [1[. Neuroblastoma rarely presents as a cystic suprarenal mass that is difficult to differentiate from adrenal hemorrhage, extralobar sequestration, or dilated upper-pole renal calyces. To our knowledge, bilateral cystic neuroblastoma has not been previously reported. We present a case of bilateral cystic adrenal neuroblastoma to demonstrate the imaging features of this unusual entity, and to expand the differential diagnosis of bilateral cystic suprarenal masses in an infant. (orig.). With 2 figs

  15. Efficacy of internal control and controlling business risks

    Directory of Open Access Journals (Sweden)

    Luminiţa IONESCU

    2010-06-01

    Full Text Available Companies can gain additional efficiency in designing and implementing or assessing internal control by focusing on only those financial reporting objectives directly applicable to the company’s activities and circumstances, taking a risk based approach to internal control. It is important for any organization to have reliable financial data for internal decision-making purpose. Financial information is often useful in many internal decisions such as product or service pricing. This is why the most important function of the controller is to create and maintain the corporate financial control system. Today’s corporation operates in an increasingly complex environment and the controller’s role is to advice the management of current or future problems of the business environment or to prevent the fraud.

  16. Neuroblastoma presenting with the nephrotic syndrome.

    Science.gov (United States)

    Zheng, H L; Maruyama, T; Matsuda, S; Satomura, K

    1979-08-01

    A case of neuroblastoma in a 4-yr-old boy presenting with the nephrotic syndrome is reported. Nether thrombosis nor stenosis of the renal veins and the inferior vena cava was present. Electron microscopy revealed lumps of subepithelial deposits as well as thickening and tortuosity of the glomerular basement membrane compatible with membranous nephropathy. It is postulated that deposition of neuroblastoma-associated immune complexes on the glomerular basement membrane-was responsible for the development of the nephrotic syndrome in this patient. Five pediatric cases of nephrotic syndrome associated with extrarenal neoplasia were collected from the world literature and are briefly discussed.

  17. International risk and preceived environmental uncertainty: The dimentionality and internal consistency of Miller's measure

    NARCIS (Netherlands)

    Brouthers, K.D.

    1996-01-01

    Increasingly, scholars have suggested that there is a need to approach the problem of international risk from a multidimensional perspective [Brouthers 1995; Miller 1993; Shan 1991]. Miller [1992, 1993] developed and tested the most comprehensive framework to date. Miller [1993] showed high

  18. Aspects Concerning the Relationship between Internal Audit and Fraud Risk

    Directory of Open Access Journals (Sweden)

    Ioana Lupasc

    2016-07-01

    Full Text Available In the current economical situation, fraud cannot be regarded as an exception with random occurrence and limited effects on credit institution. Major fraud scandals that shook the financial markets required a rethinking of the organization and control of the banks to keep intact the trust of customers. Identifying and assessing risks is a concern not only for managers, but also for internal and external auditors. Management may implement programs or measures to limit the risks or deciding to accept some risks. In order to identify the main causes generating fraud risk and increasing the quality of banking activity we used a quantitative research method that was based on a questionnaire administered individually, using SPSS.

  19. Risk factors for oligodendroglial tumors: a pooled international study

    DEFF Research Database (Denmark)

    McCarthy, Bridget J; Rankin, Kristin M; Aldape, Ken

    2011-01-01

    Oligodendroglial tumors are rare subtypes of brain tumors and are often combined with other glial tumors in epidemiological analyses. However, different demographic associations and clinical characteristics suggest potentially different risk factors. The purpose of this study was to investigate p...... that additional factors specific to oligodendroglial tumors have yet to be identified. Large, multi-institution international studies will be necessary to better characterize these etiological risk factors.......Oligodendroglial tumors are rare subtypes of brain tumors and are often combined with other glial tumors in epidemiological analyses. However, different demographic associations and clinical characteristics suggest potentially different risk factors. The purpose of this study was to investigate...... possible risk factors for oligodendroglial tumors (including oligodendroglioma, anaplastic oligodendroglioma, and mixed glioma). Data from 7 case-control studies (5 US and 2 Scandinavian) were pooled. Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals...

  20. Validation Techniques of the Intern Models for Credit Risk

    Directory of Open Access Journals (Sweden)

    Bogdan Moinescu

    2006-11-01

    Full Text Available The new own funds adequacy device, officialy named “ International Convergence of Capital Measurement and Capital Standards”, describes the most important benchmark framework for micro-prudential supervision at the moment. The publication of the final text in June 2004, after five years of deliberations, represents the result of multiple analyses and comments provided by all interested parties, banking supervision authorities, associations and credit institutions. Provided the development of complex methodologies of risk measurement and management, on a large scale, by credit institutions, simple and static rules of the first accord have become less and less relevant during the last years. And so, the need of setting up a own funds adequacy framework which is much more risk sensitive and provides incentives to credit institutions on what concerns the improvement of risk measurement and management systems was met by approval of the Basel II Accord, which will, therefore, lead to the strengthening of financial stability. The revisal of the Accord was mainly focused on the increase of risk analysis and internal measurement and the changes made to their estimation allow banks to create their own methodological framework to calculate capital requirements (also considering each credit institution’ risk appetite.

  1. Cervical neonatal neuroblastoma with recurrent SVT.

    Science.gov (United States)

    Al-Shammari, N F; Redha, E; Al Hajeri, M H

    2009-07-01

    Neuroblastoma is the most common extracranial solid tumor of childhood and the third most common paediatric malignancy after leukemia and central nervous system (CNS) tumors. It constitutes 10% of all paediatric malignancies and 75% of them present in children below 4 years of age. Seventy five percent of neuroblastoma arise in the abdomen and pelvis, 20% in the thorax and 5% in the neck. The median age at diagnosis is 22 months. Up to 95% of cases are diagnosed by the age of ten years. Neuroblastomas have been diagnosed in utero as early as 19 weeks of gestational age. They can arise anywhere along the sympathetic chain. They occur most commonly in the adrenal medulla (35%). Neuroblastomas also occur as primary tumors in the extra-adrenal retroperitoneum in 30% of cases, in the posterior mediastinum in 20% of cases , in the neck up to 5% of cases and in the pelvis in 5% of cases. Approximately 50% of patients will have metastasis at presentation.

  2. Monoclonal Antibody Therapy for Advanced Neuroblastoma

    Science.gov (United States)

    NCI is sponsoring two clinical trials of a monoclonal antibody called ch14.18, in combination with other drugs, to see if the antibody may be helpful for children or young adults (up to age 21) with relapsed or refractory neuroblastoma.

  3. Neonatal acute megakaryoblastic leukemia mimicking congenital neuroblastoma

    OpenAIRE

    Kawasaki, Yukako; Makimoto, Masami; Nomura, Keiko; Hoshino, Akihiro; Hamashima, Takeru; Hiwatari, Mitsuteru; Nakazawa, Atsuko; Takita, Junko; Yoshida, Taketoshi; Kanegane, Hirokazu

    2014-01-01

    Key Clinical Message We describe a neonate with abdominal distension, massive hepatomegaly, and high serum neuron-specific enolase level suggestive of congenital neuroblastoma. The patient died of pulmonary hemorrhage after therapy. Autopsy revealed that the tumor cells in the liver indicated acute megakaryocytic leukemia with the RBM15-MKL1 fusion gene.

  4. Molecular events during tumor progression in neuroblastoma

    NARCIS (Netherlands)

    Bernards, R.A.; Lenardo, M.

    1990-01-01

    The N-myc oncogene was first identified as an amplified DNA element with homology to c-myc in human neuroblastoma. Since this initial observation, amplification of N-myc has also been observed in other types of human cancer, predominantly in retinoblastoma and small cell lung cancer. The

  5. Overcoming the Mechanism of Radioresistance in Neuroblastoma

    Science.gov (United States)

    2014-06-01

    expression in human neuroblastoma: up- regulation by hypoxia. Int J Cancer, 1999. 81(1): p. 113-7. 4. Yang, Q.W., et al., Methylation -associated silencing...64. 11. Martin, L., et al., Recognition of O6MeG lesions by MGMT and mismatch repair proficiency may be a prerequisite for low-dose radiation

  6. The use of risk management principles in planning an internal audit ...

    African Journals Online (AJOL)

    Kirstam

    12Key words: risk management, key risks, internal auditing, risk-based internal auditing, internal audit .... a structured approach, regardless of the engagement type (for example, a compliance audit), the level of the ... risk management approach (also referred to as 'organisational' or 'enterprise-wide'), rather than a silo ...

  7. Focal nodular hyperplasia of the liver in longterm survivors of neuroblastoma

    International Nuclear Information System (INIS)

    Benz-Bohm, Gabriele; Hero, Barbara; Gossmann, Axel; Simon, Thorsten; Koerber, Friederike; Berthold, Frank

    2010-01-01

    Objectives: Focal nodular hyperplasia of the liver is a tumor-like lesion, uncommon in children, but it has recently been more frequently observed in children treated for malignant diseases, especially neuroblastoma. The aetiology is unclear, the pathogenesis remains controversial. Focal nodular hyperplasia of the liver is suspected to be a sequela of tumor therapy. Methods: Besides the clinical data we evaluated the imaging modalities needed to diagnose focal nodular hyperplasia of the liver in children with neuroblastoma who have been followed in our institution for more than 5 years. Results: Out of 60 children six developed focal nodular hyperplasia at a median time of 10.5 years after diagnosis of neuroblastoma and 9.4 years after the end of treatment. The diagnosis of focal nodular hyperplasia was based on imaging criteria which are variable in ultrasonography and specific in MRI. Only one child underwent surgical biopsies to rule out liver metastases. Conclusions: Longterm survivors of neuroblastoma are at risk of developing focal nodular hyperplasia, especially if they underwent toxic chemotherapy and/or radiotherapy to the liver during initial treatment. The recommended diagnostic imaging tools are ultrasonography for detecting liver lesions and MRI for confirming and characterizing these lesions as focal nodular hyperplasia.

  8. Going international? Risk taking by cryptomarket drug vendors.

    Science.gov (United States)

    Décary-Hétu, David; Paquet-Clouston, Masarah; Aldridge, Judith

    2016-09-01

    Since 2011, we have witnessed the rise of 'dark net' drug marketplaces known as cryptomarkets. Cryptomarkets operate on the same model as eBay as they provide a platform where authorized vendors can set up a virtual shop and place listings. Building on a growing body of literature that seeks to understand cryptomarket participants, this paper seeks to explain the decision of cryptomarket vendors to take on risk. We collected data on Silk Road 1 (SR1), the first cryptomarket launched in 2011. We propose a multilevel model that takes into account the characteristics of listings, vendors and their environment to explain the decision of vendors to take on risk. Our results demonstrate that all levels in the model significantly explain the decision to take on risk. Risk taking, operationalized as a willingness to ship drugs across international borders, was associated with the weights of drug packages mailed, the vendors' reputations and numbers of listings, the country-level perceived effectiveness of law enforcement according to experts, and the opportunities available to vendors as measured by the wealth and the drug expenditures of potential customers. Our results support some previous research findings on the factors explaining risk taking. We extend existing literature by emphasizing the relevance of the environment of drug dealers to predict risk taking. Copyright © 2016 Elsevier B.V. All rights reserved.

  9. Inhibition ofSTAT3with the Generation 2.5 Antisense Oligonucleotide, AZD9150, Decreases Neuroblastoma Tumorigenicity and Increases Chemosensitivity.

    Science.gov (United States)

    Odate, Seiichi; Veschi, Veronica; Yan, Shuang; Lam, Norris; Woessner, Richard; Thiele, Carol J

    2017-04-01

    Purpose: Neuroblastoma is a pediatric tumor of peripheral sympathoadrenal neuroblasts. The long-term event-free survival of children with high-risk neuroblastoma is still poor despite the improvements with current multimodality treatment protocols. Activated JAK/STAT3 pathway plays an important role in many human cancers, suggesting that targeting STAT3 is a promising strategy for treating high-risk neuroblastoma. Experimental Design: To evaluate the biologic consequences of specific targeting of STAT3 in neuroblastoma, we assessed the effect of tetracycline (Tet)-inducible STAT3 shRNA and the generation 2.5 antisense oligonucleotide AZD9150 which targets STAT3 in three representative neuroblastoma cell line models (AS, NGP, and IMR32). Results: Our data indicated that Tet-inducible STAT3 shRNA and AZD9150 inhibited endogenous STAT3 and STAT3 target genes. Tet-inducible STAT3 shRNA and AZD9150 decreased cell growth and tumorigenicity. In vivo , STAT3 inhibition by Tet-inducible STAT3 shRNA or AZD9150 alone had little effect on growth of established tumors. However, when treated xenograft tumor cells were reimplanted into mice, there was a significant decrease in secondary tumors in the mice receiving AZD9150-treated tumor cells compared with the mice receiving ntASO-treated tumor cells. This indicates that inhibition of STAT3 decreases the tumor-initiating potential of neuroblastoma cells. Furthermore, inhibition of STAT3 significantly increased neuroblastoma cell sensitivity to cisplatin and decreased tumor growth and increased the survival of tumor-bearing mice in vivo Conclusions: Our study supports the development of strategies targeting STAT3 inhibition in combination with conventional chemotherapy for patients with high-risk neuroblastoma. Clin Cancer Res; 23(7); 1771-84. ©2016 AACR . ©2016 American Association for Cancer Research.

  10. Treatment of extradural paraspinal neuroblastoma with an intraspinal component

    International Nuclear Information System (INIS)

    Ho, K.S.Y.; Wara, W.M.; Ablin, A.R.

    1982-01-01

    Neuroblastoma originates from neural crest cells and can be found wherever sympathetic neural tissue is normally located. When the tumor arises from a paraspinal sympathetic ganglion, it has a propensity to extend through the intervertebral foramina, producing an extradural paraspinal neuroblastoma with an interspinal component (''dumbell'' neuroblastoma) which may result in spinal cord compression. The records of all children with neuroblastomas referred to the UCSF Department of Radiation Oncology and the Division of Pediatric Oncology from January 1, 1970, to December 31, 1979, are reviewed in this report. Patients who at initial presentation had a ''dumbell'' neuroblastoma were selected for study. Neuroblastoma was diagnosed histologically in all patients except one. Disease-free interval and length of survival was measured from the date of completion of radiotherapy, mostly after surgery. The results of diagnostic X-rays and laboratory studies are shown. Radiotherapeutic doses and results are tabulated. (Auth.)

  11. Incidence, Survival, and Treatment of Localized and Metastatic Neuroblastoma in Germany 1979-2015.

    Science.gov (United States)

    Berthold, Frank; Spix, Claudia; Kaatsch, Peter; Lampert, Fritz

    2017-12-01

    A comprehensive clinical long-term survey over the complete spectrum of neuroblatoma disease is lacking in the literature. Our objective was to describe the incidence, risk profiles, therapies, and outcomes for the total cohort of German patients with neuroblastoma including all clinical stages and risk groups. Epidemiological, clinical, and outcome data of neuroblastoma patients who participated in one of the six consecutive national trials between 1979 and 2015 were analyzed retrospectively. Of all German neuroblastoma patients known to the national childhood cancer registry, ninety seven percent enrolled in one of the trials. The absolute neuroblastoma rate has increased slightly, whereas the median age at diagnosis has decreased. Except for the screening period (1995-2000), the risk factors lactate dehydrogenase (LDH), ferritin, chromosome 1p, and the MYCN oncogene have remained largely constant, with the exception of an increase in MYCN amplification at stage 4 for those aged ≥18 months between trials NB97 (27%) and NB2004 (35%). The 10-year overall survival increased in patients with stage 1-3 neuroblastoma from 83 to 91%, for stage 4S from 80 to 85%, and for stage 4 aged ≥18 months from 2 to 38%. The fraction of patients in stages 1-3 who never received chemotherapy (neither for frontline nor at recurrence) increased from 35 to 60%. The proportion of macroscopically complete surgical resections of the primary tumor decreased for the total population as well as for patients with stage 4 aged ≥18 months. The impact of chemotherapy response on the outcome was trial dependent. The overall proportion of toxic death during the time of the protocol therapy was 6% for stage 4 patients aged ≥18 months and 2% for low-/intermediate-risk patients. The most frequently reported late sequelae in stage 4 patients aged ≥18 months were renal dysfunctions, hypothyroidism, major hearing impairment, and second malignancies. The body of data for incidences, risk

  12. Long-Term International Space Station (ISS) Risk Reduction Activities

    Science.gov (United States)

    Fodroci, M. P.; Gafka, G. K.; Lutomski, M. G.; Maher, J. S.

    2012-01-01

    As the assembly of the ISS nears completion, it is worthwhile to step back and review some of the actions pursued by the Program in recent years to reduce risk and enhance the safety and health of ISS crewmembers, visitors, and space flight participants. While the initial ISS requirements and design were intended to provide the best practicable levels of safety, it is always possible to further reduce risk - given the determination, commitment, and resources to do so. The following is a summary of some of the steps taken by the ISS Program Manager, by our International Partners, by hardware and software designers, by operational specialists, and by safety personnel to continuously enhance the safety of the ISS, and to reduce risk to all crewmembers. While years of work went into the development of ISS requirements, there are many things associated with risk reduction in a Program like the ISS that can only be learned through actual operational experience. These risk reduction activities can be divided into roughly three categories: Areas that were initially noncompliant which have subsequently been brought into compliance or near compliance (i.e., Micrometeoroid and Orbital Debris [MMOD] protection, acoustics) Areas where initial design requirements were eventually considered inadequate and were subsequently augmented (i.e., Toxicity Hazard Level- 4 [THL] materials, emergency procedures, emergency equipment, control of drag-throughs) Areas where risks were initially underestimated, and have subsequently been addressed through additional mitigation (i.e., Extravehicular Activity [EVA] sharp edges, plasma shock hazards) Due to the hard work and cooperation of many parties working together across the span of more than a decade, the ISS is now a safer and healthier environment for our crew, in many cases exceeding the risk reduction targets inherent in the intent of the original design. It will provide a safe and stable platform for utilization and discovery for years

  13. The association of congenital neuroblastoma and congenital heart disease

    International Nuclear Information System (INIS)

    Bellah, R.; D'Andrea, A.; Children's Hospital, Boston, MA; Darillis, E.; Fellows, K.E.

    1989-01-01

    Several authors have reported an association between neuroblastoma and congenital heart disease; others contend that, unlike specific wellknown associations between malignancy and congenital defects (Wilm's tumor and aniridia, leukemia and Down's syndrome), no real relationship exists. We present three cases of cyanotic congenital heart disease in which subclinical neuroblastoma was found. We speculate that abnormal neural crest cell migration and development may be a common link between cardiac malformations and congenital neuroblastoma. (orig.)

  14. Risk of lung cancer by radon, disagreement in international regulation

    International Nuclear Information System (INIS)

    Balcazar, M.; Pena, P.; Villamares, A.; Avelar, J. R.

    2013-10-01

    Diverse international organizations have evaluated the risk of lung cancer starting from epidemic studies in miners of uranium mines, where the corresponding effective dose was determined relating with the dose received by the population during Hiroshima and Nagasaki events. Alternately, the equivalent dose has been calculated by means of based models on the energy deposited by the breathable radon fractions and its decay products in the breathing ducts. A unique factor agreed by the diverse organizations that allows converting radon concentration to effective dose does not exist. Neither an agreement exists among the different countries on which duty to be the value of the maximum concentration of radon, in interiors starting from which an intervention is required and if this intervention is standardized, recommended or nonexistent. In this work study cases in Mexico are presented and their interpretation alternative based on the international agreements absence. (Author)

  15. International and Russian practice of banking risk-management. Mortgage risks

    Directory of Open Access Journals (Sweden)

    A. V. Nikolaeva

    2016-01-01

    Full Text Available The goal of the work is to compare Russian norms and standards of risk management of mortgage lending with international standards of risk management based on the documents of the Basel Committee. The article also aims to analyze new banking tools of risk management of mortgage lending, that arise in connection with the application of international norms and standards of risk management.Materials and Methods: The main documents considered in the article are the agreements on capital, issued by the Basel Committee on Banking Supervision: Basel-I (1988, Basel-II (2004 and Basel-III (2010, as well as instructions and standing orders issued by the Central Bank of Russia, including: Instruction № 139-I "Ob obiazatel'nykh normativakh bankov", instruction № 1 "O poriadke regulirovaniia deiatel'nosti kommercheskikh bankov", the standing order number 215-P "O metodike opredeleniia sobstvennykh sredstv (kapitala kreditnykh organizatsii", the standing order № 395-P "O metodike opredeleniia velichiny sobstvennykh sredstv (kapitala kreditnykh organizatsii («BAZEL III»" and others. On the basis of these documents the work examines and summarizes the main methods of risk management of mortgage lending, such as: comparison and analysis of risk management techniques, study of the basic documents regulating risk management in banks and generalization of risk management methods in the segment of mortgage lending.Results: The article analyzes the legal and methodological basis of risk management and provides practical methods that can be used in practice for managerial decisions in a constantly changing external economic environment. It also analyses international and native risk management. Russian standards of risk-management are compared with international. The work conducts a critical review of the effects of introduction of international standards in Russia. Special attention is paid to the practice of mortgage risk

  16. Constitutional 11q14-q22 chromosome deletion syndrome in a child with neuroblastoma MYCN single copy.

    Science.gov (United States)

    Passariello, Annalisa; De Brasi, Daniele; Defferrari, Raffaella; Genesio, Rita; Tufano, Maria; Mazzocco, Katia; Capasso, Maria; Migliorati, Roberta; Martinsson, Tommy; Siani, Paolo; Nitsch, Lucio; Tonini, Gian Paolo

    2013-11-01

    Constitutional 11q deletion is a chromosome imbalance possibly found in MCA/MR patients analyzed for chromosomal anomalies. Its role in determining the phenotype depends on extension and position of deleted region. Loss of heterozygosity of 11q (region 11q23) is also associated with neuroblastoma, the most frequent extra cranial cancer in children. It represents one of the most frequent cytogenetic abnormalities observed in the tumor of patients with high-risk disease even if germline deletion of 11q in neuroblastoma is rare. Hereby, we describe a 18 months old girl presenting with trigonocephaly and dysmorphic facial features, including hypotelorism, broad depressed nasal bridge, micrognathia, synophrys, epicanthal folds, and with a stage 4 neuroblastoma without MYCN amplification, carrying a germline 11q deletion (11q14.1-q22.3), outside from Jacobsen syndrome and from neuroblastoma 11q critical regions. The role of 11q deletion in determining the clinical phenotype and its association with neuroblastoma development in the patient are discussed. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  17. Polymorphisms in genes encoding drug metabolizing enzymes and their influence on the outcome of children with neuroblastoma.

    Science.gov (United States)

    Ashton, Lesley J; Murray, Jayne E; Haber, Michelle; Marshall, Glenn M; Ashley, David M; Norris, Murray D

    2007-09-01

    Although several studies have shown that drug metabolizing enzyme gene polymorphisms may influence the impact of therapy in childhood leukemia, no comprehensive investigations have been carried out in children with neuroblastoma. The aim of this study was to identify polymorphisms in the genes encoding phase I and II drug metabolizing enzymes associated with the risk of relapse or death in a cohort of 209 children with neuroblastoma. Real-time PCR allelic discrimination was used to characterize the presence of polymorphisms in DNA from children with neuroblastoma. Three broad gene categories were examined: cytochrome P450, glutathione-S-transferase and N-acetyltransferase. Cumulative event-free survival was computed by the Kaplan-Meier method. The influence of selected factors on event-free survival was tested using the Cox proportional hazards model. As previously reported, amplification of MYCN (hazards ratio=4.25, 95% confidence interval=2.76-6.56, Pchildren who were GSTM1 null were more likely to relapse or die during follow-up after adjusting for MYCN amplification, stage and age at diagnosis (hazard ratio=1.6, 95% confidence interval=1.02-2.9, P=0.04). These observations suggest that the NAT1*11 variant and the GSTM1 wild-type genotype contribute to a more favorable outcome in patients treated for neuroblastoma and are the first to demonstrate a relationship between NAT1 and GSTM1 genotypes in childhood neuroblastoma.

  18. Market risk stress testing for internationally active financial institutions

    Directory of Open Access Journals (Sweden)

    Marković Petar

    2011-01-01

    Full Text Available The paper develops a comprehensive framework for market risk stress testing in internationally active financial institutions. We begin by defining the scope and type of the stress test and explaining how to select risk factors and the stress time horizon. We then address challenges related to data gathering, followed by in-depth discussion of techniques for developing realistic shock scenarios. Next the process of shock application to a particular portfolio is described, followed by determination of portfolio profit and loss. We conclude by briefly discussing the issue of assigning probability to stress scenarios. We illustrate the framework by considering the development of a ‘worst case’ scenario using global financial market data from Thomson Reuters Datastream.

  19. Environment-Mediated Drug Resistance in Neuroblastoma

    Science.gov (United States)

    2013-10-01

    neuroblastoma. Five specimens were classified as positive for tumor involvement in themarrow (as assessed by the presence of tyrosine hydroxylase –positive cells ...presence of tyrosine hydroxylase – positive tumor cells (black arrow; bar, 50 mm). Right, the data represent the mean percentage (SD) of positive...H, et al. Tyrosine hydroxylase indicates cell differentiation of catechol- amine biosynthesis in neuroendocrine tumors. J Endocrinol Invest 1994;17

  20. Changes in MYCN expression in human neuroblastoma cell lines following cisplatin treatment may not be related to MYCN copy numbers

    Czech Academy of Sciences Publication Activity Database

    Procházka, Pavel; Hraběta, J.; Vícha, A.; Cipro, S.; Stejskalová, E.; Musil, Z.; Vodička, Pavel; Eckschlager, T.

    2013-01-01

    Roč. 29, č. 6 (2013), s. 2415-2421 ISSN 1021-335X Grant - others:GA ČR(CZ) GAP301/10/0356 Institutional support: RVO:68378041 Keywords : high-risk neuroblastoma cell line * multiplex ligation-dependent probe amplification * fluorescent in situ hybridization Subject RIV: CE - Biochemistry Impact factor: 2.191, year: 2013

  1. COMMUNICATION SKILLS, A SOLUTION DIMINISHING RISKS IN INTERNATIONAL BUSINESS

    Directory of Open Access Journals (Sweden)

    Anisoara Duica

    2015-05-01

    Full Text Available According to the latest approaches in the field, the integrated marketing communication requires a planned organizational approach, creating and maintaining in time good relations with the customers of its products or services, but also with its other stakeholders. According to the data provided by the National Statistics Institute (INS, the year 2014 is the first year in history when the Romanian exports exceeded the amount of EUR 50 billion. However, within the context of the economic crisis, numerous Romanian brands have disappeared from the market and Romania risks becoming a simple outlet market if the local companies do not improve their communication processes and skills, as sources of competitive advantage by which the Romanian products and services may differ in relation to those of the E.U. member countries. Within the context of business globalization and of the knowledge society, the present paper is trying to identify ways of developing the communication skills, which can be integrated in a formal risk management system, allowing the decrease of the risks triggered by the cultural differences specific of communication in international business.

  2. Quantitative Risk Modeling of Fire on the International Space Station

    Science.gov (United States)

    Castillo, Theresa; Haught, Megan

    2014-01-01

    The International Space Station (ISS) Program has worked to prevent fire events and to mitigate their impacts should they occur. Hardware is designed to reduce sources of ignition, oxygen systems are designed to control leaking, flammable materials are prevented from flying to ISS whenever possible, the crew is trained in fire response, and fire response equipment improvements are sought out and funded. Fire prevention and mitigation are a top ISS Program priority - however, programmatic resources are limited; thus, risk trades are made to ensure an adequate level of safety is maintained onboard the ISS. In support of these risk trades, the ISS Probabilistic Risk Assessment (PRA) team has modeled the likelihood of fire occurring in the ISS pressurized cabin, a phenomenological event that has never before been probabilistically modeled in a microgravity environment. This paper will discuss the genesis of the ISS PRA fire model, its enhancement in collaboration with fire experts, and the results which have informed ISS programmatic decisions and will continue to be used throughout the life of the program.

  3. Occupational emerging risks affecting international virtual project Team Results

    Directory of Open Access Journals (Sweden)

    Dumitraşcu-Băldău Iulia

    2017-01-01

    Full Text Available The expansion of internet access, high-speed connection services, collaborative work platforms and tools, allowed employees to interact virtually offering companies the possibility to develop projects around the world, reducing operational costs and gain competitive advantage. Realizing the advantages and disadvantages of developing a project team in an international virtual work environment, requires adopting specific strategies to construct an effective team and ensure the project success. One of the most important disadvantages that we identified is that the new work environment brings new risks for both team members and managers. So, it becomes mandatory to identify and analyze the occupational emerging risks and their impact on the productivity of virtual team members, in order to prevent them efficiently and to ensure the safety and health of employees in a virtual working environment. This paper aims to highlight the necessity for project managers and organizations, to include in their specific project strategies, an efficient occupational risks management in the virtual workplace, to obtain a continuously improved virtual working environment, so to achieve a high performance from virtual employees.

  4. Lifetime health risks from internally deposited beta-emitting radionuclides

    International Nuclear Information System (INIS)

    Boecker, B.B.; Griffith, W.C.; Hahn, F.F.; Nikula, K.J.; Lundgren, D.L.; Muggenburg, B.A.

    1997-01-01

    Much of our knowledge on the lifetime health risks resulting from internal depositions of beta- and gamma-emitting radionuclides has come from studies in laboratory animals conducted to provide information not available from human epidemiological studies. This paper is focused primarily on results of experiments in which laboratory animals (dogs and rodents) were exposed once, briefly, by inhalation or intravenous injection to an individual fission-product radionuclide and were studied for radionuclide metabolism, dosimetry, and lifetime health effects. The relative importance of many dose- and effect-modifying factors was studied. The main long-term biological effects were cancers in the organs and tissues receiving the highest doses. Results for three different patterns of irradiation (skeleton, lung, and whole-body) are presented. The risks of bone cancers produced by 90 Sr are compared with those from 238 Pu in dogs. Lung cancer risks for several beta emitters inhaled in a relatively insoluble form by dogs are compared with results for 144 CeO 2 inhaled by rats. Late-occurring biological effects from the relatively uniform whole-body irradiation from intravenously injected 137 Cs are also presented. In addition to radionuclide-specific results, cross-cutting analyses of these studies provide valuable information on broader issues such as dose protraction, relative biological effectiveness, threshold considerations, and inter-species comparisons including extrapolation to human exposure situations. (authors)

  5. Historical time to disease progression and progression-free survival in patients with recurrent/refractory neuroblastoma treated in the modern era on Children's Oncology Group early-phase trials.

    Science.gov (United States)

    London, Wendy B; Bagatell, Rochelle; Weigel, Brenda J; Fox, Elizabeth; Guo, Dongjing; Van Ryn, Collin; Naranjo, Arlene; Park, Julie R

    2017-12-15

    Early-phase trials in patients with recurrent neuroblastoma historically used an objective "response" of measureable disease (Response Evaluation Criteria In Solid Tumors [RECIST], without bone/bone marrow assessment) to select agents for further study. Historical cohorts may be small and potentially biased; to the authors' knowledge, disease recurrence studies from international registries are outdated. Using a large recent cohort of patients with recurrent/refractory neuroblastoma from Children's Oncology Group (COG) modern-era early-phase trials, the authors determined outcome and quantified parameters for designing future studies. The first early-phase COG trial enrollment (sequential) of 383 distinct patients with recurrent/refractory neuroblastoma on 23 phase 1, 3 phase 1/2, and 9 phase 2 trials (August 2002 to January 2014) was analyzed for progression-free survival (PFS), overall survival (OS), and time to disease progression (TTP). Planned frontline therapy for patients with high-risk neuroblastoma included hematopoietic stem cell transplantation (approximately two-thirds of patients underwent ≥1 hematopoietic stem cell transplantation); 13.2% of patients received dinutuximab. From the time of the patient's first early-phase trial enrollment (383 patients), the 1-year and 4-year PFS rates ( ± standard error) were 21% ± 2% and 6% ± 1%, respectively, whereas the 1-year and 4-year OS rates were 57% ± 3% and 20% ± 2%, respectively. The median TTP was 58 days (interquartile range, 31-183 days [350 patients]); the median follow-up was 25.3 months (33 patients were found to be without disease recurrence/progression). The median time from diagnosis to first disease recurrence/progression was 18.7 months (range, 1.4-64.8 months) (176 patients). MYCN amplification and 11q loss of heterozygosity were prognostic of worse PFS and OS (P = .003 and P<.0001, respectively, and P = .02 and P = .03, respectively) after early-phase trial

  6. International status of application of probabilistic risk analysis

    International Nuclear Information System (INIS)

    Cullingford, M.C.

    1984-01-01

    Probabilistic Risk Assessment (PRA) having been practised for about ten years and with more than twenty studies completed has reached a level of maturity such that the insights and other products derived from specific studies may be assessed. The first full-scale PRA studies were designed to develop the methodology and assess the overall risk from nuclear power. At present PRA is performed mostly for individual plants to identify core damage accident sequences and significant contributors to such sequences. More than 25 countries are utilizing insights from PRA, some from full-scale PRA studies and other countries by performing reliability analyses on safety systems identified as important contributors to one or more core melt sequences. Many Member States of the IAEA fall into one of three groups: those having (a) a large, (b) a medium number of reactor-years of operating experience and (c) those countries in the planning or feasibility study stages of a nuclear power programme. Of the many potential uses of PRA the decision areas of safety improvement by backfitting, development of operating procedures and as the basis of standards are felt to be important by countries of all three groups. The use of PRA in showing compliance with safety goals and for plant availability studies is held to be important only by those countries which have operating experience. The evolution of the PRA methodology has led to increased attention to quantification of uncertainties both in the probabilities and consequences. Although many products from performing a PRA do not rely upon overall risk numbers, increasing emphasis is being placed on the interpretation of uncertainties in risk numbers for use in decisions. International co-operation through exchange of information regarding experience with PRA methodology and its application to nuclear safety decisions will greatly enhance the widespread use of PRA. (author)

  7. Proptosis as a manifestation of neuroblastoma | Hlongwane | SA ...

    African Journals Online (AJOL)

    Neuroblastoma occurs mainly in childhood and approximately 20% of cases have orbital metastases. Proptosis can be the only manifestation of metastatic neuroblastoma. Early investigation is important, as metastatic disease requires aggressive management. We present a case of a 7-yearold girl initially presenting with ...

  8. Targeted BCL2 inhibition effectively inhibits neuroblastoma tumour growth

    NARCIS (Netherlands)

    Lamers, Fieke; Schild, Linda; den Hartog, Ilona J. M.; Ebus, Marli E.; Westerhout, Ellen M.; Ora, Ingrid; Koster, Jan; Versteeg, Rogier; Caron, Huib N.; Molenaar, Jan J.

    2012-01-01

    Genomic aberrations of key regulators of the apoptotic pathway have hardly been identified in neuroblastoma. We detected high BCL2 mRNA and protein levels in the majority of neuroblastoma tumours by Affymetrix expression profiling and Tissue Micro Array analysis. This BCL2 mRNA expression is

  9. Analysis of 1;17 translocation breakpoints in neuroblastoma: implications for mapping of neuroblastoma genes

    NARCIS (Netherlands)

    van Roy, N.; Laureys, G.; van Gele, M.; Opdenakker, G.; Miura, R.; van der Drift, P.; Chan, A.; Versteeg, R.; Speleman, F.

    1997-01-01

    Deletions and translocations resulting in loss of distal 1p-material are known to occur frequently in advanced neuroblastomas. Fluorescence in situ hybridisation (FISH) showed that 17q was most frequently involved in chromosome 1p translocations. A review of the literature shows that 10 of 27 cell

  10. Rare MYC-amplified Neuroblastoma With Large Cell Histology.

    Science.gov (United States)

    Matsuno, Ryosuke; Gifford, Andrew J; Fang, Junming; Warren, Mikako; Lukeis, Robyn E; Trahair, Toby; Sugimoto, Tohru; Marachelian, Araz; Asgharzadeh, Shahab; Maris, John M; Ikegaki, Naohiko; Shimada, Hiroyuki

    2018-01-01

    Background Although MYCN (aka N-myc) amplification is reported in ∼20% of neuroblastomas, MYC (aka C-myc) amplification appears to be a rare event in this disease. As of today, only 2 MYC-amplified neuroblastomas have been briefly mentioned in the literature. Methods We studied here the clinicopathological features of 3 MYC-amplified neuroblastomas. Results All 3 patients (2 females and 1 male) had stage 4 disease. One female is currently alive and well 52 months after the diagnosis, while the other female and male patients died of disease 24 and 20 months after the diagnosis, respectively. Further analysis on 2 tumors revealed unfavorable histology with MYC protein overexpression but with neither MYCN amplification nor MYCN protein overexpression. Both of these tumors exhibited "large cell neuroblastoma" histology with enlarged, uniquely open nuclei and nucleolar hypertrophy, along with "aberrant" desmin expression. Conclusions MYC-amplified neuroblastomas are extremely rare and seem to present with distinct clinicopathological features.

  11. Dielectrophoretic capture and genetic analysis of single neuroblastoma tumor cells

    Directory of Open Access Journals (Sweden)

    Erica L Carpenter

    2014-07-01

    Full Text Available Our understanding of the diversity of cells that escape the primary tumor and seed micrometastases remains rudimentary, and approaches for studying circulating and disseminated tumor cells have been limited by low throughput and sensitivity, reliance on single parameter sorting, and a focus on enumeration rather than phenotypic and genetic characterization. Here we utilize a highly sensitive microfluidic and dielectrophoretic approach for the isolation and genetic analysis of individual tumor cells. We employed fluorescence labeling to isolate 208 single cells from spiking experiments conducted with 11 cell lines, including 8 neuroblastoma cell lines, and achieved a capture sensitivity of 1 tumor cell per 106 white blood cells. Sample fixation or freezing had no detectable effect on cell capture. Point mutations were accurately detected in the whole genome amplification product of captured single tumor cells but not in negative control white blood cells. We applied this approach to capture 144 single tumor cells from 10 bone marrow samples from patients suffering from neuroblastoma. In this pediatric malignancy, high-risk patients often exhibit wide-spread hematogenous metastasis, but access to primary tumor can be difficult or impossible. Here we used flow-based sorting to pre-enrich samples with tumor involvement below 0.02%. For all patients for whom a mutation in the Anaplastic Lymphoma Kinase gene had already been detected in their primary tumor, the same mutation was detected in single cells from their marrow. These findings demonstrate a novel, non-invasive, and adaptable method for the capture and genetic analysis of single tumor cells from cancer patients.

  12. Environmental risk comparisons with internal methods of UST leak detection

    International Nuclear Information System (INIS)

    Durgin, P.B.

    1993-01-01

    The past five years have seen a variety of advances in how leaks can be detected from within underground storage tanks. Any leak-detection approach employed within a storage tanks must be conducted at specific time intervals and meet certain leak-rate criteria according to federal and state regulations. Nevertheless, the potential environmental consequences of leak detection approaches differ widely. Internal, volumetric UST monitoring techniques have developed over time including: (1) inventory control with stick measurements, (2) precision tank testing, (3) automatic tank gauging (ATG), (4) statistical inventory reconciliation (SIR), and (5) statistical techniques with automatic tank gauging. An ATG focuses on the advantage of precise data but measured for only a brief period. On the other hand, stick data has less precision but when combined with SIR over extended periods it too can detect low leak rates. Graphs demonstrate the comparable amounts of fuel than can leak out of a tank before being detected by these techniques. The results indicate that annual tank testing has the greatest potential for large volumes of fuel leaking without detection while new statistical approaches with an ATG have the least potential. The environmental implications of the volumes of fuel leaked prior to detection are site specific. For example, if storage tank is surrounded by a high water table and in a sole-source aquifer even small leaks may cause problems. The user must also consider regulatory risks. The level of environmental and regulatory risk should influence selection of the UST leak detection method

  13. The use of risk management principles in planning an internal audit ...

    African Journals Online (AJOL)

    However, it is unclear whether the current concept of a risk-based internal audit engagement is in line with modern business practices, such as enterprise-wide risk management principles. Furthermore, it is also uncertain whether internal auditors share a single set of risk management principles and concepts, and how (or ...

  14. Evaluating the Investment Benefit of Multinational Enterprises' International Projects Based on Risk Adjustment: Evidence from China

    Science.gov (United States)

    Chen, Chong

    2016-01-01

    This study examines the international risks faced by multinational enterprises to understand their impact on the evaluation of investment projects. Moreover, it establishes a 'three-dimensional' theoretical framework of risk identification to analyse the composition of international risk indicators of multinational enterprises based on the theory…

  15. Association of MYCN copy number with clinical features, tumor biology, and outcomes in neuroblastoma: A report from the Children's Oncology Group.

    Science.gov (United States)

    Campbell, Kevin; Gastier-Foster, Julie M; Mann, Meegan; Naranjo, Arlene H; Van Ryn, Collin; Bagatell, Rochelle; Matthay, Katherine K; London, Wendy B; Irwin, Meredith S; Shimada, Hiroyuki; Granger, M Meaghan; Hogarty, Michael D; Park, Julie R; DuBois, Steven G

    2017-11-01

    High-level MYCN amplification (MNA) is associated with poor outcome and unfavorable clinical and biological features in patients with neuroblastoma. To the authors' knowledge, less is known regarding these associations in patients with low-level MYCN copy number increases. In this retrospective study, the authors classified patients has having tumors with MYCN wild-type tumors, MYCN gain (2-4-fold increase in MYCN signal compared with the reference probe), or MNA (>4-fold increase). Tests of trend were used to investigate ordered associations between MYCN copy number category and features of interest. Log-rank tests and Cox models compared event-free survival and overall survival by subgroup. Among 4672 patients, 3694 (79.1%) had MYCN wild-type tumors, 133 (2.8%) had MYCN gain, and 845 (18.1%) had MNA. For each clinical/biological feature, the percentage of patients with an unfavorable feature was lowest in the MYCN wild-type category, intermediate in the MYCN gain category, and highest in the MNA category (P<.0001), except for 11q aberration, for which the highest rates were in the MYCN gain category. Patients with MYCN gain had inferior event-free survival and overall survival compared with those with MYCN wild-type. Among patients with high-risk disease, MYCN gain was associated with the lowest response rate after chemotherapy. Patients with non-stage 4 disease (according to the International Neuroblastoma Staging System) and patients with non-high-risk disease with MYCN gain had a significantly increased risk for death, a finding confirmed on multivariable testing. Increasing MYCN copy number is associated with an increasingly higher rate of unfavorable clinical/biological features, with 11q aberration being an exception. Patients with MYCN gain appear to have inferior outcomes, especially in otherwise more favorable groups. Cancer 2017;123:4224-4235. © 2017 American Cancer Society. © 2017 American Cancer Society.

  16. Heterogeneity of neuroblastoma cell identity defined by transcriptional circuitries.

    Science.gov (United States)

    Boeva, Valentina; Louis-Brennetot, Caroline; Peltier, Agathe; Durand, Simon; Pierre-Eugène, Cécile; Raynal, Virginie; Etchevers, Heather C; Thomas, Sophie; Lermine, Alban; Daudigeos-Dubus, Estelle; Geoerger, Birgit; Orth, Martin F; Grünewald, Thomas G P; Diaz, Elise; Ducos, Bertrand; Surdez, Didier; Carcaboso, Angel M; Medvedeva, Irina; Deller, Thomas; Combaret, Valérie; Lapouble, Eve; Pierron, Gaelle; Grossetête-Lalami, Sandrine; Baulande, Sylvain; Schleiermacher, Gudrun; Barillot, Emmanuel; Rohrer, Hermann; Delattre, Olivier; Janoueix-Lerosey, Isabelle

    2017-09-01

    Neuroblastoma is a tumor of the peripheral sympathetic nervous system, derived from multipotent neural crest cells (NCCs). To define core regulatory circuitries (CRCs) controlling the gene expression program of neuroblastoma, we established and analyzed the neuroblastoma super-enhancer landscape. We discovered three types of identity in neuroblastoma cell lines: a sympathetic noradrenergic identity, defined by a CRC module including the PHOX2B, HAND2 and GATA3 transcription factors (TFs); an NCC-like identity, driven by a CRC module containing AP-1 TFs; and a mixed type, further deconvoluted at the single-cell level. Treatment of the mixed type with chemotherapeutic agents resulted in enrichment of NCC-like cells. The noradrenergic module was validated by ChIP-seq. Functional studies demonstrated dependency of neuroblastoma with noradrenergic identity on PHOX2B, evocative of lineage addiction. Most neuroblastoma primary tumors express TFs from the noradrenergic and NCC-like modules. Our data demonstrate a previously unknown aspect of tumor heterogeneity relevant for neuroblastoma treatment strategies.

  17. YAP promotes tumorigenesis and cisplatin resistance in neuroblastoma.

    Science.gov (United States)

    Yang, Chao; Tan, Juan; Zhu, Jun; Wang, Shan; Wei, Guanghui

    2017-06-06

    The transcriptional co-activator Yes-associated protein (YAP) is essential for Hippo pathway-driven tumorigenesis in various cancers. However, the expression and function of YAP in neuroblastoma remains elusive. Here, we show that YAP was highly expressed in Neuroblastoma (NB) and expression levels correlated with advanced tumor staging. Knockdown of YAP significantly impaired neuroblastoma proliferation, tumorigenesis, and invasion in vitro. Injection of the YAP inhibitor, Peptide 17, dramatically prevented neuroblastoma subcutaneous tumor growth by efficiently downregulating YAP expression in tumors. Additionally, less proliferative and more apoptotic cells were found in the Peptide 17 treatment group. Furthermore, YAP inhibition significantly inhibited cisplatin-resistant neuroblastoma proliferation, tumorigenesis, and invasion in vitro. The combination of Peptide 17 with low-dose cisplatin efficiently impaired cisplatin-resistant NB subcutaneous tumor growth, being as effective as high-dose cisplatin. Notably, the combination therapy caused lesser liver toxicity in mice compared to the high-dose cisplatin treatment group. Collectively, this work identifies YAP as a novel regulator of neuroblastoma proliferation, tumorigenesis, and invasion and indicates that YAP is a potential therapeutic target for cisplatin-resistant neuroblastoma.

  18. Risk factors for psychological stress among international business travellers

    Science.gov (United States)

    Striker, J.; Luippold, R. S.; Nagy, L.; Liese, B.; Bigelow, C.; Mundt, K. A.

    1999-01-01

    OBJECTIVES: This study investigated sources of self reported psychological stress among international business travellers at the World Bank, following up on a previous study showing that travellers submitted more insurance claims for psychological disorders. Hypotheses were that work, personal, family, and health concerns, as well as time zone travel, contribute to travel stress. METHODS: A travel survey was developed from focus groups and consisted of questions about these potential sources of travel stress. Surveys were sent to a random sample of staff, stratified by number of travel missions, age range, and sex. Canonical correlation analyses estimated the association between key survey items on sources of stress and two measures of travel stress. RESULTS: 498 staff completed the survey. More than a third reported high to very high travel stress. Correlations between predictors and travel stress showed that social and emotional concerns (such as impact of travel on family and sense of isolation) contributed the most to such stress, followed by health concerns, and workload upon return from travel. Surprisingly, time zone travel did not contribute to the self reported stress of these travellers. There were few modifiers of stress, although respondents suggested that a day of rest after travel and reduced workloads would help. CONCLUSIONS: The current study confirms clinical impressions about several correlates of travel stress. Similar research with travellers in other organisations could help to determine whether the findings from this study are valid and what measures can be taken to reduce the psychological health risks to travellers.   PMID:10450241

  19. Internal modelling under Risk-Based Capital (RBC) framework

    Science.gov (United States)

    Ling, Ang Siew; Hin, Pooi Ah

    2015-12-01

    Very often the methods for the internal modelling under the Risk-Based Capital framework make use of the data which are in the form of run-off triangle. The present research will instead extract from a group of n customers, the historical data for the sum insured si of the i-th customer together with the amount paid yij and the amount aij reported but not yet paid in the j-th development year for j = 1, 2, 3, 4, 5, 6. We model the future value (yij+1, aij+1) to be dependent on the present year value (yij, aij) and the sum insured si via a conditional distribution which is derived from a multivariate power-normal mixture distribution. For a group of given customers with different original purchase dates, the distribution of the aggregate claims liabilities may be obtained from the proposed model. The prediction interval based on the distribution for the aggregate claim liabilities is found to have good ability of covering the observed aggregate claim liabilities.

  20. High dose melphalan in the treatment of advanced neuroblastoma: results of a randomised trial (ENSG-1) by the European Neuroblastoma Study Group

    NARCIS (Netherlands)

    Pritchard, Jon; Cotterill, Simon J.; Germond, Shirley M.; Imeson, John; de Kraker, Jan; Jones, David R.

    2005-01-01

    High dose myeloablative chemotherapy ("megatherapy"), with haematopoietic stem cell support, is now widely used to consolidate response to induction chemotherapy in patients with advanced neuroblastoma. In this study (European Neuroblastoma Study Group, ENSG1), the value of melphalan myeloablative

  1. Identification of Neuroblastoma Subgroups Based on Three-Dimensional Telomere Organization

    Directory of Open Access Journals (Sweden)

    Alexandra Kuzyk

    2016-08-01

    Full Text Available Using 3D telomere quantitative fluorescence in situ hybridization, we determined the 3D telomere organization of 74 neuroblastoma tissue samples. Hierarchical cluster analysis of the measured telomere parameters identified three subgroups from our patient cohort. These subgroups have unique telomere profiles based on telomere length and nuclear architecture. Subgroups with higher levels of telomere dysfunction were comprised of tumors with greater numbers of telomeres, telomeric aggregates, and short telomeres (P < .0001. Tumors with greater telomere dysfunction were associated with unfavorable tumor characteristics (greater age at diagnosis, unfavorable histology, higher stage of disease, MYCN amplification, and higher MYCN expression and poor prognostic risk (P < .001. Subgroups with greater telomere dysfunction also had higher intratumor heterogeneity. MYCN overexpression in two neuroblastoma cell lines with constitutively low MYCN expression induced changes in their telomere profile that were consistent with increased telomere dysfunction; this illustrates a functional relationship between MYCN and 3D telomere organization. This study demonstrates the ability to classify neuroblastomas based on the level of telomere dysfunction, which is a novel approach for this cancer.

  2. Pre-clinical evaluation of rHDL encapsulated retinoids for the treatment of Neuroblastoma

    Directory of Open Access Journals (Sweden)

    Nirupama eSabnis

    2013-03-01

    Full Text Available Despite major advances in pediatric cancer research, there has been only modest progress in the survival of children with high risk neuroblastoma (HRNB. The long term survival rates of HRNB in the United States are still only 30-50%. Due to resistance that often develops during therapy, development of new effective strategies is essential to improve the survival and overcome the tendency of HRNB patients to relapse subsequent to initial treatment. Current chemotherapy regimens also have a serious limitation due to off target toxicity. In the present work, we evaluated the potential application of reconstituted high density lipoprotein (rHDL containing fenretinide (FR nanoparticles as a novel approach to current neuroblastoma therapeutics. The characterization and stability studies of rHDL-FR nanoparticles showed small size (<40nm and high encapsulation efficiency. The cytotoxicity studies of free FR vs. rHDL/ FR towards the neuroblastoma cell lines SK-N-SH and SMS-KCNR showed 2.8 and 2 fold lower IC50 values for the rHDL encapsulated FR vs. free FR. More importantly, the IC50 value for retinal pigment epithelial cells (ARPE-19, a recipient of off target toxicity during FR therapy, was over 40 times higher for the rHDL/ FR as compared to that of free FR. The overall improvement in in vitro selective therapeutic efficiency was thus about 100 fold upon encapsulation of the drug into the rHDL nanoparticles. These studies support the potential value of this novel drug delivery platform for treating pediatric cancers in general, and neuroblastoma in particular

  3. Seleno methionine-75 as a scanning agent for neuroblastoma

    International Nuclear Information System (INIS)

    Covington, E.E.; D'Angio, G.J.; Helson, L.; Romano, R.W.

    1974-01-01

    Neuroblastoma is a functioning tumor and patients with this tumor are known to excrete vanilmandelic acid and other degradation products of norepinephrine. It also accumulates and produces excess cystathionine for which methionine is a precursor in the normal anabolic pathway. This was the rationale for testing 75 Se-methionine as a possible scanning agent in patients with neuroblastoma. D'Angio et al reported the results of a preliminary investigation in which 3 of 4 patients with neuroblastoma, all with known metastases of the skull, had positive scans correctly localizing the disease. These preliminary data seemed encouraging, and further investigation was undertaken. The results are reported

  4. Estimating internal exposure risks by the relative risk and the National Institute of Health risk models

    International Nuclear Information System (INIS)

    Mehta, S.K.; Sarangapani, R.

    1995-01-01

    This paper presents tabulations of risk (R) and person-years of life lost (PYLL) for acute exposures of individual organs at ages 20 and 40 yrs for the Indian and Japanese populations to illustrate the effect of age at exposure in the two models. Results are also presented for the organ wise nominal probability coefficients (NPC) and PYLL for individual organs for the age distributed Indian population by the two models. The results presented show that for all organs the estimates of PYLL and NPC for the Indian population are lower than those for the Japanese population by both models except for oesophagus, breast and ovary by the relative risk (RR) model, where the opposite trend is observed. The results also show that the Indian all-cancer values of NPC averaged over the two models is 2.9 x 10 -2 Sv -1 , significantly lower than the world average value of 5x10 -2 Sv -1 estimated by the ICRP. (author). 9 refs., 2 figs., 2 tabs

  5. Do Global Risk Factors Matter for International Cost of Capital Computations?

    NARCIS (Netherlands)

    C.G. Koedijk (Kees); M.A. van Dijk (Mathijs)

    2002-01-01

    textabstractInternational financial markets are becoming integrated. Hence, global risk factor are increasingly important for portfolio selection and asset pricing. The recent empirical finance literature has confirmed that both the global market portfolio and exchange rate risk factors constitute

  6. Internal risks of factoring business: identification, cause-effect relationships, accounting and management aspects

    Directory of Open Access Journals (Sweden)

    I.M. Vygivska

    2017-12-01

    Full Text Available The article identifies the risks of the economic activity of a factoring company. The identified risks are divided into internal (fraud risk, credit risk, liquidity, nonpayment, staff, supplier's failure to meet the terms of the supply / factoring contract and external (legal, inflation, currency, interest, industry risks, country risk. The cause-effect relationships of the identified risks have been established. The content of information requests of the leading part of the factoring company, as well as the management subsystems (accounting, economic analysis, control and planning, and the direction of information flows between them (to manage the company's internal risks is determined. These proposals contribute to the improvement of accounting and analytical support for risk management of the factoring business, the choice of alternative risk management methods, the impact on their possible consequences, minimizing the negative impact of risks on the financial condition of the company, and establishing the effectiveness of factoring operations under risk.

  7. Risk assessment, session 1-4. International conference 1992. Part 1

    International Nuclear Information System (INIS)

    1992-01-01

    The international conference on Risk Assessment, 5-9 October 1992, London was organised by the Health and Safety Commission of the UK and co-sponsored by a number of regional and international organizations namely: the European Commission, the ILO, the OECD and WHO. The main sessions of the conference cover what risk assessment means, the role of risk assessment in devising policies and regulations; and risk assessment in practice

  8. Integrin α4 Enhances Metastasis and May Be Associated with Poor Prognosis in MYCN-low Neuroblastoma.

    Directory of Open Access Journals (Sweden)

    Shanique A Young

    Full Text Available High-risk neuroblastoma is associated with an overall survival rate of 30-50%. Neuroblastoma-expressed cell adhesion receptors of the integrin family impact cell adhesion, migration, proliferation and survival. Integrin α4 is essential for neural crest cell motility during development, is highly expressed on leukocytes, and is critical for transendothelial migration. Thus, cancer cells that express this receptor may exhibit increased metastatic potential. We show that α4 expression in human and murine neuroblastoma cell lines selectively enhances in vitro interaction with the alternatively spliced connecting segment 1 of fibronectin, as well as vascular cell adhesion molecule-1 and increases migration. Integrin α4 expression enhanced experimental metastasis in a syngeneic tumor model, reconstituting a pattern of organ involvement similar to that seen in patients. Accordingly, antagonism of integrin α4 blocked metastasis, suggesting adhesive function of the integrin is required. However, adhesive function was not sufficient, as mutants of integrin α4 that conserved the matrix-adhesive and promigratory function in vitro were compromised in their metastatic capacity in vivo. Clinically, integrin α4 is more frequently expressed in non-MYNC amplified tumors, and is selectively associated with poor prognosis in this subset of disease. These results reveal an unexpected role for integrin α4 in neuroblastoma dissemination and identify α4 as a potential prognostic indicator and therapeutic target.

  9. [Health risks of residual fumigants in international transport containers].

    Science.gov (United States)

    Baur, X; Budnik, L T; Preisser, A M

    2010-03-01

    The increasing transport of goods worldwide is mainly carried in standard containers. These containers are frequently fumigated in order to protect freight from pests and to follow regulations of importing countries. Fumigants as well as toxic industrial chemicals can adsorb to goods and be emitted from them over various periods of time. This review is based on a literature search, analyses of air samples from a randomized selection of import containers at the port of Hamburg and clinical investigations of intoxicated subject. These data indicate that about 70% of imported containers exceed national or international threshold levels, about one sixth exceeding occupational exposure limits of fumigants and/or toxic industrial chemical, 0.5% had concentrations immediately dangerous to life or health. Intoxications by inhalation mainly occur in workers in the logistics area. No information exists on possible fumigation in small and medium-sized companies where the container units are unloaded. Neurological and respiratory ailments dominated in patients from our outpatient clinic and those reported in the literature: symptoms were often misdiagnosed. Our results confirm findings of other investigators that subjects who unload containers or have otherwise intensive contact with imported goods are frequently exposed to toxic or very toxic volatile chemicals. It can be assumed that there are many unrecognized cases and also health risks to the ultimate consumers of transported goods. History taking targeted on potential exposure is of great diagnostic importance in elucidating typical temporal relationship between exposure by inhalation and symptoms such as headache, skin irritation, cough, dyspnea, diarrhoea and neurological deficits. Detailed investigations by medical specialists is necessary to confirm suspected diagnoses. This should be combined with immediate special analyses of air samples and laboratory tests (biological monitoring). Georg Thieme Verlag KG Stuttgart

  10. Host-Country Related Risk Factors in International Construction: Meta-Analysis

    Directory of Open Access Journals (Sweden)

    Güzin AYDOGAN

    2014-09-01

    Full Text Available Internationalization has been on the agenda of construction firms as a strategic option in global competition. Due to globalization every sector including the construction industry has faced with high levels of competitiveness, uncertainty, and risk. International construction involves common risks to domestic construction, as well as risks that are related to the host country. These risks have serious effects on the performance of international projects. Since the sustainable competitiveness of international contractors depends largely on the effective management of these risks, their assessment becomes vital for the success of international contractors. The main aim of this study is to analyse the risks for international construction projects that are related to the host country. Meta-analysis technique is used in order to determine these risks. This paper, therefore, reviews the literature that has been published in four most respected construction and management journals, these being; Journal of Construction Engineering and Management, Journal of Management in Engineering, Construction Management and Economics, and International Journal of Project Management for the period of 2000-2010. International construction risk assessment models are also reviewed within the context of this study, since host country related risk factors were found to have serious effects on the profitability of international contractors due to literature review. As a result; political stability, law and regulations, exchange rate risk, cultural differences, inflation, expropriation, tax discrimination, language barrier, bribery and corruption, force majeure, and societal conflicts in the host country are found to be the most important risk factors in international construction. Findings of this study can be used in risk assessment models for international construction projects.

  11. Primary pancreatic neuroblastoma presenting with opsoclonus–myoclonus syndrome

    Directory of Open Access Journals (Sweden)

    Samuel Galgano, MD

    2016-03-01

    Full Text Available Although neuroblastoma is a common solid organ malignancy in children, primary pancreatic neuroblastoma is a rare entity in children, with very few cases reported in the literature. The case discusses the presentation of a 21-month-old female presenting to the neurology clinic with ataxia and erratic eye movements. Our case illustrates the computed tomography, ultrasound, and scintigraphic findings of primary pancreatic neuroblastoma presenting as opsoclonus–myoclonus syndrome. Computed tomography and ultrasound demonstrated a vascular, enhancing mass in the pancreatic body clearly separate from the adrenal gland. Metaiodobenzylguanidine scan demonstrates focal intense uptake in the pancreatic body. The patient's diagnosis was confirmed with biopsy, and her malignancy responded well to conventional chemotherapy. The case is important in that it demonstrates the unusual imaging appearance of a primary pancreatic neuroblastoma.

  12. RISK MANAGEMENT FROM THE PERSPECTIVE OF INTERNAL AUDIT

    Directory of Open Access Journals (Sweden)

    Florin-Constantin, DIMA

    2013-12-01

    Full Text Available The existence of a wide range of risks with actual or potential impact on business entities is a certainty, as well as their influence on company results. In this context, the increase of the economic performance and the implementation of effective activities is strictly related to implementing a risk management system, allowing to define the principal risks of the entity, to identify and assess the risks it faces, and the creation of effective strategies to reduce them.

  13. Mesenchymal change and drug resistance in neuroblastoma.

    Science.gov (United States)

    Naiditch, Jessica A; Jie, Chunfa; Lautz, Timothy B; Yu, Songtao; Clark, Sandra; Voronov, Dimitry; Chu, Fei; Madonna, Mary Beth

    2015-01-01

    Metastatic initiation has many phenotypic similarities to epithelial-to-mesenchymal transition, including loss of cell-cell adhesion, increased invasiveness, and increased cell mobility. We have previously demonstrated that drug resistance is associated with a metastatic phenotype in neuroblastoma (NB). The purpose of this project was to determine if the development of doxorubicin resistance is associated with characteristics of mesenchymal change in human NB cells. Total RNA was isolated from wild type (WT) and doxorubicin-resistant (DoxR) human NB cell lines (SK-N-SH and SK-N-BE(2)C) and analyzed using the Illumina Human HT-12 version 4 Expression BeadChip. Differentially expressed genes (DEGs) were identified. Volcano plots and heat maps were generated. Genes of interest with a fold change in expression >1.5 and an adjusted P change via multiple pathways in the transition to a drug-resistant state. Copyright © 2015 Elsevier Inc. All rights reserved.

  14. Stochastic Discount Factor Approach to International Risk-Sharing:A Robustness Check of the Bilateral Setting

    NARCIS (Netherlands)

    Hadzi-Vaskov, M.; Kool, C.J.M.

    2007-01-01

    This paper presents a robustness check of the stochastic discount factor approach to international (bilateral) risk-sharing given in Brandt, Cochrane, and Santa-Clara (2006). We demonstrate two main inherent limitations of the bilateral SDF approach to international risk-sharing. First, the discount

  15. KOMISARIS INDEPENDEN, KOMITE AUDIT, INTERNAL AUDIT DAN RISK MANAGEMENT COMMITTEE TERHADAP MANAJEMEN LABA

    Directory of Open Access Journals (Sweden)

    Nurika Restuningdiah

    2017-03-01

    Full Text Available The purpose of this research was to examine the impact of independency of board commisioner, audit committee,internal audit and risk management comittee to earning management. Regression Analysis of 35 publiccompanies listing in Indonesia Stock Exchange on year 2009 through a random sampling technique indicatedthat there was no significant impact of independency of board commisioner, audit committee, internal auditand risk management comittee to earning management. The implication of this study was relevant to thedecision maker of public companies to consider the skill and expertise of board commisioner, audit committe,internal audit and risk management comittee to support the internal corporate governance mechanism.

  16. Managerial Risk-taking in International Acquisitions in the Brewery Industry

    DEFF Research Database (Denmark)

    Geppert, Mike; Dörrenbächer, Christoph; Gammelgaard, Jens

    2013-01-01

    This paper deals with the role that institutional differences play in managerial risk-taking when firms engage in international acquisitions. It is assumed that multinational corporations (MNCs) have different interests and capabilities when dealing with international acquisition, which...... international acquisitions. Comparing a total of 12 large acquisitions of four leading MNCs in the global brewery industry, the paper shows that mutually reinforcing influences of country of origin (coordinated vs liberal market economies) and ownership (family ownership vs stock market ownership) lead...... to different risk profiles and managerial risk-taking with regard to international acquisitions...

  17. Sociobehavioural risk factors in dental caries - international perspectives

    DEFF Research Database (Denmark)

    Petersen, Poul Erik

    2005-01-01

    - and middle-income countries have been published in recent years. World Health Organization international collaborative studies and other international studies of social factors in dental caries using the same methodology provide empirical evidence of social inequality in oral health across countries...

  18. Reputational risk impact of internal frauds on bank customers in ...

    African Journals Online (AJOL)

    ... laws to coherently safeguard lenders and borrowers. The study recommends a stiffer control measures within all financial organizations in the country as well as the enactment of enabling laws by the government to checkmate these ugly incidences. Keywords: Internal bank frauds, Forgeries, Internal control, Compliance, ...

  19. 78 FR 32231 - Pioneer Hi-Bred International, Inc.; Availability of Plant Pest Risk Assessment, Environmental...

    Science.gov (United States)

    2013-05-29

    ...] Pioneer Hi-Bred International, Inc.; Availability of Plant Pest Risk Assessment, Environmental Assessment... has prepared a preliminary determination regarding a request from Pioneer Hi-Bred International, Inc... 340. APHIS received a petition (APHIS Petition Number 11-063-01p) from Pioneer Hi-Bred International...

  20. Risk reduction of international mining projects by means of investor consortia and diversification of external financing

    International Nuclear Information System (INIS)

    Kirchner, C.

    1982-01-01

    Investors and creditors of international mining projects bear specific risks which may be reduced by means of forming investor and financing consortia. Risk is defined for each actor separately. Project risk and investor risk respectively credit risk are useful categories in order to analyze risk reduction. In each case formation of consortia has a positive influence on the economic viability of the project, and thus reduces the project risk. Furthermore, formation of consortia leads to better compliance of the host country of the mining project with the project and financing agreements. Thus, investor and credit risk may be reduced. (orig.) [de

  1. Natural killer cells facilitate PRAME-specific T-cell reactivity against neuroblastoma

    Science.gov (United States)

    Spel, Lotte; Boelens, Jaap-Jan; van der Steen, Dirk M.; Blokland, Nina J.G.; van Noesel, Max M.; Molenaar, Jan J.; Heemskerk, Mirjam H.M.

    2015-01-01

    Neuroblastoma is the most common solid tumor in children with an estimated 5-year progression free survival of 20–40% in stage 4 disease. Neuroblastoma actively avoids recognition by natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). Although immunotherapy has gained traction for neuroblastoma treatment, these immune escape mechanisms restrain clinical results. Therefore, we aimed to improve neuroblastoma immunogenicity to further the development of antigen-specific immunotherapy against neuroblastoma. We found that neuroblastoma cells significantly increase surface expression of MHC I upon exposure to active NK cells which thereby readily sensitize neuroblastoma cells for recognition by CTLs. We show that oncoprotein PRAME serves as an immunodominant antigen for neuroblastoma as NK-modulated neuroblastoma cells are recognized by PRAMESLLQHLIGL/A2-specific CTL clones. Furthermore, NK cells induce MHC I upregulation in neuroblastoma through contact-dependent secretion of IFNγ. Our results demonstrate remarkable plasticity in the peptide/MHC I surface expression of neuroblastoma cells, which is reversed when neuroblastoma cells experience innate immune attack by sensitized NK cells. These findings support the exploration of NK cells as adjuvant therapy to enforce neuroblastoma-specific CTL responses. PMID:26452036

  2. Radiation and society: Comprehending radiation risk. V. 2. Poster papers. Proceedings of an international conference

    International Nuclear Information System (INIS)

    1996-01-01

    This IAEA international conference on Radiation and Society was the first major international meeting devoted to the comprehension of radiation risk, public attitude towards radiation risk and hazards encountered by the general public in contaminated areas. Volume two of the proceedings mainly deals with assessment of radiation exposure levels, radiation health effects, impact of radiation on the environment, perception of and managing radiation risk. Refs, figs, tabs

  3. TIME VARIATION AND ASYMMETRY IN THE WORLD PRICE OF COVARIANCE RISK: THE IMPLICATIONS FOR INTERNATIONAL DIVERSIFICATION

    OpenAIRE

    Olan T. Henry; Nilss Olekalns; Kalvinder Shields

    2004-01-01

    The International Capital Asset Pricing Model measures country risk in terms of the conditional covariance of national returns with the world return. Using impulse responses from a multivariate nonlinear model we provide evidence of time variation and asymmetry in the measure of country risk. and the implied benefit to international diversification. The evidence implies that the price of risk and the benefits from diversification may differ in a statistically and economically meaningful fashi...

  4. Mutations in PIK3CA are infrequent in neuroblastoma

    International Nuclear Information System (INIS)

    Dam, Vincent; Morgan, Brian T; Mazanek, Pavel; Hogarty, Michael D

    2006-01-01

    Neuroblastoma is a frequently lethal pediatric cancer in which MYCN genomic amplification is highly correlated with aggressive disease. Deregulated MYC genes require co-operative lesions to foster tumourigenesis and both direct and indirect evidence support activated Ras signaling for this purpose in many cancers. Yet Ras genes and Braf, while often activated in cancer cells, are infrequent targets for activation in neuroblastoma. Recently, the Ras effector PIK3CA was shown to be activated in diverse human cancers. We therefore assessed PIK3CA for mutation in human neuroblastomas, as well as in neuroblastomas arising in transgenic mice with MYCN overexpressed in neural-crest tissues. In this murine model we additionally surveyed for Ras family and Braf mutations as these have not been previously reported. Sixty-nine human neuroblastomas (42 primary tumors and 27 cell lines) were sequenced for PIK3CA activating mutations within the C2, helical and kinase domain 'hot spots' where 80% of mutations cluster. Constitutional DNA was sequenced in cases with confirmed alterations to assess for germline or somatic acquisition. Additionally, Ras family members (Hras1, Kras2 and Nras) and the downstream effectors Pik3ca and Braf, were sequenced from twenty-five neuroblastomas arising in neuroblastoma-prone transgenic mice. We identified mutations in the PIK3CA gene in 2 of 69 human neuroblastomas (2.9%). Neither mutation (R524M and E982D) has been studied to date for effects on lipid kinase activity. Though both occurred in tumors with MYCN amplification the overall rate of PIK3CA mutations in MYCN amplified and single-copy tumors did not differ appreciably (2 of 31 versus 0 of 38, respectively). Further, no activating mutations were identified in a survey of Ras signal transduction genes (including Hras1, Kras2, Nras, Pik3ca, or Braf genes) in twenty-five neuroblastic tumors arising in the MYCN-initiated transgenic mouse model. These data suggest that activating

  5. Financial Risk Evaluation in the Context of International Accounting Normalization

    OpenAIRE

    Victor Munteanu; Lavinia Copcinschi; Anda Laceanu; Carmen Luschi

    2015-01-01

    Within the framework of the normalization phenomenon, the quality of the accounting information has improved as the companies have stepped up with their competitiveness parameters; compared to the opponents on the local and international markets by means of the accounting information they have access to. The main explanation of the phenomena of normalization, harmonization, convergence, internationalization is the augmentation of the global processes of the international markets, capital and ...

  6. The Pricing of Tail Risk and the Equity Premium: Evidence from International Option Markets

    DEFF Research Database (Denmark)

    Andersen, Torben Gustav; Fusari, Nicola; Todorov, Viktor

    We explore the pricing of tail risk as manifest in index options across international equity markets. The risk premium associated with negative tail events displays persistent shifts, unrelated to volatility. This tail risk premium is a potent predictor of future equity returns, while option......, suggesting a high degree of integration among the major global equity markets....

  7. Student nurse perceptions of risk in relation to international placements: a phenomenological research study.

    Science.gov (United States)

    Morgan, Debra A

    2012-11-01

    International nursing electives have been identified as a positive learning experience for students. However, whilst there are risks associated with international student placements in general, there is a scarcity of research specifically relating to student nurse's experiences of risk. This study aimed to investigate UK undergraduate student nurse experiences of risk during an international placement. A phenomenological methodology was applied and semi-structured interviews were conducted with student nurses who had recently returned from an international clinical placement abroad. Ten, second year student nurses, studying on a pre-registration diploma/BSc (Hons) Nursing Studies/Registered Nurse programme from one UK University participated in the study. Findings from the study highlighted that students felt that three types of risk existed; physical risk, clinical-professional risk and socio-cultural risk. Perceptions of risk were influenced by sociological theory relating to the concept of 'the other' and students attempted to reduce risk by employing strategies to reduce 'Otherness'. They also applied psychological theory relating to heuristics such as 'safety in numbers.' It also emerged from the study that exposure to perceived risk enhanced learning as students reported that it encouraged personal and professional development in particular and so assisted students in their move toward self-actualisation. It is suggested, and intended, that findings from this study can be applied to the preparation of students to further enhance their safety and learning experience during international placements abroad. Copyright © 2011 Elsevier Ltd. All rights reserved.

  8. Effect of internal controls on credit risk among listed Spanish banks

    Directory of Open Access Journals (Sweden)

    Ellis Kofi Akwaa-Sekyi

    2016-02-01

    Full Text Available Purpose: The paper examines the effectiveness of internal control systems, explores the exposure of Spanish banks to the dangers of default as a result of internal control systems and establishes a relationship between internal controls and credit risk. Design/Methodology/Approach: Quantitative research approach is used to test hypotheses on the relationship between internal controls and credit risk among listed banks in Spain. Data from Bankscope and company websites from 2004-2013 were used. Generalized Least Squares (random effect econometric estimation technique was used for the model. Findings: We find that internal control systems are in place but their effectiveness cannot be guaranteed. This exposes Spanish listed banks to serious default situations. There is significant effect of internal controls on credit risk especially the control environment, risk management, control activities and monitoring. The non-disclosure of material internal control weakness is a contributory factor to the ineffective internal control systems. There is however a perceived board ineffectiveness which does not augur well for effective internal control systems. Board characteristics for Spanish banks confirm the agency theory. Research Limitations and Implications: Data unavailability for certain years, variables and many inactive banks did not permit a larger sample size than expected. The use of quantitative variables lacks flexibility. Practical Implications: Bank management will find the work useful to ensure strict enforcement of internal control mechanisms and see it as both credit risk and operational risk issues. Central bank should hurry to compel banks to disclose material internal control weakness as provided in the reviewed COSO framework. Social Implications: Ineffective internal controls lead to credit risks, bank closure and loss of investments. Society suffers a lot from such losses and contagion. Disclosure of material internal control

  9. Biological Risks to Public Health: Lessons from an International Conference to Inform the Development of National Risk Communication Strategies.

    Science.gov (United States)

    Dickmann, Petra; Bhatiasevi, Aphaluck; Chaib, Fadela; Baggio, Ombretta; Banluta, Christina; Hollenweger, Lilian; Maaroufi, Abderrahmane

    Biological risk management in public health focuses on the impact of outbreaks on health, the economy, and other systems and on ensuring biosafety and biosecurity. To address this broad range of risks, the International Health Regulations (IHR, 2005) request that all member states build defined core capacities, risk communication being one of them. While there is existing guidance on the communication process and on what health authorities need to consider to design risk communication strategies that meet the requirements on a governance level, little has been done on implementation because of a number of factors, including lack of resources (human, financial, and others) and systems to support effective and consistent capacity for risk communication. The international conference on "Risk communication strategies before, during and after public health emergencies" provided a platform to present current strategies, facilitate learning from recent outbreaks of infectious diseases, and discuss recommendations to inform risk communication strategy development. The discussion concluded with 4 key areas for improvement in risk communication: consider communication as a multidimensional process in risk communication, broaden the biomedical paradigm by integrating social science intelligence into epidemiologic risk assessments, strengthen multisectoral collaboration including with local organizations, and spearhead changes in organizations for better risk communication governance. National strategies should design risk communication to be proactive, participatory, and multisectoral, facilitating the connection between sectors and strengthening collaboration.

  10. Silencing Intersectin 1 Slows Orthotopic Neuroblastoma Growth in Mice.

    Science.gov (United States)

    Harris, Jamie; Herrero-Garcia, Erika; Russo, Angela; Kajdacsy-Balla, Andre; O'Bryan, John P; Chiu, Bill

    2017-11-01

    Neuroblastoma accounts for 15% of all pediatric cancer deaths. Intersectin 1 (ITSN1), a scaffold protein involved in phosphoinositide 3-kinase (PI3K) signaling, regulates neuroblastoma cells independent of MYCN status. We hypothesize that by silencing ITSN1 in neuroblastoma cells, tumor growth will be decreased in an orthotopic mouse tumor model. SK-N-AS neuroblastoma cells transfected with empty vector (pSR), vectors expressing scrambled shRNA (pSCR), or shRNAs targeting ITSN1 (sh#1 and sh#2) were used to create orthotopic neuroblastoma tumors in mice. Volume was monitored weekly with ultrasound. End-point was tumor volume >1000 mm. Tumor cell lysates were analyzed with anti-ITSN1 antibody by Western blot. Orthotopic tumors were created in all cell lines. Twenty-five days post injection, pSR tumor size was 917.6±247.7 mm, pSCR was 1180±159.9 mm, sh#1 was 526.3±212.8 mm, and sh#2 was 589.2±74.91 mm. sh#1-tumors and sh#2-tumors were smaller than pSCR (P=0.02), no difference between sh#1 and sh#2. Survival was superior in sh#2-tumors (P=0.02), trended towards improved survival in sh#1-tumors (P=0.09), compared with pSCR-tumors, no difference in pSR tumors. Western blot showed decreased ITSN1 expression in sh#1 and sh#2 compared with pSR and pSCR. Silencing ITSN1 in neuroblastoma cells led to decreased tumor growth in an orthotopic mouse model. Orthotopic animal models can provide insight into the role of ITSN1 pathways in neuroblastoma tumorigenesis.

  11. Integrative analysis of neuroblastoma and pheochromocytoma genomics data

    Directory of Open Access Journals (Sweden)

    Szabó Peter M

    2012-10-01

    Full Text Available Abstract Background Pheochromocytoma and neuroblastoma are the most common neural crest-derived tumors in adults and children, respectively. We have performed a large-scale in silico analysis of altogether 1784 neuroblastoma and 531 pheochromocytoma samples to establish similarities and differences using analysis of mRNA and microRNA expression, chromosome aberrations and a novel bioinformatics analysis based on cooperative game theory. Methods Datasets obtained from Gene Expression Omnibus and ArrayExpress have been subjected to a complex bioinformatics analysis using GeneSpring, Gene Set Enrichment Analysis, Ingenuity Pathway Analysis and own software. Results Comparison of neuroblastoma and pheochromocytoma with other tumors revealed the overexpression of genes involved in development of noradrenergic cells. Among these, the significance of paired-like homeobox 2b in pheochromocytoma has not been reported previously. The analysis of similar expression patterns in neuroblastoma and pheochromocytoma revealed the same anti-apoptotic strategies in these tumors. Cancer regulation by stathmin turned out to be the major difference between pheochromocytoma and neuroblastoma. Underexpression of genes involved in neuronal cell-cell interactions was observed in unfavorable neuroblastoma. By the comparison of hypoxia- and Ras-associated pheochromocytoma, we have found that enhanced insulin like growth factor 1 signaling may be responsible for the activation of Src homology 2 domain containing transforming protein 1, the main co-factor of RET. Hypoxia induced factor 1α and vascular endothelial growth factor signaling included the most prominent gene expression changes between von Hippel-Lindau- and multiple endocrine neoplasia type 2A-associated pheochromocytoma. Conclusions These pathways include previously undescribed pathomechanisms of neuroblastoma and pheochromocytoma and associated gene products may serve as diagnostic markers and therapeutic

  12. Vesicular monoamine transporter protein expression correlates with clinical features, tumor biology, and MIBG avidity in neuroblastoma: a report from the Children's Oncology Group

    Energy Technology Data Exchange (ETDEWEB)

    Temple, William; Mendelsohn, Lori; Nekritz, Erin; Gustafson, W.C.; Matthay, Katherine K. [UCSF School of Medicine, Department of Pediatrics, San Francisco, CA (United States); UCSF Benioff Children' s Hospital, San Francisco, CA (United States); Kim, Grace E. [UCSF School of Medicine, Department of Pathology, San Francisco, CA (United States); Lin, Lawrence; Giacomini, Kathy [UCSF School of Pharmacy, Department of Bioengineering and Therapeutic Sciences, San Francisco, CA (United States); Naranjo, Arlene; Van Ryn, Collin [University of Florida, Children' s Oncology Group Statistics and Data Center, Gainesville, FL (United States); Yanik, Gregory A. [University of Michigan, CS Mott Children' s Hospital, Ann Arbor, MI (United States); Kreissman, Susan G. [Duke University Medical Center, Durham, NC (United States); Hogarty, Michael [University of Pennsylvania, Children' s Hospital of Philadelphia and Perelman School of Medicine, Philadelphia, PA (United States); DuBois, Steven G. [UCSF School of Medicine, Department of Pediatrics, San Francisco, CA (United States); UCSF Benioff Children' s Hospital, San Francisco, CA (United States); UCSF School of Medicine, San Francisco, CA (United States)

    2016-03-15

    Vesicular monoamine transporters 1 and 2 (VMAT1 and VMAT2) are thought to mediate MIBG uptake in adult neuroendocrine tumors. In neuroblastoma, the norepinephrine transporter (NET) has been investigated as the principal MIBG uptake protein, though some tumors without NET expression concentrate MIBG. We investigated VMAT expression in neuroblastoma and correlated expression with MIBG uptake and clinical features. We evaluated VMAT1 and VMAT2 expression by immunohistochemistry (IHC) in neuroblastoma tumors from 76 patients with high-risk metastatic disease treated in a uniform cooperative group trial (COG A3973). All patients had baseline MIBG diagnostic scans centrally reviewed. IHC results were scored as the product of intensity grading (0 - 3+) and percent of tumor cells expressing the protein of interest. The association between VMAT1 and VMAT2 scores and clinical and biological features was tested using Wilcoxon rank-sum tests. Patient characteristics were typical of high-risk neuroblastoma, though the cohort was intentionally enriched in patients with MIBG-nonavid tumors (n = 20). VMAT1 and VMAT2 were expressed in 62 % and 75 % of neuroblastoma tumors, respectively. VMAT1 and VMAT2 scores were both significantly lower in MYCN amplified tumors and in tumors with high mitotic karyorrhectic index. MIBG-avid tumors had significantly higher VMAT2 scores than MIBG-nonavid tumors (median 216 vs. 45; p = 0.04). VMAT1 expression did not correlate with MIBG avidity. VMAT1 and VMAT2 are expressed in the majority of neuroblastomas. Expression correlates with other biological features. The expression level of VMAT2 but not that of VMAT1 correlates with avidity for MIBG. (orig.)

  13. Toxicity of upfront ¹³¹I-metaiodobenzylguanidine (¹³¹I-MIBG) therapy in newly diagnosed neuroblastoma patients: a retrospective analysis

    NARCIS (Netherlands)

    Bleeker, Gitta; Schoot, Reineke A.; Caron, Huib N.; de Kraker, Jan; Hoefnagel, Cees A.; van Eck, Berthe L.; Tytgat, Godelieve A.

    2013-01-01

    In the treatment of patients with high-risk neuroblastoma, different doses of (131)I-metaiodobenzylguanidine ((131)I-MIBG) are administered at different time points during treatment. Toxicity, mainly haematological (thrombocytopenia), from (131)I-MIBG therapy is known to occur in extensively

  14. File list: ALL.Neu.05.AllAg.Neuroblastoma [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  1. File list: His.Neu.50.AllAg.Neuroblastoma [Chip-atlas[Archive

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  5. File list: InP.Neu.05.AllAg.Neuroblastoma [Chip-atlas[Archive

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  6. Cyclin D1 is a direct transcriptional target of GATA3 in neuroblastoma tumor cells

    NARCIS (Netherlands)

    Molenaar, J. J.; Ebus, M. E.; Koster, J.; Santo, E.; Geerts, D.; Versteeg, R.; Caron, H. N.

    2010-01-01

    Almost all neuroblastoma tumors express excess levels of Cyclin D1 (CCND1) compared to normal tissues and other tumor types. Only a small percentage of these neuroblastoma tumors have high-level amplification of the Cyclin D1 gene. The other neuroblastoma tumors have equally high Cyclin D1

  7. Internal audits of psychosocial risks at workplaces with certified OHS management systems

    OpenAIRE

    Helbo, Anne; Hohnen, Pernille; Hasle, Peter

    2016-01-01

    Psychosocial risks are widely recognized as a major challenge at work, a challenge that most organizationsfind difficult to manage in practice. The OHSAS 18001 standard provides a framework for the managementof occupational health and safety risks, including psychosocial risks. However, suchoccupational health and safety management (OHSM) systems tend to have difficulties in adequatelyaddressing psychosocial risks at work. A crucial element in the OHSM system is internal audits. We haveinvest...

  8. Proceedings of the International conference on energy alternatives/risk education V. 2

    International Nuclear Information System (INIS)

    Marx, Gyoergy

    1990-02-01

    This Proceedings volume on Energy and Risk within the context of the International Conference on Energy Alternatives/Risk Education contains papers on Nuclear Energy, on Background Radiation and on Risks of Energy Alternatives. 15 papers concerning safety of nuclear reactors, case stories of reactor and radiation accidents, monitoring low-level indoor radiation, educational tods, comparison of energy system risks, and catalyzed fusion were indexed and abstracted separately for the INIS database. (R.P.)

  9. Genetic risk by experience interaction for childhood internalizing problems: converging evidence across multiple methods.

    Science.gov (United States)

    Vendlinski, Matthew K; Lemery-Chalfant, Kathryn; Essex, Marilyn J; Goldsmith, H Hill

    2011-05-01

    Identifying how genetic risk interacts with experience to predict psychopathology is an important step toward understanding the etiology of mental health problems. Few studies have examined genetic risk by experience interaction (G×E) in the development of childhood psychopathology. We used both co-twin and parent mental health as markers of genetic risk to test whether G×E predicted internalizing problems in a sample of 8-year-old twins. Multi-instrument composites were used to characterize both parent and child psychopathology, and five experiential risk factors (socioeconomic status, single parent upbringing, negative parent-child interactions, number of negative life events, negative impact of negative life events) composed a cumulative risk index. We found consistent evidence for G×E for child internalizing problems, with significant interaction effects emerging both when genetic risk was indexed by co-twin mental health and when it was based on parent mental health. When co-twin mental health was used to estimate genetic risk, child internalizing problems were more heritable for children at low rather than high experiential risk. When parent mental health was used to estimate genetic risk, the association between genetic risk and internalizing problems was stronger for children at elevated experiential risk. Consideration of the interaction effect sizes helps to reconcile these findings. Our results suggest that the processes involved in both diathesis-stress and bioecological models of development may operate for child internalizing problems. Effect sizes indicated that the main effects of genetic and experiential risk were much better predictors of child internalizing problems than was their interaction. © 2010 The Authors. Journal of Child Psychology and Psychiatry © 2010 Association for Child and Adolescent Mental Health.

  10. Does I-131-MIBG underestimate skeletal disease burden in neuroblastoma?

    Directory of Open Access Journals (Sweden)

    Barai Sukanta

    2004-10-01

    Full Text Available Background: Controversy persists as to the need for both MIBG and bone scanning in routine evaluation of neuroblastoma. Aim: To compare the efficacy of I-131- metaiodobenzylguanidine (MIBG scan against that of conventional Tc99m- methylene diphosphonate (MDP bone scan for the detection of skeletal deposition of neuroblastoma. Methods and Material: The study included 57 patients (36 boys, 21 girls: age range 1-14 years of neuroblastoma who underwent both bone scan with Tc99m-MDP and I-131-MIBG scan within 15 days of each other at presentation and during follow-up. Results: At presentation 11(19.2% patients had evidence of skeletal metastases on MDP scan against 7 patients who showed bony secondaries on MIBG scan. Of the 7 patients, with positive MIBG and MDP scans, MDP scan detected 11 sites whereas MIBG scan detected 7 sites. On follow-up study, 3 patients with initial abnormal MDP scan but normal MIBG scan, developed skeletal metastases detectable on MIBG scan, whereas 3 of the 46 patients who had normal MDP and MIBG scan at presentation; developed skeletal metastases detectable on MDP scan. MIBG scan was concordant in 2 of them but was normal in the third patient. Conclusion: I-131-MIBG underestimates skeletal disease burden in neuroblastoma. Therefore, Tc99m-MDP bone scan should remain a part of routine assessment of patients with neuroblastoma.

  11. A comprehensive characterization of rare mitochondrial DNA variants in neuroblastoma.

    Science.gov (United States)

    Calabrese, Francesco Maria; Clima, Rosanna; Pignataro, Piero; Lasorsa, Vito Alessandro; Hogarty, Michael D; Castellano, Aurora; Conte, Massimo; Tonini, Gian Paolo; Iolascon, Achille; Gasparre, Giuseppe; Capasso, Mario

    2016-08-02

    Neuroblastoma, a tumor of the developing sympathetic nervous system, is a common childhood neoplasm that is often lethal. Mitochondrial DNA (mtDNA) mutations have been found in most tumors including neuroblastoma. We extracted mtDNA data from a cohort of neuroblastoma samples that had undergone Whole Exome Sequencing (WES) and also used snap-frozen samples in which mtDNA was entirely sequenced by Sanger technology. We next undertook the challenge of determining those mutations that are relevant to, or arisen during tumor development. The bioinformatics pipeline used to extract mitochondrial variants from matched tumor/blood samples was enriched by a set of filters inclusive of heteroplasmic fraction, nucleotide variability, and in silico prediction of pathogenicity. Our in silico multistep workflow applied both on WES and Sanger-sequenced neuroblastoma samples, allowed us to identify a limited burden of somatic and germline mitochondrial mutations with a potential pathogenic impact. The few singleton germline and somatic mitochondrial mutations emerged, according to our in silico analysis, do not appear to impact on the development of neuroblastoma. Our findings are consistent with the hypothesis that most mitochondrial somatic mutations can be considered as 'passengers' and consequently have no discernible effect in this type of cancer.

  12. Neuroblastoma, a Paradigm for Big Data Science in Pediatric Oncology.

    Science.gov (United States)

    Salazar, Brittany M; Balczewski, Emily A; Ung, Choong Yong; Zhu, Shizhen

    2016-12-27

    Pediatric cancers rarely exhibit recurrent mutational events when compared to most adult cancers. This poses a challenge in understanding how cancers initiate, progress, and metastasize in early childhood. Also, due to limited detected driver mutations, it is difficult to benchmark key genes for drug development. In this review, we use neuroblastoma, a pediatric solid tumor of neural crest origin, as a paradigm for exploring "big data" applications in pediatric oncology. Computational strategies derived from big data science-network- and machine learning-based modeling and drug repositioning-hold the promise of shedding new light on the molecular mechanisms driving neuroblastoma pathogenesis and identifying potential therapeutics to combat this devastating disease. These strategies integrate robust data input, from genomic and transcriptomic studies, clinical data, and in vivo and in vitro experimental models specific to neuroblastoma and other types of cancers that closely mimic its biological characteristics. We discuss contexts in which "big data" and computational approaches, especially network-based modeling, may advance neuroblastoma research, describe currently available data and resources, and propose future models of strategic data collection and analyses for neuroblastoma and other related diseases.

  13. Neuroblastoma, a Paradigm for Big Data Science in Pediatric Oncology

    Directory of Open Access Journals (Sweden)

    Brittany M. Salazar

    2016-12-01

    Full Text Available Pediatric cancers rarely exhibit recurrent mutational events when compared to most adult cancers. This poses a challenge in understanding how cancers initiate, progress, and metastasize in early childhood. Also, due to limited detected driver mutations, it is difficult to benchmark key genes for drug development. In this review, we use neuroblastoma, a pediatric solid tumor of neural crest origin, as a paradigm for exploring “big data” applications in pediatric oncology. Computational strategies derived from big data science–network- and machine learning-based modeling and drug repositioning—hold the promise of shedding new light on the molecular mechanisms driving neuroblastoma pathogenesis and identifying potential therapeutics to combat this devastating disease. These strategies integrate robust data input, from genomic and transcriptomic studies, clinical data, and in vivo and in vitro experimental models specific to neuroblastoma and other types of cancers that closely mimic its biological characteristics. We discuss contexts in which “big data” and computational approaches, especially network-based modeling, may advance neuroblastoma research, describe currently available data and resources, and propose future models of strategic data collection and analyses for neuroblastoma and other related diseases.

  14. A Bibliometric Review on Risk Management and Building Information Modeling for International Construction

    Directory of Open Access Journals (Sweden)

    Tsenguun Ganbat

    2018-01-01

    Full Text Available International construction is complicated and involves high risks. However, with the development of technological innovation, Building Information Modeling (BIM emerged and seems to be able to address certain risks. To understand BIM applications in risk management for international construction, a state-of-the-art review is required. Therefore, this paper aims to identify the research trends and opportunities for risk management in BIM-enabled international construction by reviewing 526 peer-reviewed journal articles for the years 2007–2017. Thus five steps of bibliometric analysis were conducted based on the proposed frameworks of BIM risk management in international construction (BIM-RM-INTL. The results show that the popularization of BIM not only attracts all stakeholders’ interests but also brings some risks. For example, financial factors are hard to detect and control through BIM, information loss during transmission stands out, and BIM has no unified standards and regulations for international construction. The research has mapped existing research results and their relationships for future risk management in BIM-enabled international construction.

  15. Appraising longitudinal trends in the strategic risks cited by risk managers in the international water utility sector, 2005-2015.

    Science.gov (United States)

    Chalker, Rosemary T C; Pollard, Simon J T; Leinster, Paul; Jude, Simon

    2018-03-15

    We report dynamic changes in the priorities for strategic risks faced by international water utilities over a 10year period, as cited by managers responsible for managing them. A content analysis of interviews with three cohorts of risk managers in the water sector was undertaken. Interviews probed the focus risk managers' were giving to strategic risks within utilities, as well as specific questions on risk analysis tools (2005); risk management cultures (2011) and the integration of risk management with corporate decision-making (2015). The coding frequency of strategic (business, enterprise, corporate) risk terms from 18 structured interviews (2005) and 28 semi-structured interviews (12 in 2011; 16 in 2015) was used to appraise changes in the perceived importance of strategic risks within the sector. The aggregated coding frequency across the study period, and changes in the frequency of strategic risks cited at three interview periods identified infrastructure assets as the most significant risk over the period and suggests an emergence of extrinsic risk over time. Extended interviews with three utility risk managers (2016) from the UK, Canada and the US were then used to contextualise the findings. This research supports the ongoing focus on infrastructure resilience and the increasing prevalence of extrinsic risk within the water sector, as reported by the insurance sector and by water research organisations. The extended interviews provided insight into how strategic risks are now driving the implementation agenda within utilities, and into how utilities can secure tangible business value from proactive risk governance. Strategic external risks affecting the sector are on the rise, involve more players and are less controllable from within a utility's own organisational boundaries. Proportionate risk management processes and structures provide oversight and assurance, whilst allowing a focus on the tangible business value that comes from managing strategic

  16. Business Process Risk Management, Compliance and Internal Control: A Research Agenda

    DEFF Research Database (Denmark)

    Rikhardsson, Pall M.; Best, Peter; Green, Peter

    (COSO). Based on an inductive methodological approach using literature review and interviews with managers engaged in risk management and internal control projects, this paper identifies three main areas that currently have management attention. These are business process risk management, compliance...... management and internal control development. This paper discusses these areas and identifies a series of research questions regarding these critical issues.......Integration of risk management and management control is emerging as an important area in the wake of the Sarbanes-Oxley Act and with ongoing development of frameworks such as the Enterprise Risk Management (ERM) framework from the Committee of Sponsoring Organizations of the Treadway Commission...

  17. MYC-family protein overexpression and prominent nucleolar formation represent prognostic indicators and potential therapeutic targets for aggressive high-MKI neuroblastomas: a report from the children's oncology group.

    Science.gov (United States)

    Niemas-Teshiba, Risa; Matsuno, Ryosuke; Wang, Larry L; Tang, Xao X; Chiu, Bill; Zeki, Jasmine; Coburn, Jeannine; Ornell, Kimberly; Naranjo, Arlene; Van Ryn, Collin; London, Wendy B; Hogarty, Michael D; Gastier-Foster, Julie M; Look, A Thomas; Park, Julie R; Maris, John M; Cohn, Susan L; Seeger, Robert C; Asgharzadeh, Shahab; Ikegaki, Naohiko; Shimada, Hiroyuki

    2018-01-19

    Neuroblastomas with a high mitosis-karyorrhexis index (High-MKI) are often associated with MYCN amplification, MYCN protein overexpression and adverse clinical outcome. However, the prognostic effect of MYC-family protein expression on these neuroblastomas is less understood, especially when MYCN is not amplified. To address this, MYCN and MYC protein expression in High-MKI cases (120 MYCN amplified and 121 non- MYCN amplified) was examined by immunohistochemistry. The majority (101) of MYCN -amplified High-MKI tumors were MYCN(+), leaving one MYC(+), 2 both(+), and 16 both(-)/(+/-), whereas non- MYCN -amplified cases appeared heterogeneous, including 7 MYCN(+), 36 MYC(+), 3 both(+), and 75 both(-)/(+/-) tumors. These MYC-family proteins(+), or MYC-family driven tumors, were most likely to have prominent nucleolar (PN) formation (indicative of augmented rRNA synthesis). High-MKI neuroblastoma patients showed a poor survival irrespective of MYCN amplification. However, patients with MYC-family driven High-MKI neuroblastomas had significantly lower survival than those with non-MYC-family driven tumors. MYCN(+), MYC-family protein(+), PN(+), and clinical stage independently predicted poor survival. Specific inhibition of hyperactive rRNA synthesis and protein translation was shown to be an effective way to suppress MYC/MYCN protein expression and neuroblastoma growth. Together, MYC-family protein overexpression and PN formation should be included in new neuroblastoma risk stratification and considered for potential therapeutic targets.

  18. Synthetic Lethal Screen Identifies NF-κB as a Target for Combination Therapy with Topotecan for patients with Neuroblastoma

    International Nuclear Information System (INIS)

    Tsang, Patricia S; Cheuk, Adam T; Chen, Qing-Rong; Song, Young K; Badgett, Thomas C; Wei, Jun S; Khan, Javed

    2012-01-01

    Despite aggressive multimodal treatments the overall survival of patients with high-risk neuroblastoma remains poor. The aim of this study was to identify novel combination chemotherapy to improve survival rate in patients with high-risk neuroblastoma. We took a synthetic lethal approach using a siRNA library targeting 418 apoptosis-related genes and identified genes and pathways whose inhibition synergized with topotecan. Microarray analyses of cells treated with topotecan were performed to identify if the same genes or pathways were altered by the drug. An inhibitor of this pathway was used in combination with topotecan to confirm synergism by in vitro and in vivo studies. We found that there were nine genes whose suppression synergized with topotecan to enhance cell death, and the NF-κB signaling pathway was significantly enriched. Microarray analysis of cells treated with topotecan revealed a significant enrichment of NF-κB target genes among the differentially altered genes, suggesting that NF-κB pathway was activated in the treated cells. Combination of topotecan and known NF-κB inhibitors (NSC 676914 or bortezomib) significantly reduced cell growth and induced caspase 3 activity in vitro. Furthermore, in a neuroblastoma xenograft mouse model, combined treatment of topotecan and bortezomib significantly delayed tumor formation compared to single-drug treatments. Synthetic lethal screening provides a rational approach for selecting drugs for use in combination therapy and warrants clinical evaluation of the efficacy of the combination of topotecan and bortezomib or other NF-κB inhibitors in patients with high risk neuroblastoma

  19. Synthetic Lethal Screen Identifies NF-κB as a Target for Combination Therapy with Topotecan for patients with Neuroblastoma

    Directory of Open Access Journals (Sweden)

    Tsang Patricia S

    2012-03-01

    Full Text Available Abstract Background Despite aggressive multimodal treatments the overall survival of patients with high-risk neuroblastoma remains poor. The aim of this study was to identify novel combination chemotherapy to improve survival rate in patients with high-risk neuroblastoma. Methods We took a synthetic lethal approach using a siRNA library targeting 418 apoptosis-related genes and identified genes and pathways whose inhibition synergized with topotecan. Microarray analyses of cells treated with topotecan were performed to identify if the same genes or pathways were altered by the drug. An inhibitor of this pathway was used in combination with topotecan to confirm synergism by in vitro and in vivo studies. Results We found that there were nine genes whose suppression synergized with topotecan to enhance cell death, and the NF-κB signaling pathway was significantly enriched. Microarray analysis of cells treated with topotecan revealed a significant enrichment of NF-κB target genes among the differentially altered genes, suggesting that NF-κB pathway was activated in the treated cells. Combination of topotecan and known NF-κB inhibitors (NSC 676914 or bortezomib significantly reduced cell growth and induced caspase 3 activity in vitro. Furthermore, in a neuroblastoma xenograft mouse model, combined treatment of topotecan and bortezomib significantly delayed tumor formation compared to single-drug treatments. Conclusions Synthetic lethal screening provides a rational approach for selecting drugs for use in combination therapy and warrants clinical evaluation of the efficacy of the combination of topotecan and bortezomib or other NF-κB inhibitors in patients with high risk neuroblastoma.

  20. Refractory diarrhea: A paraneoplastic syndrome of neuroblastoma.

    Science.gov (United States)

    Han, Wei; Wang, Huan-Min

    2015-07-07

    Neuroblastoma (NB) is the most common extracranial solid tumor in children. Diarrheal NB is quite rare and is not easy to diagnose in the early stage. Six cases of diarrheal NB in our hospital treated from 1996 to 2006 were retrospectively analyzed, including characteristics such as electrolyte imbalance, pathologic features, vasoactive intestinal peptide (VIP) immunohistochemical staining results, treatment, and prognosis. All patients were boys with 3-8 loose or watery stools each day and routine fecal tests were normal. Abdominal tumors were identified by B-ultrasound. Drugs were ineffective. Three patients underwent surgery, and the remaining three patients received surgery and chemotherapy. Diarrhea stopped after treatment in five patients. Two patients died due to intractable hypokalemia. The tumor was located in the adrenal gland in four patients, in the upper retroperitoneum in one patient, and in the presacral area in one patient. Pathologic findings were NB and ganglioneuroblastoma. Five patients were at clinical stage I-II, and one was at stage III. Four patients survived (followed-up for 6 mo to 4 years). Immunohistochemical staining for VIP was positive. Refractory diarrhea is a paraneoplastic syndrome of NB and is rare. Patients aged 1-3 years who present with chronic intractable diarrhea should be followed closely. Intractable diarrhea, hypokalemia, and dysplasia are the initial clinical manifestations. Increased VIP is characteristic of this disease. Potassium supplementation plays a vital role in the treatment procedure, especially preoperatively. The prognosis of diarrheal NB is good following appropriate treatment.

  1. Cytopathogenicity of Naegleria for cultured neuroblastoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Fulford, D.E.

    1985-01-01

    The cytopathic activity of live Naegleria amoebae and cell-free lysates of Naegleria for B-103 rat neuroblastoma cells was investigated using a /sup 51/Cr release assay. Live amoebae and cell-free lysates of N. fowleri, N. australiensis, N. lovaniensis, and N. gruberi all induced sufficient damage to radiolabeled B-103 cells to cause a significant release of chromium. The cytotoxic activity present in the cell-free lysates of N. fowleri can be recovered in the supernatant fluid following centrifugation at 100,000xg and precipitation of the 100,000xg supernatant fluid with ammonium sulfate. Initial characterization of the cytotoxic factor indicates that it is a heat labile, pH sensitive, soluble protein. The cytotoxic activity is abolished by either extraction, unaffected by repeated freeze-thawing, and is not sensitive to inhibitors of proteolytic enzymes. Phospholipase A activity was detected in the cytotoxic ammonium sulfate precipitable material, suggesting that this enzyme activity may have a role in the cytotoxic activity of the cell-free lysates.

  2. Validation Techniques of the Intern Models for Credit Risk

    OpenAIRE

    Bogdan Moinescu; Nicolae Dardac

    2006-01-01

    The new own funds adequacy device, officialy named “ International Convergence of Capital Measurement and Capital Standards”, describes the most important benchmark framework for micro-prudential supervision at the moment. The publication of the final text in June 2004, after five years of deliberations, represents the result of multiple analyses and comments provided by all interested parties, banking supervision authorities, associations and credit institutions. Provided the development of ...

  3. An Ounce of Prevention Is Worth. . . The Life of a Student: Reducing Risk in International Programs.

    Science.gov (United States)

    Hoye, William P.; Rhodes, Gary M.

    2000-01-01

    Highlights the issues of risk and legal liability in international study abroad programs for college and university administrators and their counsel. Seeks to encourage increased institutional commitment of resources to protect participants from reasonably foreseeable harm. (EV)

  4. International pharmaceutical social risk regulation: An ethical perspective.

    Science.gov (United States)

    Gordon, Cameron

    2011-03-01

    Pharmaceutical production and distribution constitute big business. For the companies the rewards can be substantial. Rates of return on drug company investments tend to be higher than many other manufacturing enterprises. But reward is only one side of the story. There is also the issue of social risk, the focus of this article. Social risk for pharmaceutical production is especially pronounced. An ineffective or, worse, dangerous drug, can have dire consequences for the population at large. For this reason, there is elaborate government regulation and oversight of drug safety and risk. These systems, especially in the US and Europe, will be the main focus of this paper. The two systems will be described, and then compared and contrasted in terms of their framing of social risk and actions governments take to limit it. Systems elsewhere, especially in the developing world, are increasing in relative importance and these will be briefly discussed as well. Ethical issues that have arisen in these various systems will be surfaced and analysed. The paper will close with some conclusions and suggestions for further research.

  5. Evaluation and Selection of International Supplier, Underscoring Risk Factors

    Directory of Open Access Journals (Sweden)

    seyed Mohammad Ali Khatami Firouzabadi

    2014-05-01

    Full Text Available This paper evaluates the decision making process for import complete manufactured pieces versus import of partial pieces to assemble in Iran, taking into account the risk factors for a manufacturing company. Since this sort of decision making confront with several risks, it is necessary to establish a process for finding the risks associated with this kind of problems in order to decrease the effects of these risks in the process. Since the problem is classified as a Multiple Criteria Decision Making (MCDM problem, Uncertain Analytical Hierarchy Process (UAHP was used to find the most attractive alternative. Because the alternatives were identified from the first point, a bottom-up procedure was used to organize the hierarchy. In initial stage, the attributes which distinct from the alternatives were obtained by literature review and experts' interviews. Then the attributes were grouped to upper level to establish the criteria. Three criteria were found from this stage. The criteria were product, partners, and environment which they encompassed 12 attributes. Forming the hierarchy and doing the uncertain pairwised comparisons, which considers a range of numbers instead of one single number for declaring the preference between two factors, a Linear Programming (LP model with two types of objective functions were formed for each individual alternative. Each single LP model can express the maximum and minimum value of each individual alternative. The research's results indicate the most appropriate alternative is to import the final product from India. The last preferred one was to import the parts of the final product from India. This study can be a suitable framework in supply chain management and purchasing decisions and risk evaluations because the major parts of manufacturing activities is always to decide about the selection of most preferred strategies for companies.

  6. Neuroblastoma cells undergo transcriptomic alterations upon dissemination into the bone marrow and subsequent tumor progression.

    Science.gov (United States)

    Rifatbegovic, Fikret; Frech, Christian; Abbasi, M Reza; Taschner-Mandl, Sabine; Weiss, Tamara; Schmidt, Wolfgang M; Schmidt, Iris; Ladenstein, Ruth; Ambros, Inge M; Ambros, Peter F

    2018-01-15

    Neuroblastoma is the most common extracranial solid tumor in childhood. The vast majority of metastatic (M) stage patients present with disseminated tumor cells (DTCs) in the bone marrow (BM) at diagnosis and relapse. Although these cells represent a major obstacle in the treatment of neuroblastoma patients, insights into their expression profile remained elusive. The present RNA-Seq study of stage 4/M primary tumors, enriched BM-derived diagnostic and relapse DTCs, as well as the corresponding BM-derived mononuclear cells (MNCs) from 53 patients revealed 322 differentially expressed genes in DTCs as compared to the tumors (q 2). Particularly, the levels of transcripts encoded by mitochondrial DNA were elevated in DTCs, whereas, for example, genes involved in angiogenesis were downregulated. Furthermore, 224 genes were highly expressed in DTCs and only slightly, if at all, in MNCs (q  6). Interestingly, we found the transcriptome of relapse DTCs largely resembling those of diagnostic DTCs with only 113 differentially expressed genes under relaxed cut-offs (q 0.5). Notably, relapse DTCs showed a positional enrichment of 31 downregulated genes on chromosome 19, including five tumor suppressor genes: SIRT6, BBC3/PUMA, STK11, CADM4 and GLTSCR2. This first RNA-Seq analysis of neuroblastoma DTCs revealed their unique expression profile in comparison to the tumors and MNCs, and less pronounced differences between diagnostic and relapse DTCs. The latter preferentially affected downregulation of genes encoded by chromosome 19. As these alterations might be associated with treatment failure and disease relapse, further functional studies on DTCs should be considered. © 2017 The Authors International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.

  7. Radiation and society: Comprehending radiation risk. V. 3. Proceedings of an international conference

    International Nuclear Information System (INIS)

    1997-01-01

    This IAEA international conference on Radiation and Society was the first major international meeting devoted to the comprehension of radiation risk, public attitude towards radiation risk and hazards encountered by the general public in contaminated areas. Volume three of the proceedings contains the speeches, ten introductory papers, summaries of the technical discussion sessions, the key note paper on uncertainties in the health impact of environmental pollutants. Refs, figs, tabs

  8. A Hybrid Robotic Control System Using Neuroblastoma Cultures

    Science.gov (United States)

    Ferrández, J. M.; Lorente, V.; Cuadra, J. M.; Delapaz, F.; Álvarez-Sánchez, José Ramón; Fernández, E.

    The main objective of this work is to analyze the computing capabilities of human neuroblastoma cultured cells and to define connection schemes for controlling a robot behavior. Multielectrode Array (MEA) setups have been designed for direct culturing neural cells over silicon or glass substrates, providing the capability to stimulate and record simultaneously populations of neural cells. This paper describes the process of growing human neuroblastoma cells over MEA substrates and tries to modulate the natural physiologic responses of these cells by tetanic stimulation of the culture. We show that the large neuroblastoma networks developed in cultured MEAs are capable of learning: establishing numerous and dynamic connections, with modifiability induced by external stimuli and we propose an hybrid system for controlling a robot to avoid obstacles.

  9. 17 CFR 240.17i-4 - Internal risk management control system requirements for supervised investment bank holding...

    Science.gov (United States)

    2010-04-01

    ... Supervised Investment Bank Holding Company Rules § 240.17i-4 Internal risk management control system...) As part of its internal risk management control system, a supervised investment bank holding company... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Internal risk management...

  10. International legal framework for geoengineering: Managing the risks of an emerging technology

    NARCIS (Netherlands)

    Du, Haomiao

    2016-01-01

    The present book “International Legal Framework for Geoengineering – Managing the Risks of an Emerging Technology” is about international law and an emerging technology called geoengineering, which refers to the large-scale manipulation of the planetary environment for counteracting anthropogenic

  11. Cultural Awareness, a Form of Risk Management in International Business: Case Study of China

    OpenAIRE

    Fadun Solomon Olajide

    2014-01-01

    Mutual awareness of cultural references is essential in international business as levels of formality vary greatly among cultures. The emergence of capitalism into China induces international firms¡¯ investment in the country. This resulted to creation of a production base to explore the inexpensive factors of production, particularly low-cost labour. The study examines cultural awareness as a form of risk management in international business, using China as a case study. The study uses ¡®XYZ...

  12. Neuroblastoma in adults. Three case reports and a review of the literature.

    Science.gov (United States)

    Kaye, J A; Warhol, M J; Kretschmar, C; Landsberg, L; Frei, E

    1986-09-01

    Three adult patients with neuroblastoma have been treated recently at the Dana-Farber Cancer Institute. One adult neuroblastoma patient experienced two distinct paraneoplastic syndromes that have not been reported previously in association with neuroblastoma. The clinical data on our three patients are presented in detail and the important features of 27 cases that have been described in the literature are summarized. This study suggests that the distribution of primary neuroblastoma sites in adults is similar to that seen in pediatric cases but that the natural history of the disease may be longer. Furthermore, this study suggests that neuroblastoma in adults may be less sensitive to chemotherapy than is the childhood disease.

  13. IT Operational Risk Measurement Model Based on Internal Loss Data of Banks

    Science.gov (United States)

    Hao, Xiaoling

    Business operation of banks relies increasingly on information technology (IT) and the most important role of IT is to guarantee the operational continuity of business process. Therefore, IT Risk management efforts need to be seen from the perspective of operational continuity. Traditional IT risk studies focused on IT asset-based risk analysis and risk-matrix based qualitative risk evaluation. In practice, IT risk management practices of banking industry are still limited to the IT department and aren't integrated into business risk management, which causes the two departments to work in isolation. This paper presents an improved methodology for dealing with IT operational risk. It adopts quantitative measurement method, based on the internal business loss data about IT events, and uses Monte Carlo simulation to predict the potential losses. We establish the correlation between the IT resources and business processes to make sure risk management of IT and business can work synergistically.

  14. MIBG avidity correlates with clinical features, tumor biology, and outcomes in neuroblastoma: A report from the Children's Oncology Group.

    Science.gov (United States)

    DuBois, Steven G; Mody, Rajen; Naranjo, Arlene; Van Ryn, Collin; Russ, Douglas; Oldridge, Derek; Kreissman, Susan; Baker, David L; Parisi, Marguerite; Shulkin, Barry L; Bai, Harrison; Diskin, Sharon J; Batra, Vandana; Maris, John M; Park, Julie R; Matthay, Katherine K; Yanik, Gregory

    2017-11-01

    Prior studies suggest that neuroblastomas that do not accumulate metaiodobenzylguanidine (MIBG) on diagnostic imaging (MIBG non-avid) may have more favorable features compared with MIBG avid tumors. We compared clinical features, biologic features, and clinical outcomes between patients with MIBG nonavid and MIBG avid neuroblastoma. Patients had metastatic high- or intermediate-risk neuroblastoma and were treated on Children's Oncology Group protocols A3973 or A3961. Comparisons of clinical and biologic features according to MIBG avidity were made with chi-squared or Fisher exact tests. Event-free (EFS) and overall (OS) survival compared using log-rank tests and modeled using Cox models. Thirty of 343 patients (8.7%) had MIBG nonavid disease. Patients with nonavid tumors were less likely to have adrenal primary tumors (34.5 vs. 57.2%; P = 0.019), bone metastases (36.7 vs. 61.7%; P = 0.008), or positive urine catecholamines (66.7 vs. 91.0%; P < 0.001) compared with patients with MIBG avid tumors. Nonavid tumors were more likely to be MYCN amplified (53.8 vs. 32.6%; P = 0.030) and had lower norepinephrine transporter expression. Patients with MIBG nonavid disease had a 5-year EFS of 50.0% compared with 38.7% for patients with MIBG avid disease (P = 0.028). On multivariate testing in high-risk patients, MIBG avidity was the sole adverse prognostic factor for EFS identified (hazard ratio 1.77; 95% confidence interval 1.04-2.99; P = 0.034). Patients with MIBG nonavid neuroblastoma have lower rates of adrenal primary tumors, bone metastasis, and catecholamine secretion. Despite being more likely to have MYCN-amplified tumors, these patients have superior outcomes compared with patients with MIBG avid disease. © 2017 Wiley Periodicals, Inc.

  15. Probenecid Sensitizes Neuroblastoma Cancer Stem Cells to Cisplatin.

    Science.gov (United States)

    Campos-Arroyo, Denise; Maldonado, Vilma; Bahena, Ivan; Quintanar, Valeria; Patiño, Nelly; Carlos Martinez-Lazcano, Juan; Melendez-Zajgla, Jorge

    2016-01-01

    We used both in vitro cultures of neuroblastoma cell lines and nude-mice xenotransplants to explore the effects of co-administration of cisplatin and probenecid. Probenecid sensitized neuroblastoma cells, including tumor cells with stem features, to the effects of cisplatin, both in vitro and in vivo. This effect was mediated by an increase in the apoptotic cell death and a concomitant decrease in cell proliferation. This effect is accompanied by modulation of the mRNA and protein of the drug efflux transporters MDR1, MRP2, and BCRP. The co-administration of probenecid with cisplatin should be explored as a possible therapeutic strategy.

  16. Central nervous system relapse of treated stage IV neuroblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Palasis, S.; Egelhoff, J.C.; Koch, B.L.; Ball, W.S. Jr. [Department of Radiology, Children`s Hospital Medical Center, Cincinnati, OH (United States); Morris, J.D. [Department of Pediatrics, Children`s Hospital Medical Center, Cincinnati, OH (United States)

    1998-12-01

    Neuroblastoma is the most common extracranial solid tumor in pediatrics. The long-term survival of patients with advanced-stage neurobastoma has remarkably improved secondary to aggressive treatment protocols including autologous bone marrow transplant (BMT). As a result, a different natural history of this disease is being reported with unusual, late manifestations. The central nervous system (CNS), once a rare site of disease, is being involved with increasing frequency. Appropriate neuroimaging in these patients is important. Two cases of patients with treated stage IV neuroblastoma who developed isolated CNS metastases are presented. The proposed pathogenesis and neuroradiologic manifestations of this complication are reviewed. (orig.) With 2 figs., 23 refs.

  17. Towards internationally acceptable standards for food additives and contaminants based on the use of risk analysis

    NARCIS (Netherlands)

    Huggett, A.; Petersen, B.J.; Walker, R.; Fisher, C.E.; Notermans, S.H.W.; Rombouts, F.M.; Abbott, P.; Debackere, M.; Hathaway, S.C.; Hecker, E.F.F.; Knaap, A.G.A.; Kuznesof, P.M.; Meyland, I.; Moy, G.; Narbonne, J.-F.; Paakkanen, J.; Smith, M.R.; Tennant, D.; Wagstaffe, P.; Wargo, J.; Würtzen, G.

    1998-01-01

    Internationally acceptable norms need to incorporate sound science and consistent risk management principles in an open and transparent manner, as set out in the Agreement on the Application of Sanitary and Phytosanitary Measures (the SPS Agreement). The process of risk analysis provides a procedure

  18. The Three Rs: Parental Risk Management Strategies in the International Secondary Education Market

    Science.gov (United States)

    Ayling, Pere

    2017-01-01

    Risk permeates all aspects of modern life, and the International Secondary Education Market (ISEM) is no exception. Drawing on empirical data, this paper considers a specific type of risk: namely, the potential loss of cultural identity, which Nigerian parents associate with educating their children in the West. This paper argues that Nigerian…

  19. Proceedings of the International conference on energy alternatives/risk education V. 1

    International Nuclear Information System (INIS)

    Marx, Gyoergy

    1990-02-01

    This Proceedings volume on Energy Education within the context of the International Conference on Energy Alternatives/Risk Education contains papers on Energy Education, on Nuclear Education and on Risk Education. Ten papers concerning nuclear science and technology, and nuclear energy, were indexed and abstracted separately for the INIS database. (R.P.)

  20. 17 CFR 240.15c3-4 - Internal risk management control systems for OTC derivatives dealers.

    Science.gov (United States)

    2010-04-01

    ...-Counter Markets § 240.15c3-4 Internal risk management control systems for OTC derivatives dealers. (a) An... controls to assist it in managing the risks associated with its business activities, including market... derivatives dealer's internal risk management control system shall include the following elements: (1) A risk...

  1. The delivery of poly(lactic acid)-poly(ethylene glycol) nanoparticles loaded with non-toxic drug to overcome drug resistance for the treatment of neuroblastoma

    Science.gov (United States)

    Dhulekar, Jhilmil

    Neuroblastoma is a rare cancer of the sympathetic nervous system. A neuroblastoma tumor develops in the nerve tissue and is diagnosed in infants and children. Approximately 10.2 per million children under the age of 15 are affected in the United States and is slightly more common in boys. Neuroblastoma constitutes 6% of all childhood cancers and has a long-term survival rate of only 15%. There are approximately 700 new cases of neuroblastoma each year in the United States. With such a low rate of survival, the development of more effective treatment methods is necessary. A number of therapies are available for the treatment of these tumors; however, clinicians and their patients face the challenges of systemic side effects and drug resistance of the tumor cells. The application of nanoparticles has the potential to provide a safer and more effective method of delivery drugs to tumors. The advantage of using nanoparticles for drug delivery is the ability to specifically or passively target tumors while reducing the harmful side effects of chemotherapeutics. Drug delivery via nanoparticles can also allow for lower dosage requirements with controlled release of the drugs, which can further reduce systemic toxicity. The aim of this research was to develop a polymeric nanoparticle drug delivery system for the treatment of high-risk neuroblastoma. Nanoparticles composed of a poly(lactic acid)-poly(ethylene glycol) block copolymer were formulated to deliver a non-toxic drug in combination with Temozolomide, a commonly used chemotherapeutic drug for the treatment of neuroblastoma. The non-toxic drug acts as an inhibitor to the DNA-repair protein present in neuroblastoma cells that is responsible for inducing drug resistance in the cells, which would potentially allow for enhanced temozolomide activity. A variety of studies were completed to prove the nanoparticles' low toxicity, loading abilities, and uptake into cells. Additionally, studies were performed to determine the

  2. HSD17B12 gene rs11037575 C>T polymorphism confers neuroblastoma susceptibility in a Southern Chinese population

    Directory of Open Access Journals (Sweden)

    Zhang ZR

    2017-04-01

    Full Text Available Zhuorong Zhang,1,2 Yan Zou,2 Jinhong Zhu,3 Ruizhong Zhang,2 Tianyou Yang,2 Fenghua Wang,2 Huimin Xia,1,2 Jing He,2 Zhichun Feng1,4–6 1Southern Medical University, Guangzhou, Guangdong, 2Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, 3Molecular Epidemiology Laboratory, Department of Laboratory Medicine, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, 4Division of Neonatology, Affiliated BaYi Children’s Hospital, Clinical Medical College in PLA Army General Hospital, Southern Medical University, 5National Engineering Laboratory for Birth Defects Prevention and Control of Key Technology, 6Beijing Key Laboratory of Pediatric Organ Failure, Beijing, People’s Republic of China Abstract: A previous genome-wide association study (GWAS identified four genetic polymorphisms (rs1027702 near DUSP12, rs10055201 in IL31RA, rs2619046 in DDX4, and rs11037575 in HSD17B12 gene that were associated with neuroblastoma susceptibility, especially for low-risk subjects. The aim of this study was to examine the association between these four polymorphisms and neuroblastoma susceptibility in a Southern Chinese population composed of 256 cases and 531 controls. Overall, among all the polymorphisms, single-locus analysis only revealed significant association between the HSD17B12 rs11037575 C>T polymorphism and neuroblastoma susceptibility (CT vs CC: adjusted odds ratio [OR] =0.71, 95% confidence interval [CI] =0.51–0.97, P=0.030. Moreover, stratified analysis indicated that the rs11037575 T allele was associated with decreased neuroblastoma risk among the children aged 0–18 months (adjusted OR =0.60, 95% CI =0.37–0.97, P=0.036; regarding the tumor site, this polymorphism protected against tumor in the mediastinum (adjusted OR =0.59, 95% CI =0.37–0.94, P=0.025. When risk genotypes were combined, we found that girls with

  3. THE FINANCIAL INSTRUMENTS FOR RISK MANAGEMENT ON THE INTERNATIONAL FINANCIAL MARKETS

    Directory of Open Access Journals (Sweden)

    Alina Hagiu

    2008-05-01

    Full Text Available The international financial market is extremely volatile because of the influence of anumerous objective and subjective factors. Because of these, în their fight for maximizing the profit, the creditinstitutes confronts permanently with all sort of risks.It is important to know that the risk is generated by a numerous operations and procedures. From thesecause, at least în the financial field, the risk must be considered as a complex of risks, în the sense that they canhave common causes, and producing a risk can generate a chain reaction, and producing other risks. As aconsequence, these operations and procedures can permanently generate an exposure to the risk.The risk management is the key function of the financial institution, which act on the internationalfinancial market. For doing this, it must be used some important instruments that can conduce to avoiding risksor dimensioning them.

  4. GD2-targeted immunotherapy and potential value of circulating microRNAs in neuroblastoma.

    Science.gov (United States)

    Gholamin, Sharareh; Mirzaei, Hamed; Razavi, Seyed-Mostafa; Hassanian, Seyed Mahdi; Saadatpour, Leila; Masoudifar, Aria; ShahidSales, Soodabeh; Avan, Amir

    2018-02-01

    Neuroblastoma (NB) with various clinical presentation is a known childhood malignancy. Despite significant progress in treatment of NB afflicted patients, high risk disease is usually associated with poor outcome, resulting in long-term survival of less that 50%. Known as a disease most commonly originated form the nerve roots, the variants involved in NB imitation and progression remain to be elucidated. The outcome of low to intermediate risk disease is favorable whereas the high risk NB disease with dismal prognosis, positing the necessity of novel approaches for early detection and prognostication of advanced disease. Tailored immunotherapy approaches have shown significant improvement in high-risk NB patients. It has found a link between Gangliosides and progression of NB. The vast majority of neuroblastoma tumors express elevated levels of GD2, opening new insight into using anti-GD2 drugs as potential treatments for NBs. Implication of anti-GD2 monoclonal antibodies for treatment of high risk NBs triggers further investigation to unearth novel biomarkers as prognostic and response biomarker to guide additional multimodal tailored treatment approaches. A growing body of evidence supports the usefulness of miRNAs to evaluate high risk NBs response to anti-GD2 drugs and further prevent drug-related toxicities in refractory or recurrent NBs. miRNAs and circulating proteins in body fluids (plasma and serum) present as potential biomarkers in early detection of NBs. Here, we summarize various biomarkers involved in diagnosis, prognosis and response to treatment in patients with NB. We further attempted to overview prognostic biomarkers in response to treatment with anti-GD2 drugs. © 2017 Wiley Periodicals, Inc.

  5. The small molecule inhibitor YK-4-279 disrupts mitotic progression of neuroblastoma cells, overcomes drug resistance and synergizes with inhibitors of mitosis.

    Science.gov (United States)

    Kollareddy, Madhu; Sherrard, Alice; Park, Ji Hyun; Szemes, Marianna; Gallacher, Kelli; Melegh, Zsombor; Oltean, Sebastian; Michaelis, Martin; Cinatl, Jindrich; Kaidi, Abderrahmane; Malik, Karim

    2017-09-10

    Neuroblastoma is a biologically and clinically heterogeneous pediatric malignancy that includes a high-risk subset for which new therapeutic agents are urgently required. As well as MYCN amplification, activating point mutations of ALK and NRAS are associated with high-risk and relapsing neuroblastoma. As both ALK and RAS signal through the MEK/ERK pathway, we sought to evaluate two previously reported inhibitors of ETS-related transcription factors, which are transcriptional mediators of the Ras-MEK/ERK pathway in other cancers. Here we show that YK-4-279 suppressed growth and triggered apoptosis in nine neuroblastoma cell lines, while BRD32048, another ETV1 inhibitor, was ineffective. These results suggest that YK-4-279 acts independently of ETS-related transcription factors. Further analysis reveals that YK-4-279 induces mitotic arrest in prometaphase, resulting in subsequent cell death. Mechanistically, we show that YK-4-279 inhibits the formation of kinetochore microtubules, with treated cells showing a broad range of abnormalities including multipolar, fragmented and unseparated spindles, together leading to disrupted progression through mitosis. Notably, YK-4-279 does not affect microtubule acetylation, unlike the conventional mitotic poisons paclitaxel and vincristine. Consistent with this, we demonstrate that YK-4-279 overcomes vincristine-induced resistance in two neuroblastoma cell-line models. Furthermore, combinations of YK-4-279 with vincristine, paclitaxel or the Aurora kinase A inhibitor MLN8237/Alisertib show strong synergy, particularly at low doses. Thus, YK-4-279 could potentially be used as a single-agent or in combination therapies for the treatment of high-risk and relapsing neuroblastoma, as well as other cancers. Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.

  6. A comparison of targeting of neuroblastoma with mIBG and anti L1-CAM antibody mAb chCE7: therapeutic efficacy in a neuroblastoma xenograft model and imaging of neuroblastoma patients

    NARCIS (Netherlands)

    Hoefnagel, C. A.; Rutgers, M.; Buitenhuis, C. K.; Smets, L. A.; de Kraker, J.; Meli, M.; Carrel, F.; Amstutz, H.; Schubiger, P. A.; Novak-Hofer, I.

    2001-01-01

    Iodine-131 labelled anti L1-CAM antibody mAb chCE7 was compared with the effective neuroblastoma-seeking agent 131I-labelled metaiodobenzylguanidine (MIBG) with regard to (a) its therapeutic efficacy in treating nude mice with neuroblastoma xenografts and (b) its tumour targeting ability in

  7. Discovery – Ch14.18 Immunotherapy to Treat Neuroblastoma

    Science.gov (United States)

    Neuroblastoma is rare yet it's the most common cancer affecting infants. Prior to a discovery 20 years in the making, there was little hope for survival in children with advanced stages of the disease. Today, research is leading to a brighter outlook.

  8. Intracranial route of a cervical neuroblastoma through skull base foramina

    International Nuclear Information System (INIS)

    Goldberg, R.M.; Keller, I.A.; Schonfeld, S.M.; Mezrich, R.S.; Rosenfeld, D.L.

    1996-01-01

    A case of primary cervical neuroblastoma gaining access to the cerebellopontine angle via direct perineural spread is described. MRI effectively delineated soft tissues, while CT demonstrated tumor calcifications and the integrity of adjacent bones. Both imaging modalities were beneficial in predicting the unique histology and pattern of disease confirmed at surgery. (orig.). With 1 fig

  9. CASE REPORT Proptosis as a manifestation of neuroblastoma ...

    African Journals Online (AJOL)

    disease requires aggressive management. We present a case of a 7-year- old girl initially presenting ... present initially with evidence of metastatic disease without a readily identifiable primary lesion. Neuroblastoma commonly ... Usually one adrenal gland is involved; bilateral involvement is rare.2. Symptoms may be due to ...

  10. Banks’ internal controls and risk management: Value-added functions in Italian credit cooperative banks

    Directory of Open Access Journals (Sweden)

    Rosaria Cerrone

    2013-12-01

    Full Text Available A critical component of safe and sound bank management is constituted by an effective and efficient system of internal controls, which help to ensure that the goals and objectives of a bank will be met, that long-term profitability targets will be achieved, and maintain reliable financial and managerial reporting. Such a system can also ensure that the bank will comply with laws and regulations as well as policies, plans, internal rules and procedures, and decrease the risk of unexpected losses or damage to the bank’s reputation. The paper describes the essential elements of a sound internal control system and through a qualitative approach, it shows how is tied to the rules attaining capital requirements and, above all, to the purpose of the Internal Capital Adequacy Assessment Process (ICAAP which aims at determining the adequate capitalisation of a bank given the risks endured as well as future risks arising from growth, and new business lines. After the recent financial crisis ICAAP is becoming more and more relevant and a central component of an effective strategy for managing risk and creating value. All principles and considerations are referred to Italian Credit Cooperative Banks particular both for dimension and for governance and risk management. They have been contacted though local federations and the results confirm the existing of weakness in internal controls.

  11. Health-promoting lifestyles and cardio-metabolic risk factors among international students in South Korea.

    Science.gov (United States)

    Kim, Chun-Ja; Park, Jeewon; Kang, Se-Won

    2015-01-01

    This study examined the health-promoting lifestyles and cardio-metabolic risks among international students in Korea. This descriptive, cross-sectional study design enrolled a convenience sample of 118 international students at a university in Korea. Collected data included items from the Health-promoting Lifestyle Profile (II) scale and cardiovascular risk factors. The participants had a moderately health-promoting lifestyle (2.5 of 4). Men engaged in more physical activity than did women (p = .002). The most prevalent risk factor was elevated blood lipid profiles (26.3%), followed by overweight/obesity (25.4%), elevated blood pressure (17.8%), and elevated fasting glucose levels (5.1%). More than half of the participants (54.2%) had one or more cardiac risk factors, and these participants also scored lower in health-promoting lifestyle factors than other students (p = .034). Regular health check-ups are needed to identify the cardio-metabolic risks of international students. A university-based programme aimed at promoting healthy lifestyles could help prevent cardio-metabolic risks among international students.

  12. Olfactory neuroblastoma: a single-center experience.

    Science.gov (United States)

    König, Marton; Osnes, Terje; Jebsen, Peter; Evensen, Jan Folkvard; Meling, Torstein R

    2018-01-01

    Olfactory neuroblastoma (ONB) is a potentially curable disease, despite being an aggressive malignancy with a poor natural history. Our goal was to evaluate management outcomes for patients with ONB treated at our institution. Our prospective database for brain tumors and the pathology registry of head and neck cancers at Oslo University Hospital were searched to identify all patients treated for ONB between 1998 and 2016. Variables extracted from these databases, supplemented by retrospective chart reviews, underwent thorough analysis. All cases were formally re-examined by a dedicated head and neck pathologist. Twenty patients were identified. Follow-up was 100%. Mean follow-up was 81.5 months for the entire cohort and 120.3 months for patients with no evidence of disease. Fourteen patients underwent treatment of choice including craniofacial resection (CFR) with or without radiotherapy (XRT). Six patients could only receive less extensive treatment; three patients underwent lateral rhinotomy (LR) with or without XRT after being deemed medically unsuitable for CFR, while another three patients received only supportive, non-surgical treatment (due to positive lymph node status in two and to extensive tumor size in one case). Overall and disease-specific survival rates were 100% after 10 years of follow-up when negative surgical margins were achieved by CFR. Positive margins were associated with poorer outcome with no patients surviving longer than 44 months. Long-term survival was also achieved in two cases among patients not eligible for CFR: one case after radical LR and one case after radio-chemotherapy. Advanced disease at presentation (tumor size ≥40 mm, Kadish grades C and D, or TNM IVa and IVb) and positive surgical margins were correlated to significantly dismal survival. Our study suggests that CFR with or without adjuvant XRT is safe and leads to excellent long-time overall and disease-specific survival. Negative surgical margins, tumor size <40

  13. The Financial Instruments for Risk Management on the International Financial Markets

    OpenAIRE

    Alina Hagiu

    2008-01-01

    The international financial market is extremely volatile because of the influence of anumerous objective and subjective factors. Because of these, în their fight for maximizing the profit, the creditinstitutes confronts permanently with all sort of risks.It is important to know that the risk is generated by a numerous operations and procedures. From thesecause, at least în the financial field, the risk must be considered as a complex of risks, în the sense that they canhave common causes, and...

  14. The perception for the risk in the basic internal control models

    Directory of Open Access Journals (Sweden)

    Galin Markov

    2017-07-01

    Full Text Available The article describes risk conception as a leading perception in the field of internal control. The clarification of its nature and characteristics allow effective risk assessment and management. And so they are the most important precondition for achieving of organizational mission. The understandings of risk of the COSO, ISACA, Co Co, The Turnbull committee and the AMF are reviewed. The used methodology is a literature analysis. After the conducted research we can conclude that the risk is an uncertainty which impedes achieving of the organizational mission.

  15. Enterprise Marketing Risks Into the Selection by the Different Strategically Position Alternatives to the International Markets

    Directory of Open Access Journals (Sweden)

    Lucretia Mariana CONSTANTINESCU

    2012-11-01

    Full Text Available Entering into the international market is placed into the strategies area to geographical diversification which offer to companies a profitable source of growth. The “products – market/strategy” area is associated with the interdependency between the decisions that need to be made by strategic top management and also the strategic marketing of the company. For the strategies portfolio oriented to the business internalization of the company, the market risks are designed as a factor with important consequences to the marketing strategy of each company that depends on the hard reality of the competition on the international markets. This paper aims to analyze the different strategic risk categories to the companies that make the decision to be implemented on the external target-markets, thus compelling the companies to associate the international marketing opportunities within in a secondary objective connected to ensure the safety of the company shares for the choice of a new external market.

  16. Global Risks as Factors that Affect the Current system of international Relations

    Directory of Open Access Journals (Sweden)

    Irina A. Zaitseva

    2017-01-01

    Full Text Available The problem of the globalization of risks is examined in this article. Based on the World Economic Forum (WEF report on global risks 2015-2017, the impact of global risks on the social and economic development of countries is examined. Economic, social, environmental, geopolitical, technological risks are analyzed in a coordinated fashion. The article notes that the main risks are in the field of environment and ecology. Anthropogenic pressure amplification, scientific and technological advance have an influence on the natural environment. The risks of infrastructure and environmental damage in danger zone are increased because of the growth of the frequency of extreme weather events. The measures for the protection of the environment are examined. The unilateral approach to solving international issues, instead of the collective efforts of the international community; the deployment of weapons of mass destruction (nuclear, chemical, biological and technologies for the production of radioactive materials; escalation of economic and resource nationalization (the desire of States to expropriate or restrict the export of important for the world economy of resources, etc. promote the increasing geopolitical risks.Economic risks include the risk in terms of their likelihood their impact on the macroeconomic, as from the financial systems and infrastructure to price volatility and regulatory issues. Social risks are the risks relating to instability of population dynamics, social crises and human survival.Technological risks include such problems as software defects, failure of important information systems, upon which today industrial production is depended, the services and communications sector; the escalation of large-scale cyber-attacks; theft of electronic information and the illegal usage of personal data. The trends that can intensify the global risks or to change the correlation between them are analyzed in this article.

  17. Application of Post Modern Portfolio Theory to Mitigate Risk in International Shipping

    Science.gov (United States)

    2011-03-24

    measure. In 1994, Dr. Frank Sortino and Dr. Lee Price set out to update the Sharpe Ratio for use with downside risk optimization models. In 1994...historical data is not available, an industry standard estimate of $28,000 per TEU is substituted ( Kirchner 2006:3). 34 Value at Final Destination Often...3), 285-311. Joint publication 4-09: Distribution Operations(2010). Kirchner , M. (2006). Container Vessels and Risk Aggregation. International

  18. Norms and international standards related to reduce risk management: A literature review

    Directory of Open Access Journals (Sweden)

    César Fuentes

    2011-09-01

    Full Text Available The current work aims to develop a revision of the literature within the main concepts in the international rules and standards related to risk management in companies. By this way, there will be an analysis of issues such as the COSO - ERM model, an introduction to the ISO 27000 and 31000 standards; and the Project Management according to PMI targeted at risk management

  19. Internal sources of risk in building employees’ attitudes of safe work in metallurgical enterprise

    Directory of Open Access Journals (Sweden)

    K. Grzybowska

    2013-04-01

    Full Text Available The aim of the article is the identification of the internal sources of risk in the process of improving the system of safety and work hygiene management. After conduction of the analysis the conclusion is that the significant source of risk in the process of improvement of safety and work hygiene management is the human factor and, in particular, the lack of employees’ awareness concerning the importance of their attitudes in the improvement of the system.

  20. MicroRNA-184-mediated inhibition of tumour growth in an orthotopic murine model of neuroblastoma.

    Science.gov (United States)

    Tivnan, Amanda; Foley, Niamh H; Tracey, Lorraine; Davidoff, Andrew M; Stallings, Raymond L

    2010-11-01

    Neuroblastoma is a paediatric cancer which originates from precursor cells of the sympathetic nervous system. Previous studies have shown that miR-184 expression has anti-proliferative effects in neuroblastoma cells grown in culture. Therefore, it was of interest to evaluate this effect in vivo. Neuroblastoma cells overexpressing miR-184 were injected retroperitoneally into CB17-SCID mice and tumour burden was assessed by measuring bioluminescence. Overall survival was also evaluated. Ectopic overexpression of miR-184 in neuroblastoma cell lines is anti-proliferative. In addition, overexpression of miR-184 led to a significant reduction in tumour growth relative to negative control-treated cohorts in a xenograft model of neuroblastoma. This study demonstrated for the first time that miR-184 significantly reduces tumour growth and increases overall survival in an orthotopic murine model of neuroblastoma through assessment of tumour growth and moribundity relative to control miRNA-treated cohorts.

  1. Metabolic syndrome in Internal Medicine patients: the pilot NIMEC study (National Internal Medicine Equivalent/Complex C-V-@Risk

    Directory of Open Access Journals (Sweden)

    R. Nardi

    2013-05-01

    Full Text Available BACKGROUND Metabolic Syndrome (MetS, currently defined as slight differences in the criteria of diagnosis – depending on which authority is quoted [i.e.: NCEP-ATP III (National Cholesterol Education Program/Adult Treatment Panel III; WHO (World Health Organization; IDF (International Diabetes Federation; AACE (American Association of Clinical Endocrinologists], designates a cluster of metabolic risk factors that come together in a single individual, leading to cardiovascular disease. MetS is quite common, approximately 20-30% of the population in industrialized countries being affected. However, most of epidemiological data regarding MetS are derived from populations consisting mostly of middle-aged and younger subjects. AIM OF THE STUDY To assess the prevalence of the MetS in Internal Medicine wards and to determine its related comorbidities, including other clinical forms of atherosclerotic disease such as CHD risk equivalents. METHODS Our study was performed in patients admitted in Internal Medicine wards and selected as a randomization list in 12 Emilia Romagna-Marche FADOI centers. 1.316 patients were registered. According to explicit inclusion/exclusion criteria, we studied overall 902 participants (50.6% men, mean of age: 71-73 years. RESULTS According to NCEP-ATP III and IDF criteria the prevalence of MetS was 45.3% (IC 95%: 41.6-49.1 and 38.6% (IC 95%: 34.9-42.3, respectively. Patients with MetS presented a higher significant rate of ALT increase, syncope, atrial fibrillation, COPD, unstable angina, chronic kidney disease, cancer, valvular heart disease, peripheral arterial disease and carotid plaques. A strong association between IDF-MetS and congestive heart failure was observed, suggesting a role of central obesity as an independent risk factor in the elderly. DISCUSSION World-wide populations are becoming older. Aging and MetS are two conditions that represent an important part of health-care spending. Trunkal fatness increases in

  2. Adult Neuroblastoma Complicated by Increased Intracranial Pressure: A Case Report and Review of the Literature

    OpenAIRE

    Stevens, Patrick L.; Johnson, Douglas B.; Thompson, Mary Ann; Keedy, Vicki L.; Frangoul, Haydar A.; Snyder, Kristen M.

    2014-01-01

    Neuroblastoma is the third most commonly occurring malignancy of the pediatric population, although it is extremely rare in the adult population. In adults, neuroblastoma is often metastatic and portends an extremely poor overall survival. Our case report documents metastatic neuroblastoma occurring in a healthy 29-year-old woman whose course was complicated by an unusual presentation of elevated intracranial pressures. The patient was treated with systemic chemotherapy, I131 metaiodobenzylgu...

  3. Proteome and Acetylome Analysis Identifies Novel Pathways and Targets Regulated by Perifosine in Neuroblastoma

    OpenAIRE

    Gu, Xiao; Hua, Zhongyan; Dong, Yudi; Zhan, Yue; Zhang, Xiaowen; Tian, Wei; Liu, Zhihui; Thiele, Carol J.; Li, Zhijie

    2017-01-01

    Perifosine, an Akt inhibitor, has been shown to be effective in controlling neuroblastoma tumor growth. However, studies indicate that in addition to the ability to inhibit Akt, other mechanisms contribute to perifosine?s anti-tumor activity. To gain insight into perifosine anti-tumor activity in neuroblastoma we have studied changes in the proteome and acetylome after perifosine treatment in SK-N-AS neuroblastoma cells using SILAC labeling, affinity enrichment, high-resolution and LC-MS/MS a...

  4. PI3K/AKT and ERK regulate retinoic acid-induced neuroblastoma cellular differentiation

    Energy Technology Data Exchange (ETDEWEB)

    Qiao, Jingbo [Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Paul, Pritha; Lee, Sora [Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Qiao, Lan; Josifi, Erlena; Tiao, Joshua R. [Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Chung, Dai H., E-mail: dai.chung@vanderbilt.edu [Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232 (United States)

    2012-08-03

    Highlights: Black-Right-Pointing-Pointer Retinoic acid (RA) induces neuroblastoma cells differentiation, which is accompanied by G0/G1 cell cycle arrest. Black-Right-Pointing-Pointer RA resulted in neuroblastoma cell survival and inhibition of DNA fragmentation; this is regulated by PI3K pathway. Black-Right-Pointing-Pointer RA activates PI3K and ERK1/2 pathway; PI3K pathway mediates RA-induced neuroblastoma cell differentiation. Black-Right-Pointing-Pointer Upregulation of p21 is necessary for RA-induced neuroblastoma cell differentiation. -- Abstract: Neuroblastoma, the most common extra-cranial solid tumor in infants and children, is characterized by a high rate of spontaneous remissions in infancy. Retinoic acid (RA) has been known to induce neuroblastoma differentiation; however, the molecular mechanisms and signaling pathways that are responsible for RA-mediated neuroblastoma cell differentiation remain unclear. Here, we sought to determine the cell signaling processes involved in RA-induced cellular differentiation. Upon RA administration, human neuroblastoma cell lines, SK-N-SH and BE(2)-C, demonstrated neurite extensions, which is an indicator of neuronal cell differentiation. Moreover, cell cycle arrest occurred in G1/G0 phase. The protein levels of cyclin-dependent kinase inhibitors, p21 and p27{sup Kip}, which inhibit cell proliferation by blocking cell cycle progression at G1/S phase, increased after RA treatment. Interestingly, RA promoted cell survival during the differentiation process, hence suggesting a potential mechanism for neuroblastoma resistance to RA therapy. Importantly, we found that the PI3K/AKT pathway is required for RA-induced neuroblastoma cell differentiation. Our results elucidated the molecular mechanism of RA-induced neuroblastoma cellular differentiation, which may be important for developing novel therapeutic strategy against poorly differentiated neuroblastoma.

  5. International Evidence on Government Support and Risk-Taking in the Banking Sector

    NARCIS (Netherlands)

    Brandao-Marques, L.; Correa, R.; Sapriza, H.

    2012-01-01

    Abstract: Government support to banks through the provision of explicit or implicit guarantees can affect the willingness of banks to take on risk by reducing market discipline or by increasing charter value. We use an international sample of bank data and government support to banks for the periods

  6. Gene-Environment Interplay in Internalizing Disorders: Consistent Findings across Six Environmental Risk Factors

    Science.gov (United States)

    Hicks, Brian M.; Dirago, Ana C.; Iacono, William G.; McGue, Matt

    2009-01-01

    Background: Behavior genetic methods can help to elucidate gene-environment (G-E) interplay in the development of internalizing (INT) disorders (i.e., major depression and anxiety disorders). To date, however, no study has conducted a comprehensive analysis examining multiple environmental risk factors with the purpose of delineating general…

  7. Health risks in international container and bulk cargo transport due to volatile toxic compounds

    DEFF Research Database (Denmark)

    Baur, Xaver; Budnik, Lygia T; Zhao, Zhiwei

    2015-01-01

    To ensure the preservation and quality of the goods, physical (i.e. radiation) or chemical pest control is needed. The dark side of such consents may bear health risks in international transport and production sharing. In fact, between 10% and 20% of all containers arriving European harbors were...

  8. Internal validation of risk models in clustered data: a comparison of bootstrap schemes

    NARCIS (Netherlands)

    Bouwmeester, W.; Moons, K.G.M.; Kappen, T.H.; van Klei, W.A.; Twisk, J.W.R.; Eijkemans, M.J.C.; Vergouwe, Y.

    2013-01-01

    Internal validity of a risk model can be studied efficiently with bootstrapping to assess possible optimism in model performance. Assumptions of the regular bootstrap are violated when the development data are clustered. We compared alternative resampling schemes in clustered data for the estimation

  9. Problem-Based Teaching in International Management: A Political/Economic Risk Assessment Exercise

    Science.gov (United States)

    Daly, Paula S.; White, Marion M.; Zisk, Daniel S.; Cavazos, David E.

    2013-01-01

    This article draws from the current literature to examine problem-based learning (PBL) as a management education tool, and provides an example of how to incorporate PBL into an undergraduate international management course. Also included are an explanation of, and specific guidelines for, a PBL exercise focused on the analysis of "country risk"…

  10. International Fatigue Risk Management Forum : Safety Promotion and Feedback in FRMS

    NARCIS (Netherlands)

    Stewart, S.; Koornneef, F.; Akselsson, R.

    2009-01-01

    Chapter 8: International Fatigue Risk Management Forum - Safety Promotion and Feedback in FRMS The European Commission HILAS project (Human Integration into the Lifecycle of Aviation Systems - a project supported by the European Commission’s 6th Framework between 2005-2009) was focused on using

  11. Effect of an internally versus externally focused acl injury prevention program on injury risk

    NARCIS (Netherlands)

    Dallinga, J.; Benjaminse, A.; Gokeler, A.; Otten, Egbert; Lemmink, K.

    2014-01-01

    BACKGROUND: Anterior cruciate ligament (ACL) injury prevention programs have shown mixed results, which may be in part due to suboptimal training components. OBJECTIVE: Determine effects of a prevention program with external and internal focus of attention on (potential) biomechanical risk factors

  12. Understanding comorbidity among internalizing problems: Integrating latent structural models of psychopathology and risk mechanisms

    Science.gov (United States)

    Hankin, Benjamin L.; Snyder, Hannah R.; Gulley, Lauren D.; Schweizer, Tina H.; Bijttebier, Patricia; Nelis, Sabine; Toh, Gim; Vasey, Michael W.

    2016-01-01

    It is well known that comorbidity is the rule, not the exception, for categorically defined psychiatric disorders, and this is also the case for internalizing disorders of depression and anxiety. This theoretical review paper addresses the ubiquity of comorbidity among internalizing disorders. Our central thesis is that progress in understanding this co-occurrence can be made by employing latent dimensional structural models that organize both psychopathology as well as vulnerabilities and risk mechanisms and by connecting the multiple levels of risk and psychopathology outcomes together. Different vulnerabilities and risk mechanisms are hypothesized to predict different levels of the structural model of psychopathology. We review the present state of knowledge based on concurrent and developmental sequential comorbidity patterns among common discrete psychiatric disorders in youth, and then we advocate for the use of more recent bifactor dimensional models of psychopathology (e.g., p factor, Caspi et al., 2014) that can help to explain the co-occurrence among internalizing symptoms. In support of this relatively novel conceptual perspective, we review six exemplar vulnerabilities and risk mechanisms, including executive function, information processing biases, cognitive vulnerabilities, positive and negative affectivity aspects of temperament, and autonomic dysregulation, along with the developmental occurrence of stressors in different domains, to show how these vulnerabilities can predict the general latent psychopathology factor, a unique latent internalizing dimension, as well as specific symptom syndrome manifestations. PMID:27739389

  13. Sustaining a Mature Risk Management Process: Ensuring the International Space Station for a Vibrant Future

    Science.gov (United States)

    Raftery, Michael; Carter-Journet, Katrina

    2013-01-01

    The International Space Station (ISS) risk management methodology is an example of a mature and sustainable process. Risk management is a systematic approach used to proactively identify, analyze, plan, track, control, communicate, and document risks to help management make risk-informed decisions that increase the likelihood of achieving program objectives. The ISS has been operating in space for over 14 years and permanently crewed for over 12 years. It is the longest surviving habitable vehicle in low Earth orbit history. Without a mature and proven risk management plan, it would be increasingly difficult to achieve mission success throughout the life of the ISS Program. A successful risk management process must be able to adapt to a dynamic program. As ISS program-level decision processes have evolved, so too has the ISS risk management process continued to innovate, improve, and adapt. Constant adaptation of risk management tools and an ever-improving process is essential to the continued success of the ISS Program. Above all, sustained support from program management is vital to risk management continued effectiveness. Risk management is valued and stressed as an important process by the ISS Program.

  14. Assessment and Prioritization of Environmental Risks in Gaz and Hara Rivers Estuary International Wetland

    Directory of Open Access Journals (Sweden)

    Samira Jafariazar

    2017-12-01

    Full Text Available Wetland ecosystems have many economic and ecological functions and values, but today their security and existence have been heavily influenced by various natural and human factors. Therefore, the present study was conducted to identify, rank and assess environmental risks threatening Khur-e- Azini International wetland located in Hormozgan province. In order to identify risk factors, the Delphi method and the multi-criteria decision-making methods, AHP and TOPSIS were used for prioritizing risks. According to the results of the technique AHP, fuel smuggling, marine transportation and oil pollution were respectively ranked first to third. The results of TOPSIS technique based on the relative proximity (Cj + indicate that the oil pollution (1 and the fuel smuggling (0.9154 are ranked first to second. In general, based on the ranking of risks, 8.6 percent of risks were placed in the unbearable category, 8.6 percent of risks were placed in the significant category, 26.08 percent of risks were placed in the average category, and 30.43 percent of risks were placed in the category of tolerable risks. According to the results, management priorities and planning should be considered seriously to minimize the risks and consequences that have irreversible effects on the environment and wetlands function.

  15. Development of an integrated risk assessment framework for internal/external events and all power models

    International Nuclear Information System (INIS)

    Yang, Joon Eon

    2012-01-01

    From the PSA point of view, the Fukushima accident of Japan in 2011 reveals some issues to be re-considered and/or improved in the PSA such as the limited scope of the PSA, site risk, etc. KAERI (Korea Atomic Energy Research Institute) has performed researches on the development of an integrated risk assessment framework related to some issues arisen after the Fukushima accident. This framework can cover the internal PSA model and external PSA models (fire, flooding, and seismic PSA models) in the full power and the low power-shutdown modes. This framework also integrates level 1, 2 and 3 PSA to quantify the risk of nuclear facilities more efficiently and consistently. We expect that this framework will be helpful to resolve the issue regarding the limited scope of PSA and to reduce some inconsistencies that might exist between (1) the internal and external PSA, and (2) full power mode PSA and low power-shutdown PSA models. In addition, KAERI is starting researches related to the extreme external events, the risk assessment of spent fuel pool, and the site risk. These emerging issues will be incorporated into the integrated risk assessment framework. In this paper the integrated risk assessment framework and the research activities on the emerging issues are outlined.

  16. Marriage as a Risk Factor for Internalizing Disorders: Clarifying Scope and Specificity

    Science.gov (United States)

    Brock, Rebecca L.; Lawrence, Erika

    2011-01-01

    Objective Marital discord has been linked to both depression and anxiety; however, our understanding of how marriage contributes to the development of internalizing symptoms is limited in scope and lacking specificity. First, it is unclear whether the marital relationship contributes to the broad dimension of internalizing symptoms as opposed to specific diagnoses. Second, it is unclear how the marital relationship contributes to internalizing symptoms: through global marital dissatisfaction or through specific relationship processes (and which processes). The purpose of the present study was to address these two issues and, more generally, to develop a comprehensive and refined framework within which to understand the role of marriage in the developmental course of internalizing symptoms. Method Questionnaire and interview data were collected from 102 husbands and wives 5 times over the first 7 years of marriage. Results Results indicated that marital discord during the transition into marriage was associated with the broad dimension of internalizing symptoms for husbands but not for wives. Further, both global marital dissatisfaction and an imbalance of power and control put husbands at significant risk for symptoms over the first 7 years of marriage, whereas low levels of emotional intimacy put wives at significant risk. Conclusions Results exemplify the need to routinely consider intimate relationship processes in etiological models of depression and anxiety, and identify specific clinical targets that can be prioritized in interventions aimed at preventing internalizing disorders. PMID:21823784

  17. Marriage as a risk factor for internalizing disorders: clarifying scope and specificity.

    Science.gov (United States)

    Brock, Rebecca L; Lawrence, Erika

    2011-10-01

    Marital discord has been linked to both depression and anxiety; however, our understanding of how marriage contributes to the development of internalizing symptoms is limited in scope and lacking specificity. First, it is unclear whether the marital relationship contributes to the broad dimension of internalizing symptoms as opposed to specific diagnoses. Second, it is unclear how the marital relationship contributes to internalizing symptoms: through global marital dissatisfaction or through specific relationship processes (and which processes). The purpose of the present study was to address these 2 issues and, more generally, to develop a comprehensive and refined framework within which to understand the role of marriage in the developmental course of internalizing symptoms. Questionnaire and interview data were collected from 102 husbands and wives 5 times over the first 7 years of marriage. Results indicated that marital discord during the transition into marriage was associated with the broad dimension of internalizing symptoms for husbands but not for wives. Further, both global marital dissatisfaction and an imbalance of power and control put husbands at significant risk for symptoms over the first 7 years of marriage, whereas low levels of emotional intimacy put wives at significant risk. Results exemplify the need to routinely consider intimate relationship processes in etiological models of depression and anxiety and to identify specific clinical targets that can be prioritized in interventions aimed at preventing internalizing disorders.

  18. International cooperation in the solution to trade-related invasive species risks.

    Science.gov (United States)

    Perrings, Charles; Burgiel, Stas; Lonsdale, Mark; Mooney, Harold; Williamson, Mark

    2010-05-01

    In this paper, we consider the factors behind the growth of invasive species as a global problem, and the scope for international cooperation and coordination in addressing that problem. This is limited by the terms of the various international agreements governing trade, health, and biodiversity. The default strategy in most cases has two parts: border protection and the control of or adaptation to introduced species that have escaped detection at the border. Most invasive species policy involves unilateral national defensive action as opposed to coordinated international action. We argue that an important part of the solution to the problem lies in global coordination and cooperation in the management of both pathways and sanitary and phytosanitary risks at all scales. More particularly, because invasive species are an externality of trade, transport, and travel that involve public goods, they require collective regulation of international markets that goes beyond that admitted under the World Trade Organization's (WTO) Agreement on the Application of Sanitary and Phytosanitary Measures. We argue that it is important to bring that agreement into conformity with the International Health Regulations (IHR), and to develop an international mechanism to generate and disseminate information on invasive species risks and their impacts.

  19. Computed tomography as a supplement to urography in the evaluation of suspected neuroblastoma

    International Nuclear Information System (INIS)

    Siegel, M. J.; Sagel, S.S.

    1982-01-01

    Eleven children in whom a retropertioneal neuroblastoma was suspected on the basis of plain radiographic or urographic findings underwent computed tomography (CT). CT identified and localized a neurogenic tumor in eight patients. Calcifications were demonstrated by CT in six lesions, but by urography in only four. One neuroblastoma detected by CT was not seen on the urogram; in five patients greater extent of the tumor was defined by CT than by conventional radiologic procedures. In three patients CT excluded a neuroblastoma, but diagnosed other disorders (hepatic tumor, pancreatitis, and retrocaval ureter). Our results confirm that CT is a simple and accurate method for diagnosis, delineation of extent, or exclusion of neuroblastoma

  20. Abnormal brain MRI in a case of acute ataxia as the only sign of abdominal neuroblastoma

    International Nuclear Information System (INIS)

    Molla Mohammadi, M.; Karimzadeh, P.; Khatami, A.; Jadali, F.

    2010-01-01

    Ataxia is a movement disorder that may manifest an acute, intermittent, non progressive or chronic progressive course. Ataxia alone is rare as a para neoplastic sign, especially if it is due to neuroblastoma (abdominal or chest). We report an abdominal neuroblastoma in a two-year-old girl presenting with only acute ataxia and abnormal neuroimaging. Brain MRI showed abnormal signal finding in the medulla, pons, cortico spinal tract and the periventricular space. In the abdominal CT, a mass was detected in the right adrenal gland with calcification and the histopathologic examination re-vealed neuroblastoma. We suggest in children with acute ataxia, with or without opalescence-myoclonus, neuroblastoma should be considered.

  1. Global warming risk in Russia: National actions and some options for international cooperation

    International Nuclear Information System (INIS)

    Sokolov, V.I.

    1995-01-01

    In the management of global environmental risks the Russia case is a special one regarding certain specific features which determine the position of the country, particularly in a new international community emerged on the territory of the former Soviet Union, large scientific interest to the global physical processes and low interest and capabilities to deal with such risks on the part of social institutions inherited from the USSR. The largest country in the world with visible geopolitical role and probably biggest regional differences could not be ignored as a one of major players in the management of global environmental risks. The understanding of all deficiencies and positive sides of global risks management process in this country are absolutely important for extrapolating the appropriate trends in some other parts of the world. At the same time the ex-Soviet Union case shows clearly how the social learning process can radically ''change the course'', diverting to the opposite direction the social goals and preferences. Starting the studies on possibilities to change the climate for improving the human being, the former soviet society perceived the risks of human impact on climate and started to regulate it and to participate in the process of international management of global warming. The level of activity in this process on the part of Russia will however depend heavily on how much national interests will be reflected in the specific prevention measures realized by the international community

  2. International Symposium on Seismic Risk Reduction. The JICA Technical Cooperation Project in Romania. Proceedings

    International Nuclear Information System (INIS)

    Hiroto; Vacareanu, Radu

    2007-01-01

    In the 5th year of the Japan International Cooperation Agency (JICA) Technical Cooperation Project 'Seismic Risk Reduction for Buildings and Structures in Romania', the implementing agency - National Center for Seismic Risk Reduction (NCSRR) and JICA jointly organized the International Symposium on Seismic Risk Reduction (ISSRR-2007) held in Bucharest at the Romanian Academy Library in the period April 26-27, 2007. The present volume contains the Proceedings of the International Symposium on Seismic Risk Reduction, ISSRR-2007. The Proceedings are organized in three parts: (I) keynote lectures, (II) papers on the results of JICA Project in Romania and (III) contributions from authors. Eight keynote lectures by specialists from Japan, USA, France and Greece, and fourteen papers on the results of JICA Project are included. The contributions from authors are divided in five sections: (i) Seismicity, Seismic Hazard and Site Effects, (ii) Seismic Vulnerability and Seismic Risk, (iii) Seismic Rehabilitation, (iv) Seismic analysis and Design and (v) Urban disaster mitigation and earthquake damage. The Proceedings contain 64 papers (from 19 countries) submitted for publication

  3. Obese and Overweight Youth: Risk for Experiencing Bullying Victimization and Internalizing Symptoms.

    Science.gov (United States)

    Waasdorp, Tracy Evian; Mehari, Krista; Bradshaw, Catherine P

    2018-01-22

    Obese and overweight youth are at an increased risk for poor peer relations and psychosocial adjustment. Of particular concern is the high rate of bullying victimization experienced by obese and overweight youth. While it is known that victimized youth are at an increased risk for internalizing symptoms, few studies have examined if weight status exacerbates the association between victimization and internalizing symptoms. The current study drew upon data from over 43,000 youth attending 107 middle and high schools. Multilevel results suggested that compared with normal weight youth, both overweight and obese youth were at an increased risk for experiencing relational, verbal, and cyber victimization, with only obese youth being at an increased risk for experiencing physical victimization. Notably, the odds for experiencing cyber victimization were higher than the odds for experiencing other forms of victimization. Frequently victimized obese youth, but not frequently victimized overweight youth, had significantly higher levels of internalizing symptoms compared to their frequently victimized, normal-weight peers. Together, these findings highlight the increased risk for psychosocial adjustment problems among frequently victimized overweight and obese youth, suggesting these youth may require preventive interventions tailored to meet their unique needs. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

  4. A regulatory perspective on the potential uses of microbial risk assessment in international trade.

    Science.gov (United States)

    Hathaway, S C; Cook, R L

    1997-05-20

    The recent ratification of the World Trade Organisation Agreement will arguably be the most important factor in developing new sanitary measures for the international trade in food over the next decade. There is a markedly increased desire for quantitative data on the microbial risks associated with different classes of foods, and traditional good manufacturing practice (GMP)-based food hygiene requirements are coming under increasing challenge. As the risk assessment paradigm is increasing applied and as decision-making criteria for risk management become established, more emphasis will be placed on predictive microbiology as a means of generating exposure data and establishing critical limits for Hazard Analysis Critical Control Point (HACCP) plans. In this respect, developing international guidelines for risk management arguably presents the greatest challenge in establishing and maintaining quantitative Sanitary and Phytosanitary (SP) measures for food in international trade, and for judging their equivalence. Where specific industry sectors and regulators do not have jurisdiction over the entire food chain, from production of raw materials through to consumption, it will be difficult to apply the risk assessment paradigm in the design of HACCP plans. Thus, it appears that default to food safety objectives for many segments of food production chains subject to application of HACCP plans is inevitable in the medium term.

  5. EVALUATING INTERNAL STAKEHOLDER PERSPECTIVES ON RISK-INFORMED REGULATORY PRACTICES FOR THE NUCLEAR REGULATORY COMMISSION

    International Nuclear Information System (INIS)

    Peterson, L.K.; Wight, E.H.; Caruso, M.A.

    2003-01-01

    The U.S. Nuclear Regulatory Commission's (NRC) Office of Nuclear Reactor Regulation has begun a program to create a risk-informed environment within the reactor program. The first step of the process is to evaluate the existing environment and internal NRC stakeholder perceptions of risk-informed regulatory practices. This paper reports on the results of the first phase of this evaluation: assessing the current environment, including the level of acceptance of risk-informed approaches throughout the reactor program, the level of integration, areas of success, and areas of difficulty. The other two phases of the evaluation will identify barriers to the integration of risk into NRC activities and gather input on how to move to a risk-informed environment

  6. EVALUATING INTERNAL STAKEHOLDER PERSPECTIVES ON RISK-INFORMED REGULATORY PRACTICES FOR THE NUCLEAR REGULATORY COMMISSION

    Energy Technology Data Exchange (ETDEWEB)

    Peterson, L.K.; Wight, E.H.; Caruso, M.A.

    2003-02-27

    The U.S. Nuclear Regulatory Commission's (NRC) Office of Nuclear Reactor Regulation has begun a program to create a risk-informed environment within the reactor program. The first step of the process is to evaluate the existing environment and internal NRC stakeholder perceptions of risk-informed regulatory practices. This paper reports on the results of the first phase of this evaluation: assessing the current environment, including the level of acceptance of risk-informed approaches throughout the reactor program, the level of integration, areas of success, and areas of difficulty. The other two phases of the evaluation will identify barriers to the integration of risk into NRC activities and gather input on how to move to a risk-informed environment.

  7. Sodium valproate does not augment Prpsc in murine neuroblastoma cells.

    Science.gov (United States)

    Legendre, C; Casagrande, F; Andrieu, T; Dormont, D; Clayette, P

    2007-10-01

    Sodium valproate (VPA) has been reported to increase the accumulation of the pathologic isoform of prion protein (PrPsc) in scrapie-infected murine neuroblastoma cells. In this study, the effect of VPA on PrPsc accumulation was investigated in murine N2a neuroblastoma cells chronically infected with scrapie strain 22L (N2a-22L). No accumulation of PrPsc was detected after short-term (3 days) or long-term (21 days) treatment of N2a-22L cells with 4.8, 12, 18 or 24 microM VPA. Higher VPA concentrations (240 and 600 microM) also failed to augment PrPsc expression. In conclusion, in our experimental conditions, no deleterious effect was induced by VPA on prions replication.

  8. The Extent and Risk of Violent Victimization Among International College Students Enrolled in the United States: A Gendered Analysis.

    Science.gov (United States)

    Daigle, Leah E; Hoffman, Chrystina Y; Johnson, Lee M

    2016-03-02

    Although the risk of being violently victimized in college has been established for college students in the United States in general, this risk has not been explored for international college students. Using data from the Fall 2012 National College Health Assessment Survey, the extent to which international college students experience violent victimization is assessed. In addition, the risk factors for violent victimization for international students are compared with those for domestic students. Finally, in multivariate analyses, whether being an international student influences risk of violent victimization is examined and whether this relationship is moderated by gender is considered. Findings indicate that international students in general have lower risk profiles, in that they reported lower rates of drug use, binge drinking, being a first-year undergraduate student, and having a disability. Multivariate analyses, however, revealed that being an international student reduces the odds of violent victimization among only females. © The Author(s) 2016.

  9. Optimization of liposomal topotecan for use in treating neuroblastoma.

    Science.gov (United States)

    Chernov, Lina; Deyell, Rebecca J; Anantha, Malathi; Dos Santos, Nancy; Gilabert-Oriol, Roger; Bally, Marcel B

    2017-06-01

    The purpose of this work was to develop an optimized liposomal formulation of topotecan for use in the treatment of patients with neuroblastoma. Drug exposure time studies were used to determine that topotecan (Hycamtin) exhibited great cytotoxic activity against SK-N-SH, IMR-32 and LAN-1 neuroblastoma human cell lines. Sphingomyelin (SM)/cholesterol (Chol) and 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)/Chol liposomes were prepared using extrusion methods and then loaded with topotecan by pH gradient and copper-drug complexation. In vitro studies showed that SM/Chol liposomes retained topotecan significantly better than DSPC/Chol liposomes. Decreasing the drug-to-lipid ratio engendered significant increases in drug retention. Dose-range finding studies on NRG mice indicated that an optimized SM/Chol liposomal formulation of topotecan prepared with a final drug-to-lipid ratio of 0.025 (mol: mol) was better tolerated than the previously described DSPC/Chol topotecan formulation. Pharmacokinetic studies showed that the optimized SM/Chol liposomal topotecan exhibited a 10-fold increase in plasma half-life and a 1000-fold increase in AUC 0-24 h when compared with Hycamtin administered at equivalent doses (5 mg/kg). In contrast to the great extension in exposure time, SM/Chol liposomal topotecan increased the life span of mice with established LAN-1 neuroblastoma tumors only modestly in a subcutaneous and systemic model. The extension in exposure time may still not be sufficient and the formulation may require further optimization. In the future, liposomal topotecan will be assessed in combination with high-dose radiotherapy such as 131 I-metaiodobenzylguanidine, and immunotherapy treatment modalities currently used in neuroblastoma therapy. © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  10. A 6-gene signature identifies four molecular subgroups of neuroblastoma

    OpenAIRE

    Abel, Frida; Dalevi, Daniel; Nethander, Maria; Jörnsten, Rebecka; De Preter, Katleen; Vermeulen, Joëlle; Stallings, Raymond; Kogner, Per; Maris, John; Nilsson, Staffan

    2011-01-01

    Abstract Background There are currently three postulated genomic subtypes of the childhood tumour neuroblastoma (NB); Type 1, Type 2A, and Type 2B. The most aggressive forms of NB are characterized by amplification of the oncogene MYCN (MNA) and low expression of the favourable marker NTRK1. Recently, mutations or high expression of the familial predisposition gene Anaplastic Lymphoma Kinase (ALK) was associated to unfavourable biology of sporadic NB. Also, various other genes have been linke...

  11. Rapidly Evoluting Congenital Cystic Neuroblastoma in a Neonate

    Energy Technology Data Exchange (ETDEWEB)

    Yun, Tae Jun; Kim, Myung Jun; Han, Seok Joo; Lee, Mi Jung [Severance Children' s Hospital, Yonsei University, College of Medicine, Seoul(Korea, Republic of)

    2012-08-15

    Perinatal detection of neonatal suprarenal masses has increased. Here, we report an unusual case of an adrenal cystic neuroblastoma that presented as a purely cystic lesion upon initial postnatal ultrasonography (US) and showed rapid evolution to a mixed cystic and solid mass during follow-up US and MRI. We suggest a short-term (two weeks) follow-up US for neonatal adrenal cystic lesions, even if they appear as purely cystic.

  12. Enhanced chromosomal fragility in neuroblastoma: correlation with poor prognosis.

    Science.gov (United States)

    Vernole, P; Tedeschi, B; Melino, G; Pianca, C; Nicoletti, B

    1992-01-01

    In a previous study we demonstrated spontaneous fragility and hypersensitivity to fragile site induction by aphidicolin in lymphocytes from some neuroblastoma patients and their parents. Here we report data based on a total of 40 patients and 37 families. Possible correlations between higher sensitivity to aphidicolin and a variety of personal and clinical characteristics were verified. Patients with a poor prognosis generally proved to be more susceptible to fragile site induction.

  13. Identifying microRNAs that Regulate Neuroblastoma Cell Differentiation

    Science.gov (United States)

    2015-10-01

    System (Promega). Firefly lucifer - ase activity was normalized to Renilla luciferase activity to evalu- ate the effect of the miRNAs. Biotinylated-miR...objective of Aim 1. We further validated the effect of miR-449a on the expression of molecular differentiation markers, on cell cycle distribution, and on...inducing effect in neuroblastoma cell lines regardless of the genetic backgrounds of the cell lines. We have completed the screen in the MYCN-amplified

  14. Marrow Derived Antibody Library for the Treatment of Neuroblastoma

    Science.gov (United States)

    2015-12-01

    identified with strong binding to tumor cells. In Figure 1, the positive binding of phage clones to MGT-003 cells were visualized using anti- M13 phage ...neuroblastoma patients using phage display and B cell hybridoma technologies. The scope of this project is to use NB patient-derived materials to...create NB cell lines, xenograft models, NB specific phage display libraries and to identify and amplify functional anti-NB specific antibodies for future

  15. Intrarenal neuroblastoma - a diagnostic dilemma: A report of three cases

    Directory of Open Access Journals (Sweden)

    Anupam Lall

    2001-01-01

    Full Text Available Differentiation between the Wilms′ tumor (WT and the intrarenal neuroblastoma (IRNB is imperative, as the prognosis and the treatment are different for these condi-tions. It may pose a diagnostic challenge to distinguish them pre-operatively. Over the period of last 10 years (1990-1999, 3 children aged 2 months to 4 years were diagnosed to have IRNB. 2 cases were operated with a provisional diagnosis of WT, but on histology were found to have neuroblastoma. Taking benefit from our previous experience, the third case we encountered with a renal lump and bony metastasis with clinical features not con-sistent with the diagnosis of Wilms′ tumor was further investigated. Urinary catecholamines were significantly elevated and there was bone marrow involvement and positive bone scan for multiple bony metastasis. 2 pa-tients are on chemotherapy and follow-up for last 6 months, while 1 died 6 years back after a follow-up of 2 years. Patients who have a renal mass on imaging, with clinical features of rapid deterioration in general condi-tion and evidence of bony secondaries, should undergo work-up for neuroblastoma pre-operatively to confirm the diagnosis.

  16. Nongenetic causes of childhood cancers: evidence from international variation, time trends, and risk factor studies

    International Nuclear Information System (INIS)

    Bunin, Greta R.

    2004-01-01

    Ionizing radiation and a variety of genetic conditions are thought to explain 5-10% of childhood cancers. Infection with Epstein-Barr virus (EBV) in parts of Africa and human immunodeficiency virus (HIV) increase the risk of Burkitt's lymphoma and Kaposi's sarcoma, respectively. Other risk factors have not been conclusively identified. A review of the data on international variation in incidence, recent changes in incidence, and risk factors suggests that many childhood cancers are likely to have nongenetic causes. The pattern of international variation and associations with surrogates of infection suggest an infectious etiology for acute lymphoblastic leukemia, although no agent has been identified. The biologic plausibility is strong that maternal consumption of food containing DNA topoisomerase II inhibitors may increase the risk of acute myeloid leukemia, although the data are limited now. For brain tumors, cured meats, polyomaviruses, and farm exposures may have etiologic roles. Changes in the incidence and characteristics of children with hepatoblastoma as well as risk factor studies suggest a role for an exposure of very low birth weight babies. High birth weight, tea or coffee consumption, and certain paternal occupations have shown some consistency in their association with Wilms' tumor. For most of the other cancers, very few epidemiologic studies have been conducted, so it is not surprising that nongenetic risk factors have not been detected. The most important difference between the cancers for which there are good etiologic clues and those for which there are not may be the number of relevant studies

  17. Problem gambling among international and domestic university students in Australia: who is at risk?

    Science.gov (United States)

    Moore, Susan M; Thomas, Anna C; Kalé, Sudhir; Spence, Mark; Zlatevska, Natalina; Staiger, Petra K; Graffam, Joseph; Kyrios, Michael

    2013-06-01

    Young people are a high risk group for gambling problems and university (college) students fall into that category. Given the high accessibility of gambling in Australia and its association with entertainment, students from overseas countries, particularly those where gambling is restricted or illegal, may be particularly vulnerable. This study examines problem gambling and its correlates among international and domestic university students using a sample of 836 domestic students (286 males; 546 females); and 764 international students (369 males; 396 females) at three Australian universities. Our findings indicate that although most students gamble infrequently, around 5 % of students are problem gamblers, a proportion higher than that in the general adult population. Popular gambling choices include games known to be associated with risk (cards, horse races, sports betting, casino games, and gaming machines) as well as lotto/scratch tickets. Males are more likely to be problem gamblers than females, and almost 10 % of male international students could be classified as problem gamblers. Hierarchical regression analysis showed that male gender, international student status, financial stress, negative affect and frequency of gambling on sports, horses/dogs, table games, casino gaming machines, internet casino games and bingo all significantly predicted problem gambling. Results from this study could inform gambling-education programs in universities as they indicate which groups are more vulnerable and specify which games pose more risk of problem gambling.

  18. ILEAL HERNIATION THROUGH THE FORAMEN OF WINSLOW: OVEREATING AS A RISK FACTOR FOR INTERNAL HERNIATION.

    Science.gov (United States)

    Kirigin, Lora Stanka; Nikolić, Marko; Kruljac, Ivan; Marjan, Domagoj; Penavić, Ivan; Ljubicić, Neven; Budimir, Ivan; Vrkljan, Milan

    2016-03-01

    Internal hernias have an overall incidence of less than 1% and are difficult to diagnose clinically due to their nonspecific presentation. Most internal hernias present as strangulating closed-loop obstruction and delay in surgical intervention is responsible for a high mortality rate (49%). We present a case of ileal herniation through the foramen of Winslow. A 29-year-old previously healthy female presented with acute onset right upper quadrant pain, abdominal fullness, and nausea. The pain was sudden in onset and began shortly after a dinner party where she consumed larger portions of food. Laboratory investigations revealed mild leukocytosis with left shift. Dual-phase multi-detector computed tomography disclosed herniation of the small bowel into the lesser sac. The patient underwent an emergency median laparotomy that revealed ileal herniation through the foramen of Winslow. Adhesiolysis and manual reduction of the bowel was performed, and the reduced bowel showed only congestive changes. The postoperative recovery was uneventful and the patient was discharged on the third postoperative day. Risk factors for internal herniation still remain unclear, although excessively mobile bowel loops and an enlarged foramen of Winslow have been described. Our case demonstrated that overeating could be an additional risk factor for internal herniation. We describe our clinical and radiology findings, as well as surgical management. Due to the high rates of morbidity and mortality, it is imperative that clinicians be aware of the possible risks factors for internal herniation. Internal hernias should be included in the differential diagnosis of small bowel obstruction so that appropriate steps can be made in the work-up of these patients, followed by timely surgical intervention.

  19. Inhibition of Neuroblastoma Tumor Growth by Targeted Delivery of MicroRNA-34a Using Anti-Disialoganglioside GD2 Coated Nanoparticles

    OpenAIRE

    Tivnan, Amanda; Orr, Wayne Shannon; Gubala, Vladimir; Nooney, Robert; Williams, David E.; McDonagh, Colette; Prenter, Suzanne; Harvey, Harry; Domingo-Fernández, Raquel; Bray, Isabella M.; Piskareva, Olga; Ng, Catherine Y.; Lode, Holger N.; Davidoff, Andrew M.; Stallings, Raymond L.

    2012-01-01

    Background: Neuroblastoma is one of the most challenging malignancies of childhood, being associated with the highest death rate in paediatric oncology, underlining the need for novel therapeutic approaches. Typically, patients with high risk disease undergo an initial remission in response to treatment, followed by disease recurrence that has become refractory to further treatment. Here, we demonstrate the first silica nanoparticle-based targeted delivery of a tumor suppressive, pro-apoptoti...

  20. Space radiation risks for astronauts on multiple International Space Station missions.

    Directory of Open Access Journals (Sweden)

    Francis A Cucinotta

    Full Text Available Mortality and morbidity risks from space radiation exposure are an important concern for astronauts participating in International Space Station (ISS missions. NASA's radiation limits set a 3% cancer fatality probability as the upper bound of acceptable risk and considers uncertainties in risk predictions using the upper 95% confidence level (CL of the assessment. In addition to risk limitation, an important question arises as to the likelihood of a causal association between a crew-members' radiation exposure in the past and a diagnosis of cancer. For the first time, we report on predictions of age and sex specific cancer risks, expected years of life-loss for specific diseases, and probability of causation (PC at different post-mission times for participants in 1-year or multiple ISS missions. Risk projections with uncertainty estimates are within NASA acceptable radiation standards for mission lengths of 1-year or less for likely crew demographics. However, for solar minimum conditions upper 95% CL exceed 3% risk of exposure induced death (REID by 18 months or 24 months for females and males, respectively. Median PC and upper 95%-confidence intervals are found to exceed 50% for several cancers for participation in two or more ISS missions of 18 months or longer total duration near solar minimum, or for longer ISS missions at other phases of the solar cycle. However, current risk models only consider estimates of quantitative differences between high and low linear energy transfer (LET radiation. We also make predictions of risk and uncertainties that would result from an increase in tumor lethality for highly ionizing radiation reported in animal studies, and the additional risks from circulatory diseases. These additional concerns could further reduce the maximum duration of ISS missions within acceptable risk levels, and will require new knowledge to properly evaluate.

  1. Space radiation risks for astronauts on multiple International Space Station missions.

    Science.gov (United States)

    Cucinotta, Francis A

    2014-01-01

    Mortality and morbidity risks from space radiation exposure are an important concern for astronauts participating in International Space Station (ISS) missions. NASA's radiation limits set a 3% cancer fatality probability as the upper bound of acceptable risk and considers uncertainties in risk predictions using the upper 95% confidence level (CL) of the assessment. In addition to risk limitation, an important question arises as to the likelihood of a causal association between a crew-members' radiation exposure in the past and a diagnosis of cancer. For the first time, we report on predictions of age and sex specific cancer risks, expected years of life-loss for specific diseases, and probability of causation (PC) at different post-mission times for participants in 1-year or multiple ISS missions. Risk projections with uncertainty estimates are within NASA acceptable radiation standards for mission lengths of 1-year or less for likely crew demographics. However, for solar minimum conditions upper 95% CL exceed 3% risk of exposure induced death (REID) by 18 months or 24 months for females and males, respectively. Median PC and upper 95%-confidence intervals are found to exceed 50% for several cancers for participation in two or more ISS missions of 18 months or longer total duration near solar minimum, or for longer ISS missions at other phases of the solar cycle. However, current risk models only consider estimates of quantitative differences between high and low linear energy transfer (LET) radiation. We also make predictions of risk and uncertainties that would result from an increase in tumor lethality for highly ionizing radiation reported in animal studies, and the additional risks from circulatory diseases. These additional concerns could further reduce the maximum duration of ISS missions within acceptable risk levels, and will require new knowledge to properly evaluate.

  2. The application of risk analysis to international trade in animals and animal products.

    Science.gov (United States)

    Kellar, J A

    1993-12-01

    In an era when arduous land and sea journeys separated exporting and recipient nations, the duration and stress of transport dictated localised sourcing of stock and provided an implicit quarantine. Clinically latent infection, which remained undetected prior to embarkation, often surfaced and was eliminated before reaching the importing country. Many nations which would not accept the risk of importation, on clinical grounds, could effectively isolate themselves by prohibiting entry. Passive acceptance characterised much of the response of industry to the perceived wisdom behind such decisions. Advances in transportation technology now permit the accumulation of an export consignment from across an entire country. The assembled shipment is a sentinel for the infection experience of the national herd. The journey to the final destination is measured in hours, rather than weeks. Parallel diagnostic and epidemiological advances face the challenge of compensating for the risks attendant in such widespread and rapid sourcing of stock. Nations which judge the risks as unacceptable face a concerted legal challenge on a series of levels, both domestic and international. Refusal of legal importation can be circumvented easily through the smuggling of germ plasm. National Veterinary Services must respond to the economic, social and political realities of this new international trading environment. The means of facing this challenge through quantitative risk analysis are described. The theory of risk analysis, as well as the qualitative and quantitative evolution of the import applications of this analysis, is explained. Current challenges and potential solutions are discussed.

  3. Health risks, travel preparation, and illness among public health professionals during international travel.

    Science.gov (United States)

    Balaban, Victor; Warnock, Eli; Ramana Dhara, V; Jean-Louis, Lee Ann; Sotir, Mark J; Kozarsky, Phyllis

    2014-01-01

    Few data currently exist on health risks faced by public health professionals (PHP) during international travel. We conducted pre- and post-travel health surveys to assess knowledge, attitudes, and practices (KAP), and illnesses among PHP international travelers. Anonymous surveys were completed by PHP from a large American public health agency who sought a pre-travel medical consult from September 1, 2009, to September 30, 2010. Surveys were completed by 122 participants; travelers went to 163 countries. Of the 122 respondents, 97 (80%) reported at least one planned health risk activity (visiting rural areas, handling animals, contact with blood or body fluids, visiting malarious areas), and 50 (41%) reported exposure to unanticipated health risks. Of the 62 travelers who visited malarious areas, 14 (23%) reported inconsistent or no use of malaria prophylaxis. Illness during travel was reported by 33 (27%) respondents. Most of the PHP travelers in our study reported at least one planned health risk activity, and almost half reported exposure to unanticipated health risks, and one-quarter of travelers to malarious areas reported inconsistent or no use of malaria chemoprophylaxis. Our findings highlight that communication and education outreach for PHP to prevent travel-associated illnesses can be improved. Published by Elsevier Ltd.

  4. A Neglected Population: Media Consumption, Perceived Risk, and Fear of Crime Among International Students.

    Science.gov (United States)

    Shi, Luzi

    2018-03-01

    The 4.5 million international students worldwide bring in multifold benefits to the advancement of culture, economy, and national security in education host countries. Surprisingly, few prior studies have explored international students' fear of crime, which may harm their mental and physical health and undermine their educational achievements. The current study aims to fill in this research void by investigating international students' fear of crime in line with the cultivation theoretical framework, which postulates that media consumption cultivates fear of crime. The analyses draw on a sample of 398 international students attending nine different public and private universities across the United States. Using structural equation modeling (SEM), I investigate the extent and correlates of students' fear of crime. The findings reveal that international students are more fearful in the United States than in their home countries. SEM results show that controlling for students' fear in their home countries, attention paid to crime news is positively related to fear in the United States, through perceived victimization risk. The SEM results also suggest that exposure to non-U.S. social media (e.g., WeChat and Weibo) is positively related to respondents' fear of crime, whereas exposure to U.S. social media (e.g., Facebook and Twitter) is not related to fear of crime. The current study highlights the importance of studying the impact of fear of crime and social media use on international students.

  5. Radiation protection - Monitoring of workers occupationally exposed to a risk of internal contamination with radioactive material

    International Nuclear Information System (INIS)

    2006-01-01

    In the course of employment, individuals might work with radioactive materials that, under certain circumstances, could be taken into the body. Protecting workers against risks of incorporated radionuclides requires the monitoring of potential intakes and/or the quantification of actual intakes and exposures. The selection of measures and programmes for this purpose requires decisions concerning methods, techniques, frequencies etc. for measurements and dose assessment. The criteria permitting the evaluation of the necessity of such a monitoring programme or for the selection of methods and frequencies of monitoring usually depend upon the legislation, the purpose of the radiation protection programme, the probabilities of potential radionuclide intakes, and the characteristics of the materials handled. This International Standard offers guidance for the decision whether a monitoring programme is required and how it should be designed. Its intention is to optimise the efforts for such a monitoring programme consistent with legal requirements and with the purpose of the radiation protection programme. Recommendations of international expert bodies and international experience with the practical application of these recommendations in radiation protection programmes have been considered in the development of this International Standard. Its application facilitates the exchanges of information between authorities, supervisory institutions and employers. The International Standard is not a substitute for legal requirements. In the International Standard, the word 'shall' is used to denote a requirement and no deviation is allowed. The word 'should' is used to denote a recommendation from which justified deviations are allowed. The word 'may' is used to denote permission

  6. THE MANAGEMENT OF CREDIT RISK ACCORDING TO INTERNAL RATINGS- BASED APPROACH

    Directory of Open Access Journals (Sweden)

    BOLOCAN DRAGOS-MIHAIL

    2010-12-01

    Full Text Available The internal ratings based approach (IRB Approach was created as part of Basel II replacing the original Basle Accord of 1988 (Basle I in an effort to create a better framework for regulating bank capital. This paper covers the methodology and components of the IRB Approach used to determine capital requirements for credit risk. Such an approach, which relies heavily upon a banks internal assessment of its counterparties and exposures, can secure two key objectives consistent with those which support the wider review of The New Basel Capital Accord.. IRB approach should promote safety and soundness in the financial system and, consistent with providing incentive compatibility, that the structure and requirements of the IRB approach do not impinge upon or undermine banks well-established lending and credit risk management practices

  7. International travel patterns and travel risks for stem cell transplant recipients.

    Science.gov (United States)

    Mikati, Tarek; Griffin, Kenneth; Lane, Dakotah; Matasar, Matthew; Shah, Monika K

    2015-01-01

    Stem cell transplantation (SCT) is being increasingly utilized for multiple medical illnesses. However, there is limited knowledge about international travel patterns and travel-related illnesses of stem cell transplant recipients (SCTRs). An observational cross-sectional study was conducted among 979 SCTRs at Memorial Sloan Kettering Cancer Center using a previously standardized and validated questionnaire. International travel post SCT, pre-travel health advice, exposure risks, and travel-related illnesses were queried. A total of 516 SCTRs completed the survey (55% response rate); of these, 40% were allogeneic SCTRs. A total of 229 (44.3%) respondents reported international travel outside the United States and Canada post SCT. The international travel incidence was 32% [95% confidence interval CI 28-36] within 2 years after SCT. Using multivariable Cox regression analysis, variables significantly associated with international travel within first 2 years after SCT were history of international travel prior to SCT [hazard ratio (HR) = 5.3, 95% CI 2.3-12.0], autologous SCT (HR = 2.6, 95% CI 1.6-2.8), foreign birth (HR = 2.3, 95% CI 1.5-3.3), and high income (HR = 2.0, 95% CI 1.8-3.7). During their first trip, 64 travelers (28%) had traveled to destinations that may have required vaccination or malaria chemoprophylaxis. Only 56% reported seeking pre-travel health advice. Of those who traveled, 16 travelers (7%) became ill enough to require medical attention during their first trip after SCT. Ill travelers were more likely to have visited high-risk areas (60 vs 26%, p = 0.005), to have had a longer mean trip duration (24 vs 12 days, p = 0.0002), and to have visited friends and relatives (69 vs 21%, p travel was common among SCTRs within 2 years after SCT and was mainly to low-risk destinations. Although the overall incidence of travel-related illnesses was low, certain subgroups of travelers were at a significantly higher risk. Pre

  8. EuroOOPS: an international, multicentre study to implement nutritional risk screening and evaluate clinical outcome.

    Science.gov (United States)

    Sorensen, Janice; Kondrup, Jens; Prokopowicz, Jacek; Schiesser, Marc; Krähenbühl, Lukas; Meier, Rémy; Liberda, Martin

    2008-06-01

    The aim of the study was to implement nutritional risk screening (NRS-2002) and to assess the association between nutritional risk and clinical outcome. NRS-2002 was implemented in 26 hospital departments (surgery, internal medicine, oncology, intensive care, gastroenterology and geriatrics) in Austria, the Czech Republic, Egypt, Germany, Hungary, Lebanon, Libya, Poland, Romania, Slovakia, Spain and Switzerland. Being a prospective cohort study, randomly selected adult patients were included at admission and followed during their hospitalisation. Data were collected on the nutritional risk screening, complications, mortality, length of stay and discharge. The correlation between risk status and clinical outcome was assessed and adjusted for confounders (age, speciality, diagnoses, comorbidity, surgery, cancer and region) by multivariate regression analysis. Of the 5051 study patients, 32.6% were defined as 'at-risk' by NRS-2002. 'At-risk' patients had more complications, higher mortality and longer lengths of stay than 'not at-risk' patients and these variables were significantly related to components of NRS-2002, also when adjusted for confounders. Components of NRS-2002 are independent predictors of poor clinical outcome.

  9. Management of bank risks in the system of internal financial monitoring

    Directory of Open Access Journals (Sweden)

    O.V. Lysenok

    2015-09-01

    Full Text Available Risk is an integral part of banking activities. That is why there are many researches on definition, measurement and monitoring of banking risks. Nowadays it is important to improve the risk management process of legalization (laundering of proceeds from crime or terrorist financing, especially in the present conditions of socio-economic development. This will improve the quality of financial monitoring in the country as a whole and will reduce the risk of attracting banks to laundering money from crime. The article reviews and examines modern management techniques and risk assessment of laundering proceeds from crime. The authors make suggestions to strengthen the tracking and detection of illegal schemes and appropriate approaches to «launder» criminal money. They also offer an appropriate model to manage the risks which accompany the process of laundering the proceeds from crime. According to the study carried out the authors provide their conclusions and recommendations to improve risk management in the system of internal financial monitoring of banks.

  10. Natural killer cells facilitate PRAME-specific T-cell reactivity against neuroblastoma

    NARCIS (Netherlands)

    Spel, Lotte; Boelens, Jaap-Jan; van der Steen, Dirk M.; Blokland, Nina J. G.; van Noesel, Max M.; Molenaar, Jan J.; Heemskerk, Mirjam H. M.; Boes, Marianne; Nierkens, Stefan

    2015-01-01

    Neuroblastoma is the most common solid tumor in children with an estimated 5-year progression free survival of 20-40% in stage 4 disease. Neuroblastoma actively avoids recognition by natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). Although immunotherapy has gained traction for

  11. Olfactory Neuroblastoma (ONB) in a 2 year old child: A case Report ...

    African Journals Online (AJOL)

    A case of olfactory neuroblastoma (ONB) presenting in a 2 year old girl as a nasal mass is presented. Although olfactory neuroblastomas have been reported from various parts of the world, this, to our knowledge is the first report from Midwestern Nigeria. We wish to emphasize the importance of histological examination of ...

  12. [Biological markers for the prognosis of neuroblastoma: proposal of a method of analysis].

    Science.gov (United States)

    Combaret, V; Delattre, O; Bénard, J; Favrot, M C

    1998-03-01

    The prognosis of pediatric neuroblastoma depends both on clinical presentation and on certain cellular and molecular characteristics. At the present time, two hypotheses can be drawn to explain both clinical and biological heterogeneity. In the first hypothesis, neuroblastoma progresses from early to late clinical stages through a classical multistep process linked to an accumulation of molecular abnormalities. In the second hypothesis, neuroblastoma represents an heterogeneous group of unrelated diseases, where most of stages I and II or stage IVS neuroblastomas can rather be considered as benign tumors, and stage IV neuroblastoma as a true malignant proliferation. To ascertain relevant biological factors for the prognosis of the disease, it is uppermost important that all investigators agree on biological criteria for analysis when neuroblastoma tissue is available in screened and unscreened populations. This paper reviews the biological tools available for prognosis in neuroblastoma, the priority for analysis of biological markers according to reliability, feasibility, and reproducibility of analysis procedure, and the conditions of tissue storage for further analysis of these biological markers. The standardized biological evaluation of neuroblastoma will allow, first, to collect sufficient data for multivariate analysis of prognostic factors and, second, to better define the putative links between various forms of the disease.

  13. N-myc amplification causes down-modulation of MHC class I antigen expression in neuroblastoma

    NARCIS (Netherlands)

    Bernards, R.A.; Dessain, S.K.; Weinberg, R.A.

    1986-01-01

    Amplification of the N-myc gene is correlated with increased metastatic ability of human neuroblastomas. We show here that overexpression of the N-myc gene in a rat neuroblastoma cell line following gene transfer causes down-modulation of class I histocompatibility antigen expression and increases

  14. N-myc down regulates neural cell adhesion molecule expression in rat neuroblastoma

    NARCIS (Netherlands)

    Akeson, R.; Bernards, R.A.

    1990-01-01

    In human neuroblastoma, amplification of the N-myc oncogene is correlated with increased metastatic ability. We recently showed that transfection of the rat neuroblastoma cell line B104 with an N-myc expression vector resulted in an increase in metastatic ability and a significant reduction in the

  15. TLR3 triggering regulates PD-L1 (CD274) expression in human neuroblastoma cells

    NARCIS (Netherlands)

    Boes, Marianne; Meyer-Wentrup, Friederike

    2015-01-01

    Neuroblastoma is the most common extracranial solid tumor in children, causing 12% of all pediatric cancer mortality. Neuroblastoma specific T-cells have been detected in patients, but usually fail to attack and eradicate the tumors. Tumor immune evasion may thus play an important role in

  16. Risk and protective factors for internalizing and externalizing outcomes among HIV-affected youth in Haiti.

    Science.gov (United States)

    Li, Michelle; Betancourt, Theresa; Eustache, Eddy; Oswald, Catherine; Louis, Ermaze; Mukherjee, Joia; Surkan, Pamela J; Smith Fawzi, Mary C

    2015-01-01

    The present study aims to: (1) estimate the levels of internalizing symptoms and externalizing behaviors among youth affected by HIV in central Haiti; and (2) examine the risk and protective factors associated with these outcomes to identify potential areas of intervention for HIV-affected youth. Baseline data for 492 youth affected by HIV (ages 10-17) and their 330 caregivers were collected for a pilot study of a psychosocial support intervention. Participants were recruited from a list of HIV-positive patients receiving care at Partners In Health/Zanmi Lasante clinic sites. Internalizing and externalizing behaviors were assessed using the Strengths and Difficulties Questionnaire. Demographic, economic, and social indicators were collected using a structured questionnaire administered by trained social workers. Youth affected by HIV in central Haiti displayed high levels of internalizing and, to a lesser degree, externalizing symptoms. Multivariate regression analysis demonstrated risk factors most strongly associated with internalizing symptoms (socioeconomic status, parental depressive symptoms) and externalizing behaviors (household living arrangements, such as living with a stepparent). Social support had a protective effect on externalizing behaviors for both caregiver (β=-0.03, p=0.01) and self-report (β=-0.05, pHaiti and similar resource-limited settings.

  17. Adult Neuroblastoma Complicated by Increased Intracranial Pressure: A Case Report and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Patrick L. Stevens

    2014-01-01

    Full Text Available Neuroblastoma is the third most commonly occurring malignancy of the pediatric population, although it is extremely rare in the adult population. In adults, neuroblastoma is often metastatic and portends an extremely poor overall survival. Our case report documents metastatic neuroblastoma occurring in a healthy 29-year-old woman whose course was complicated by an unusual presentation of elevated intracranial pressures. The patient was treated with systemic chemotherapy, I131 metaiodobenzylguanidine (MIBG radiotherapy, and autologous stem cell transplant (SCT. Unfortunately the patient’s response to therapy was limited and she subsequently died. We aim to review neuroblastoma in the context of increased intracranial pressure and the limited data of neuroblastoma occurring in the adult population, along with proposed treatment options.

  18. Ectopic olfactory neuroblastoma: report of four cases and a review of the literature.

    LENUS (Irish Health Repository)

    Wormald, R

    2011-04-01

    Our objective is to present a short series of four rare cases of ectopic olfactory neuroblastoma. Our methods present four case reports of ectopic olfactory neuroblastoma and a review of the literature for management and treatment of this disease. The results indicate short case series reports of ectopic olfactory neuroblastoma arising from the anterior ethmoidal sinuses, the nasopharynx, the lateral nasal wall and the floor of the nose. The discussion focuses on likely origins of ectopic olfactory neuroblastoma, its clinical features and management. We conclude that ectopic olfactory neuroblastoma is a rare disease. Treatment principles are the same for non-ectopic disease and guided by extension into adjacent structures such as the orbit or anterior cranial fossa and usually involves surgery with or without adjuvant radiotherapy.

  19. Dosimetry study of [I-131] and [I-125]- meta-iodobenz guanidine in a simulating model for neuroblastoma metastasis.

    Science.gov (United States)

    Roa, W H; Yaremko, B; McEwan, A; Amanie, J; Yee, D; Cho, J; McQuarrie, S; Riauka, T; Sloboda, R; Wiebe, L; Loebenberg, R; Janicki, C

    2013-02-01

    The physical properties of I-131 may be suboptimal for the delivery of therapeutic radiation to bone marrow metastases, which are common in the natural history of neuroblastoma. In vitro and preliminary clinical studies have implied improved efficacy of I-125 relative to I-131 in certain clinical situations, although areas of uncertainty remain regarding intratumoral dosimetry. This prompted our study using human neuroblastoma multicellular spheroids as a model of metastasis. 3D dose calculations were made using voxel-based Medical Internal Radiation Dosimetry (MIRD) and dose-point-kernel (DPK) techniques. Dose distributions for I-131 and I-125 labeled mIBG were calculated for spheroids (metastases) of various sizes from 0.01 cm to 3 cm diameter, and the relative dose delivered to the tumors was compared for the same limiting dose to the bone marrow. Based on the same data, arguments were advanced based upon the principles of tumor control probability (TCP) to emphasize the potential theoretical utility of I-125 over I-131 in specific clinical situations. I-125-mIBG can deliver a higher and more uniform dose to tumors compared to I-131 mIBG without increasing the dose to the bone marrow. Depending on the tumor size and biological half-life, the relative dose to tumors of less than 1 mm diameter can increase several-fold. TCP calculations indicate that tumor control increases with increasing administered activity, and that I-125 is more effective than I-131 for tumor diameters of 0.01 cm or less. This study suggests that I-125-mIBG is dosimetrically superior to I-131-mIBG therapy for small bone marrow metastases from neuroblastoma. It is logical to consider adding I-125-mIBG to I-131-mIBG in multi-modality therapy as these two isotopes could be complementary in terms of their cumulative dosimetry.

  20. Epigenetic dysregulation in neuroblastoma: A tale of miRNAs and DNA methylation.

    Science.gov (United States)

    Parodi, Federica; Carosio, Roberta; Ragusa, Marco; Di Pietro, Cinzia; Maugeri, Marco; Barbagallo, Davide; Sallustio, Fabio; Allemanni, Giorgio; Pistillo, Maria Pia; Casciano, Ida; Forlani, Alessandra; Schena, Francesco P; Purrello, Michele; Romani, Massimo; Banelli, Barbara

    2016-12-01

    In neuroblastoma, the epigenetic landscape is more profoundly altered in aggressive compared to lower grade tumors and the concomitant hypermethylation of many genes, defined as "methylator phenotype", has been associated with poor outcome. DNA methylation can interfere with gene expression acting at distance through the methylation or demethylation of the regulatory regions of miRNAs. The multiplicity of miRNA targets may result in the simultaneous alteration of many biological pathways like cell proliferation, apoptosis, migration and differentiation. We have analyzed the methylation status of a set of miRNAs in a panel of neuroblastoma cell lines and identified a subset of hypermethylated and down-regulated miRNAs (miRNA 34b-3p, miRNA 34b-5p, miRNA34c-5p, and miRNA 124-2-3p) involved in the regulation of cell cycle, apoptosis and in the control of MYCN expression. These miRNAs share, in part, some of the targets whose expression is inversely correlated to the methylation and expression of the corresponding miRNA. To simulate the effect of the demethylation of miRNAs, we transfected the corresponding miRNA-mimics in the same cell lines and observed the down-regulation of a set of their target genes as well as the partial block of the cell cycle and the activation of the apoptotic pathway. The epigenetic alterations of miRNAs described in the present study were found also in a subset of patients at high risk of progression. Our data disclosed a complex network of interactions between epigenetically altered miRNAs and target genes, that could interfere at multiple levels in the control of cell homeostasis. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. Mainstreaming risk reduction in urban planning and housing: a challenge for international aid organisations.

    Science.gov (United States)

    Wamsler, Christine

    2006-06-01

    The effects of 'natural' disasters in cities can be worse than in other environments, with poor and marginalised urban communities in the developing world being most at risk. To avoid post-disaster destruction and the forced eviction of these communities, proactive and preventive urban planning, including housing, is required. This paper examines current perceptions and practices within international aid organisations regarding the existing and potential roles of urban planning as a tool for reducing disaster risk. It reveals that urban planning confronts many of the generic challenges to mainstreaming risk reduction in development planning. However, it faces additional barriers. The main reasons for the identified lack of integration of urban planning and risk reduction are, first, the marginal position of both fields within international aid organisations, and second, an incompatibility between the respective professional disciplines. To achieve better integration, a conceptual shift from conventional to non-traditional urban planning is proposed. This paper suggests related operative measures and initiatives to achieve this change.

  2. Understanding gender, sexuality and HIV risk in HEIs: narratives of international post-graduate students

    Directory of Open Access Journals (Sweden)

    Mathabo Khau

    2013-12-01

    Full Text Available Thirty years into the HIV&AIDS pandemic, the world is still striving to reduce new HIV infections and halve AIDS related deaths by 2015. However, sub-Saharan Africa still faces the burden of HIV infections as governments and private institutions try out different prevention strategies (UNAIDS 2011. Several scholars have argued that multiple concurrent sexual partnerships (MCSP pose the greatest risk for new HIV infections. Furthermore, research has also linked MCSPs to mobility and migration. This paper draws from the project ‘Sexual identities and HIV&AIDS: an exploration of international university students’ experiences” which employed memory work, photo-voice, drawings and focus group discussions with ten (5male and 5female Post Graduate international students at a South African university. Focussing on the data produced through memory work, I present university students’ lived-experience narratives of mobility and migration in relation to how they perceive MCSPs and HIV risk. The findings show how students construct their gendered and sexual identities in a foreign context and how these constructions intersect with their choices of sexual relationships and HIV risk. I argue from the findings that Higher Education Institutions should be treated as high risk ‘spaces of vulnerability’ and hence health support services and HIV intervention programming policies should be geared towards addressing such vulnerabilities in order to create sustainable teaching and learning environments that allow for all students to explore their full capabilities.

  3. Adaptation to flood risk: Results of international paired flood event studies

    Science.gov (United States)

    Kreibich, Heidi; Di Baldassarre, Giuliano; Vorogushyn, Sergiy; Aerts, Jeroen C. J. H.; Apel, Heiko; Aronica, Giuseppe T.; Arnbjerg-Nielsen, Karsten; Bouwer, Laurens M.; Bubeck, Philip; Caloiero, Tommaso; Chinh, Do T.; Cortès, Maria; Gain, Animesh K.; Giampá, Vincenzo; Kuhlicke, Christian; Kundzewicz, Zbigniew W.; Llasat, Maria Carmen; Mârd, Johanna; Matczak, Piotr; Mazzoleni, Maurizio; Molinari, Daniela; Dung, Nguyen V.; Petrucci, Olga; Schröter, Kai; Slager, Kymo; Thieken, Annegret H.; Ward, Philip J.; Merz, Bruno

    2017-10-01

    As flood impacts are increasing in large parts of the world, understanding the primary drivers of changes in risk is essential for effective adaptation. To gain more knowledge on the basis of empirical case studies, we analyze eight paired floods, that is, consecutive flood events that occurred in the same region, with the second flood causing significantly lower damage. These success stories of risk reduction were selected across different socioeconomic and hydro-climatic contexts. The potential of societies to adapt is uncovered by describing triggered societal changes, as well as formal measures and spontaneous processes that reduced flood risk. This novel approach has the potential to build the basis for an international data collection and analysis effort to better understand and attribute changes in risk due to hydrological extremes in the framework of the IAHSs Panta Rhei initiative. Across all case studies, we find that lower damage caused by the second event was mainly due to significant reductions in vulnerability, for example, via raised risk awareness, preparedness, and improvements of organizational emergency management. Thus, vulnerability reduction plays an essential role for successful adaptation. Our work shows that there is a high potential to adapt, but there remains the challenge to stimulate measures that reduce vulnerability and risk in periods in which extreme events do not occur.

  4. Leading internal and external sources of credit risk in the top South African banks

    Directory of Open Access Journals (Sweden)

    Tankiso Moloi

    2014-09-01

    Full Text Available This paper aimed at identifying the leading credit risk indicators in the South African banking context as well as the development of an integrated leading credit risk indicator model. A content analysis was used as a data extraction methodology and structural equation modelling was used as a data analysis methodology. The results obtained indicated that utilising the structural equation modelling, gross savings, and prime overdraft rates, number of judgements, business insolvencies and unemployment rates were formulated as leading economic and market (external indicators of credit risk in the South African banking context. Similarly, utilising the principal component analysis, bank asset quality, bank asset concentration as well as bank trading and hedging activities were formulated as leading bank specific (internal indicators of credit risk in the South African banking context. The Integrated Leading Credit Risk Indicator Model (ICRIM was formulated utilising the accepted leading credit risk indicators. The ICRIM parameters were benchmarked against the generally accepted fit indices such as the RMSEA, comparative fit (baseline comparison as well as the Hoelter and its results output were found to be consistent with these generally accepted fit indices

  5. Heap leach cyanide irrigation and risk to wildlife: Ramifications for the international cyanide management code.

    Science.gov (United States)

    Donato, D B; Madden-Hallett, D M; Smith, G B; Gursansky, W

    2017-06-01

    Exposed cyanide-bearing solutions associated with gold and silver recovery processes in the mining industry pose a risk to wildlife that interact with these solutions. This has been documented with cyanide-bearing tailings storage facilities, however risks associated with heap leach facilities are poorly documented, monitored and audited. Gold and silver leaching heap leach facilities use cyanide, pH-stabilised, at concentrations deemed toxic to wildlife. Their design and management are known to result in exposed cyanide-bearing solutions that are accessible to and present a risk to wildlife. Monitoring of the presence of exposed solutions, wildlife interaction, interpretation of risks and associated wildlife deaths are poorly documented. This paper provides a list of critical monitoring criteria and attempts to predict wildlife guilds most at risk. Understanding the significance of risks to wildlife from exposed cyanide solutions is complex, involving seasonality, relative position of ponding, temporal nature of ponding, solution palatability, environmental conditions, in situ wildlife species inventory and provision of alternative drinking sources for wildlife. Although a number of heap leach operations are certified as complaint with the International Cyanide Management Code (Cyanide Code), these criteria are not considered by auditors nor has systematic monitoring regime data been published. Without systematic monitoring and further knowledge, wildlife deaths on heap leach facilities are likely to remain largely unrecorded. This has ramifications for those operations certified as compliance with the Cyanide Code. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Autocrine prostaglandin E2 signaling promotes tumor cell survival and proliferation in childhood neuroblastoma.

    Directory of Open Access Journals (Sweden)

    Agnes Rasmuson

    Full Text Available BACKGROUND: Prostaglandin E(2 (PGE(2 is an important mediator in tumor-promoting inflammation. High expression of cyclooxygenase-2 (COX-2 has been detected in the embryonic childhood tumor neuroblastoma, and treatment with COX inhibitors significantly reduces tumor growth. Here, we have investigated the significance of a high COX-2 expression in neuroblastoma by analysis of PGE(2 production, the expression pattern and localization of PGE(2 receptors and intracellular signal transduction pathways activated by PGE(2. PRINCIPAL FINDINGS: A high expression of the PGE(2 receptors, EP1, EP2, EP3 and EP4 in primary neuroblastomas, independent of biological and clinical characteristics, was detected using immunohistochemistry. In addition, mRNA and protein corresponding to each of the receptors were detected in neuroblastoma cell lines. Immunofluorescent staining revealed localization of the receptors to the cellular membrane, in the cytoplasm, and in the nuclear compartment. Neuroblastoma cells produced PGE(2 and stimulation of serum-starved neuroblastoma cells with PGE(2 increased the intracellular concentration of calcium and cyclic AMP with subsequent phosphorylation of Akt. Addition of 16,16-dimethyl PGE(2 (dmPGE(2 increased cell viability in a time, dose- and cell line-dependent manner. Treatment of neuroblastoma cells with a COX-2 inhibitor resulted in a diminished cell growth and viability that was reversed by the addition of dmPGE(2. Similarly, PGE(2 receptor antagonists caused a decrease in neuroblastoma cell viability in a dose-dependent manner. CONCLUSIONS: These findings demonstrate that PGE(2 acts as an autocrine and/or paracrine survival factor for neuroblastoma cells. Hence, specific targeting of PGE(2 signaling provides a novel strategy for the treatment of childhood neuroblastoma through the inhibition of important mediators of tumor-promoting inflammation.

  7. Risk factors for preterm birth in an international prospective cohort of nulliparous women.

    Directory of Open Access Journals (Sweden)

    Gustaaf Albert Dekker

    Full Text Available OBJECTIVES: To identify risk factors for spontaneous preterm birth (birth <37 weeks gestation with intact membranes (SPTB-IM and SPTB after prelabour rupture of the membranes (SPTB-PPROM for nulliparous pregnant women. DESIGN: Prospective international multicentre cohort. PARTICIPANTS: 3234 healthy nulliparous women with a singleton pregnancy, follow up was complete in 3184 of participants (98.5%. RESULTS: Of the 3184 women, 156 (4.9% had their pregnancy complicated by SPTB; 96 (3.0% and 60 (1.9% in the SPTB-IM and SPTB-PPROM categories, respectively. Independent risk factors for SPTB-IM were shorter cervical length, abnormal uterine Doppler flow, use of marijuana pre-pregnancy, lack of overall feeling of well being, being of Caucasian ethnicity, having a mother with diabetes and/or a history of preeclampsia, and a family history of low birth weight babies. Independent risk factors for SPTB-PPROM were shorter cervical length, short stature, participant's not being the first born in the family, longer time to conceive, not waking up at night, hormonal fertility treatment (excluding clomiphene, mild hypertension, family history of recurrent gestational diabetes, and maternal family history of any miscarriage (risk reduction. Low BMI (<20 nearly doubled the risk for SPTB-PPROM (odds ratio 2.64; 95% CI 1.07-6.51. The area under the receiver operating characteristics curve (AUC, after internal validation, was 0.69 for SPTB-IM and 0.79 for SPTB-PPROM. CONCLUSION: The ability to predict PTB in healthy nulliparous women using clinical characteristics is modest. The dissimilarity of risk factors for SPTB-IM compared with SPTB-PPROM indicates different pathophysiological pathways underlie these distinct phenotypes. TRIAL REGISTRATION: ACTR.org.au ACTRN12607000551493.

  8. Restriction in hip internal rotation is associated with an increased risk of ACL injury.

    Science.gov (United States)

    Bedi, Asheesh; Warren, Russell F; Wojtys, Edward M; Oh, You Keun; Ashton-Miller, James A; Oltean, Hanna; Kelly, Bryan T

    2016-06-01

    Evidence suggests that femoroacetabular impingement (FAI) in athletes may increase the risk of anterior cruciate ligament (ACL) injury. This study correlates ACL injury with hip range of motion in a consecutive series of elite, contact athletes and tests the hypothesis that a restriction in the available hip axial rotation in a dynamic in silico model of a simulated pivot landing would increase ACL strain and the risk of ACL rupture. Three hundred and twenty-four football athletes attending the 2012 NFL National Invitational Camp were examined. Hip range of internal rotation was measured and correlated with a history of ACL injury and surgical repair. An in silico biomechanical model was used to study the effect of FAI on the peak relative ACL strain developed during a simulated pivot landing. The in vivo results demonstrated that a reduction in internal rotation of the left hip was associated with a statistically significant increased odds of ACL injury in the ipsilateral or contralateral knee (OR 0.95, p = 0.0001 and p < 0.0001, respectively). A post-estimation calculation of odds ratio for ACL injury based on deficiency in hip internal rotation demonstrated that a 30-degree reduction in left hip internal rotation was associated with 4.06 and 5.29 times greater odds of ACL injury in the ipsilateral and contralateral limbs, respectively. The in silico model demonstrated that FAI systematically increased the peak ACL strain predicted during the pivot landing. FAI may be associated with ACL injury because of the increased resistance to femoral internal axial rotation during a dynamic maneuver such as a pivot landing. This insight may lead to better interventions to prevent ACL injury and improved understanding of ACL reconstruction failure. Cohort study, Level IV.

  9. The role of local irradiation for advanced neuroblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Masunaga, Ken; Mugishima, Hideo; Harada, Kensuke [Nihon Univ., Tokyo (Japan). School of Medicine

    1995-06-01

    Since 1985, 30 patients with advanced neuroblastoma were treated with a comprehensive therapy including chemotherapy, radiotherapy, operation, and autologous bone marrow transplant (A-BMT). After surgery, many patients received local irradiation at the primary tumor site. We investigated the role of local irradiation for advanced neuroblastoma. Of the 30 patients, 22 received local irradiation. These patients included 2 with stage III, 17 with stage IV{sub A}, and 3 with stage IV{sub B}. Most patients were 1 year of age or older at the time of diagnosis. Adrenal tumors were present in 13, retroperitoneal in 5, thoracic in 3, and both retroperitoneal and thoracic in 1. N-myc amplification was present in 8 patients. In terms of patient characteristics, there were no difference between local irradiation group and non-local irradiation group. All patients received induction chemotherapy, as described by Sawaguchi and others. After surgery, 22 patients received local irradiation of 10 to 26 Gy in 1 to 16 fractions at the primary tumor site. Intraoperative irradiation in a dose of 10 to 15 Gy in single fraction had been administered to 15 patients. Most patients received purged marrow using immunomagnetic beads. All patients received preconditioning regimen (VAMP, modified VAMP with or without TBI) and then transplanted. Following A-BMT, 13-cis-retinoic acid was administered for the purpose of tumor differentiation. Of the 22 patients with local irradiation, 6 relapsed and 5 died. Of the 8 patients without local irradiation, 2 relapsed and 1 died. Patients who completely received local irradiation showed no evidence of primary tumor recurrence. Patients who did not receive or incompletely received local irradiation showed primary tumor recurrence. Local irradiation for advanced neuroblastoma is very useful treatment to prevent primary tumor recurrence. (author).

  10. Association of telomerase activity with radio- and chemosensitivity of neuroblastomas

    Directory of Open Access Journals (Sweden)

    Willich Normann

    2010-07-01

    Full Text Available Abstract Background Telomerase activity compensates shortening of telomeres during cell division and enables cancer cells to escape senescent processes. It is also supposed, that telomerase is associated with radio- and chemoresistance. In the here described study we systematically investigated the influence of telomerase activity (TA and telomere length on the outcome of radio- and chemotherapy in neuroblastoma. Methods We studied the effects on dominant negative (DN mutant, wild type (WT of the telomerase catalytic unit (hTERT using neuroblastoma cell lines. The cells were irradiated with 60Co and treated with doxorubicin, etoposide, cisplatin and ifosfamide, respectively. Viability was determined by MTS/MTT-test and the GI50 was calculated. Telomere length was measured by southernblot analysis and TA by Trap-Assay. Results Compared to the hTERT expressing cells the dominant negative cells showed increased radiosensitivity with decreased telomere length. Independent of telomere length, telomerase negative cells are significantly more sensitive to irradiation. The effect of TA knock-down or overexpression on chemosensitivity were dependent on TA, the anticancer drug, and the chemosensitivity of the maternal cell line. Conclusions Our results supported the concept of telomerase inhibition as an antiproliferative treatment approach in neuroblastomas. Telomerase inhibition increases the outcome of radiotherapy while in combination with chemotherapy the outcome depends on drug- and cell line and can be additive/synergistic or antagonistic. High telomerase activity is one distinct cancer stem cell feature and the here described cellular constructs in combination with stem cell markers like CD133, Aldehyddehydrogenase-1 (ALDH-1 or Side population (SP may help to investigate the impact of telomerase activity on cancer stem cell survival under therapy.

  11. WT1 Alternative Splicing: Role of Its Isoforms in Neuroblastoma.

    Science.gov (United States)

    Rasà, Daniela Maria; D'Amico, Agata Grazia; Maugeri, Grazia; Cavallaro, Sebastiano; D'Agata, Velia

    2017-06-01

    Wilms tumor 1 (WT1), a tumor suppressor gene, was originally identified in the homonymous renal neoplasm but is also involved in other cancers. Its function is still unclear, since it acts both as a pro- and an anti-oncogene. At least 14 WT1 transcriptional variants have been described; yet most investigations have focused on a small number of isoforms. We describe their structural features and review the evidence of their involvement in cancer with emphasis on neuroblastoma. In future, full characterization of all WT1 isoforms is expected to identify new molecular tumor markers and/or therapeutic targets.

  12. Lupus risk variants in the PXK locus alter B-cell receptor internalization

    Directory of Open Access Journals (Sweden)

    Samuel E. Vaughn

    2015-01-01

    Full Text Available Genome wide association studies have identified variants in PXK that confer risk for humoral autoimmune diseases, including systemic lupus erythematosus (SLE or lupus, rheumatoid arthritis and more recently systemic sclerosis. While PXK is involved in trafficking of epidermal growth factor Receptor (EGFR in COS-7 cells, mechanisms linking PXK to lupus pathophysiology have remained undefined. In an effort to uncover the mechanism at this locus that increases lupus-risk, we undertook a fine-mapping analysis in a large multi-ancestral study of lupus patients and controls. We define a large (257kb common haplotype that confers lupus risk detected only in European ancestral populations and spans the promoter through the 3’ UTR of PXK. The strongest association was found at rs6445972 with P < 4.62 x 10-10, OR 0.81 (0.75 – 0.86. Using stepwise logistic regression analysis, we demonstrate that one signal drives the genetic association in the region. Bayesian analysis confirms our results, identifying a 95% credible set consisting of 172 variants spanning 200kb.Functionally, we found that PXK operates on the B-cell antigen receptor (BCR; we confirmed that PXK influenced the rate of BCR internalization. Furthermore, we demonstrate that individuals carrying the risk haplotype exhibited a decreased rate of BCR internalization, a process known to impact B cell survival and cell fate. Taken together, these data define a new candidate mechanism for the genetic association of variants around PXK with lupus risk and highlight the regulation of intracellular trafficking as a genetically regulated pathway mediating human autoimmunity.

  13. The risk of endoleak following stent covering of the internal iliac artery during endovascular aneurysm repair

    International Nuclear Information System (INIS)

    Rajesparan, K.; Partridge, W.; Refson, J.; Abidia, A.; Aldin, Z.

    2014-01-01

    Aim: To investigate the risk of endoleak during endovascular aneurysm repair (EVAR) involving the distal common iliac artery (CIA) when the internal iliac artery (IIA) is covered without prior coil embolization. Materials and methods: Retrospective analysis of 145 (125 men, 20 women) consecutive EVAR cases. Clinical notes and radiological images were reviewed, and data collected on patient demographics, aneurysm morphology, covering of the IIA with or without embolization, presence of endoleaks, and patient symptoms relating to IIA ischaemia. Results: A total of 29 IIAs (10%) were covered in a total of 25 patients. Seven IIAs (24%) were embolized before stent covering (Embolization group), and 22 IIAs (76%) were covered only without embolization (Cover group). There was no statistically significant difference in the mean size of the abdominal aortic aneurysm diameter or CIA diameter between each group. No endoleaks from IIA retrograde filling were found in either group. Conclusion: The results of the present study do not support the traditional view that coverage of the IIA without prior embolization carries a high risk of endoleak, with no endoleaks seen in all 22 cases. Large-scale trials are required. However, the advent of branched-stenting techniques and the emergence of their success in long-term follow-up may preclude the former. - Highlights: • No EVAR endoleaks due to retrograde filling of the internal iliac artery (IIA). • No increased risk of endoleak with stent coverage of the IIA without embolisation. • Current evidence does not support traditional views

  14. SURF - SUrvey of Risk Factor management: first report of an international audit.

    Science.gov (United States)

    Cooney, Mt; Reiner, Z; Sheu, W; Ryden, L; Sutter, J de; De Bacquer, D; DeBacker, G; Mithal, A; Chung, N; Lim, Yt; Dudina, A; Reynolds, A; Dunney, K; Graham, I

    2014-07-01

    Despite the fact that subjects with established coronary heart disease (CHD) are at high risk of further events and deserve meticulous secondary prevention, current audits such as EUROASPIRE show poor control of major risk factors. Ongoing monitoring is required. We present a new risk factor audit system, SURF (Survey of Risk Factor management), that can be conducted much more quickly and easily than existing audit systems and has the potential to allow hospitals of all sizes to participate in a unified international audit system that will complement EUROASPIRE. Initial experience indicates that SURF is truly simple to undertake in an international setting, and this is illustrated with the results of a substantive pilot project conducted in Europe and Asia. The data collection system was designed to allow rapid and easy data collection as part of routine clinic work. Consecutive patients (aged 18 and over) with established CHD attending outpatient cardiology clinics were included. Information on demographics, previous coronary medical history, smoking history, history of hypertension, dyslipidaemia or diabetes, physical activity, attendance at cardiac rehabilitation, cardiac medications, lipid and glucose levels (and HbA1c in diabetics) if available within the last year, blood pressure, heart rate, body mass index, and waist circumference were collected using a one-page data collection sheet. Years spent in full time education was added as an additional question during the pilot phase. Three European countries - Ireland (n = 251), Belgium (n = 122), and Croatia (n = 124) - and four Asian countries - Singapore (n = 142), Taiwan (n = 334), India (n = 97), and Korea (n = 45) - were included in the pilot study. The results of initial field testing were confirmed in that it proved possible to collect data within 60-90 seconds per subject. There was poor control of several risk factors including high levels of physical inactivity (41

  15. International classification of function, disability and health framework for fall risk stratification in community dwelling older adults

    OpenAIRE

    Majumi M. Noohu; Aparajit B. Dey; Shashi Sharma; Mohammed E. Hussain

    2017-01-01

    Falls is an important cause for mortality and morbidity in older adults. The fall risk assessment is an integral component of fall prevention in older adults. The international classification of function, disability and health (ICF) can be an ideal comprehensive model for fall risk assessment. There is lack of information relating ICF and fall risk assessment in community dwelling older adults. In this study we tried to assess the fall risk using different domains of ICF using various clinica...

  16. Influences of Internal Control Risk Influence When Planning an Audit: An Empirical Study of the Coso Conceptual Framework

    OpenAIRE

    Pedro Carmona Ibáñez

    2007-01-01

    This paper studies whether the audit profession understands and follows the internal control framework developed in the COSO Report about the assessment of control risks. That is to say, the extent to which auditors assess control risks and transmit such assessments on substantive testing work when planning an audit, and take into account the assumptions of COSO which affect the identification of risks, in line with the new audit approach based on business risks. The results of the statistica...

  17. Treatment Strategy Based on Plaque Vulnerability and the Treatment Risk Evaluation for Internal Carotid Artery Stenosis.

    Science.gov (United States)

    Ito, Yoshiro; Tsuruta, Wataro; Nakai, Yasunobu; Takigawa, Tomoji; Marushima, Aiki; Masumoto, Tomohiko; Matsumaru, Yuji; Ishikawa, Eiichi; Matsumura, Akira

    2018-03-03

    Carotid endarterectomy (CEA) and carotid artery stenting (CAS) are not appropriate treatment procedure for internal carotid artery stenosis (ICAS) in some patients. The importance of plaque vulnerability and the treatment risk evaluation has been reported. We analyzed whether treatment selection contributes to the outcome. We retrospectively examined 121 patients who underwent CEA or CAS. Treatment was selected based on plaque vulnerability and the treatment risk evaluation. We selected CAS for patients with stable plaques and CEA for patients with unstable plaques, and considered the other treatment for high-risk patients. The patients were classified as the stable plaque (Stable: n = 42), the unstable plaque and CEA low risk (Unstable/Low: n = 30), and the CEA high-risk (Unstable/High: n = 49). Frequency of perioperative stroke, myocardial infarction, death, and systemic complications was examined. CEA and CAS were performed in 35 and 86 patients, respectively. One patient (2.9%) had a stroke in CEA and five patients (5.8%) in CAS (P = 0.50). Systemic complications were observed in two patients (5.7%) in CEA and six (7.1%) in CAS (P = 0.80). There were no differences in stroke (Stable; 2.4%, Unstable/Low; 3.2%, and Unstable/High; 8.2%) and systemic complications (Stable; 9.5%, Unstable/Low; 3.3%, and Unstable/High; 6.1%) among three groups (P = 0.44 and P = 0.59, respectively). The treatment selection based on plaque vulnerability and the treatment risk evaluation could provide good treatment outcome for high-risk patients. It is ideal to select an appropriate treatment for ICAS by one neurovascular team.

  18. A cross-sectional study of the relationships between illness insight, internalized stigma, and suicide risk in individuals with schizophrenia.

    Science.gov (United States)

    Sharaf, Amira Y; Ossman, Laila H; Lachine, Ola A

    2012-12-01

    Suicide is the major cause of premature death among individuals with schizophrenia. Ironically, one factor that heightens suicide risk is insight into mental illness. Little is known, however, about how insight contributes to suicidality. Recent evidence suggests that negative outcomes related to insight might depend on whether or not the individual accepts the stigmatizing beliefs about the mental illness. The present study examined the interactive effects of insight and internalized stigma on suicide risk in individuals with schizophrenia. We hypothesized that insight into mental illness and internalized stigma would increase suicide risk and that internalized stigma would moderate the effect of insight on suicide risk. A cross-sectional design was used in this study. A convenience sample of 200 individuals with schizophrenia was recruited from an outpatient clinic in the Eastern catchment area in Alexandria, Egypt. Eligible study participants were individuals with an illness duration not exceeding ten years, currently in outpatient treatment and follow-up, and post-acute or in a stable phase of their disorder. Individuals provided signed consent to participate and were interviewed to assess suicide risk, insight, internalized stigma of mental illness and depression. Slightly more than 38% of the study participants were classified as having a severe suicide risk. As predicted, suicide risk was positively associated with insight (r=.55, psuicide risk, explaining 74% of variance in suicide risk, F(change) (6, 191)=11.54, psuicide risk. The present study draws attention to the robust influence of internalized stigma in increasing suicide risk and suggests clinical approaches for managing internalized stigma and suicide risk among individuals with schizophrenia. Copyright © 2012 Elsevier Ltd. All rights reserved.

  19. Has the economic crisis led to a new risk profile for international travellers?

    Science.gov (United States)

    Roure, S; Pérez-Quílez, O; Vallès, X; Martínez-Cuevas, O; Sabrià, M; Valerio, L

    2015-11-01

    The economic world crisis has led to the migration of European workers to developing countries with a high incidence of infectious diseases. The objective of this study was to assess whether this context has produced an increase in the risks to international travellers for work reasons (TWR). Observational, retrospective study. The study population included TWR who were attended before travelling at an International Health Unit in the year 2007 (the year before the initiation of the European crisis) and in the year 2012 (when the structural crisis was established). A comparative socioeconomic analysis was performed as well as an analysis of the risk factors present in both groups. In 2007 and 2012 a total of 9,197 travellers were attended. Of these, there were 344 TWR (3.4%); 101 TWR (2.8%) in 2007 and 243 TWR (4.5%) in 2012 (p<0.001). The average age of the travellers was 38.1 years (SD: 10.57). The most common destination was Sub-Saharan Africa, in 164 (47.6%) of the cases. Malaria chemoprophylaxis was prescribed to 152 travellers (44%) and 80 presented comorbidity (23.25%). The TWR from 2012 presented a significantly greater age (p=0.05), more comorbidity (p=0.018) and a greater proportion of stays in rural areas (p=0.0009) for longer time periods (p=0.001). At 5 years from the start of the economic crisis, there was a change in the profile of TWR. Their number has increased significantly, as has the proportion who present risk factors for contracting imported diseases. The International Health Units should adapt to these new circumstances and adopt preventive measures for this population. Copyright © 2015 Elsevier España, S.L.U. y Sociedad Española de Medicina Interna (SEMI). All rights reserved.

  20. Neuroblastoma arginase activity creates an immunosuppressive microenvironment that impairs autologous and engineered immunity

    Science.gov (United States)

    Mussai, Francis; Egan, Sharon; Hunter, Stuart; Webber, Hannah; Fisher, Jonathan; Wheat, Rachel; McConville, Carmel; Sbirkov, Yordan; Wheeler, Kate; Bendle, Gavin; Petrie, Kevin; Anderson, John; Chesler, Louis; De Santo, Carmela

    2015-01-01

    Neuroblastoma is the most common extra cranial solid tumour of childhood, and survival remains poor for patients with advanced disease. Novel immune therapies are currently in development, but clinical outcomes have not matched preclinical results. Here, we describe key mechanisms in which neuroblastoma inhibits the immune response. We show that murine and human neuroblastoma tumour cells suppress T cell proliferation, through increased arginase activity. Arginase II is the predominant isoform expressed and creates an arginine deplete local and systemic microenvironment. Neuroblastoma arginase activity results in inhibition of myeloid cell activation and suppression of bone marrow CD34+ progenitor proliferation. Finally we demonstrate that the arginase activity of neuroblastoma impairs NY-ESO-1 specific TCR and GD2-specific CAR engineered T cell proliferation and cytotoxicity. High arginase II expression correlates with poor survival for neuroblastoma patients. The results support the hypothesis that neuroblastoma creates an arginase-dependent immunosuppressive microenvironment in both the tumour and blood that leads to impaired immune surveillance and sub-optimal efficacy of immunotherapeutic approaches. PMID:26054597

  1. Gene expression profiling in response to the histone deacetylase inhibitor BL1521 in neuroblastoma

    International Nuclear Information System (INIS)

    Ruijter, Annemieke J.M. de; Meinsma, Rutger J.; Bosma, Peter; Kemp, Stephan; Caron, Huib N.; Kuilenburg, Andre B.P. van

    2005-01-01

    Neuroblastoma is a childhood tumor with a poor survival in advanced stage disease despite intensive chemotherapeutic regimes. The new histone deacetylase (HDAC) inhibitor BL1521 has shown promising results in neuroblastoma. Inhibition of HDAC resulted in a decrease in proliferation and metabolic activity, induction of apoptosis and differentiation of neuroblastoma cells. In order to elucidate the mechanism mediating the effects of BL1521 on neuroblastoma cells, we investigated the gene expression profile of an MYCN single copy (SKNAS) and an MYCN amplified (IMR32) neuroblastoma cell line after treatment with BL1521 using the Affymetrix oligonucleotide array U133A. An altered expression of 255 genes was observed in both neuroblastoma cell lines. The majority of these genes were involved in gene expression, cellular metabolism, and cell signaling. We observed changes in the expression of vital genes belonging to the cell cycle (cyclin D1 and CDK4) and apoptosis (BNIP3, BID, and BCL2) pathway in response to BL1521. The expression of 37 genes was altered by both BL1521 and Trichostatin A, which could indicate a common gene set regulated by different HDAC inhibitors. BL1521 treatment changed the expression of a number of MYCN-associated genes. Several genes in the Wnt and the Delta/Notch pathways were changed in response to BL1521 treatment, suggesting that BL1521 is able to induce the differentiation of neuroblastoma cells into a more mature phenotype

  2. QUANTITATIVE APPROACH TO ASSIST NEUROBLASTOMA ASSESSMENT BY MEASURING I-123 mIBG UPTAKE IN SCINTIGRAPHIC IMAGES

    Directory of Open Access Journals (Sweden)

    Rafael Martínez-Díaz

    2015-03-01

    Full Text Available Whole-body 123I-Metaiodobenzylguanidine (mIBG scintigraphy is used as the primary image modality in neuroblastoma detection. It is the most sensitive and specific method for staging and response evaluation. Validated semi-quantitative scoring methods with low interobserver variability and high reproducibility have shown to be indispensable for the evaluation of response to therapy. However, low resolution, noise and acquisition difficulties, specially in children, make low definition scans. These facts increase observer dependent interpretations that limit assessment and complicate to put a scoring method successfully into practice. It is essential to have an objective and reliable measure of response to test the activity of therapies. In this paper we propose the use of a quantitative observer-independent measurement of the strength of uptake to be used as an additional tool for assisting the International Society of Paediatric Oncology Europe Neuroblastoma Group (SIOPEN semi-quantitative scoring method. This is the scoring method recommended by the SIOPEN Nuclear Medicine and Physics Committee, in collaborative work with the Children’s Oncology Group, as the standard one for acquiring and reporting diagnostic paediatric mIBG scans across Europe. Our proposed method is based on the ratio between the amount of specific uptake at tumours and the amount of non-specific uptake at SIOPEN anatomical sectors which has shown to be constant in all the scans of the patients.

  3. International Space Station (ISS) Orbital Replaceable Unit (ORU) Wet Storage Risk Assessment

    Science.gov (United States)

    Squire, Michael D.; Rotter, Henry A.; Lee, Jason; Packham, Nigel; Brady, Timothy K.; Kelly, Robert; Ott, C. Mark

    2014-01-01

    The International Space Station (ISS) Program requested the NASA Engineering and Safety Center (NESC) to evaluate the risks posed by the practice of long-term wet storage of ISS Environmental Control and Life Support (ECLS) regeneration system orbital replacement units (ORUs). The ISS ECLS regeneration system removes water from urine and humidity condensate and converts it into potable water and oxygen. A total of 29 ORUs are in the ECLS system, each designed to be replaced by the ISS crew when necessary. The NESC assembled a team to review the ISS ECLS regeneration system and evaluate the potential for biofouling and corrosion. This document contains the outcome of the evaluation.

  4. Measurement and Internalization of Systemic Risk in a Global Banking Network

    Science.gov (United States)

    Feng, Xiaobing; Hu, Haibo

    2013-12-01

    The negative externalities from an individual bank failure to the whole system can be huge. One of the key purposes of bank regulation is to internalize the social costs of potential bank failures via capital charges. This study proposes a method to evaluate and allocate the systemic risk to different countries/regions using a Susceptible-Infected-Removable (SIR) type of epidemic spreading model and the Shapley value (SV) in game theory. The paper also explores features of a constructed bank network using real globe-wide banking data.

  5. Oral contraceptives and breast cancer risk in the international BRCA1/2 carrier cohort study

    DEFF Research Database (Denmark)

    Brohet, Richard M; Goldgar, David E; Easton, Douglas F

    2007-01-01

    PURPOSE Earlier studies have shown that endogenous gonadal hormones play an important role in the etiology of breast cancer among BRCA1/2 mutation carriers. So far, little is known about the safety of exogenous hormonal use in mutation carriers. In this study, we examined the association between...... oral contraceptive use and risk of breast cancer among BRCA1/2 carriers. PATIENTS AND METHODS In the International BRCA1/2 Carrier Cohort study (IBCCS), a retrospective cohort of 1,593 BRCA1/2 mutation carriers was analyzed with a weighted Cox regression analysis. Results We found an increased risk...... of breast cancer for BRCA1/2 mutation carriers who ever used oral contraceptives (adjusted hazard ratio [HR] = 1.47; 95% CI, 1.16 to 1.87). HRs did not vary according to time since stopping use, age at start, or calendar year at start. However, a longer duration of use, especially before first full...

  6. Costs and Difficulties of Interstellar 'Messaging' and the Need for International Debate on Potential Risks

    Science.gov (United States)

    Billingham, J.; Benford, James

    We advocate international consultations on societal and technical issues to address the risk of Messaging to Extraterrestrial Intelligence (METI) transmissions, and a moratorium on future transmissions until such issues are resolved. Instead, we recommend continuing to conduct SETI by listening, with no innate risk, while using powerful new search systems to give a better total probability of detection of beacons and messages than METI for the same cost, and with no need for a long obligatory wait for a response. Realistically, beacons are costly. In light of recent work on the economics of contact by radio, we offer alternatives to the current standard methods of SETI searches. METI transmissions to date are faint and very unlikely to be detected, even by nearby stars. We show that historical leakage from Earth has been undetectable for Earth-scale receiver systems. Future space microwave and laser power systems will likely be more detectable.

  7. A 6-gene signature identifies four molecular subgroups of neuroblastoma

    Directory of Open Access Journals (Sweden)

    Kogner Per

    2011-04-01

    Full Text Available Abstract Background There are currently three postulated genomic subtypes of the childhood tumour neuroblastoma (NB; Type 1, Type 2A, and Type 2B. The most aggressive forms of NB are characterized by amplification of the oncogene MYCN (MNA and low expression of the favourable marker NTRK1. Recently, mutations or high expression of the familial predisposition gene Anaplastic Lymphoma Kinase (ALK was associated to unfavourable biology of sporadic NB. Also, various other genes have been linked to NB pathogenesis. Results The present study explores subgroup discrimination by gene expression profiling using three published microarray studies on NB (47 samples. Four distinct clusters were identified by Principal Components Analysis (PCA in two separate data sets, which could be verified by an unsupervised hierarchical clustering in a third independent data set (101 NB samples using a set of 74 discriminative genes. The expression signature of six NB-associated genes ALK, BIRC5, CCND1, MYCN, NTRK1, and PHOX2B, significantly discriminated the four clusters (p ALK, BIRC5, and PHOX2B, and was significantly associated with higher tumour stage, poor outcome and poor survival compared to the Type 1-corresponding favourable group (INSS stage 4 and/or dead of disease, p Conclusions Based on expression profiling we have identified four molecular subgroups of neuroblastoma, which can be distinguished by a 6-gene signature. The fourth subgroup has not been described elsewhere, and efforts are currently made to further investigate this group's specific characteristics.

  8. A case of primary cerebral neuroblastoma in adolescence

    International Nuclear Information System (INIS)

    White, B.D.; Pozza, C.H.; Davies, R.; Hanieh, A.

    2002-01-01

    Primary cerebral neuroblastoma is one of a group of highly malignant undifferentiated primitive neuroectodermal tumours arising from germinal matrix cells of the embryonic neural tube. They occur primarily in young children and are extremely rare in adults. They may be multicentric and have often spread throughout the central nervous system at the time of diagnosis. A case of a 16-year-old man is described, and the recent literature is reviewed. On MRI examination, these lesions demonstrated heterogeneous low signal intensity on T1 -weighted sequences and heterogeneous high signal intensity on T2-weighted and fluid attenuated inversion recovery (FLAIR) sequences. There was no enhancement following IV contrast administration. A MRI of the spine was normal. Areas of low T1 and T2 signal intensity in the right temporo-occipital region were consistent with haemorrhage within the lesion. The patient underwent complete resection of the lesion in the right lateral ventricle and subtotal resection of the lesions in the right temporal-occipital lobes and suprasellar region. Histo-pathological findings confirmed primary cerebral neuroblastoma. Copyright (2002) Blackwell Science Pty Ltd

  9. Anti-Neuroblastoma Properties of a Recombinant Sunflower Lectin

    Directory of Open Access Journals (Sweden)

    Marcela Pinedo

    2017-01-01

    Full Text Available According to their sugar recognition specificity, plant lectins are proposed as bioactive proteins with potential in cancer treatment and diagnosis. Helja is a mannose-specific jacalin-like lectin from sunflower which was shown to inhibit the growth of certain fungi. Here, we report its recombinant expression in a prokaryotic system and its activity in neurobalstoma cells. Helja coding sequence was fused to the pET-32 EK/LIC, the enterokinase/Ligation-independent cloning vector and a 35 kDa protein was obtained in Escherichia coli representing Helja coupled to thioredoxin (Trx. The identity of this protein was verified using anti-Helja antibodies. This chimera, named Trx-rHelja, was enriched in the soluble bacterial extracts and was purified using Ni+2-Sepharose and d-mannose-agarose chromatography. Trx-rHelja and the enterokinase-released recombinant Helja (rHelja both displayed toxicity on human SH-SY5Y neuroblastomas. rHelja decreased the viability of these tumor cells by 75% according to the tetrazolium reduction assay, and microscopic analyses revealed that the cell morphology was disturbed. Thus, the stellate cells of the monolayer became spheroids and were isolated. Our results indicate that rHelja is a promising tool for the development of diagnostic or therapeutic methods for neuroblastoma cells, the most common solid tumors in childhood.

  10. Identification of nuclear τ isoforms in human neuroblastoma cells

    International Nuclear Information System (INIS)

    Loomis, P.A.; Howard, T.H.; Castleberry, R.P.; Binder, L.I.

    1990-01-01

    The τ proteins have been reported only in association with microtubules and with ribosomes in situ, in the normal central nervous system. In addition, τ has been shown to be an integral component of paired helical filaments, the principal constituent of the neurofibrillary tangles found in brains of patients with Alzheimer's disease and of most aged individuals with Down syndrome (trisomy 21). The authors report here the localization of the well-characterized Tau-1 monoclonal antibody to the nucleolar organizer regions of the acrocentric chromosomes and to their interphase counterpart, the fibrillar component of the nucleolus, in human neuroblastoma cells. Similar localization to the nucleolar organizer regions was also observed in other human cell lines and in one monkey kidney cell line but was not seen in non-primate species. Immunochemically, they further demonstrated the existence of the entire τ molecule in the isolated nuclei of neuroblastoma cells. Nuclear τ proteins, like the τ proteins of the paired helical filaments, cannot be extracted in standard SDS-containing electrophoresis sample buffer but require pretreatment with formic acid prior to immunoblot analysis. This work indicates that τ may function in processes not directly associated with microtubules and that highly insoluble complexes of τ may also play a role in normal cellular physiology

  11. Neuroblastoma in a Case with Congenital Horner’s Syndrome

    Directory of Open Access Journals (Sweden)

    Hüseyin Mayalı

    2014-08-01

    Full Text Available Miosis, ptosis, and ipsilateral facial anhidrosis are normally present in Horner’s syndrome. Pathologies which show central, preganglionic and postganglionic residence in sympathetic chain are present in its etiology. A 3-month-old girl baby was admitted to our clinic for ptosis in the left eye. Heterochromia, ptosis in the left eye, myosis and, ipsilateral anhidrosis were detected in her examination. In view of these findings, it seemed possible that her disease could be congenital Horner’s syndrome. Brachial plexus injury due to birth trauma plays a major role in the etiology of congenital Horner’s syndrome. There was not any birth trauma history in our patient. The patient was diagnosed to have neuroblastoma as a result of etiologic tests. In conclusion, Horner’s syndrome can be the presenting sign of childhood neuroblastoma. Therefore, it is advisable to examine the oculosympathetic system in detail in order to leave out any underlying serious disorder. (Turk J Ophthalmol 2014; 44: 325-6

  12. The mechanism of epithelial-mesenchymal transition induced by TGF-β1 in neuroblastoma cells.

    Science.gov (United States)

    Shao, Jing-Bo; Gao, Zhi-Mei; Huang, Wen-Yan; Lu, Zhi-Bao

    2017-05-01

    Neuroblastoma is the second most common extracranial malignant solid tumor that occurs in childhood, and metastasis is one of the major causes of death in neuroblastoma patients. The epithelial-mesenchymal transition (EMT) is an important mechanism for both the initiation of tumor invasion and subsequent metastasis. Therefore, this study investigated the mechanism by which transforming growth factor (TGF)-β1 induces EMT in human neuroblastoma cells. Using quantitative RT-qPCR and western blot analyses, we found that the mRNA and protein expression levels of E-cadherin were significantly decreased, whereas that of α-SMA was significantly increased after neuroblastoma cells were treated with different concentrations of TGF-β1. A scratch test and Transwell migration assay revealed that cell migration significantly and directly correlated with the concentration of TGF-β1 indicating that TGF-β1 induced EMT in neuroblastoma cells and led to their migration. Inhibiting Smad2/3 expression did not affect the expression of the key molecules involved in EMT. Further investigation found that the expression of the glioblastoma transcription factor (Gli) significantly increased in TGF-β1-stimulated neuroblastoma cells undergoing EMT, accordingly, interfering with Gli1/2 expression inhibited TGF-β1-induced EMT in neuroblastoma cells. GANT61, which is a targeted inhibitor of Gli1 and Gli2, decreased cell viability and promoted cell apoptosis. Thus, TGF-β1 induced EMT in neuroblastoma cells to increase their migration. Specifically, EMT induced by TGF-β1 in neuroblastoma cells did not depend on the Smad signaling pathway, and the transcription factor Gli participated in TGF-β1-induced EMT independent of Smad signaling.

  13. Low levels of breast cancer risk awareness in young women: an international survey.

    Science.gov (United States)

    Peacey, Victoria; Steptoe, Andrew; Davídsdóttir, Sigurlína; Baban, Adriana; Wardle, Jane

    2006-10-01

    At least a fifth of breast cancer cases in Western countries are likely to be due to modifiable lifestyle factors. Previous work has found that while women in Western countries are aware that breast cancer can be hereditary, their knowledge of the influence of lifestyle is poor. This survey investigated on the awareness of breast cancer risk factors in university students from 23 countries between 1999 and 2001. Data were collected on awareness of links with heredity, alcohol use, exercise, obesity, stress, smoking and diet. Almost a third of women were not aware that any of these factors influenced breast cancer. Just 57% were aware of the genetic link and fewer than 1 in 20 women correctly identified alcohol, exercise or obesity as factors influencing breast cancer. Stress and smoking were the most commonly chosen lifestyle risk factors although current data suggest that they have little actual impact on breast cancer risk. There was considerable international variation, with highest levels of awareness in students in the United States of America (USA). Knowledge of risk in this sample was poorer than previously observed in older women. Health messages concerning cancer in general may be more relevant for this age group, because of the lower salience of breast cancer for younger women.

  14. Ultraviolet radiation: effects on risks of prostate cancer and other internal cancers

    Energy Technology Data Exchange (ETDEWEB)

    Moon, Samuel J. [Human Genomics Research Group, Institute of Science and Technology in Medicine and Department of Urology, Keele University School of Medicine, University Hospital of North Staffordshire, Hartshill Campus, Stoke-on-Trent, ST4 7PA Staffordshire (United Kingdom); Fryer, Anthony A. [Human Genomics Research Group, Institute of Science and Technology in Medicine and Department of Urology, Keele University School of Medicine, University Hospital of North Staffordshire, Hartshill Campus, Stoke-on-Trent, ST4 7PA Staffordshire (United Kingdom); Strange, Richard C. [Human Genomics Research Group, Institute of Science and Technology in Medicine and Department of Urology, Keele University School of Medicine, University Hospital of North Staffordshire, Hartshill Campus, Stoke-on-Trent, ST4 7PA Staffordshire (United Kingdom)]. E-mail: paa00@keele.ac.uk

    2005-04-01

    Governmental and research agencies worldwide have strongly advocated sun avoidance strategies in an attempt to counter marked increases in skin cancer incidence. Concurrently, there are reports describing widespread Vitamin D{sub 3} deficiency. Because 1,25-dihydroxyvitamin D{sub 3}, through interaction with the Vitamin D receptor, exerts pleiotrophic effects, such deficiency might be expected to have clinical consequences. Indeed, various reports indicate that exposure to ultraviolet radiation (UVR) exerts a protective effect on development of some common diseases including internal cancers and multiple sclerosis. We describe studies indicating that modest exposure reduces risk of prostate cancer. The effect of UVR is mediated by skin type; at lower levels of exposure a relative inability to effect skin pigmentation is protective presumably because it allows more efficient Vitamin D{sub 3} synthesis. Polymorphic variants in genes associated with pigmentation including melanocyte stimulating hormone receptor and tyrosinase are also associated with prostate cancer risk. Overall, though preliminary and requiring cautious interpretation, these data indicate that moderate UVR exposure together with characteristics linked with less effective tanning confer reduced prostate cancer risk. Clearly, it is important to define safe levels of UVR that do not result in increased risk of skin cancers such as malignant melanoma.

  15. Thyroid cancer in the Marshallese: relative risk of short-lived internal emitters and external radiation exposure

    International Nuclear Information System (INIS)

    Lessard, E.T.; Brill, A.B.; Adams, W.H.

    1986-01-01

    In a study of the comparative effects of internal versus external irradiation of the thyroid in young people, we determined that the dose from internal irradiation of the thyroid with short-lived internal emitters produced several times less thyroid cancer than did the same dose of radiation given externally. The authors determined this finding for a group of 85 Marshall Islands children, who were less than 10 years of age at the time of exposure and who were accidentally exposed to internal and external thyroid radiation at an average level of 1400 rad. The external risk coefficient ranged between 2.5 and 4.9 cancers per million person-rad-years at risk, and thus, from our computations, the internal risk coefficient for the Marshallese children was estimated to range between 1.0 and 1.4 cancers per million person-rad-years at risk. In contrast, for individuals more than 10 years of age at the time of exposure, the dose from internal irradiation of the thyroid with short-lived internal emitters produced several times more thyroid cancer than did the same dose of radiation given externally. The external risk coefficients for the older age groups were reported in the above literature to be in the range of 1.0 to 3.3 cancers per million person-rad-years-at risk. The authors computed internal risk coefficients of 3.3 to 8.1 cancers per million person-rad-years at risk for adolescent and adult groups. This higher sensitivity to cancer induction in the exposed adolescents and adults, is different from that seen in other exposed groups. The small number of cancers in the exposed population and the influence of increased levels of TSH, nonuniform irradiation of the thyroid, and thyroid cell killing at high dose make it difficult to draw firm conclusions from these studies. 14 references, 8 tables

  16. Thyroid cancer in the Marshallese: relative risk of short-lived internal emitters and external radiation exposure

    International Nuclear Information System (INIS)

    Lessard, E.T.; Brill, A.B.; Adams, W.H.

    1985-01-01

    In a study of the comparative effects of internal versus external irradiation of the thyroid in young people, we determined that the dose from internal irradiation of the thyroid with short-lived internal emitters produced several times less thyroid cancer than did the same dose of radiation given externally. We determined this finding for a group of 85 Marshall Islands children, who were less than 10 years of age at the time of exposure and who were accidentially exposed to internal and external thyroid radiation at an average level of 1400 rad. The external risk coefficient ranged between 2.5 and 4.9 cancers per million person-rad-years at risk, and thus, from our computations, the internal risk coefficient for the Marshallese children was estimated to range between 1.0 and 1.4 cancers per million person-rad-years at risk. In contrast, for individual more than 10 years of age at the time of exposure, the dose from internal irradiation of the thyroid with short-lived internal emitters produced several times more thyroid cancer than did the same dose of radiation given externally. The external risk coefficients for the older age groups were reported in the literature to be in the range of 1.0 to 3.3 cancers per million person-rad-years-at risk. We computed internal risk coefficients of 3.3 to 8.1 cancers per million person-rad-years at risk for adolescent and adult groups. This higher sensitivity to cancer induction in the exposed adolescents and adults, is different from that seen in other exposed groups. 14 refs., 8 tabs

  17. Communication About Behavioral Health Risks: A Study of Videotaped Encounters in 2 Internal Medicine Practices

    Science.gov (United States)

    Makoul, Gregory; Dhurandhar, Anjali; Goel, Mita Sanghavi; Scholtens, Denise; Rubin, Alan S

    2006-01-01

    BACKGROUND As behavioral health risks account for the major causes of preventable morbidity and mortality in the United States, national guidelines recommend that physicians routinely screen patients for risk factors, and counsel as appropriate. OBJECTIVES To assess the scope of health risk screening and characterize the communication content of counseling for health behavior change in 2 general internal medicine practices. DESIGN AND PARTICIPANTS We studied videotapes of 125 new patient visits to General Internists affiliated with academic medical centers in Chicago, IL (70%) and Burlington, VT (30%). All videotapes were content analyzed to examine (1) the incidence and outcome of screening for diet, exercise, tobacco, alcohol, drugs, sex, seatbelt use, helmet use, firearms, smoke detectors, and sun exposure; (2) the content of counseling for at-risk behaviors, with a focus on 11 counseling tasks associated with health behavior change. RESULTS Patient age in these 125 initial visits ranged from 22 to 85 years. Within the 91 visits that included at least 1 screening attempt, there were a total of 361 distinct screening discussions (mean = 3.9, SD = 2.2, range = 1 to 9). Seventy-four (20.5%) of the 361 screening discussions revealed an at-risk behavior. On average, 2.4 of the 11 counseling tasks were accomplished for each of the 74 behavioral health risks (SD = 2.2, range 0 to 9); only education about the problem (56.8%) and general advice about the solution (62.2%) were evident in more than half of the counseling attempts. CONCLUSIONS This observational study reveals that communication tasks associated with successful counseling were relatively infrequent occurrences during initial visits in 2 primary care practices. PMID:16808769

  18. Expression of granulocyte colony-stimulating factor and its receptor in childhood neuroblastoma

    OpenAIRE

    Xin WU; Da-wei HE; Yong-bo ZHANG; Wen-fei HE; Ze-dong BIAN; Qin-jun YI; Guang-hui WEI

    2012-01-01

    Objective  To study the expression of granulocyte colony-stimulating factor (G-CSF) and its receptor (G-CSFR) in neuroblastoma of children. Methods  Twenty-five specimens of neuroblastoma were collected in our department during 2009.1–2011.6. G-CSF and G-CSFR were determined by immunohistochemistry. The correlation between expressions of G-CSF and G-CSFR and age, gender and clinical stage were analyzed. Results  The expression of G-CSF and G-CSFR in neuroblastoma specimens was 68%, 72% respec...

  19. Genome-wide analysis of HOXC9-induced neuronal differentiation of neuroblastoma cells

    Directory of Open Access Journals (Sweden)

    Xiangwei Wang

    2014-12-01

    Full Text Available Induction of differentiation is a therapeutic strategy in neuroblastoma, a common pediatric cancer of the sympathetic nervous system. The homeobox protein HOXC9 is a key regulator of neuroblastoma differentiation. To gain a molecular understanding of the function of HOXC9 in promoting differentiation of neuroblastoma cells, we conducted a genome-wide analysis of the HOXC9-induced differentiation program by microarray gene expression profiling and chromatin immunoprecipitation in combination with massively parallel sequencing (ChIP-seq. Here we describe in detail the experimental system, methods, and quality control for the generation of the microarray and ChIP-seq data associated with our recent publication [1].

  20. A Validation of the Student Risk Screening Scale for Internalizing and Externalizing Behaviors: Patterns in Rural and Urban Elementary Schools

    Science.gov (United States)

    Lane, Kathleen Lynne; Menzies, Holly M.; Oakes, Wendy P.; Lambert, Warren; Cox, Meredith; Hankins, Katy

    2012-01-01

    We report findings of two studies, one conducted in a rural school district (N = 982) and a second conducted in an urban district (N = 1,079), offering additional evidence of the reliability and validity of a revised instrument, the Student Risk Screening Scale-Internalizing and Externalizing (SRSS-IE), to accurately detect internalizing and…

  1. High-Dose, Single-Fraction Irradiation Rapidly Reduces Tumor Vasculature and Perfusion in a Xenograft Model of Neuroblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Jani, Ashish; Shaikh, Fauzia; Barton, Sunjay [Department of Radiation Oncology, Columbia University Medical Center, New York, New York (United States); Willis, Callen [Department of Surgery, Columbia University Medical Center, New York, New York (United States); Banerjee, Debarshi [Department of Pediatrics, Columbia University Medical Center, New York, New York (United States); Mitchell, Jason [Department of Surgery, Columbia University Medical Center, New York, New York (United States); Hernandez, Sonia L. [Department of Surgery, University of Chicago, Chicago, Illinois (United States); Hei, Tom [Department of Radiation Oncology, Columbia University Medical Center, New York, New York (United States); Kadenhe-Chiweshe, Angela [Department of Surgery, Columbia University Medical Center, New York, New York (United States); Yamashiro, Darrell J. [Department of Surgery, Columbia University Medical Center, New York, New York (United States); Department of Pediatrics, Columbia University Medical Center, New York, New York (United States); Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York (United States); Connolly, Eileen P., E-mail: epc2116@cumc.columbia.edu [Department of Radiation Oncology, Columbia University Medical Center, New York, New York (United States)

    2016-04-01

    Purpose: To characterize the effects of high-dose radiation therapy (HDRT) on neuroblastoma tumor vasculature, including the endothelial cell (EC)–pericyte interaction as a potential target for combined treatment with antiangiogenic agents. Methods and Materials: The vascular effects of radiation therapy were examined in a xenograft model of high-risk neuroblastoma. In vivo 3-dimensional contrast-enhanced ultrasonography (3D-CEUS) imaging and immunohistochemistry (IHC) were performed. Results: HDRT significantly reduced tumor blood volume 6 hours after irradiation compared with the lower doses used in conventionally fractionated radiation. There was a 63% decrease in tumor blood volume after 12-Gy radiation compared with a 24% decrease after 2 Gy. Analysis of tumor vasculature by lectin angiography showed a significant loss of small vessel ends at 6 hours. IHC revealed a significant loss of ECs at 6 and 72 hours after HDRT, with an accompanying loss of immature and mature pericytes at 72 hours. Conclusions: HDRT affects tumor vasculature in a manner not observed at lower doses. The main observation was an early reduction in tumor perfusion resulting from a reduction of small vessel ends with a corresponding loss of endothelial cells and pericytes.

  2. Complex treatment of primary brain neuroblastoma with four local recurrences for period of 5 years -clinical case from our practice

    International Nuclear Information System (INIS)

    Marinova, L.; Georgiev, R.; Mihaylova, I.; Belcheva, M.

    2017-01-01

    We present a clinical case of 17 years old girl with primary brain neuroblastoma (supratentorial primitive neuro-ectodermal tumor - PNET in right temporo-parietal brain region). Complex treatment has been applied, including subtotal operation, standard fractioned cranio-spinal external beam radiotherapy with boost up to 56 Gy in the locus of the tumor remnant and 6 courses of adjuvant chemotherapy with Carboplatin and Etoposide. Despite the applied local treatment methods (radical surgery, standard fractioned cranio-spinal external beam radiotherapy and radio-surgery with single total dose of 14 Gy), four recurrences have appeared for period of 5 years in the locus of the primary tumor. The risk of appearance of local recurrences, necessitating re-operations, chemotherapy, bone marrow transplantation of stem cells and radio-surgery was discussed. We are also discussing the radio sensitivity of the PNET and the possibilities for overcoming it with implementation of hyper fractioned cranio-spinal external beam radiotherapy in combination with chemotherapy, followed by bone marrow transplantation of stem cells. Key words: Primary Brain Neuroblastoma. Radio Sensitivity. Cranio-Spinal External Beam Radiotherapy. Adjuvant Chemotherapy [bg

  3. Technical benefit and risk analysis on cement clinkering process with compact internal burning of carbon

    International Nuclear Information System (INIS)

    Chen, Hanmin

    2015-01-01

    This article demonstrates the potential technical benefit and risk for cement clinkering process with compact internal burning of carbon, a laboratory-phase developing technique, from 9 aspects, including the heat consumption of clinkering and exhaust heat utilization, clinker quality, adaptability to alternative fuels, the disposal ability of industrial offal and civil garbage, adaptability to the raw materials and fuels with high content of chlorine, sulphur and alkali, the feasibility of process scale up, the briquetting process of the coal-containing cement raw meal pellet, NO x emission and the capital cost and benefit of conversion project. It is concluded that it will be able to replace the modern precalciner rotary kiln process and to become the main stream technique of cement clinkering process in low carbon economy times. - Highlights: • Compact internal burning of carbon enables cement shaft kiln to run stably. • Compact internal burning of carbon enables cement shaft kiln to scale up. • New process triples energy efficiency with excellent environmental performance. • It will be able to compete with and replace the existing precalciner kiln process. • It will become the mainstream clinkering process in low carbon economy

  4. Loss of international medical experiences: knowledge, attitudes and skills at risk

    Directory of Open Access Journals (Sweden)

    Legome Eric

    2007-11-01

    Full Text Available Background Despite the great influence International Medical Experiences (IMs can have on young physicians and their impact on patients and communities, they are not offered in all training programs and are at risk of being reduced in some due to stringent guidelines for funding of graduate medical education. Discussion IMs provide unique experiences in clinical, epidemiologic, cultural, and political arenas. From an educational perspective, they broaden a physician's differential diagnostic skills and introduce clinical entities rarely seen in the U.S. Time spent in developing countries emphasizes the importance of community health and increases cultural and linguistic competence. Experience working with the underserved during an IM has been shown to increase interest in volunteerism, humanitarian efforts, and work with underserved populations both in the US and abroad. IMs also afford physicians the opportunity to learn about the delivery of health care abroad and are associated with an increase in primary care specialty choice. Summary It is time for the leaders in graduate medical education to prioritize international health opportunities. Leaders in academic medicine can press for changes in reimbursement patterns at the national level or special funds for international electives. Hospitals can set up separate accounts to help finance resident salaries and benefits while abroad. Individual departments must be flexible with resident schedules to allow elective time. Medical students and housestaff can organize and lobby larger organizations such as the American Medical Association (AMA, the American Association of Medical Colleges (AAMC, and specialty groups to make IMs universally accessible.

  5. Assessment and Control of Spacecraft Charging Risks on the International Space Station

    Science.gov (United States)

    Koontz, Steve; Valentine, Mark; Keeping, Thomas; Edeen, Marybeth; Spetch, William; Dalton, Penni

    2004-01-01

    The International Space Station (ISS) operates in the F2 region of Earth's ionosphere, orbiting at altitudes ranging from 350 to 450 km at an inclination of 51.6 degrees. The relatively dense, cool F2 ionospheric plasma suppresses surface charging processes much of the time, and the flux of relativistic electrons is low enough to preclude deep dielectric charging processes. The most important spacecraft charging processes in the ISS orbital environment are: 1) ISS electrical power system interactions with the F2 plasma, 2) magnetic induction processes resulting from flight through the geomagnetic field and, 3) charging processes that result from interaction with auroral electrons at high latitude. Recently, the continuing review and evaluation of putative ISS charging hazards required by the ISS Program Office revealed that ISS charging could produce an electrical shock hazard to the ISS crew during extravehicular activity (EVA). ISS charging risks are being evaluated in an ongoing measurement and analysis campaign. The results of ISS charging measurements are combined with a recently developed model of ISS charging (the Plasma Interaction Model) and an exhaustive analysis of historical ionospheric variability data (ISS Ionospheric Specification) to evaluate ISS charging risks using Probabilistic Risk Assessment (PRA) methods. The PRA combines estimates of the frequency of occurrence and severity of the charging hazards with estimates of the reliability of various hazard controls systems, as required by NASA s safety and risk management programs, to enable design and selection of a hazard control approach that minimizes overall programmatic and personnel risk. The PRA provides a quantitative methodology for incorporating the results of the ISS charging measurement and analysis campaigns into the necessary hazard reports, EVA procedures, and ISS flight rules required for operating ISS in a safe and productive manner.

  6. Risk Profile of the RET A883F Germline Mutation: An International Collaborative Study.

    Science.gov (United States)

    Mathiesen, Jes Sloth; Habra, Mouhammed Amir; Bassett, John Howard Duncan; Choudhury, Sirazum Mubin; Balasubramanian, Sabapathy Prakash; Howlett, Trevor A; Robinson, Bruce G; Gimenez-Roqueplo, Anne-Paule; Castinetti, Frederic; Vestergaard, Peter; Frank-Raue, Karin

    2017-06-01

    The A883F germline mutation of the rearranged during transfection (RET) proto-oncogene causes multiple endocrine neoplasia 2B. In the revised American Thyroid Association (ATA) guidelines for the management of medullary thyroid carcinoma (MTC), the A883F mutation has been reclassified from the highest to the high-risk level, although no well-defined risk profile for this mutation exists. To create a risk profile for the A883F mutation for appropriate classification among the ATA risk levels. Retrospective analysis. International collaboration. Included were 13 A883F carriers. The intervention was thyroidectomy. Earliest age of MTC, regional lymph node metastases, distant metastases, age-related penetrance of MTC and pheochromocytoma (PHEO), overall and disease-specific survival, and biochemical cure rate. One and three carriers were diagnosed at age 7 to 9 years (median, 7.5 years) with a normal thyroid and C-cell hyperplasia, respectively. Nine carriers were diagnosed with MTC at age 10 to 39 years (median, 19 years). The earliest age of MTC, regional lymph node metastasis, and distant metastasis was 10, 20, and 20 years, respectively. Fifty percent penetrance of MTC and PHEO was achieved by age 19 and 34 years, respectively. Five- and 10-year survival rates (both overall and disease specific) were 88% and 88%, respectively. Biochemical cure for MTC at latest follow-up was achieved in 63% (five of eight carriers) with pertinent data. MTC of A883F carriers seems to have a more indolent natural course compared with that of M918T carriers. Our results support the classification of the A883F mutation in the ATA high-risk level. Copyright © 2017 Endocrine Society

  7. CARDIOVASCULAR RISK FACTORS IN MEDICAL UNIVERSITY STUDENTS (RESEARCH WITHIN INTERNATIONAL PROJECT MAY MEASUREMENT MONTH INITIATIVE

    Directory of Open Access Journals (Sweden)

    Анастасия Михайловна Кочергина

    2018-03-01

    Full Text Available Subject of study. Arterial hypertension and other cardiovascular risk factors in students of medical universities. Aim – to determine incidence of arterial hypertension and modifiable cardiovascular risk factors in students of medical university. Methods. The study included 146 students of KemSMU, as well as 67 students of SamSMU who were surveyed during May 1-10, 2017 within the framework of the international project «MAY MEASUREMENT MONTH 2017 (MMM17» using a standard questionnaire supplemented with a developed questionnaire including questions about the daily consumption of coffee and energy drinks, the amount of vegetables and fruits consumed, salt, physical activity level and night duty as paramedical personnel. All students underwent a three-fold measurement of blood pressure (BP after 5 minutes of rest sitting. Results. The frequency of arterial hypertension among KemSMU students at the age of 22.04 ± 1.8 years is 4.1 %, among the SamSMU students at the age of 21.2 ± 0.73 years – 1.5 %. Individuals with arterial hypertension – more often men gender who regularly drink coffee. Male students have a higher incidence of several risk factors than female students. The high frequency of tabacco smoking among medical students (13 % – KemSMU, 7.5 % – SamSMU was detected, while 31.6 % of all smokers began to smoke during their studies. Conclusions. The most common risk factors determined among students were smoking, increased intake of salt. Young men significantly more often demonstrated the presence of risk factors than women of similar age.

  8. Risk Factors for Borderline Personality Disorder in Treatment Seeking Patients with a Substance Use Disorder : An International Multicenter Study

    NARCIS (Netherlands)

    Wapp, Manuela; van de Glind, Geurt; van Emmerik-van Oortmerssen, Katelijne; Dom, Geert; Verspreet, Sofie; Carpentier, Pieter Jan; Ramos-Quiroga, Josep Antoni; Skutle, Arvid; Bu, Eli-Torlid; Franck, Johan; Konstenius, Maija; Kaye, Sharlene; Demetrovics, Zsolt; Barta, Csaba; Fatseas, Melina; Auriacombe, Marc; Johnson, Brian; Faraone, Stephen V.; Levin, Frances R.; Allsop, Steve; Carruthers, Susan; Schoevers, Robert A.; Koeter, Maarten W. J.; van den Brink, Wim; Moggi, Franz

    2015-01-01

    Borderline personality disorder (BPD) and substance use disorders (SUDs) often co-occur, partly because they share risk factors. In this international multicenter study, risk factors for BPD were examined for SUD patients. In total, 1,205 patients were comprehensively examined by standardized

  9. 12 CFR Appendix C to Part 567 - Risk-Based Capital Requirements-Internal-Ratings-Based and Advanced Measurement Approaches

    Science.gov (United States)

    2010-01-01

    ... association's underlying business risk factors and internal control environment. Carrying value means, with... zero or the market value of a transaction or portfolio of transactions within the netting set that... credit risk exposures. Expected operational loss (EOL) means the expected value of the distribution of...

  10. Health risk assessment of haloacetonitriles in drinking water based on internal dose.

    Science.gov (United States)

    Zhang, Ying; Han, Xuemei; Niu, Zhiguang

    2018-05-01

    To estimate the health risk of haloacetonitriles in different kinds of drinking water, the concentrations of haloacetonitriles in tap water, boiled water and direct drinking water were detected. The physiologically based pharmacokinetic (PBPK) model was used to calculate internal dose in the human body for haloacetonitriles through ingestion, and the probability distributions of the non-carcinogenic risk of haloacetonitriles for human via drinking water were assessed. This study found that the mean concentrations of dichloroacetonitrile (DCAN) in tap water, boiled water and direct drinking water were 0.955 μg/L, 0.207 μg/L and 0.127 μg/L, and those of dibromoacetonitrile (DBAN) were 0.221 μg/L, 0.104 μg/L, 0.089 μg/L, respectively. In China, direct drinking water is used most frequently, so the concentrations of haloacetonitriles in direct drinking water were used to obtain data on the internal dose of haloacetonitriles. In addition, the simulation results for the PBPK model showed that the highest and lowest concentrations of DCAN occurred in the liver and venous blood, respectively. The peak concentrations of DBAN in each tissue were in the decreasing order liver > rapidly perfused tissue > kidney > slowly perfused tissues > fat > arterial blood (venous blood). In addition, the highest 95th percentile hazard quotients (HQ) value of haloacetonitriles via drinking water for humans was 8.89 × 10 -3 , much lower than 1. The 95th percentile hazard index (HI) was 0.046, which was also lower than 1, suggesting that there was no obvious non-carcinogenic risk. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. Resilience and risk competence in schools: theory/knowledge and international application in project rebound.

    Science.gov (United States)

    Brown, Joel H; Jean-Marie, Gaetane; Beck, Jerome

    2010-01-01

    Despite a 50-year interdisciplinary and longitudinal research legacy--showing that nearly 80% of young people considered most "at risk" thrive by midlife-only recently have practitioners/researchers engaged in the explicit, prospective facilitation of "resilience" in educational settings. Here, theory/knowledge distinguishing and extending risk and resilience from its risk-based social history to resilience's normative occurrence leads to the first known international and prospective application of resilience in school-based drug education, Project REBOUND [resilience-bound]. It will be implemented as a controlled pilot study, first in Germany, then expand to the United States, as well as other parts of Europe. With evaluation occurring throughout, the goal is to enhance the quality of drug decisions among young people, as well as support their overall competence-based learning and development throughout school. With limitations and underlying psychological mechanisms discussed, it is concluded Project REBOUND offers promising potential for supporting positive drug decisions as well as youth learning and development.

  12. MYCN and HDAC5 transcriptionally repress CD9 to trigger invasion and metastasis in neuroblastoma

    NARCIS (Netherlands)

    Fabian, Johannes; Opitz, Desirée; Althoff, Kristina; Lodrini, Marco; Hero, Barbara; Volland, Ruth; Beckers, Anneleen; de Preter, Katleen; Decock, Anneleen; Patil, Nitin; Abba, Mohammed; Kopp-Schneider, Annette; Astrahantseff, Kathy; Wünschel, Jasmin; Pfeil, Sebastian; Ercu, Maria; Künkele, Annette; Hu, Jamie; Thole, Theresa; Schweizer, Leonille; Mechtersheimer, Gunhild; Carter, Daniel; Cheung, Belamy B.; Popanda, Odilia; von Deimling, Andreas; Koster, Jan; Versteeg, Rogier; Schwab, Manfred; Marshall, Glenn M.; Speleman, Frank; Erb, Ulrike; Zoeller, Margot; Allgayer, Heike; Simon, Thorsten; Fischer, Matthias; Kulozik, Andreas E.; Eggert, Angelika; Witt, Olaf; Schulte, Johannes H.; Deubzer, Hedwig E.

    2016-01-01

    The systemic and resistant nature of metastatic neuroblastoma renders it largely incurable with current multimodal treatment. Clinical progression stems mainly from the increasing burden of metastatic colonization. Therapeutically inhibiting the migration-invasion-metastasis cascade would be of

  13. Genomewide analysis of gene expression associated with Tcof1 in mouse neuroblastoma.

    Science.gov (United States)

    Mogass, Michael; York, Timothy P; Li, Lin; Rujirabanjerd, Sinitdhorn; Shiang, Rita

    2004-12-03

    Mutations in the Treacher Collins syndrome gene, TCOF1, cause a disorder of craniofacial development. We manipulated the levels of Tcof1 and its protein treacle in a murine neuroblastoma cell line to identify downstream changes in gene expression using a microarray platform. We identified a set of genes that have similar expression with Tcof1 as well as a set of genes that are negatively correlated with Tcof1 expression. We also showed that the level of Tcof1 and treacle expression is downregulated during differentiation of neuroblastoma cells into neuronal cells. Inhibition of Tcof1 expression by siRNA induced morphological changes in neuroblastoma cells that mimic differentiation. Thus, expression of Tcof1 and treacle synthesis play an important role in the proliferation of neuroblastoma cells and we have identified genes that may be important in this pathway.

  14. Gene therapy as a potential tool for treating neuroblastoma-a focused review.

    Science.gov (United States)

    Kumar, M D; Dravid, A; Kumar, A; Sen, D

    2016-05-01

    Neuroblastoma, a solid tumor caused by rapid division of undifferentiated neuroblasts, is the most common childhood malignancy affecting children aged genes is restored to normalcy. Gene therapy is a powerful tool with the potential to inhibit the deleterious effects of oncogenes by inserting corrected/normal genes into the genome. Both viral and non-viral vector-based gene therapies have been developed and adopted to deliver the target genes into neuroblastoma cells. These attempts have given hope to bringing in a new regime of treatment against neuroblastoma. A few gene-therapy-based treatment strategies have been tested in limited clinical trials yielding some positive results. This mini review is an attempt to provide an overview of the available options of gene therapy to treat neuroblastoma.

  15. MicroRNA-34a is a potent tumor suppressor molecule in vivo in neuroblastoma.

    LENUS (Irish Health Repository)

    Tivnan, Amanda

    2011-01-01

    Neuroblastoma is a paediatric cancer which originates from precursor cells of the sympathetic nervous system and accounts for 15% of childhood cancer mortalities. With regards to the role of miRNAs in neuroblastoma, miR-34a, mapping to a chromosome 1p36 region that is commonly deleted, has been found to act as a tumor suppressor through targeting of numerous genes associated with cell proliferation and apoptosis.

  16. A high-content morphological screen identifies novel microRNAs that regulate neuroblastoma cell differentiation.

    Science.gov (United States)

    Zhao, Zhenze; Ma, Xiuye; Hsiao, Tzu-Hung; Lin, Gregory; Kosti, Adam; Yu, Xiaojie; Suresh, Uthra; Chen, Yidong; Tomlinson, Gail E; Pertsemlidis, Alexander; Du, Liqin

    2014-05-15

    Neuroblastoma, the most common extracranial solid tumor of childhood, arises from neural crest cell precursors that fail to differentiate. Inducing cell differentiation is an important therapeutic strategy for neuroblastoma. We developed a direct functional high-content screen to identify differentiation-inducing microRNAs, in order to develop microRNA-based differentiation therapy for neuroblastoma. We discovered novel microRNAs, and more strikingly, three microRNA seed families that induce neuroblastoma cell differentiation. In addition, we showed that microRNA seed families were overrepresented in the identified group of fourteen differentiation-inducing microRNAs, suggesting that microRNA seed families are functionally more important in neuroblastoma differentiation than microRNAs with unique sequences. We further investigated the differentiation-inducing function of the microRNA-506-3p/microRNA-124-3p seed family, which was the most potent inducer of differentiation. We showed that the differentiation-inducing function of microRNA-506-3p/microRNA-124-3p is mediated, at least partially, by down-regulating expression of their targets CDK4 and STAT3. We further showed that expression of miR-506-3p, but not miR-124-3p, is dramatically upregulated in differentiated neuroblastoma cells, suggesting the important role of endogenous miR-506-3p in differentiation and tumorigenesis. Overall, our functional screen on microRNAs provided the first comprehensive analysis on the involvements of microRNA species in neuroblastoma cell differentiation and identified novel differentiation-inducing microRNAs. Further investigations are certainly warranted to fully characterize the function of the identified microRNAs in order to eventually benefit neuroblastoma therapy.

  17. Transcription factor activating protein 2 beta (TFAP2B) mediates noradrenergic neuronal differentiation in neuroblastoma.

    Science.gov (United States)

    Ikram, Fakhera; Ackermann, Sandra; Kahlert, Yvonne; Volland, Ruth; Roels, Frederik; Engesser, Anne; Hertwig, Falk; Kocak, Hayriye; Hero, Barbara; Dreidax, Daniel; Henrich, Kai-Oliver; Berthold, Frank; Nürnberg, Peter; Westermann, Frank; Fischer, Matthias

    2016-02-01

    Neuroblastoma is an embryonal pediatric tumor that originates from the developing sympathetic nervous system and shows a broad range of clinical behavior, ranging from fatal progression to differentiation into benign ganglioneuroma. In experimental neuroblastoma systems, retinoic acid (RA) effectively induces neuronal differentiation, and RA treatment has been therefore integrated in current therapies. However, the molecular mechanisms underlying differentiation are still poorly understood. We here investigated the role of transcription factor activating protein 2 beta (TFAP2B), a key factor in sympathetic nervous system development, in neuroblastoma pathogenesis and differentiation. Microarray analyses of primary neuroblastomas (n = 649) demonstrated that low TFAP2B expression was significantly associated with unfavorable prognostic markers as well as adverse patient outcome. We also found that low TFAP2B expression was strongly associated with CpG methylation of the TFAP2B locus in primary neuroblastomas (n = 105) and demethylation with 5-aza-2'-deoxycytidine resulted in induction of TFAP2B expression in vitro, suggesting that TFAP2B is silenced by genomic methylation. Tetracycline inducible re-expression of TFAP2B in IMR-32 and SH-EP neuroblastoma cells significantly impaired proliferation and cell cycle progression. In IMR-32 cells, TFAP2B induced neuronal differentiation, which was accompanied by up-regulation of the catecholamine biosynthesizing enzyme genes DBH and TH, and down-regulation of MYCN and REST, a master repressor of neuronal genes. By contrast, knockdown of TFAP2B by lentiviral transduction of shRNAs abrogated RA-induced neuronal differentiation of SH-SY5Y and SK-N-BE(2)c neuroblastoma cells almost completely. Taken together, our results suggest that TFAP2B is playing a vital role in retaining RA responsiveness and mediating noradrenergic neuronal differentiation in neuroblastoma. Copyright © 2015 Federation of European Biochemical Societies

  18. Identification of BIRC6 as a novel intervention target for neuroblastoma therapy

    Directory of Open Access Journals (Sweden)

    Lamers Fieke

    2012-07-01

    Full Text Available Abstract Background Neuroblastoma are pediatric tumors of the sympathetic nervous system with a poor prognosis. Apoptosis is often deregulated in cancer cells, but only a few defects in apoptotic routes have been identified in neuroblastoma. Methods Here we investigated genomic aberrations affecting genes of the intrinsic apoptotic pathway in neuroblastoma. We analyzed DNA profiling data (CGH and SNP arrays and mRNA expression data of 31 genes of the intrinsic apoptotic pathway in a dataset of 88 neuroblastoma tumors using the R2 bioinformatic platform (http://r2.amc.nl. BIRC6 was selected for further analysis as a tumor driving gene. Knockdown experiments were performed using BIRC6 lentiviral shRNA and phenotype responses were analyzed by Western blot and MTT-assays. In addition, DIABLO levels and interactions were investigated with immunofluorescence and co-immunoprecipitation. Results We observed frequent gain of the BIRC6 gene on chromosome 2, which resulted in increased mRNA expression. BIRC6 is an inhibitor of apoptosis protein (IAP, that can bind and degrade the cytoplasmic fraction of the pro-apoptotic protein DIABLO. DIABLO mRNA expression was exceptionally high in neuroblastoma but the protein was only detected in the mitochondria. Upon silencing of BIRC6 by shRNA, DIABLO protein levels increased and cells went into apoptosis. Co-immunoprecipitation confirmed direct interaction between DIABLO and BIRC6 in neuroblastoma cell lines. Conclusion Our findings indicate that BIRC6 may have a potential oncogenic role in neuroblastoma by inactivating cytoplasmic DIABLO. BIRC6 inhibition may therefore provide a means for therapeutic intervention in neuroblastoma.

  19. Altered expression of miRNAs and methylation of their promoters are correlated in neuroblastoma.

    Science.gov (United States)

    Maugeri, Marco; Barbagallo, Davide; Barbagallo, Cristina; Banelli, Barbara; Di Mauro, Stefania; Purrello, Francesco; Magro, Gaetano; Ragusa, Marco; Di Pietro, Cinzia; Romani, Massimo; Purrello, Michele

    2016-12-13

    Neuroblastoma is the most common human extracranial solid tumor during infancy. Involvement of several miRNAs in its pathogenesis has been ascertained. Interestingly, most of their encoding genes reside in hypermethylated genomic regions: thus, their tumor suppressor function is normally disallowed in these tumors. To date, the therapeutic role of the demethylating agent 5'-Aza-2 deoxycytidine (5'-AZA) and its effects on miRNAome modulation in neuroblastoma have not been satisfactorily explored. Starting from a high-throughput expression profiling of 754 miRNAs and based on a proper selection, we focused on miR-29a-3p, miR-34b-3p, miR-181c-5p and miR-517a-3p as candidate miRNAs for our analysis. They resulted downregulated in four neuroblastoma cell lines with respect to normal adrenal gland. MiRNAs 29a-3p and 34b-3p also resulted downregulated in vivo in a murine neuroblastoma progression model. Unlike the amount of methylation of their encoding gene promoters, all these miRNAs were significantly overexpressed following treatment with 5'-AZA. Transfection with candidate miRNAs mimics significantly decreased neuroblastoma cells proliferation rate. A lower expression of miR-181c was significantly associated to a worse overall survival in a public dataset of 498 neuroblastoma samples (http://r2.amc.nl). Our data strongly suggest that CDK6, DNMT3A, DNMT3B are targets of miR-29a-3p, while CCNE2 and E2F3 are targets of miR-34b-3p. Based on all these data, we propose that miR-29a-3p, miR-34b-3p, miR-181c-5p and miR-517a-3p are disallowed tumor suppressor genes in neuroblastoma and suggest them as new therapeutic targets in neuroblastoma.

  20. Intracellular fragment of NLRR3 (NLRR3-ICD) stimulates ATRA-dependent neuroblastoma differentiation

    International Nuclear Information System (INIS)

    Akter, Jesmin; Takatori, Atsushi; Islam, Md. Sazzadul; Nakazawa, Atsuko; Ozaki, Toshinori; Nagase, Hiroki; Nakagawara, Akira

    2014-01-01

    Highlights: • NLRR3 is a membrane protein highly expressed in favorable neuroblastoma. • NLRR3-ICD was produced through proteolytic processing by secretases. • NLRR3-ICD was induced to be translocated into cell nucleus following ATRA exposure. • NLRR3-ICD plays a pivotal role in ATRA-mediated neuroblastoma differentiation. - Abstract: We have previously identified neuronal leucine-rich repeat protein-3 (NLRR3) gene which is preferentially expressed in favorable human neuroblastomas as compared with unfavorable ones. In this study, we have found for the first time that NLRR3 is proteolytically processed by secretases and its intracellular domain (NLRR3-ICD) is then released to translocate into cell nucleus during ATRA-mediated neuroblastoma differentiation. According to our present observations, NLRR3-ICD was induced to accumulate in cell nucleus of neuroblastoma SH-SY5Y cells following ATRA treatment. Since the proteolytic cleavage of NLRR3 was blocked by α- or γ-secretase inhibitor, it is likely that NLRR3-ICD is produced through the secretase-mediated processing of NLRR3. Intriguingly, forced expression of NLRR3-ICD in neuroblastoma SK-N-BE cells significantly suppressed their proliferation as examined by a live-cell imaging system and colony formation assay. Similar results were also obtained in neuroblastoma TGW cells. Furthermore, overexpression of NLRR3-ICD stimulated ATRA-dependent neurite elongation in SK-N-BE cells. Together, our present results strongly suggest that NLRR3-ICD produced by the secretase-mediated proteolytic processing of NLRR3 plays a crucial role in ATRA-mediated neuronal differentiation, and provide a clue to develop a novel therapeutic strategy against aggressive neuroblastomas

  1. Intracellular fragment of NLRR3 (NLRR3-ICD) stimulates ATRA-dependent neuroblastoma differentiation

    Energy Technology Data Exchange (ETDEWEB)

    Akter, Jesmin [Laboratory of Innovative Cancer Therapeutics, Chiba Cancer Center Research Institute, Chiba 260-8717 (Japan); Takatori, Atsushi, E-mail: atakatori@chiba-cc.jp [Laboratory of Cancer Genetics, Chiba Cancer Center Research Institute, Chiba 260-8717 (Japan); Islam, Md. Sazzadul [Laboratory of Innovative Cancer Therapeutics, Chiba Cancer Center Research Institute, Chiba 260-8717 (Japan); Nakazawa, Atsuko [Department of Pathology, National Center for Child Health and Development, Tokyo (Japan); Ozaki, Toshinori, E-mail: tozaki@chiba-cc.jp [Laboratory of DNA Damage Signaling, Chiba Cancer Center Research Institute, Chiba 260-8717 (Japan); Nagase, Hiroki [Laboratory of Cancer Genetics, Chiba Cancer Center Research Institute, Chiba 260-8717 (Japan); Nakagawara, Akira [Saga Medical Centre, 840-8571 (Japan)

    2014-10-10

    Highlights: • NLRR3 is a membrane protein highly expressed in favorable neuroblastoma. • NLRR3-ICD was produced through proteolytic processing by secretases. • NLRR3-ICD was induced to be translocated into cell nucleus following ATRA exposure. • NLRR3-ICD plays a pivotal role in ATRA-mediated neuroblastoma differentiation. - Abstract: We have previously identified neuronal leucine-rich repeat protein-3 (NLRR3) gene which is preferentially expressed in favorable human neuroblastomas as compared with unfavorable ones. In this study, we have found for the first time that NLRR3 is proteolytically processed by secretases and its intracellular domain (NLRR3-ICD) is then released to translocate into cell nucleus during ATRA-mediated neuroblastoma differentiation. According to our present observations, NLRR3-ICD was induced to accumulate in cell nucleus of neuroblastoma SH-SY5Y cells following ATRA treatment. Since the proteolytic cleavage of NLRR3 was blocked by α- or γ-secretase inhibitor, it is likely that NLRR3-ICD is produced through the secretase-mediated processing of NLRR3. Intriguingly, forced expression of NLRR3-ICD in neuroblastoma SK-N-BE cells significantly suppressed their proliferation as examined by a live-cell imaging system and colony formation assay. Similar results were also obtained in neuroblastoma TGW cells. Furthermore, overexpression of NLRR3-ICD stimulated ATRA-dependent neurite elongation in SK-N-BE cells. Together, our present results strongly suggest that NLRR3-ICD produced by the secretase-mediated proteolytic processing of NLRR3 plays a crucial role in ATRA-mediated neuronal differentiation, and provide a clue to develop a novel therapeutic strategy against aggressive neuroblastomas.

  2. Management of VIP Associated Diarrhea in a Case with Neuroblastoma

    Directory of Open Access Journals (Sweden)

    Begul Yagci-Kupeli

    2013-06-01

    Full Text Available Watery diarrhea associated with hypokalemia and achlorhydria (WDHA syndrome is commonly caused by vasoactive intestinal peptide (VIP secreting tumors in adults and generally associated with neural crest tumors in pediatric population. VIP secretion is associated with neuroblastic cell differentiation. Octreotide treatment can be a choice for diarrhea in such cases. However, its benefit is controversial and surgery is usually needed. A 14-month-old female with diagnosis of inoperable undifferantiated intraabdominal neuroblastoma who developed chronic diarrhea at first year of chemotherapy is reported. Octreotide treatment was used to control diarrhea. Because of the failure of octreotide treatment, debulking surgery was performed and diarrhea subsided after the surgery. [Cukurova Med J 2013; 38(3.000: 528-530

  3. Neuroblastoma in a patient with Coffin-Siris syndrome.

    Science.gov (United States)

    Pollono, Daniel; Drut, Ricardo; Cecotti, Norma; Pollono, Agustina

    2009-01-01

    We report the case of an 8-year-old boy with the phenotypic features of Coffin-Siris syndrome diffuse hypertrichosis, flat occiput, scant scalp hair, flat supraorbital arch, triangular eyebrows, horizontal palpebral fissure, anteverted nares, triangular philtrum, coarse lips, high-arched palate, micrognathia, low set and dorsaly rotated ears, short neck, wide thorax, widely set nipples, transverse palmar crease, psychomotor delay, urinary malformations (paraurethral diverticulum, hypoplasia of left kidney associated with vesicoureteral reflux grade 3-4), bilateral inguinal hernia, and dorsolumbar kyphoscoliosis. In the follow-up he presented a retroperitoneal neuroblastoma. Although this type of tumor has been referred to develop in several genetic and mutimalformative syndromes, it seems that present association has not been previously reported.

  4. Cell cycle control by the thyroid hormone in neuroblastoma cells

    International Nuclear Information System (INIS)

    Garcia-Silva, Susana; Perez-Juste, German; Aranda, Ana

    2002-01-01

    The thyroid hormone (T3) blocks proliferation and induces differentiation of neuroblastoma N2a-β cells that overexpress the β1 isoform of the T3 receptor. An element in the region responsible for premature termination of transcription mediates a rapid repression of c-myc gene expression by T3. The hormone also causes a decrease of cyclin D1 gene transcription, and is able to antagonize the activation of the cyclin D1 promoter by Ras. In addition, a strong and sustained increase of the levels of the cyclin kinase inhibitor (CKI) p27 Kip1 are found in T3-treated cells. The increased levels of p27 Kip1 lead to a marked inhibition of the kinase activity of the cyclin-CDK2 complexes. As a consequence of these changes, retinoblastoma proteins are hypophosphorylated in T3-treated N2a-β cells, and progression through the restriction point in the cell cycle is blocked

  5. In vitro assessment of curcumin against murine neuroblastoma cells.

    Science.gov (United States)

    Vanisree, Arambakkam Janardhanam; Ramanan, Ramya

    2007-04-01

    Neuroblastoma (NB) is a well-known malignant disease in infants, which comprises 10% of childhood malignancies. Despite recent advances in understanding the neuro-oncology, NB still accounts for more death in childhood than any other cancer. Research in childhood tumors should not only be focused on the malignant signatures of cancer cells but also novel drug prototypes using phytochemicals. The present study was aimed to determine the role of curcumin against murine neuroblastoma cell line (N2a). The in vitro assessment of curcumin against was made in N2a cell line in a dose-dependent manner (group I (control) and group II - IX (10 microM-80 microM). The efficacy of the drug was evaluated by estimating the levels of protein bound carbohydrates, glycoprotein, genomic DNA, total RNA levels, and inhibition of MMP-9 were studied. The gap junctional communication in the cells was also assessed. The levels of protein bound carbohydrates, DNA, RNA levels, glycoprotein were found to be altered on drug supplementation in NB cells. Inhibition of MMP-9 in curcumin-supplemented N2a cells was revealed by zymographic analysis. Assessment of Lucifer yellow dye uptake in curcumin-supplemented N2a cells showed the up-regulation of GJIC. These observations suggest that the curcumin, the active principle of curcuma longa, could be developed into an effective chemo preventive and chemotherapeutic agent. This selected concentration range needs further studies at molecular level, for conforming its role and its action against uncontrolled proliferation of NB.

  6. A 6-gene signature identifies four molecular subgroups of neuroblastoma

    LENUS (Irish Health Repository)

    Abel, Frida

    2011-04-14

    Abstract Background There are currently three postulated genomic subtypes of the childhood tumour neuroblastoma (NB); Type 1, Type 2A, and Type 2B. The most aggressive forms of NB are characterized by amplification of the oncogene MYCN (MNA) and low expression of the favourable marker NTRK1. Recently, mutations or high expression of the familial predisposition gene Anaplastic Lymphoma Kinase (ALK) was associated to unfavourable biology of sporadic NB. Also, various other genes have been linked to NB pathogenesis. Results The present study explores subgroup discrimination by gene expression profiling using three published microarray studies on NB (47 samples). Four distinct clusters were identified by Principal Components Analysis (PCA) in two separate data sets, which could be verified by an unsupervised hierarchical clustering in a third independent data set (101 NB samples) using a set of 74 discriminative genes. The expression signature of six NB-associated genes ALK, BIRC5, CCND1, MYCN, NTRK1, and PHOX2B, significantly discriminated the four clusters (p < 0.05, one-way ANOVA test). PCA clusters p1, p2, and p3 were found to correspond well to the postulated subtypes 1, 2A, and 2B, respectively. Remarkably, a fourth novel cluster was detected in all three independent data sets. This cluster comprised mainly 11q-deleted MNA-negative tumours with low expression of ALK, BIRC5, and PHOX2B, and was significantly associated with higher tumour stage, poor outcome and poor survival compared to the Type 1-corresponding favourable group (INSS stage 4 and\\/or dead of disease, p < 0.05, Fisher\\'s exact test). Conclusions Based on expression profiling we have identified four molecular subgroups of neuroblastoma, which can be distinguished by a 6-gene signature. The fourth subgroup has not been described elsewhere, and efforts are currently made to further investigate this group\\'s specific characteristics.

  7. Irradiation spine deformity in children treated for neuroblastoma

    International Nuclear Information System (INIS)

    Mayfield, J.K.; Riseborough, E.J.; Nehme, M.

    1978-01-01

    A retrospective long-term follow-up review of 56 children with neuroblastoma surviving five years and longer following treatment since 1946 revealed that 57% had developed spine deformity (S.D.) following treatment with 250 kilovolt irradiation at the time of review. The average age at diagnosis was 17 months. Irradiation therapy was delivered to most children before 24 months of age. Follow-up averaged 12.9 years with a range of 5-31 years. Eighty-five per cent of the children had developed structural spine deformity at skeletal maturity and 54% of these children had scoliosis greater than 20 degrees. Sixteen per cent of irradiated children developed structural kyphosis. Non-midline opposing anterior and posterior ports were used most frequently. Mean dosage in patients who developed scoliosis of 20 degrees or more was 3588 rads (spine dosage) and 3746 rads in patients who developed kyphosis. Irradiation through opposing anterior and posterior ports was more commonly associated with the development of S.D. Sixty-six per cent of children who had more than 2000 rads developed S.D. The adolescent growth spurt was associated with an increase in the frequency and severity of spine deformity. This study indicated that moderate to severe S.D. was produced by irradiation in excess of 2000 rads administered with a 250-kilovoltage machine. This study would also suggest that children with neuroblastoma treated with orthovoltage irradiation should be followed closely by the orthopaedic surgeon, the oncologist, the radiotherapist and the paediatrician until the completion of skeletal growth for the development of unsightly structural spine deformity. Early bracing and surgery may be helpful in controlling these deformities in the pre-adolescent to early adolescent years. Continued observation is necessary to determine if current irradiation techniques will minimize or eradicate the incidence and severity of these complications. (author)

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

    Directory of Open Access Journals (Sweden)

    Yonatan Y Mahller

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

  9. T cells targeting NY-ESO-1 demonstrate efficacy against disseminated neuroblastoma.

    Science.gov (United States)

    Singh, Nathan; Kulikovskaya, Irina; Barrett, David M; Binder-Scholl, Gwendolyn; Jakobsen, Bent; Martinez, Daniel; Pawel, Bruce; June, Carl H; Kalos, Michael D; Grupp, Stephan A

    The cancer-testis antigen NY-ESO-1 is expressed by many solid tumors and has limited expression by mature somatic tissues, making it a highly attractive target for tumor immunotherapy. Targeting NY-ESO-1 using engineered T cells has demonstrated clinical efficacy in the treatment of some adult tumors. Neuroblastoma is a significant cause of cancer mortality in children, and is a tumor type shown to be responsive to immunotherapies. We evaluated a large panel of primarily resected neuroblastoma samples and demonstrated that 23% express NY-ESO-1. After confirming antigen-specific activity of T cells genetically engineered to express an NY-ESO-1 directed high-affinity transgenic T cell receptor in vitro , we performed xenograft mouse studies assessing the efficacy of NY-ESO-1-targeted T cells in both localized and disseminated models of neuroblastoma. Disease responses were monitored by tumor volume measurement and in vivo bioluminescence. After delivery of NY-ESO-1 transgenic TCR T cells, we observed significant delay of tumor progression in mice bearing localized and disseminated neuroblastoma, as well as enhanced animal survival. These data demonstrate that NY-ESO-1 is an antigen target in neuroblastoma and that targeted T cells represent a potential therapeutic option for patients with neuroblastoma.

  10. Iodine-131 Metaiodobenzylguanidine Therapy for Neuroblastoma: Reports So Far and Future Perspective

    Directory of Open Access Journals (Sweden)

    Daiki Kayano

    2015-01-01

    Full Text Available Neuroblastoma, which derives from neural crest, is the most common extracranial solid cancer in childhood. The tumors express the norepinephrine (NE transporters on their cell membrane and take in metaiodobenzylguanidine (MIBG via a NE transporter. Since iodine-131 (I-131 MIBG therapy was firstly reported, many trails of MIBG therapy in patients with neuroblastoma were performed. Though monotherapy with a low dose of I-131 MIBG could achieve high-probability pain reduction, the objective response was poor. In contrast, more than 12 mCi/kg I-131 MIBG administrations with or without hematopoietic cell transplantation (HCT obtain relatively good responses in patients with refractory or relapsed neuroblastoma. The combination therapy with I-131 MIBG and other modalities such as nonmyeloablative chemotherapy and myeloablative chemotherapy with HCT improved the therapeutic response in patients with refractory or relapsed neuroblastoma. In addition, I-131 MIBG therapy incorporated in the induction therapy was proved to be feasible in patients with newly diagnosed neuroblastoma. To expand more the use of MIBG therapy for neuroblastoma, further studies will be needed especially in the use at an earlier stage from diagnosis, in the use with other radionuclide formations of MIBG, and in combined use with other therapeutic agents.

  11. The analysis of risk of the radiation failures in Russian navy. Experience of international cooperation

    International Nuclear Information System (INIS)

    Lisovsky, I.V.

    2000-01-01

    The international research program 'Risk and nuclear waste' is carried out under a management FOA - Swedish Defence Research Establishment and CERUM - Centre for Regional Science of the University of Umea (Sweden) at participation UAF - University of Alaska, Fairbanks, KNC - Kola Centre of Science of Russian Academy Science (RAN), MMBI - Murmansk Sea Bbiological Institute KNC of RAN. A component of the program is the project INTAS 96-1802 An Estimation of potential risk of radioactive pollution of an environment on Europe from nuclear sources on Russia'. This project (scientific official responsible for the project - Mr R. BERGMAN) consists of 5 directions and is carried out by forces Swedish Defence Research Establishment (Sweden) - direction 1, Oulu University (Finland) - direction 2, Institute of applied Mathematicians of RAN (Russia) - direction 3, Laboratory of Modeling of an Environment of KNC of RAN (Russia) - direction 4 and St. -Petersburg State Technical University (Russia) - direction 5 (scientific official responsible for this part of the project - Mr I. LISOVSKY). The working program of researches on a direction 5 project INTAS 96-1802 provides: determination of the list of typical sources of danger emergency radioactive emissions in an environment in connection with military activity in Russia; the description of the basic scripts of development of failures, resulting to emission of radionuclides in an environment; the analysis of radiation risk for the population and environment, connected to an emergency condition of the storage for radioactive waste 'Mironova mountain'; the description of models, used for accounts of fields of concentration and the migration of radionuclides in a ground and coastal waters; an estimation higienic and ecological danger of nuclear submarines removed from operation and solid radioactive waste; an estimation of risk of failures with air excharge of radionuclides; an estimation of possible doses of chronic exposure for

  12. International collaboration towards a global analysis of volcanic hazards and risk

    Science.gov (United States)

    Loughlin, Susan; Duncan, Melanie; Volcano Model Network, Global

    2017-04-01

    Approximately 800 million people live within 100km of an active volcano and such environments are often subject to multiple natural hazards. Volcanic eruptions and related volcanic hazards are less frequent than many other natural hazards but when they occur they can have immediate and long-lived impacts so it is important that they are not overlooked in a multi-risk assessment. Based on experiences to date, it's clear that natural hazards communities need to address a series of challenges in order to move to a multi-hazard approach to risk assessment. Firstly, the need to further develop synergies and coordination within our own communities at local to global scales. Secondly, we must collaborate and identify opportunities for harmonisation across natural hazards communities: for instance, by ensuring our databases are accessible and meet certain standards, a variety of users will be then able to contribute and access data. Thirdly, identifying the scale and breadth of multi-risk assessments needs to be co-defined with decision-makers, which will constrain the relevant potential cascading/compounding hazards to consider. Fourthly, and related to all previous points, multi-risk assessments require multi-risk knowledge, requiring interdisciplinary perspectives, as well as discipline specific expertise. The Global Volcano Model network (GVM) is a growing international network of (public and private) institutions and organisations, which have the collective aim of identifying and reducing volcanic risks. GVM's values embody collaboration, scientific excellence, open-access (wherever possible) and, above all, public good. GVM highlights and builds on the best research available within the volcanological community, drawing on the work of IAVCEI Commissions and other research initiatives. It also builds on the local knowledge of volcano observatories and collaborating scientists, ensuring that global efforts are underpinned by local evidence. Some of GVM's most

  13. Seismic risk analysis for the Atomics International Nuclear Materials Development Facility, Santa Susana California

    International Nuclear Information System (INIS)

    1978-01-01

    This report presents the results of a detailed seismic risk analysis of the Nuclear Materials Development Facility (NMDF) operated by Atomics International at Santa Susana, California. The historical seismic record was established after a review of available literature, consultation with operators of local seismic arrays and examination of appropriate seismic data bases including the USGS, California Institute of Technology and NEIS data bases. The resulting seismic record, covering the period 1969 to 1977, was used to identify all possible sources of seismicity that could affect the site. The best estimate curve indicates that the facility will experience 30% g with a return period of 55 years and 60% g with a return period of 750 years

  14. Diablo Canyon internal events PRA [Probabilistic Risk Assessment] review: Methodology and findings

    International Nuclear Information System (INIS)

    Fitzpatrick, R.G.; Bozoki, G.; Sabek, M.

    1990-01-01

    The review of the Diablo Canyon Probabilistic Risk Assessment (DCRPA) incorporated some new and innovative approaches. These were necessitated by the unprecedented size, scope and level of detail of the DCRPA, which was submitted to the NRC for licensing purposes. This paper outlines the elements of the internal events portion of the review citing selected findings to illustrate the various approaches employed. The paper also provides a description of the extensive and comprehensive importance analysis applied by BNL to the DCRPA model. Importance calculations included: top event/function level; individual split fractions; pair importances between frontline-support and support-support systems; system importance by initiator; and others. The paper concludes with a brief discussion of the effectiveness of the applied methodology. 3 refs., 5 tabs

  15. International negotiation methods on climatic risks, the limits of global incentives: Natural gas example

    International Nuclear Information System (INIS)

    Hourcade, J.C.; Journe, V.

    1992-01-01

    The discussion on economic instruments for coordinating an international strategy for climatic risks prevention does not take sufficiently into account the importance of the relevant scientific controversies. These ones determine strongly the negotiation process for the settlement of such a system. We illustrate this point with the simple case of the natural gas whose superiority in terms of emission contents compared to the other fossil fuels, could be contested in case of too important CH 4 releases. We show that the negotiation process cannot come to a positive end if the incentive system relies only on the price signal. This process can converge only if one thinks about the combination of various tools, namely technological norms and ad hoc funds for the renewal of transmission and distribution networks combined with tax systems. 17 refs., 6 tabs

  16. Personality Predicts Mortality Risk: An Integrative Data Analysis of 15 International Longitudinal Studies.

    Science.gov (United States)

    Graham, Eileen K; Rutsohn, Joshua P; Turiano, Nicholas A; Bendayan, Rebecca; Batterham, Philip J; Gerstorf, Denis; Katz, Mindy J; Reynolds, Chandra A; Sharp, Emily S; Yoneda, Tomiko B; Bastarache, Emily D; Elleman, Lorien G; Zelinski, Elizabeth M; Johansson, Boo; Kuh, Diana; Barnes, Lisa L; Bennett, David A; Deeg, Dorly J H; Lipton, Richard B; Pedersen, Nancy L; Piccinin, Andrea M; Spiro, Avron; Muniz-Terrera, Graciela; Willis, Sherry L; Schaie, K Warner; Roan, Carol; Herd, Pamela; Hofer, Scott M; Mroczek, Daniel K

    2017-10-01

    This study examined the Big Five personality traits as predictors of mortality risk, and smoking as a mediator of that association. Replication was built into the fabric of our design: we used a Coordinated Analysis with 15 international datasets, representing 44,094 participants. We found that high neuroticism and low conscientiousness, extraversion, and agreeableness were consistent predictors of mortality across studies. Smoking had a small mediating effect for neuroticism. Country and baseline age explained variation in effects: studies with older baseline age showed a pattern of protective effects (HRstudies showed a pattern of protective effects for extraversion. This study demonstrated coordinated analysis as a powerful approach to enhance replicability and reproducibility, especially for aging-related longitudinal research.

  17. Título da página electrónica: International Risk Governance Council

    Directory of Open Access Journals (Sweden)

    Pedro Pinto dos Santos

    2012-12-01

    Full Text Available O International Risk Governance Council (IRGC é uma organização independente cuja missão é ajudar a compreender e a gerir riscos globais emergentes que têm impacto na segurança, saúde humana, ambiente, economia e na sociedade. O IRGC focaliza a sua acção no desenvolvimento de conceitos e estratégias de governação do risco, sendo esta uma área crucial perante a necessidade de tomar decisões relacionadas com o risco e de conseguir uma maximização da confiança das comunidades nos processos e na...

  18. HIV-Related Stigma, Shame, and Avoidant Coping: Risk Factors for Internalizing Symptoms Among Youth Living with HIV?

    Science.gov (United States)

    Bennett, David S; Hersh, Jill; Herres, Joanna; Foster, Jill

    2016-08-01

    Youth living with HIV (YLH) are at elevated risk of internalizing symptoms, although there is substantial individual variability in adjustment. We examined perceived HIV-related stigma, shame-proneness, and avoidant coping as risk factors of internalizing symptoms among YLH. Participants (N = 88; ages 12-24) completed self-report measures of these potential risk factors and three domains of internalizing symptoms (depressive, anxiety, and PTSD) during a regularly scheduled HIV clinic visit. Hierarchical regressions were conducted for each internalizing symptoms domain, examining the effects of age, gender, and maternal education (step 1), HIV-related stigma (step 2), shame- and guilt-proneness (step 3), and avoidant coping (step 4). HIV-related stigma, shame-proneness, and avoidant coping were each correlated with greater depressive, anxiety, and PTSD symptoms. Specificity was observed in that shame-proneness, but not guilt-proneness, was associated with greater internalizing symptoms. In multivariable analyses, HIV-related stigma and shame-proneness were each related to greater depressive and PTSD symptoms. Controlling for the effects of HIV-related stigma and shame-proneness, avoidant coping was associated with PTSD symptoms. The current findings highlight the potential importance of HIV-related stigma, shame, and avoidant coping on the adjustment of YLH, as interventions addressing these risk factors could lead to decreased internalizing symptoms among YLH.

  19. Metastatic neuroblastoma presenting as refusal to use the left upper extremity in a six-year-old girl

    OpenAIRE

    Casey Grover; Elizabeth Crawford

    2014-01-01

    Neuroblastoma is the most common extracranial neoplasm in children, commonly presenting at an advanced stage. Despite the high prevalence of metastatic disease with neuroblastoma, metastases to the central nervous system are rare and predominantly involve the spinal cord. We present a case of neuroblastoma with metastases to the brain presenting as refusal to move the left arm. The lesion initially appeared to be both a subdural and epidural hematoma on computed tomography of the head, but up...

  20. International approaches to the hydraulic control of surface water runoff in mitigating flood and environmental risks

    Directory of Open Access Journals (Sweden)

    Ballard Bridget Woods

    2016-01-01

    Full Text Available This paper compares and contrasts a number of international approaches to the hydraulic control of surface water runoff from new development and redevelopment, known as sustainable drainage systems (SuDS or low impact development (LID. The paper provides a commentary on the progress and current status of national standards for SuDS in the UK to control the frequency, flow rate and volume of runoff from both frequent and extreme rainfall events, and the best practice design criteria presented in the revised UK CIRIA SuDS Manual, published in November 2015. The paper then compares these design criteria and standards with those developed and applied in China, USA, France and Germany and also looks at the drivers behind their development. The benefits of these different approaches are assessed in the context of flood risk mitigation, climate resilience and wider environmental protection objectives, including water quality, morphology and ecology. The paper also reviews the design approaches promoted by the new SuDS Manual and internationally for delivering additional benefits for urban spaces (such as recreation, visual character, education and economic growth through multi-functional urban design.

  1. Airport Casualties: Non-Admission and Return Risks at Times of Internalized/Externalized Border Controls

    Directory of Open Access Journals (Sweden)

    Maybritt Jill Alpes

    2015-09-01

    Full Text Available This article analyzes what can happen to forced returnees upon arrival in their country of nationality. Subjective configurations of state agents in the Global South have created return risks, which in turn transform subjectivities of post-colonial citizens. The article contributes to this Special Issue by tracing repercussions of the externalization and internalization of border controls. In the case of Cameroon, these connections have resulted in the criminalization of emigration. Aspiring migrants are prosecuted if their departure projects fail to respect the entry requirements of countries in the Global North. The article is based on research conducted in Douala, Cameroon, in the form of discussions with control agents at the international airport, investigations at a prison, a review of related case law, police registers and interviews with Cameroonians returnees (November 2013–January 2014. Border controls and connected anti-fraud programs suppress family-based forms of solidarity and allow only for subjectivities rooted in state-managed forms of national identity. The article illustrates how efforts to combat fraud fuel corruption in returnees’ social networks, whereby, instead of receiving remittances, families in emigration countries have to mobilize financial resources in order to liberate returnees from police stations or prison complexes. Migration related detention of nationals in the Global South highlights the growing significance of exit controls in migration management.

  2. Sexual risk taking in a community sample of international backpackers visiting Brisbane, Australia.

    Science.gov (United States)

    Fischer, Jane A; Debattista, Joseph; Rostami, Soulmaz; Peet, Anthony R; Dean, Judith A; Allen, Kate E; Stewart, Mary

    2015-03-01

    We sought to examine correlations between international backpackers' alcohol consumption and sexual behaviors and determine the prevalence of Chlamydia trachomatis and Neisseria gonorrhoea in this population. A cross-sectional study design consisting of a convenience sample (N = 168) of non-treatment-seeking international backpackers visiting Brisbane, Australia was recruited. Participants were asked to self-complete a questionnaire on sexual behavior and to undertake a urine-based polymerase chain reaction test for C trachomatis and N gonorrhoea. Since arriving in Australia, 73.2% reported having had sex, with a median number of 2 different sex partners (range = 0-21). Most participants had consumed alcohol (53.7%) and used condoms (46.3%) the last time they had sex. In our sample, there was a 4.3% prevalence of C trachomatis and a 0% prevalence of N gonorrhoea. This study identified a variable pattern of risk among backpackers, with those spending longer periods in the country more likely to have sex with Australians. © 2013 APJPH.

  3. Review of the Shoreham Nuclear Power Station Probabilistic Risk Assessment: internal events and core damage frequency

    International Nuclear Information System (INIS)

    Ilberg, D.; Shiu, K.; Hanan, N.; Anavim, E.

    1985-11-01

    A review of the Probabilistic Risk Assessment of the Shoreham Nuclear Power Station was conducted with the broad objective of evaluating its risks in relation to those identified in the Reactor Safety Study (WASH-1400). The scope of the review was limited to the ''front end'' part, i.e., to the evaluation of the frequencies of states in which core damage may occur. Furthermore, the review considered only internally generated accidents, consistent with the scope of the PRA. The review included an assessment of the assumptions and methods used in the Shoreham study. It also encompassed a reevaluation of the main results within the scope and general methodological framework of the Shoreham PRA, including both qualitative and quantitative analyses of accident initiators, data bases, and accident sequences which result in initiation of core damage. Specific comparisons are given between the Shoreham study, the results of the present review, and the WASH-1400 BWR, for the core damage frequency. The effect of modeling uncertainties was considered by a limited sensitivity study so as to show how the results would change if other assumptions were made. This review provides an independently assessed point value estimate of core damage frequency and describes the major contributors, by frontline systems and by accident sequences. 17 figs., 81 tabs

  4. Incretin based drugs and the risk of pancreatic cancer: international multicentre cohort study

    Science.gov (United States)

    Filion, Kristian B; Platt, Robert W; Dahl, Matthew; Dormuth, Colin R; Clemens, Kristin K; Durand, Madeleine; Juurlink, David N; Targownik, Laura E; Turin, Tanvir C; Paterson, J Michael; Ernst, Pierre

    2016-01-01

    Objective To determine whether the use of incretin based drugs compared with sulfonylureas is associated with an increased risk of incident pancreatic cancer in people with type 2 diabetes. Design Population based cohort. Setting Large, international, multicentre study combining the health records from six participating sites in Canada, the United States, and the United Kingdom. Participants A cohort of 972 384 patients initiating antidiabetic drugs between 1 January 2007 and 30 June 2013, with follow-up until 30 June 2014. Main outcome measures Within each cohort we conducted nested case-control analyses, where incident cases of pancreatic cancer were matched with up to 20 controls on sex, age, cohort entry date, duration of treated diabetes, and duration of follow-up. Hazard ratios and 95% confidence intervals for incident pancreatic cancer were estimated, comparing use of incretin based drugs with use of sulfonylureas, with drug use lagged by one year for latency purposes. Secondary analyses assessed whether the risk varied by class (dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists) or by duration of use (cumulative duration of use and time since treatment initiation). Site specific hazard ratios were pooled using random effects models. Results During 2 024 441 person years of follow-up (median follow-up ranging from 1.3 to 2.8 years; maximum 8 years), 1221 patients were newly diagnosed as having pancreatic cancer (incidence rate 0.60 per 1000 person years). Compared with sulfonylureas, incretin based drugs were not associated with an increased risk of pancreatic cancer (pooled adjusted hazard ratio 1.02, 95% confidence interval 0.84 to 1.23). Similarly, the risk did not vary by class and evidence of a duration-response relation was lacking. Conclusions In this large, population based study the use of incretin based drugs was not associated with an increased risk of pancreatic cancer compared with sulfonylureas

  5. Applicability of Two International Risk Scores in Cardiac Surgery in a Reference Center in Brazil

    Energy Technology Data Exchange (ETDEWEB)

    Garofallo, Silvia Bueno; Machado, Daniel Pinheiro; Rodrigues, Clarissa Garcia; Bordim, Odemir Jr.; Kalil, Renato A. K.; Portal, Vera Lúcia, E-mail: veraportal.pesquisa@gmail.com [Post-Graduation Program in Health Sciences: Cardiology, Instituto de Cardiologia/Fundação Universitária de Cardiologia, Porto Alegre, RS (Brazil)

    2014-06-15

    The applicability of international risk scores in heart surgery (HS) is not well defined in centers outside of North America and Europe. To evaluate the capacity of the Parsonnet Bernstein 2000 (BP) and EuroSCORE (ES) in predicting in-hospital mortality (IHM) in patients undergoing HS at a reference hospital in Brazil and to identify risk predictors (RP). Retrospective cohort study of 1,065 patients, with 60.3% patients underwent coronary artery bypass grafting (CABG), 32.7%, valve surgery and 7.0%, CABG combined with valve surgery. Additive and logistic scores models, the area under the ROC (Receiver Operating Characteristic) curve (AUC) and the standardized mortality ratio (SMR) were calculated. Multivariate logistic regression was performed to identify the RP. Overall mortality was 7.8%. The baseline characteristics of the patients were significantly different in relation to BP and ES. AUCs of the logistic and additive BP were 0.72 (95% CI, from 0.66 to 0.78 p = 0.74), and of ES they were 0.73 (95% CI; 0.67 to 0.79 p = 0.80). The calculation of the SMR in BP was 1.59 (95% CI; 1.27 to 1.99) and in ES, 1.43 (95% CI; 1.14 to 1.79). Seven RP of IHM were identified: age, serum creatinine > 2.26 mg/dL, active endocarditis, systolic pulmonary arterial pressure > 60 mmHg, one or more previous HS, CABG combined with valve surgery and diabetes mellitus. Local scores, based on the real situation of local populations, must be developed for better assessment of risk in cardiac surgery.

  6. Notch ligand Delta-like 1 as a novel molecular target in childhood neuroblastoma.

    Science.gov (United States)

    Bettinsoli, P; Ferrari-Toninelli, G; Bonini, S A; Prandelli, C; Memo, M

    2017-05-19

    Neuroblastoma is the most common extracranial solid malignancy in childhood, responsible for 15% of all pediatric cancer deaths. It is an heterogeneous disease that does not always respond to classical therapy; so the identification of new and specific molecular targets to improve existing therapy is needed. We have previously demonstrated the involvement of the Notch pathway in the onset and progression of neuroblastoma. In this study we further investigated the role of Notch signaling and identified Delta-like 1 (DLL1) as a novel molecular target in neuroblastoma cells with a high degree of MYCN amplification, which is a major oncogenic driver in neuroblastoma. The possibility to act on DLL1 expression levels by using microRNAs (miRNAs) was assessed. DLL1 mRNA and protein expression levels were measured in three different neuroblastoma cell lines using quantitative real-time PCR and Western Blot analysis, respectively. Activation of the Notch pathway as a result of increased levels of DLL1 was analyzed by Immunofluorescence and Western Blot methods. In silico tools revealed the possibility to act on DLL1 expression levels with miRNAs, in particular with the miRNA-34 family. Neuroblastoma cells were transfected with miRNA-34 family members, and the effect of miRNAs transfection on DLL1 mRNA expression levels, on cell differentiation, proliferation and apoptosis was measured. In this study, the DLL1 ligand was identified as the Notch pathway component highly expressed in neuroblastoma cells with MYCN amplification. In silico analysis demonstrated that DLL1 is one of the targets of miRNA-34 family members that maps on chromosome regions that are frequently deregulated or deleted in neuroblastoma. We studied the possibility to use miRNAs to target DLL1. Among all miRNA-34 family members, miRNA-34b is able to significantly downregulate DLL1 mRNA expression levels, to arrest cell proliferation and to induce neuronal differentiation in malignant neuroblastoma cells

  7. International

    International Nuclear Information System (INIS)

    Anon.

    1997-01-01

    This rubric reports on 10 short notes about international economical facts about nuclear power: Electricite de France (EdF) and its assistance and management contracts with Eastern Europe countries (Poland, Hungary, Bulgaria); Transnuclear Inc. company (a 100% Cogema daughter company) acquired the US Vectra Technologies company; the construction of the Khumo nuclear power plant in Northern Korea plays in favour of the reconciliation between Northern and Southern Korea; the delivery of two VVER 1000 Russian reactors to China; the enforcement of the cooperation agreement between Euratom and Argentina; Japan requested for the financing of a Russian fast breeder reactor; Russia has planned to sell a floating barge-type nuclear power plant to Indonesia; the control of the Swedish reactor vessels of Sydkraft AB company committed to Tractebel (Belgium); the renewal of the nuclear cooperation agreement between Swiss and USA; the call for bids from the Turkish TEAS electric power company for the building of the Akkuyu nuclear power plant answered by three candidates: Atomic Energy of Canada Limited (AECL), Westinghouse (US) and the French-German NPI company. (J.S.)

  8. Prediction of incidence and stability of alcohol use disorders by latent internalizing psychopathology risk profiles in adolescence and young adulthood.

    Science.gov (United States)

    Behrendt, Silke; Bühringer, Gerhard; Höfler, Michael; Lieb, Roselind; Beesdo-Baum, Katja

    2017-10-01

    Comorbid internalizing mental disorders in alcohol use disorders (AUD) can be understood as putative independent risk factors for AUD or as expressions of underlying shared psychopathology vulnerabilities. However, it remains unclear whether: 1) specific latent internalizing psychopathology risk-profiles predict AUD-incidence and 2) specific latent internalizing comorbidity-profiles in AUD predict AUD-stability. To investigate baseline latent internalizing psychopathology risk profiles as predictors of subsequent AUD-incidence and -stability in adolescents and young adults. Data from the prospective-longitudinal EDSP study (baseline age 14-24 years) were used. The study-design included up to three follow-up assessments in up to ten years. DSM-IV mental disorders were assessed with the DIA-X/M-CIDI. To investigate risk-profiles and their associations with AUD-outcomes, latent class analysis with auxiliary outcome variables was applied. AUD-incidence: a 4-class model (N=1683) was identified (classes: normative-male [45.9%], normative-female [44.2%], internalizing [5.3%], nicotine dependence [4.5%]). Compared to the normative-female class, all other classes were associated with a higher risk of subsequent incident alcohol dependence (p<0.05). AUD-stability: a 3-class model (N=1940) was identified with only one class (11.6%) with high probabilities for baseline AUD. This class was further characterized by elevated substance use disorder (SUD) probabilities and predicted any subsequent AUD (OR 8.5, 95% CI 5.4-13.3). An internalizing vulnerability may constitute a pathway to AUD incidence in adolescence and young adulthood. In contrast, no indication for a role of internalizing comorbidity profiles in AUD-stability was found, which may indicate a limited importance of such profiles - in contrast to SUD-related profiles - in AUD stability. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Post-Flight Back Pain Following International Space Station Missions: Evaluation of Spaceflight Risk Factors

    Science.gov (United States)

    Laughlin, M. S.; Murray, J. D.; Wear, M. L.; Van Baalen, M.

    2016-01-01

    INTRODUCTION Back pain during spaceflight has often been attributed to the lengthening of the spinal column due to the absence of gravity during both short and long-duration missions. Upon landing and re-adaptation to gravity, the spinal column reverts back to its original length thereby causing some individuals to experience pain and muscular spasms, while others experience no ill effects. With International Space Station (ISS) missions, cases of back pain and injury are more common post-flight, but little is known about the potential risk factors. Thus, the purpose of this project was to perform an initial evaluation of reported post-flight back pain and injury cases to relevant spaceflight risk factors in United States astronauts that have completed an ISS mission. METHODS All US astronauts who completed an ISS mission between Expeditions (EXP) 1 and 41 (2000-2015) were included in this evaluation. Forty-five astronauts (36 males and 9 females) completed 50 ISS missions during the study time period, as 5 astronauts completed 2 ISS missions. Researchers queried medical records of the 45 astronauts for occurrences of back pain and injury. A case was defined as any reported event of back pain or injury to the cervical, thoracic, lumbar, sacral, or coccyx spine regions. Data sources for the cases included the Flight Medicine Clinic's electronic medical record; Astronaut Strength, Conditioning and Rehabilitation electronic documentation; the Private Medical Conference tool; and the Space Medicine Operations Team records. Post-flight cases were classified as an early case if reported within 45 days of landing (R + 45) or a late case if reported from R + 46 to R + 365 days after landing (R + 1y). Risk factors in the astronaut population for back pain include age, sex, prior military service, and prior history of back pain. Additionally, spaceflight specific risk factors such as type of landing vehicle and onboard exercise countermeasures were included to evaluate their

  10. Activated ALK signals through the ERK-ETV5-RET pathway to drive neuroblastoma oncogenesis.

    Science.gov (United States)

    Lopez-Delisle, Lucille; Pierre-Eugène, Cécile; Louis-Brennetot, Caroline; Surdez, Didier; Raynal, Virginie; Baulande, Sylvain; Boeva, Valentina; Grossetête-Lalami, Sandrine; Combaret, Valérie; Peuchmaur, Michel; Delattre, Olivier; Janoueix-Lerosey, Isabelle

    2018-03-01

    Activating mutations of the ALK receptor occur in a subset of neuroblastoma tumors. We previously demonstrated that Alk mutations cooperate with MYCN overexpression to induce neuroblastoma in mice and identified Ret as being strongly upregulated in MYCN/Alk mut tumors. By a genetic approach in vivo, we now document an oncogenic cooperation between activated Ret and MYCN overexpression in neuroblastoma formation. We show that MYCN/Ret M919T tumors exhibit histological features and expression profiles close to MYCN/Alk mut tumors. We show that RET transcript levels decrease precedes RET protein levels decrease upon ALK inhibition in neuroblastoma cell lines. Etv5 was identified as a candidate transcription factor regulating Ret expression from murine MYCN/Alk mut tumor transcriptomic data. We demonstrate that ETV5 is regulated both at the protein and mRNA levels upon ALK activation or inhibition in neuroblastoma cell lines and that this regulation precedes RET modulation. We document that ALK activation induces ETV5 protein upregulation through stabilization in a MEK/ERK-dependent manner. We show that RNAi-mediated inhibition of ETV5 decreases RET expression. Reporter assays indicate that ETV5 is able to drive RET gene transcription. ChIP-seq analysis confirmed ETV5 binding on the RET promoter and identified an enhancer upstream of the promoter. Finally, we demonstrate that combining RET and ALK inhibitors reduces tumor growth more efficiently than each single agent in MYCN and Alk F1178L -driven murine neuroblastoma. Altogether, these results define the ERK-ETV5-RET pathway as a critical axis driving neuroblastoma oncogenesis downstream of activated ALK.

  11. Prioritization of Delay Factors for NPP Construction Risk in International Project by Using AHP Methodology

    International Nuclear Information System (INIS)

    Hossen, Muhammed Mufazzal; Kang, Sunkoo; Kim, Jonghyun

    2014-01-01

    It is crucial for the nuclear power plant project decision makers and management personnel to identify the actual factors of construction delay and their ranking in order to take preventive actions. NPP project is complex in nature and the construction phase is one of the most key phase which is subject to many factors result from many sources. From experience, nuclear projects have faced challenges similar to other complex mega projects with additional nuclear specific issues and life time cost of nuclear reactor is concentrated upfront as capital cost, and therefore delays in construction may become intolerable in terms of both lost revenues and interest on the capital. Budget over-runs and delays on next generation new build nuclear projects in recent years clearly demonstrate that the nuclear industry continues to repeat its failed management and project control processes of the past. Similar to major infra-structure projects, actual completion times can vary substantially from initial estimates but this uncertainty is too crucial to the nuclear industry due to high levels of capital at risk, for every year a project is delayed the levelized cost of electricity increases by approximately 8-10%. causes of delay, to develop a generalized AHP model for delay factors, and to prioritize the risk in different factors in various levels of construction phase in international turnkey NPP project. This paper describes and prioritizes Nuclear Power Plant (NPP) construction schedule delay factor for turnkey international project. This study also determines the different party's importance in percentage behind the construction schedule delay of NPP which constitutes main contractor (28.4%), regulatory authority (27.3%), financial and country factor (23.5%), and utility (20.8%). Decision makers of nuclear industry can understand the significance of different factors on NPP construction phase and they can apply risk informed decision making to avoid unexpected

  12. Population attributable risk for chlamydia infection in a cohort of young international travellers (backpackers) and residents in Australia

    OpenAIRE

    Wand, Handan; Guy, Rebecca; Donovan, Basil; McNulty, Anna

    2011-01-01

    Aim To estimate the population attributable risk (PAR) for Chlamydia trachomatis infection in young men and women in Sydney, Australia. Method Multivariate logistic regression was used to examine the association between demographic, sexual behaviour and other potential risk factors and chlamydia positivity in young (?30?years) heterosexual international travellers (backpackers) and Australian residents attending a sexual health clinic. Point and interval estimates of PAR were calculated to qu...

  13. Epidemiological study of workers at risk of internal exposure to uranium

    International Nuclear Information System (INIS)

    Guseva Canu, I.

    2008-09-01

    This work is a pilot-study among nuclear fuel cycle workers potentially exposed to alpha radiation. Internal exposure from inhalation of uranium compounds during uranium conversion and enrichment operations was estimated at the AREVA NC Pierrelatte plant. A plant specific semi-quantitative job exposure matrix (JEM) was elaborated for 2709 workers employed at this plant between 1960 and 2006. The JEM has permitted to estimate the exposure to uranium and 16 other categories of pollutants and to calculate individual cumulative exposure score. Numerous correlations were detected between uranium compounds exposure and exposure to other pollutants, such as asbestos, ceramic refractive fibers, TCE and so on. 1968-2005 mortality follow-up showed an increasing risk of mortality from pleural cancer, rectal cancer and lymphoma on the basis of national mortality rates. Analyses of association between cancer mortality and uranium exposure suggested an increase in mortality due to lung cancer among workers exposed to slowly soluble uranium compounds derived from natural and reprocessed uranium. However these results are not statistically significant and based on a small number of observed deaths. These results are concordant with previously reported results from other cohorts of workers potentially exposed to uranium. Experimental studies of biokinetic and action mechanism of slowly soluble uranium oxides bear the biological plausibility of the observed results. Influence of bias was reduced by taking into account of possible confounding including co-exposure to other carcinogenic pollutants and tobacco consumption in the study. Nevertheless, at this stage statistical power of analyses is too limited to obtain more conclusive results. This pilot study shows the interest and feasibility of an epidemiological investigation among workers at risk of internal exposure to uranium and other alpha emitters at the national level. It demonstrates the importance of exposure assessment for

  14. Risks and Benefits with International Technology Transfer from Brazil to Angola

    Directory of Open Access Journals (Sweden)

    Rafael Vaisman

    2013-12-01

    Full Text Available Thanks to the transfer of technology from Brazil, Angola is entering the sucroalcooleiro sector with multiple aims. These include creating jobs in rural areas, diversifying the energy mix and boosting exports. Angola is one of the countries that has envisioned international technology transfer as a strategy to increase participation in the global market, while decreasing its dependence on sugar imports. While the production of ethanol and sugar can bring about some benefits, technology transfer in this area is not without risks. It needs to be carefully crafted and executed, especially in accordance with the principles of sustainable development, which is by the government plan of Angola to include, rather than exclude, the rural poor. This study shows that stakeholders presented different opinions in relation to Biocom and sustainable development. The main reason is linked to the distinction between global, national and local levels. On the global level, ITT and Biocom are seen as alternative renewable sources of energy (ethanol to fossil fuels, on the local level there is a concern with the socio-environmental issues which local communities might face, indeed ITT and Biocom are perceived as a risk in case locals  lose their lands and do not receive compensation. On the national level, while there is the expectancy of employment, infrastructure development and attraction of investments in the country, there is a lack of trust in governance by Angolan civil society; which argues that Angolan government and enterprises do not encourage public participation nor allows it to happen. Technology transfer is perceived as a business and geopolitical strategy driven by private and state interests, undermining environmental and social costs. On the other hand technology transfer is seen as a key to foster economic opportunities towards sustainable development.

  15. Risk assessment of student performance in the International Foundations of Medicine Clinical Science Examination by the use of statistical modeling.

    Science.gov (United States)

    David, Michael C; Eley, Diann S; Schafer, Jennifer; Davies, Leo

    2016-01-01

    The primary aim of this study was to assess the predictive validity of cumulative grade point average (GPA) for performance in the International Foundations of Medicine (IFOM) Clinical Science Examination (CSE). A secondary aim was to develop a strategy for identifying students at risk of performing poorly in the IFOM CSE as determined by the National Board of Medical Examiners' International Standard of Competence. Final year medical students from an Australian university medical school took the IFOM CSE as a formative assessment. Measures included overall IFOM CSE score as the dependent variable, cumulative GPA as the predictor, and the factors age, gender, year of enrollment, international or domestic status of student, and language spoken at home as covariates. Multivariable linear regression was used to measure predictor and covariate effects. Optimal thresholds of risk assessment were based on receiver-operating characteristic (ROC) curves. Cumulative GPA (nonstandardized regression coefficient [B]: 81.83; 95% confidence interval [CI]: 68.13 to 95.53) and international status (B: -37.40; 95% CI: -57.85 to -16.96) from 427 students were found to be statistically associated with increased IFOM CSE performance. Cumulative GPAs of 5.30 (area under ROC [AROC]: 0.77; 95% CI: 0.72 to 0.82) and 4.90 (AROC: 0.72; 95% CI: 0.66 to 0.78) were identified as being thresholds of significant risk for domestic and international students, respectively. Using cumulative GPA as a predictor of IFOM CSE performance and accommodating for differences in international status, it is possible to identify students who are at risk of failing to satisfy the National Board of Medical Examiners' International Standard of Competence.

  16. THE FOOD RUSH. A SECURITY RISK AND A CAUSE FOR INTERNATIONAL INTERVENTION

    Directory of Open Access Journals (Sweden)

    Liliana FILIP

    2017-04-01

    Full Text Available Access to food is more than ever a question of interest. The world needs to produce at least 50% more food to feed 9 billion people by 2050. The land, biodiversity, oceans, forests, and other forms of natural capital are being depleted at unprecedented rates. Unless we change how we grow our food and manage our natural capital, food security – especially for the world’s poorest – will be at risk. In this context we expect that the struggle for food to generate migration, conflicts and, why not, international intervention defined by the new Copenhagen School of Security Studies paradigm. Since March 2008 governments, UN agencies and many social movements have adopted positions on the causes of the food crisis and the means to address it. Unfortunately, while these parties are trying to coordinate their activities and suggest new approaches, the old recipes for producing more food are often brought up. Contradictory proposals are made and the thought given to the causes underlying hunger and the food crisis (social, economic and political discrimination and exclusion has gone largely unheeded. The first Millennium Development Goal, which called for cutting the percentage of hungry people by half by 2015, is clearly out of reach. But the food crisis might lead to a new world food order.

  17. How much is too much? (Part 1) International Olympic Committee consensus statement on load in sport and risk of injury

    NARCIS (Netherlands)

    Soligard, Torbjørn; Schwellnus, Martin; Alonso, Juan-Manuel; Bahr, Roald; Clarsen, Ben; Dijkstra, H. Paul; Gabbett, Tim; Gleeson, Michael; Hägglund, Martin; Hutchinson, Mark R.; Janse van Rensburg, Christa; Khan, Karim M.; Meeusen, Romain; Orchard, John W.; Pluim, Babette M.; Raftery, Martin; Budgett, Richard; Engebretsen, Lars

    2016-01-01

    Athletes participating in elite sports are exposed to high training loads and increasingly saturated competition calendars. Emerging evidence indicates that poor load management is a major risk factor for injury. The International Olympic Committee convened an expert group to review the scientific

  18. Time-lapse imaging of neuroblastoma cells to determine cell fate upon gene knockdown.

    Directory of Open Access Journals (Sweden)

    Richa Batra

    Full Text Available Neuroblastoma is the most common extra-cranial solid tumor of early childhood. Standard therapies are not effective in case of poor prognosis and chemotherapy resistance. To improve drug therapy, it is imperative to discover new targets that play a substantial role in tumorigenesis of neuroblastoma. The mitotic machinery is an attractive target for therapeutic interventions and inhibitors can be developed to target mitotic entry, spindle apparatus, spindle activation checkpoint, and mitotic exit. We present an elaborate analysis pipeline to determine cancer specific therapeutic targets by first performing a focused gene expression analysis to select genes followed by a gene knockdown screening assay of live cells. We interrogated gene expression studies of neuroblastoma tumors and selected 240 genes relevant for tumorigenesis and cell cycle. With these genes we performed time-lapse screening of gene knockdowns in neuroblastoma cells. We classified cellular phenotypes and used the temporal context of the perturbation effect to determine the sequence of events, particularly the mitotic entry preceding cell death. Based upon this phenotype kinetics from the gene knockdown screening, we inferred dynamic gene functions in mitosis and cell proliferation. We identified six genes (DLGAP5, DSCC1, SMO, SNRPD1, SSBP1, and UBE2C with a vital role in mitosis and these are promising therapeutic targets for neuroblastoma. Images and movies of every time point of all screened genes are available at https://ichip.bioquant.uni-heidelberg.de.

  19. LMNA knock-down affects differentiation and progression of human neuroblastoma cells.

    Directory of Open Access Journals (Sweden)

    Giovanna Maresca

    Full Text Available BACKGROUND: Neuroblastoma (NB is one of the most aggressive tumors that occur in childhood. Although genes, such as MYCN, have been shown to be involved in the aggressiveness of the disease, the identification of new biological markers is still desirable. The induction of differentiation is one of the strategies used in the treatment of neuroblastoma. A-type lamins are components of the nuclear lamina and are involved in differentiation. We studied the role of Lamin A/C in the differentiation and progression of neuroblastoma. METHODOLOGY/PRINCIPAL FINDINGS: Knock-down of Lamin A/C (LMNA-KD in neuroblastoma cells blocked retinoic acid-induced differentiation, preventing neurites outgrowth and the expression of neural markers. The genome-wide gene-expression profile and the proteomic analysis of LMNA-KD cells confirmed the inhibition of differentiation and demonstrated an increase of aggressiveness-related genes and molecules resulting in augmented migration/invasion, and increasing the drug resistance of the cells. The more aggressive phenotype acquired by LMNA-KD cells was also maintained in vivo after injection into nude mice. A preliminary immunohistochemistry analysis of Lamin A/C expression in nine primary stages human NB indicated that this protein is poorly expressed in most of these cases. CONCLUSIONS/SIGNIFICANCE: We demonstrated for the first time in neuroblastoma cells that Lamin A/C plays a central role in the differentiation, and that the loss of this protein gave rise to a more aggressive tumor phenotype.

  20. Depletion of TFAP2E attenuates adriamycin-mediated apoptosis in human neuroblastoma cells.

    Science.gov (United States)

    Hoshi, Reina; Watanabe, Yosuke; Ishizuka, Yoshiaki; Hirano, Takayuki; Nagasaki-Maeoka, Eri; Yoshizawa, Shinsuke; Uekusa, Shota; Kawashima, Hiroyuki; Ohashi, Kensuke; Sugito, Kiminobu; Fukuda, Noboru; Nagase, Hiroki; Soma, Masayoshi; Ozaki, Toshinori; Koshinaga, Tsugumichi; Fujiwara, Kyoko

    2017-04-01

    Neuroblastoma is a childhood malignancy originating from the sympathetic nervous system and accounts for approximately 15% of all pediatric cancer-related deaths. To newly identify gene(s) implicated in the progression of neuroblastoma, we investigated aberrantly methylated genomic regions in mouse skin tumors. Previously, we reported that TFAP2E, a member of activator protein-2 transcription factor family, is highly methylated within its intron and its expression is strongly suppressed in mouse skin tumors compared with the normal skin. In the present study, we analyzed public data of neuroblastoma patients and found that lower expression levels of TFAP2E are significantly associated with a shorter survival. The data indicate that TFAP2E acts as a tumor suppressor of neuroblastoma. Consistent with this notion, TFAP2E-depleted neuroblastoma NB1 and NB9 cells displayed a substantial resistance to DNA damage arising from adriamycin (ADR), cisplatin (CDDP) and ionizing radiation (IR). Silencing of TFAP2E caused a reduced ADR-induced proteolytic cleavage of caspase-3 and PARP. Of note, compared with the untransfected control cells, ADR-mediated stimulation of CDK inhibitor p21WAF1 was markedly upregulated in TFAP2E‑knocked down cells. Therefore, our present findings strongly suggest that TFAP2E has a pivotal role in the regulation of DNA damage response in NB cells through the induction of p21WAF1.

  1. Suberoylanilide hydroxamic acid sensitizes neuroblastoma to paclitaxel by inhibiting thioredoxin-related protein 14-mediated autophagy.

    Science.gov (United States)

    Zhen, Zijun; Yang, Kaibin; Ye, Litong; You, Zhiyao; Chen, Rirong; Liu, Ying; He, Youjian

    2017-07-01

    Paclitaxel is not as effective for neuroblastoma as most of the front-line chemotherapeutics due to drug resistance. This study explored the regulatory mechanism of paclitaxel-associated autophagy and potential solutions to paclitaxel resistance in neuroblastoma. The formation of autophagic vesicles was detected by scanning transmission electron microscopy and flow cytometry. The autophagy-associated proteins were assessed by western blot. Autophagy was induced and the autophagy-associated proteins LC3-I, LC3-II, Beclin 1, and thioredoxin-related protein 14 (TRP14), were found to be upregulated in neuroblastoma cells that were exposed to paclitaxel. The inhibition of Beclin 1 or TRP14 by siRNA increased the sensitivity of the tumor cells to paclitaxel. In addition, Beclin 1-mediated autophagy was regulated by TRP14. Furthermore, the TRP14 inhibitor suberoylanilide hydroxamic acid (SAHA) downregulated paclitaxel-induced autophagy and enhanced the anticancer effects of paclitaxel in normal control cancer cells but not in cells with upregulated Beclin 1 and TRP14 expression. Our findings showed that paclitaxel-induced autophagy in neuroblastoma cells was regulated by TRP14 and that SAHA could sensitize neuroblastoma cells to paclitaxel by specifically inhibiting TRP14. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  2. The Role of Intracellular Calcium for the Development and Treatment of Neuroblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Satheesh, Noothan Jyothi; Büsselberg, Dietrich, E-mail: dib2015@qatar-med.cornell.edu [Weill Cornell Medical College in Qatar, Qatar Foundation-Education City, POB 24144, Doha (Qatar)

    2015-05-22

    Neuroblastoma is the second most common paediatric cancer. It develops from undifferentiated simpatico-adrenal lineage cells and is mostly sporadic; however, the aetiology behind the development of neuroblastoma is still not fully understood. Intracellular calcium ([Ca{sup 2+}]{sub i}) is a secondary messenger which regulates numerous cellular processes and, therefore, its concentration is tightly regulated. This review focuses on the role of [Ca{sup 2+}]{sub i} in differentiation, apoptosis and proliferation in neuroblastoma. It describes the mechanisms by which [Ca{sup 2+}]{sub i} is regulated and how it modulates intracellular pathways. Furthermore, the importance of [Ca{sup 2+}]{sub i} for the function of anti-cancer drugs is illuminated in this review as [Ca{sup 2+}]{sub i} could be a target to improve the outcome of anti-cancer treatment in neuroblastoma. Overall, modulations of [Ca{sup 2+}]{sub i} could be a key target to induce apoptosis in cancer cells leading to a more efficient and effective treatment of neuroblastoma.

  3. The value of anterior displacement of the abdominal aorta in diagnosing neuroblastoma in children

    Directory of Open Access Journals (Sweden)

    Jose Luiz de Oliveira Schiavon

    Full Text Available Abstract Objective: To determine the value of anterior displacement of the abdominal aorta, when present at any level or only at the level of the adrenal gland, contralateral to the mass, in diagnosing neuroblastoma on computed tomography or magnetic resonance imaging in children up to 7 years of age. Materials and Methods: Imaging examinations of 66 patients were classified by consensus as for the presence of anterior aorta displacement and were compared with the pathology report. Results: We found anterior abdominal aorta displacement in 26 (39.39% of the 66 patients evaluated. Among those 26 patients, we identified neuroblastoma in 22 (84.62%, nephroblastoma in 3 (11.54%, and Burkitt lymphoma in 1 (3.85%. The positive predictive value was 84.62%, and the specificity was 88.24%. The displacement of the aorta was at the adrenal level, contralateral to the mass, in 14 cases, all of which were attributed to neuroblastoma. Conclusion: When the abdominal aorta is displaced at the level of the adrenal gland, contralateral to the mass, it can be said that the diagnosis is neuroblastoma, whereas abdominal aorta displacement occurring at other abdominal levels has a positive predictive value for neuroblastoma of approximately 85%.

  4. The value of anterior displacement of the abdominal aorta in diagnosing neuroblastoma in children

    Energy Technology Data Exchange (ETDEWEB)

    Schiavon, Jose Luiz de Oliveira; Caran, Eliana Maria Monteiro; Lederman, Henrique Manoel, E-mail: schiavon00@gmail.com [Universidade Federal de Sao Paulo (EPM/UNIFESP), Sao Paulo, SP (Brazil). Escola Paulista de Medicina; Odone Filho, Vicente [Universidade de Sao Paulo (FM/USP), Sao Paulo, SP (Brazil). Faculdade de Medicina

    2016-11-15

    Objective: To determine the value of anterior displacement of the abdominal aorta, when present at any level or only at the level of the adrenal gland, contralateral to the mass, in diagnosing neuroblastoma on computed tomography or magnetic resonance imaging in children up to 7 years of age. Materials and Methods: Imaging examinations of 66 patients were classified by consensus as for the presence of anterior aorta displacement and were compared with the pathology report. Results: We found anterior abdominal aorta displacement in 26 (39.39%) of the 66 patients evaluated. Among those 26 patients, we identified neuroblastoma in 22 (84.62%), nephroblastoma in 3 (11.54%), and Burkitt lymphoma in 1 (3.85%). The positive predictive value was 84.62%, and the specificity was 88.24%. The displacement of the aorta was at the adrenal level, contralateral to the mass, in 14 cases, all of which were attributed to neuroblastoma. Conclusion: When the abdominal aorta is displaced at the level of the adrenal gland, contralateral to the mass, it can be said that the diagnosis is neuroblastoma, whereas abdominal aorta displacement occurring at other abdominal levels has a positive predictive value for neuroblastoma of approximately 85%. (author)

  5. Role of the GM1 ganglioside oligosaccharide portion in the TrkA-dependent neurite sprouting in neuroblastoma cells.

    Science.gov (United States)

    Chiricozzi, Elena; Pomè, Diego Yuri; Maggioni, Margherita; Di Biase, Erika; Parravicini, Chiara; Palazzolo, Luca; Loberto, Nicoletta; Eberini, Ivano; Sonnino, Sandro

    2017-12-01

    GM1 ganglioside (II 3 NeuAc-Gg 4 Cer) is known to promote neurite formation in neuroblastoma cells by activating TrkA-MAPK pathway. The molecular mechanism by which GM1 is involved in the neurodifferentiation process is still unknown, however, in vitro and in vivo evidences have suggested that the oligosaccharide portion of this ganglioside could be involved. Here, we report that, similarly to the entire GM1 molecule, its oligosaccharide II 3 NeuAc-Gg 4, rather than its ceramide (Cer) portion is responsible for the neurodifferentiation process by augmenting neurite elongation and increasing the neurofilament protein expression in murine neuroblastoma cells, Neuro2a. Conversely, asialo-GM1, GM2 and GM3 oligosaccharides are not effective in neurite elongation on Neuro2a cells, whereas the effect exerted by the Fuc-GM1 oligosaccharide (IV 2 αFucII 3 Neu5Ac-Gg 4 ) is similar to that exerted by GM1 oligosaccharide. The neurotrophic properties of GM1 oligosaccharide are exerted by activating the TrkA receptor and the following phosphorylation cascade. By photolabeling experiments performed with a nitrophenylazide containing GM1 oligosaccharide, labeled with tritium, we showed a direct interaction between the GM1 oligosaccharide and the extracellular domain of TrkA receptor. Moreover, molecular docking analyses confirmed that GM1 oligosaccharide binds the TrkA-nerve growth factor complex leading to a binding free energy of approx. -11.5 kcal/mol, acting as a bridge able to increase and stabilize the TrkA-nerve growth factor molecular interactions. © 2017 International Society for Neurochemistry.

  6. RISK ANALYSIS AND INTERNAL CONTROL ASSESSMENT - PREMISES FOR IMPROVING MANAGEMENT AT THE LEVEL OF ROMANIAN PUBLIC ENTITIES

    Directory of Open Access Journals (Sweden)

    CRISTINA MARIA VOINEA

    2015-10-01

    Full Text Available Romania, as a European Union member state, has undergone, in recent years, a complex process of reform in all activity fields. This includes the current process of public administration reform, which aims to improve the management, the administrative capacity and the manner in which the entire Romanian public sector is organized. In this study, we intend to portray the manner in which the internal control system and the internal audit structure of a Romanian public entity are shaped into form. For exemplification, we chose the internal audit mission titled “The Accounting System and Its Reliability”. We will identify the risks, we will assess them and we will also propose measures through which the entity’s management may mitigate these risks by correcting registered deviations.

  7. Allelic loss of the short arm of chromosome 4 in neuroblastoma suggests a novel tumour suppressor gene locus

    NARCIS (Netherlands)

    Caron, H.; van Sluis, P.; Buschman, R.; Pereira do Tanque, R.; Maes, P.; Beks, L.; de Kraker, J.; Voûte, P. A.; Vergnaud, G.; Westerveld, A.; Slater, R.; Versteeg, R.

    1996-01-01

    Neuroblastoma is a childhood neural crest tumour, genetically characterized by frequent deletions of the short arm of chromosome 1 and amplification of N-myc. Here we report the first evidence for a neuroblastoma tumour suppressor locus on 4pter. Cytogenetically we demonstrated rearrangements of 4p

  8. Genome-wide DNA methylation analysis identifies MEGF10 as a novel epigenetically repressed candidate tumor suppressor gene in neuroblastoma.

    Science.gov (United States)

    Charlet, Jessica; Tomari, Ayumi; Dallosso, Anthony R; Szemes, Marianna; Kaselova, Martina; Curry, Thomas J; Almutairi, Bader; Etchevers, Heather C; McConville, Carmel; Malik, Karim T A; Brown, Keith W

    2017-04-01

    Neuroblastoma is a childhood cancer in which many children still have poor outcomes, emphasising the need to better understand its pathogenesis. Despite recent genome-wide mutation analyses, many primary neuroblastomas do not contain recognizable driver mutations, implicating alternate molecular pathologies such as epigenetic alterations. To discover genes that become epigenetically deregulated during neuroblastoma tumorigenesis, we took the novel approach of comparing neuroblastomas to neural crest precursor cells, using genome-wide DNA methylation analysis. We identified 93 genes that were significantly differentially methylated of which 26 (28%) were hypermethylated and 67 (72%) were hypomethylated. Concentrating on hypermethylated genes to identify candidate tumor suppressor loci, we found the cell engulfment and adhesion factor gene MEGF10 to be epigenetically repressed by DNA hypermethylation or by H3K27/K9 methylation in neuroblastoma cell lines. MEGF10 showed significantly down-regulated expression in neuroblastoma tumor samples; furthermore patients with the lowest-expressing tumors had reduced relapse-free survival. Our functional studies showed that knock-down of MEGF10 expression in neuroblastoma cell lines promoted cell growth, consistent with MEGF10 acting as a clinically relevant, epigenetically deregulated neuroblastoma tumor suppressor gene. © 2016 The Authors. Molecular Carcinogenesis Published by Wiley Periodicals, Inc. © 2016 The Authors. Molecular Carcinogenesis Published by Wiley Periodicals, Inc.

  9. Genome‐wide DNA methylation analysis identifies MEGF10 as a novel epigenetically repressed candidate tumor suppressor gene in neuroblastoma

    Science.gov (United States)

    Charlet, Jessica; Tomari, Ayumi; Dallosso, Anthony R.; Szemes, Marianna; Kaselova, Martina; Curry, Thomas J.; Almutairi, Bader; Etchevers, Heather C.; McConville, Carmel; Malik, Karim T. A.

    2016-01-01

    Neuroblastoma is a childhood cancer in which many children still have poor outcomes, emphasising the need to better understand its pathogenesis. Despite recent genome‐wide mutation analyses, many primary neuroblastomas do not contain recognizable driver mutations, implicating alternate molecular pathologies such as epigenetic alterations. To discover genes that become epigenetically deregulated during neuroblastoma tumorigenesis, we took the novel approach of comparing neuroblastomas to neural crest precursor cells, using genome‐wide DNA methylation analysis. We identified 93 genes that were significantly differentially methylated of which 26 (28%) were hypermethylated and 67 (72%) were hypomethylated. Concentrating on hypermethylated genes to identify candidate tumor suppressor loci, we found the cell engulfment and adhesion factor gene MEGF10 to be epigenetically repressed by DNA hypermethylation or by H3K27/K9 methylation in neuroblastoma cell lines. MEGF10 showed significantly down‐regulated expression in neuroblastoma tumor samples; furthermore patients with the lowest‐expressing tumors had reduced relapse‐free survival. Our functional studies showed that knock‐down of MEGF10 expression in neuroblastoma cell lines promoted cell growth, consistent with MEGF10 acting as a clinically relevant, epigenetically deregulated neuroblastoma tumor suppressor gene. © 2016 The Authors. Molecular Carcinogenesis Published by Wiley Periodicals, Inc. PMID:27862318

  10. FOXO3a is a major target of inactivation by PI3K/AKT signaling in aggressive neuroblastoma

    NARCIS (Netherlands)

    Santo, Evan E.; Stroeken, Peter; Sluis, Peter V.; Koster, Jan; Versteeg, Rogier; Westerhout, Ellen M.

    2013-01-01

    Neuroblastoma is a pediatric tumor of the peripheral sympathetic nervous system with a highly variable prognosis. Activation of the phosphoinositide 3-kinase (PI3K)/AKT pathway in neuroblastoma is correlated with poor patient prognosis, but the precise downstream effectors mediating this effect have

  11. 1;17 translocations and other chromosome 17 rearrangements in human primary neuroblastoma tumors and cell lines

    NARCIS (Netherlands)

    van Roy, N.; Laureys, G.; Cheng, N. C.; Willem, P.; Opdenakker, G.; Versteeg, R.; Speleman, F.

    1994-01-01

    We report on the finding of a t(1;17) in two primary neuroblastomas. Subsequent fluorescence in situ hybridization (FISH) analysis revealed the presence of 1;17 translocations in four out of nine neuroblastoma cell lines. The chromosome 1 short arm breakpoints were determined using region-specific

  12. Allelic variants of CAMTA1 and FLJ10737 within a commonly deleted region at 1p36 in neuroblastoma

    DEFF Research Database (Denmark)

    Henrich, Kai-Oliver; Claas, Andreas; Praml, Christian

    2007-01-01

    of poor outcome in neuroblastoma patients. The present study surveys CAMTA1 and FLJ10737 for genetic alterations by fluorescence-based single strand conformation polymorphism (SSCP) using a panel of DNAs from 88 neuroblastomas, their matching blood samples and 97 unaffected individuals. Nucleotide...

  13. Estimation of the Cardiovascular Risk Using World Health Organization/International Society of Hypertension (WHO/ISH Risk Prediction Charts in a Rural Population of South India

    Directory of Open Access Journals (Sweden)

    Arun Gangadhar Ghorpade

    2015-08-01

    Full Text Available Background World Health Organization/International Society of Hypertension (WHO/ISH charts have been employed to predict the risk of cardiovascular outcome in heterogeneous settings. The aim of this research is to assess the prevalence of Cardiovascular Disease (CVD risk factors and to estimate the cardiovascular risk among adults aged >40 years, utilizing the risk charts alone, and by the addition of other parameters. Methods A cross-sectional study was performed in two of the villages availing health services of a medical college. Overall 570 subjects completed the assessment. The desired information was obtained using a pretested questionnaire and participants were also subjected to anthropometric measurements and laboratory investigations. The WHO/ISH risk prediction charts for the South-East Asian region was used to assess the cardiovascular risk among the study participants. Results The study covered 570 adults aged above 40 years. The mean age of the subjects was 54.2 (±11.1 years and 53.3% subjects were women. Seventeen percent of the participants had moderate to high risk for the occurrence of cardiovascular events by using WHO/ISH risk prediction charts. In addition, CVD risk factors like smoking, alcohol, low High-Density Lipoprotein (HDL cholesterol were found in 32%, 53%, 56.3%, and 61.5% study participants, respectively. Conclusion Categorizing people as low (20% risk is one of the crucial steps to mitigate the magnitude of cardiovascular fatal/non-fatal outcome. This cross-sectional study indicates that there is a high burden of CVD risk in the rural Pondicherry as assessed by WHO/ISH risk prediction charts. Use of WHO/ISH charts is easy and inexpensive screening tool in predicting the cardiovascular event.

  14. HIV, violence, blame and shame: pathways of risk to internalized HIV stigma among South African adolescents living with HIV.

    Science.gov (United States)

    Pantelic, Marija; Boyes, Mark; Cluver, Lucie; Meinck, Franziska

    2017-08-21

    Internalized HIV stigma is a key risk factor for negative outcomes amongst adolescents living with HIV (ALHIV), including non-adherence to anti-retroviral treatment, loss-to-follow-up and morbidity. This study tested a theoretical model of multi-level risk pathways to internalized HIV stigma among South African ALHIV. From 2013 to 2015, a survey using t otal population sampling of ALHIV who had ever initiated anti-retroviral treatment (ART) in 53 public health facilities in the Eastern Cape, South Africa was conducted. Community-tracing ensured inclusion of ALHIV who were defaulting from ART or lost to follow-up. 90.1% of eligible ALHIV were interviewed ( n  = 1060, 55% female, mean age = 13.8, 21% living in rural locations). HIV stigma mechanisms (internalized, enacted, and anticipated), HIV-related disability, violence victimization (physical, emotional, sexual abuse, bullying victimization) were assessed using well-validated self-report measures. Structural equation modelling was used to test a theoretically informed model of risk pathways from HIV-related disability to internalized HIV stigma. The model controlled for age, gender and urban/rural address. Prevalence of internalized HIV stigma was 26.5%. As hypothesized, significant associations between internalized stigma and anticipated stigma, as well as depression were obtained. Unexpectedly, HIV-related disability, victimization, and enacted stigma were not directly associated with internalized stigma. Instead significant pathways were identified via anticipated HIV stigma and depression. The model fitted the data well (RMSEA = .023; CFI = .94; TLI = .95; WRMR = 1.070). These findings highlight the complicated nature of internalized HIV stigma. Whilst it is seemingly a psychological process, indirect pathways suggest multi-level mechanisms leading to internalized HIV stigma. Findings suggest that protection from violence within homes, communities and schools may interrupt risk pathways from HIV

  15. Outcomes in multifocal neuroblastoma as part of the neurocristopathy syndrome.

    Science.gov (United States)

    Williams, Phoebe; Wegner, Eva; Ziegler, David S

    2014-08-01

    The neurocristopathy syndrome occurs because of a germline mutation of the paired-like homeobox 2b (PHOX2B) gene at 4p12, a neurogenesis regulator gene. The result is abnormal neural crest cell development resulting in congenital central hypoventilation syndrome, Hirschsprung disease, and neuroblastoma (NB), which is often multifocal and disseminated in its presentation. Previously, such widespread disease was regarded as highly aggressive and treated either with palliative intent or, conversely, with very intense, high-dose chemotherapy. We now present a patient who had neurocristopathy syndrome who had multifocal NB associated with an underlying germline PHOX2B mutation. He was treated conservatively with surgery and low-dose chemotherapy. After treatment he had extensive residual disease that has continued to mature despite no further treatment. A literature review identified 26 similar patients presenting with multifocal NB as part of the neurocristopathy syndrome. In all cases the NB behaved in an indolent manner with no deaths from tumor reported when patients received appropriate treatment. These provocative findings suggest for the first time that children who have neurocristopathy-associated NB should be treated conservatively, despite the aggressive appearance of their disease. Copyright © 2014 by the American Academy of Pediatrics.

  16. Molecular mechanism of action of opioids in human neuroblastoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Yu, V.C.K.

    1987-01-01

    A series of human neuroblastoma cell lines was screened for the presence of opioid receptor sites. Of these cell lines, SK-N-SH was found to express approximately 50,000 ..mu.. and 10,000 delta opioid receptor sites/cell. In vitro characterization revealed that the binding properties of these receptor sites closely resembled those of human and rodent brain. Phosphatidylinositol turnover as a potential second messenger system for the ..mu.. receptor was examined in SK-N-SH cells. Neurotransmitter receptor systems were determined in the three sub-clones of SK-N-SH cells. Cells of the SH-SY5Y line, a phenotypically stable subclone of SK-N-SH cells, were induced to differentiate by treatment with various inducing agents, and changes of several neurotransmitter receptor systems were determined. Nerve growth factor (NGF) and retinoic acid (RA) up-regulated, while dBcAMP down-regulated opioid receptor sites. (/sup 3/H)Dopamine uptake was slightly enhanced only in RA-treated cells. Strikingly, the efficacy of PGE/sub 1/-stimulated accumulation of cAMP was enhanced by 15- to 30-fold upon RA treatment.

  17. Radiotherapy of the cephalic segment in patients with advanced neuroblastoma

    International Nuclear Information System (INIS)

    Weltman, Eduardo

    1995-01-01

    Although the treatment results have significantly improved for several pediatric malignant neoplasms, particularly Wilms's tumor, lymphomas and leukemia, in the last decade, the prognosis of the INSS, stage 4 neuroblastoma over one year one old patients remains poor. Even for the more advanced centers, using the more aggressive treatment schedules, such as bone marrow transplantation, the probability of a 2 year progression free interval varies from 6 to 50% and at 3 to 6 years, from 13 to 54%. Thereby, at least, 46 to 94% of these patients are expected to die due to the merciless neoplasm progression. The hypothesis here to be tested is regarding the impact of the cephalic irradiation on the outcome of stage 4 patients with skull metastasis at diagnosis. The end point was to establish, under the NEURO-III-85 protocol chemotherapy schedule, the possible benefit of this radiotherapy in preventing the cephalic recurrence, and its reflex on these patients total and diseases free survival. These results disclosed that the cephalic segment irradiation may prevent recurrences at this site. Unfortunatel