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Sample records for account individual radiosensitivity

  1. Analysis of individual differences in radiosensitivity using genome editing.

    PubMed

    Matsuura, S; Royba, E; Akutsu, S N; Yanagihara, H; Ochiai, H; Kudo, Y; Tashiro, S; Miyamoto, T

    2016-06-01

    Current standards for radiological protection of the public have been uniformly established. However, individual differences in radiosensitivity are suggested to exist in human populations, which could be caused by nucleotide variants of DNA repair genes. In order to verify if such genetic variants are responsible for individual differences in radiosensitivity, they could be introduced into cultured human cells for evaluation. This strategy would make it possible to analyse the effect of candidate nucleotide variants on individual radiosensitivity, independent of the diverse genetic background. However, efficient gene targeting in cultured human cells is difficult due to the low frequency of homologous recombination (HR) repair. The development of artificial nucleases has enabled efficient HR-mediated genome editing to be performed in cultured human cells. A novel genome editing strategy, 'transcription activator-like effector nuclease (TALEN)-mediated two-step single base pair editing', has been developed, and this was used to introduce a nucleotide variant associated with a chromosomal instability syndrome bi-allelically into cultured human cells to demonstrate that it is the causative mutation. It is proposed that this editing technique will be useful to investigate individual radiosensitivity.

  2. Rh factor is associated with individual radiosensitivity: A cytogenetic study

    PubMed Central

    Khosravifarsani, Meysam; Monfared, Ali Shabestani; Borzoueisileh, Sajad

    2016-01-01

    Introduction Radiosensitivity is an inherent trait, associated with a raised reaction to ionizing radiation on the human body. In radiotherapy and radiation protection fields, individualization of the patient’s treatment is one of the main topics. With the goal of determining biomarkers capable of anticipating normal tissue side reactions, we studied the association between the Rh factor and radiosensitivity. Methods This experimental study was carried out from January to June 2014 among 50 normal responders with A blood group (25Rh+ and 25Rh−) between the ages of 22 and 23 in Babol, Iran. Human peripheral blood samples were taken from subjects and, using CBMN assay, the biological effects of gamma irradiation, including the frequency of micronuclei (MN) and nuclear division index (NDI), were measured. A data analysis was performed using SPSS version 18 to determine the independent and paired samples t-tests. Results A significant increment occurred in the frequency of MN in group Rh+ (196 ± 18.23) compared with Rh- (169 ± 17.11) following irradiation (p<0.001). Conclusions The Rh factor might be a predicting marker in an individual’s radiosensitivity to ionizing radiations. However, we believe that additional investigations are needed to prove this hypothesis. PMID:27757196

  3. Comparison of Individual Radiosensitivity to γ-Rays and Carbon Ions.

    PubMed

    Shim, Grace; Normil, Marie Delna; Testard, Isabelle; Hempel, William M; Ricoul, Michelle; Sabatier, Laure

    2016-01-01

    Carbon ions are an up-and-coming ion species, currently being used in charged particle radiotherapy. As it is well established that there are considerable interindividual differences in radiosensitivity in the general population that can significantly influence clinical outcomes of radiotherapy, we evaluate the degree of these differences in the context of carbon ion therapy compared with conventional radiotherapy. In this study, we evaluate individual radiosensitivity following exposure to carbon-13 ions or γ-rays in peripheral blood lymphocytes of healthy individuals based on the frequency of ionizing radiation (IR)-induced DNA double strand breaks (DSBs) that was either misrepaired or left unrepaired to form chromosomal aberrations (CAs) (simply referred to here as DSBs for brevity). Levels of DSBs were estimated from the scoring of CAs visualized with telomere/centromere-fluorescence in situ hybridization (TC-FISH). We examine radiosensitivity at the dose of 2 Gy, a routinely administered dose during fractionated radiotherapy, and we determined that a wide range of DSBs were induced by the given dose among healthy individuals, with highly radiosensitive individuals harboring more IR-induced breaks in the genome than radioresistant individuals following exposure to the same dose. Furthermore, we determined the relative effectiveness of carbon irradiation in comparison to γ-irradiation in the induction of DSBs at each studied dose (isodose effect), a quality we term "relative dose effect" (RDE). This ratio is advantageous, as it allows for simple comparison of dose-response curves. At 2 Gy, carbon irradiation was three times more effective in inducing DSBs compared with γ-irradiation (RDE of 3); these results were confirmed using a second cytogenetic technique, multicolor-FISH. We also analyze radiosensitivity at other doses (0.2-15 Gy), to represent hypo- and hyperfractionation doses and determined that RDE is dose dependent: high ratios at low doses

  4. Comparison of Individual Radiosensitivity to γ-Rays and Carbon Ions

    PubMed Central

    Shim, Grace; Normil, Marie Delna; Testard, Isabelle; Hempel, William M.; Ricoul, Michelle; Sabatier, Laure

    2016-01-01

    Carbon ions are an up-and-coming ion species, currently being used in charged particle radiotherapy. As it is well established that there are considerable interindividual differences in radiosensitivity in the general population that can significantly influence clinical outcomes of radiotherapy, we evaluate the degree of these differences in the context of carbon ion therapy compared with conventional radiotherapy. In this study, we evaluate individual radiosensitivity following exposure to carbon-13 ions or γ-rays in peripheral blood lymphocytes of healthy individuals based on the frequency of ionizing radiation (IR)-induced DNA double strand breaks (DSBs) that was either misrepaired or left unrepaired to form chromosomal aberrations (CAs) (simply referred to here as DSBs for brevity). Levels of DSBs were estimated from the scoring of CAs visualized with telomere/centromere-fluorescence in situ hybridization (TC-FISH). We examine radiosensitivity at the dose of 2 Gy, a routinely administered dose during fractionated radiotherapy, and we determined that a wide range of DSBs were induced by the given dose among healthy individuals, with highly radiosensitive individuals harboring more IR-induced breaks in the genome than radioresistant individuals following exposure to the same dose. Furthermore, we determined the relative effectiveness of carbon irradiation in comparison to γ-irradiation in the induction of DSBs at each studied dose (isodose effect), a quality we term “relative dose effect” (RDE). This ratio is advantageous, as it allows for simple comparison of dose–response curves. At 2 Gy, carbon irradiation was three times more effective in inducing DSBs compared with γ-irradiation (RDE of 3); these results were confirmed using a second cytogenetic technique, multicolor-FISH. We also analyze radiosensitivity at other doses (0.2–15 Gy), to represent hypo- and hyperfractionation doses and determined that RDE is dose dependent: high ratios at low

  5. Report on Federal Individual Training Accounts.

    ERIC Educational Resources Information Center

    President's Task Force on Federal Training Technology, Washington, DC.

    To explore options to establish Federal Individual Training Accounts (ITAs), a study reviewed Pennsylvania's Individual Learning Accounts, Cedar Company's Individual Learning Accounts, ITAs under the Workforce Investment Act, and the United Kingdom's Individual Learning Accounts. ITAs were defined as a base amount of resources--dollars or…

  6. Evidence for predictive validity of blood assays to evaluate individual radiosensitivity

    SciTech Connect

    Severin, Erhard . E-mail: severie@uni-muenster.de; Greve, Burkhard; Pascher, Elke; Wedemeyer, Niels; Hacker-Klom, Ursula; Silling, Gerda; Kienast, Joachim; Willich, Normann; Goehde, Wolfgang

    2006-01-01

    Purpose: An escalation in standard irradiation dose ensuring improved local tumor control is estimated, but this strategy would require the exclusion of the most sensitive individuals from treatment. Therefore, fast and reliable assays for prediction of the individual radiosensitivity are urgently required. Methods and Materials: Seven parameters in lymphocytes of 40 patients with leukemia were analyzed before, during, and after total body irradiation (TBI) and in vitro X-ray irradiation. These were: cell proliferation, nuclear damage, activation of cytokines, and numbers of total leukocytes of CD34+ hematopoietic blood stem cells and of CD4+ and CD8+ lymphocytes. Additionally, antioxidative capacity of blood plasma, uric acid, and hemoglobin levels were measured. Blood samples of 67 healthy donors were used as controls. Results: In vivo and in vitro irradiations showed comparable results. A dose-response relationship was found for most parameters. Three parameters were associated with severe acute oral mucositis (Grade 3 or 4 vs. Grade 0 to 2): leukocytes fewer than 6200/{mu}L after 4 Gy TBI, a rate of >19% lymphocytes with reduced DNA and protein content ('necroses') after 4 Gy in vitro irradiation, and a small antioxidative capacity in blood plasma (<0.68 mMol) after 8 Gy TBI. Conclusion: Three simple blood assays were associated with oral mucositis that are posed here hypothetically as an early symptom of enhanced radiosensitivity in leukemic patients: leukocyte count, damaged lymphocyte score, and the antioxidative capacity after exposure.

  7. Chromosomal radiosensitivity during the G2 cell-cycle period of skin fibroblasts from individuals with familial cancer

    SciTech Connect

    Parshad, R.; Sanford, K.K.; Jones, G.M.

    1985-08-01

    The authors reported previously that human cells after neoplastic transformation in culture had acquired an increased susceptibility to chromatid damage induced by x-irradiation during the G2 phase of the cell cycle. Evidence suggested that this results from deficient DNA repair during G2 phase. Cells derived from human tumors also showed enhanced G2-phase chromosomal radiosensitivity. Furthermore, skin fibroblasts from individuals with genetic diseases predisposing to a high risk of cancer, including ataxia-telangiectasia, Bloom syndrome, Fanconi anemia, and xeroderma pigmentosum exhibited enhanced G2-phase chromosomal radiosensitivity. The present study shows that apparently normal skin fibroblasts from individuals with familial cancer--i.e., from families with a history of neoplastic disease--also exhibit enhanced G2-phase chromosomal radiosensitivity. This radiosensitivity appears, therefore, to be associated with both a genetic predisposition to cancer and a malignant neoplastic state. Furthermore, enhanced G2-phase chromosomal radiosensitivity may provide the basis for an assay to detect genetic susceptibility to cancer.

  8. A Modest Proposal: The Individual Tuition Account.

    ERIC Educational Resources Information Center

    Hull, Roger H.

    1989-01-01

    A cooperative, interinstitutional plan offering individual tuition accounts based on lump-sum payments as a means of saving for college expenses is proposed as an alternative to loan options, savings bonds, and tuition futures. (MSE)

  9. 17 CFR 300.101 - Individual accounts.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 17 Commodity and Securities Exchanges 3 2013-04-01 2013-04-01 false Individual accounts. 300.101 Section 300.101 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) Schedule A to Part 285 RULES OF THE SECURITIES INVESTOR PROTECTION CORPORATION Accounts of...

  10. 17 CFR 300.101 - Individual accounts.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 17 Commodity and Securities Exchanges 3 2011-04-01 2011-04-01 false Individual accounts. 300.101 Section 300.101 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) Schedule A to Part 285 RULES OF THE SECURITIES INVESTOR PROTECTION CORPORATION Accounts of...

  11. 17 CFR 300.101 - Individual accounts.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 17 Commodity and Securities Exchanges 4 2014-04-01 2014-04-01 false Individual accounts. 300.101 Section 300.101 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) Schedule A to Part 285 RULES OF THE SECURITIES INVESTOR PROTECTION CORPORATION Accounts of...

  12. 17 CFR 300.101 - Individual accounts.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Individual accounts. 300.101 Section 300.101 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) Schedule A to Part 285 RULES OF THE SECURITIES INVESTOR PROTECTION CORPORATION Accounts of...

  13. 17 CFR 300.101 - Individual accounts.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 17 Commodity and Securities Exchanges 3 2012-04-01 2012-04-01 false Individual accounts. 300.101 Section 300.101 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) Schedule A to Part 285 RULES OF THE SECURITIES INVESTOR PROTECTION CORPORATION Accounts of...

  14. Annotated Bibliography: Perspectives on Individual Development Accounts

    ERIC Educational Resources Information Center

    Kezar, Adrianna; Yang, Hannah; Anderson, Christian K.

    2009-01-01

    During their three-year research project, the authors found that most practitioners, researchers, and policymakers in the education field were not familiar with Individual Development Accounts (IDAs) or the existing research on IDAs. Therefore, in this paper the authors compiled a list of some of the references that they found useful and that they…

  15. 26 CFR 1.408-2 - Individual retirement accounts.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 5 2014-04-01 2014-04-01 false Individual retirement accounts. 1.408-2 Section... retirement accounts. (a) In general. An individual retirement account must be a trust or a custodial account... in order to qualify as an individual retirement account. It may be established and maintained by...

  16. 26 CFR 1.408-2 - Individual retirement accounts.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 5 2011-04-01 2011-04-01 false Individual retirement accounts. 1.408-2 Section... retirement accounts. (a) In general. An individual retirement account must be a trust or a custodial account... in order to qualify as an individual retirement account. It may be established and maintained by...

  17. 26 CFR 1.408-2 - Individual retirement accounts.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 5 2012-04-01 2011-04-01 true Individual retirement accounts. 1.408-2 Section 1... retirement accounts. (a) In general. An individual retirement account must be a trust or a custodial account... in order to qualify as an individual retirement account. It may be established and maintained by...

  18. [Blood DNA Radiosensitivity May Be Predictive Marker for Efficacy of Radiation Therapy in Glioma Tumorbearing Individuals].

    PubMed

    Ivanov, S D; Korytova, L I; Yamshanov, V A; Zhabina, R M; Semenov, A L; Krasnikova, V G

    2015-01-01

    Animal and clinical studies were conducted to evaluate the association between the blood DNA radiosensitivity, assessed by determining the original S-index ex vivo, and the response of gliomas to irradiation in vivo. Possible modifications of the latter after administration of iron-containing water (ICW) in rats were also explored. The study was performed on the rats with subcutaneously implanted experimental glioma-35. The tumors were locally X-irradiated with a single 15 Gy dose as a radiation therapy (RT). ICW (60-63 mg · Fe 2+/l) was administered as a drinking water for 3 days before treatment. The animals underwent blood sampling for analysis of the DNA concentration and leukocyte count. The DNA index was estimated 24 h after RT. The S-index was evaluated within 4 h before RT. The mean initial S-index in the blood samples of glioma-bearing rats was 0.73 ± 0.05. Addition of ICW ex vivo resulted in a significantly increased S-index in a half of the samples. In general, the irradiated rats, which had been given pretreatment with ICW and demonstrated an ex vivo increase of the S-index to > 1.0, showed the most marked inhibition of tumor progression and the smallest tumor volume 25 days after irradiation. They also exhibited the lowest rate of growth and the longest survival. Determination of the biochemical S-index and evaluation of its changes ex vivo caused by ICW may be predictive of the response of experimental glioma to irradiation with radiomodification. The S-index may serve as a predictive indicator in clinic of the efficient evaluation of RT in patients with glioma.

  19. Accountable Individual Assessment for Cooperative Performance Assignments.

    ERIC Educational Resources Information Center

    Bastick, Tony

    This paper aims to make the techniques of cooperative learning more attractive to teachers by presenting a method of assessment that avoids the drawbacks associated with trying to extract valid and reliable individual marks from cooperative performances. The paper presents an easy-to-use method of assessing an individual's contribution to a…

  20. Radiosensitizers, radioprotectors, and radiation mitigators.

    PubMed

    Raviraj, Jayam; Bokkasam, Vijay Kumar; Kumar, Venkata Suneel; Reddy, Uday Shankar; Suman, Venkata

    2014-01-01

    Radiotherapy is regarded as one of the most important therapeutic modality for the treatment of malignant lesions. This field is undergoing rapid advancements in the recent times. With the use of radiosensitizers and radioprotective agents, the course of radiotherapy has improved the sensitization of tumor cells and protection of normal cells, respectively. The aim of this paper was to critically review and analyze the available compounds used as radiosensitizers, radioprotectors, and radiation mitigators. For reviewing, the author used the electronic search for the keywords 'Radiosensitizers', 'Radioprotectors', 'Radiation mitigators' on PubMed for inclusion of previously published articles and further search of reference papers on individual radiosensitizing and radioprotecting agents was done. Radiosensitizers are agents that sensitize the tumor cells to radiation. These compounds apparently promote fixation of the free radicals produced by radiation damage at the molecular level. The mechanism of action is similar to the oxygen effect, in which biochemical reactions in the damaged molecules prevent repair of the cellular radiation damage. Free radicals such as OH + are captured by the electron affinity of the radiosensitizers, rendering the molecules incapable of repair. Radioprotectors are compounds that are designed to reduce the damage in normal tissues caused by radiation. These compounds are often antioxidants and must be present before or at the time of radiation for effectiveness. Other agents, termed mitigators, may be used to minimize toxicity even after radiation has been delivered. This article tries to discuss the various aspects of radiosensitizers, radioprotectors, and radiation mitigators including the newer agents.

  1. Incorporating More Individual Accountability in Group Activities in General Chemistry

    ERIC Educational Resources Information Center

    Cox, Charles T., Jr.

    2015-01-01

    A modified model of cooperative learning known as the GIG model (for group-individual-group) designed and implemented in a large enrollment freshman chemistry course. The goal of the model is to establish a cooperative environment while emphasizing greater individual accountability using both group and individual assignments. The assignments were…

  2. Using Individualized Self-Paced Instruction When Teaching Elementary Accounting.

    ERIC Educational Resources Information Center

    Carr, Glenna D.; Echord, Barbara S.

    1981-01-01

    A study was conducted to see if junior college and high school students do as well in learning elementary accounting through an individualized self-paced approach as through the traditional teacher-led method. (CT)

  3. 78 FR 37598 - Missing Participants in Individual Account Plans

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-06-21

    ..., and the contours of diligent search requirements. DATES: Comments must be received on or before August... search.'' What ``diligent search'' requirements should apply for individual account plans? Should PBGC offer diligent search services for a fee or post on its Web site the names of private sector...

  4. Does Individual Development Account Participation Help the Poor? A Review

    ERIC Educational Resources Information Center

    Richards, Kristin V.; Thyer, Bruce A.

    2011-01-01

    Objectives: The purpose of this study is to review the current empirical research regarding the financial effects of participation in Individual Development Account (IDA) programs. Methods: Peer-reviewed outcome studies identified through electronic bibliographic databases and manual searches of article reference lists are reviewed. A total of 1…

  5. Individuals with Disabilities Education Act Reauthorization: Accountability and Personal Responsibility

    ERIC Educational Resources Information Center

    Turnbull, H. Rutherford

    2005-01-01

    The reauthorized Individuals with Disabilities Education Act (IDEA) is a school-reform law closely aligned with the No Child Left Behind Act (NCLB); a civil rights law; and a "cousin" of the 1996 welfare reform law. By imposing new or strengthened accountability expectations on students with disabilities and their parents, the…

  6. Individual Learning Accounts and Other Models of Financing Lifelong Learning

    ERIC Educational Resources Information Center

    Schuetze, Hans G.

    2007-01-01

    To answer the question "Financing what?" this article distinguishes several models of lifelong learning as well as a variety of lifelong learning activities. Several financing methods are briefly reviewed, however the principal focus is on Individual Learning Accounts (ILAs) which were seen by some analysts as a promising model for…

  7. Welfare Recipiency and Savings Outcomes in Individual Development Accounts

    ERIC Educational Resources Information Center

    Zhan, Min; Sherraden, Michael; Schreiner, Mark

    2004-01-01

    The authors examined how welfare recipiency is associated with savings outcomes in individual development accounts (IDAs), a structured savings program for low-income people. They investigated whether welfare recipients can save if they are provided with incentives. Data for this study ore from the American Dream Demonstration (ADD), the first…

  8. Chromosomes, cancer and radiosensitivity

    SciTech Connect

    Samouhos, E.

    1983-08-01

    Some specific chromosomal abnormalities are associated with certain cancers. The earliest description of such a specific association is the one of the Philadelphia chromosome and myelogenous leukemia (1960). Other congenital karyotype abnormalities are associated with specific cancers. Examples of these are Down's syndrome with leukemia and Klinefelter's syndrome with male breast cancer. Genetic diseases of increased chromosome breakage, or of defective chromosome repair, are associated with greatly increased cancer incidence. Three such diseases have been recognized: 1) Fanconi's anemia, associated with leukemias and lymphomas, 2) Bloom's syndrome, associated with acute leukemias and lymphosarcoma, and 3) ataxia telangiectasia, associated with Hodgkin's disease, leukemia, and lymphosarcomas. Ten percent of individuals with ataxia telangiectasia will develop one of these neoplasms. Individuals with certain of these syndromes display an unusually high radiosensitivity. Radiation therapy for cancers has been fatal in patients who received as low as 3000 rad. This remarkable radiosensitivity has been quantitated in cell cultures from such cases. Evidence suggests that the apparent sensitivity may reflect subnormal ability to repair radiation damage. The rapid proliferation of information in this field stems from the interdigitation of many disciplines and specialties, including cytogenetics, cell biology, molecular biology, epidemiology, radiobiology, and several others. This paper is intended for clinicians; it presents a structured analytic scheme for correlating and classifying this multidisciplinary information as it becomes available.

  9. The Impact of Individual Learning Accounts: A Study of the Early and Potential Impact of Individual Learning Accounts on Learning Providers and Learning. Research Report.

    ERIC Educational Resources Information Center

    Gray, Michael; Peters, Jane; Fletcher, Mick; Kirk, Gordon

    The impact of individual learning accounts (ILAs) on the success of learners in post-16 education sector in the United Kingdom was explored through an examination of available research on ILAs. The following were among the study's 12 messages for providers, the Department for Education and Skills, and the Individual Learning Account Centre: (1)…

  10. 5 CFR 1640.3 - Statement of individual account.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... number, and date of birth under which the account is established; (b) Retirement system coverage and... participant has a beneficiary designation on file with the TSP record keeper; (d) Contribution allocation...

  11. Accounting for taste: individual differences in preference for harmony.

    PubMed

    Palmer, Stephen E; Griscom, William S

    2013-06-01

    Although empirical research on aesthetics has had some success in explaining the average preferences of groups of observers, relatively little is known about individual differences in preference, and especially about how such differences might covary across different domains. In this study, we identified a new factor underlying aesthetic response-preference for harmonious stimuli-and examined how it varies over four domains (color, shape, spatial location, and music) across individuals with different levels of training in art and music. We found that individual preferences for harmony are strongly correlated across all four dimensions tested and decrease consistently with training in the relevant aesthetic domains. Confirmatory factor analysis revealed that cross-domain preference for harmony is well-represented as a single, unified factor, with effects separate from those of training and of common personality measures.

  12. Object Individuation and Physical Reasoning in Infancy: An Integrative Account

    ERIC Educational Resources Information Center

    Baillargeon, Renee; Stavans, Maayan; Wu, Di; Gertner, Yael; Setoh, Peipei; Kittredge, Audrey K.; Bernard, Amelie

    2012-01-01

    Much of the research on object individuation in infancy has used a task in which two different objects emerge in alternation from behind a large screen, which is then removed to reveal either one or two objects. In their seminal work, Xu and Carey (1996) found that it is typically not until the end of the first year that infants detect a violation…

  13. Process and Protest: Accounting for Individual Protest Participation

    ERIC Educational Resources Information Center

    Schussman, Alan; Soule, Sarah Anne

    2005-01-01

    Using American Citizen Participation Survey data (Verba et al. 1995a), we perform logistic regression analyses to adjudicate between three core explanations for individual protest: biographical availability, political engagement and structural availability. We calculate estimated probabilities to weigh the relative effects of these factors on the…

  14. Individual Learning Accounts: A Strategy for Lifelong Learning?

    ERIC Educational Resources Information Center

    Renkema, Albert

    2006-01-01

    Purpose: Since the end of the previous century social partners in different branches of industry have laid down measures to stimulate individual learning and competence development of workers in collective labour agreements. Special attention is given to stimulating learning demand among traditional non-participants to lifelong learning, such as…

  15. 26 CFR 54.4974-1 - Excise tax on accumulations in individual retirement accounts or annuities.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... retirement accounts or annuities. 54.4974-1 Section 54.4974-1 Internal Revenue INTERNAL REVENUE SERVICE...-1 Excise tax on accumulations in individual retirement accounts or annuities. (a) General rule. A... individual retirement account or annuity described in section 408 during the taxable year of the payee...

  16. An evacuation model accounting for elementary students' individual properties

    NASA Astrophysics Data System (ADS)

    Tang, Tie-Qiao; Chen, Liang; Guo, Ren-Yong; Shang, Hua-Yan

    2015-12-01

    In this paper, we propose a cellular automata model for pedestrian flow to investigate the effects of elementary students' individual properties on the evacuation process in a classroom with two exits. In this model, each student's route choice behavior is determined by the capacity of his current route to each exit, the distance between his current position and the corresponding exit, the repulsive interactions between his adjacent students and him, and the congestion degree near each exit; the elementary students are sorted into rational and irrational students. The simulation results show that the irrational students' proportion has significant impacts on the evacuation process and efficiency, and that all students simultaneously evacuating may be inefficient.

  17. 26 CFR 11.408(a)(2)-1 - Trustee of individual retirement accounts.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 14 2012-04-01 2012-04-01 false Trustee of individual retirement accounts. 11... TREASURY (CONTINUED) INCOME TAX (CONTINUED) TEMPORARY INCOME TAX REGULATIONS UNDER THE EMPLOYEE RETIREMENT INCOME SECURITY ACT OF 1974 § 11.408(a)(2)-1 Trustee of individual retirement accounts. A person...

  18. 26 CFR 11.408(a)(2)-1 - Trustee of individual retirement accounts.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 14 2011-04-01 2010-04-01 true Trustee of individual retirement accounts. 11... TREASURY (CONTINUED) INCOME TAX (CONTINUED) TEMPORARY INCOME TAX REGULATIONS UNDER THE EMPLOYEE RETIREMENT INCOME SECURITY ACT OF 1974 § 11.408(a)(2)-1 Trustee of individual retirement accounts. A person...

  19. 26 CFR 11.408(a)(2)-1 - Trustee of individual retirement accounts.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 14 2014-04-01 2013-04-01 true Trustee of individual retirement accounts. 11... TREASURY (CONTINUED) INCOME TAX (CONTINUED) TEMPORARY INCOME TAX REGULATIONS UNDER THE EMPLOYEE RETIREMENT INCOME SECURITY ACT OF 1974 § 11.408(a)(2)-1 Trustee of individual retirement accounts. A person...

  20. 26 CFR 11.408(a)(2)-1 - Trustee of individual retirement accounts.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 14 2010-04-01 2010-04-01 false Trustee of individual retirement accounts. 11... TREASURY (CONTINUED) INCOME TAX (CONTINUED) TEMPORARY INCOME TAX REGULATIONS UNDER THE EMPLOYEE RETIREMENT INCOME SECURITY ACT OF 1974 § 11.408(a)(2)-1 Trustee of individual retirement accounts. A person...

  1. 26 CFR 11.408(a)(2)-1 - Trustee of individual retirement accounts.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 14 2013-04-01 2013-04-01 false Trustee of individual retirement accounts. 11... TREASURY (CONTINUED) INCOME TAX (CONTINUED) TEMPORARY INCOME TAX REGULATIONS UNDER THE EMPLOYEE RETIREMENT INCOME SECURITY ACT OF 1974 § 11.408(a)(2)-1 Trustee of individual retirement accounts. A person...

  2. Nuclear 3D organization and radiosensitivity

    NASA Astrophysics Data System (ADS)

    Eidelman, Y. A.; Slanina, S. V.; Aleshchenko, A. V.; Sen’ko, O. V.; Kononkova, A. D.; Andreev, S. G.

    2017-01-01

    Current mechanisms of radiation-induced chromosomal aberration (CA) formation suggest misrepair of chromosomal lesions being in spatial proximity. In this case CAs have to depend on pattern of chromosomal contacts and on chromosome spatial organization in a cell nucleus. We were interested in whether variation of nucleus 3D organization results in difference of radiation induced CA formation frequency. Experimental data available do not provide information sufficient for definite conclusions. To have more deep insight in this issue we developed the biophysical modeling technique taking into account different levels of chromosome/nuclear organization and radiation damage of DNA and chromosomes. Computer experiments on gamma irradiation were carried out for two types of cells with different 3D organization of nuclei, preferentially peripheral and internal. CA frequencies were found to depend on spatial positioning of chromosomes within a nucleus which determines a pattern of interchromosomal contacts. For individual chromosomes this effect can be more pronounced than for genome averaged. Since significant part of aberrations, for example dicentrics, results in cell death, the proposed technique is capable of evaluating radiosensitivity of cells, both normal and cancer, with the incorporation of 3D genome information. This predictive technology allows to reduce uncertainties of prognosis of biological effects of radiation compared to phenomenological methods and may have variety of biomedical applications, in particular, in cancer radiation therapy.

  3. Asset Building in Rural Communities: The Experience of Individual Development Accounts

    ERIC Educational Resources Information Center

    Grinstein-Weiss, Michal; Curley, Jami; Charles, Pajarita

    2007-01-01

    This study examines the unique experiences of low-income rural participants in an asset building program--the Individual Development Account. Using data from the American Dream Demonstration, this study addresses three main questions: (1) What are the individual characteristics associated with saving outcomes among rural IDA participants? (2) What…

  4. Individual retirement account balances, contributions, and rollovers, 2010: the EBRI IRA database.

    PubMed

    Copeland, Craig

    2012-05-01

    In 2010, IRA owners were more likely to be male, especially those whose accounts originated from a rollover or were a SEP/SIMPLE. Among all IRA owners in the database, nearly one-half (45.8 percent) were ages 45-64. The average and median IRA account balance in 2010 was $67,438 and $17,863, respectively, while the average and median IRA individual balance (all accounts from the same person combined) was $91,864 and $25,296. Individuals with a traditional-originating from rollovers had the highest average and median balance of $123,426 and $38,138, respectively. Roth owners had the lowest average and median balance at $22,437 and $11,471. The average and median individual IRA balance increased with age through age 70. The average amount contributed to an IRA in the database was $3,335 in 2010. The average contribution was highest for accounts owned by those ages 65-69, and more contributions were made to Roth accounts than to traditional accounts (both those originating from contributions and rollovers). However, the average contribution to a traditional account was higher, at $3,517, compared with $3,240 to a Roth account. Yet, a higher overall amount was contributed to Roths ($2.3 billion for Roths compared with $1.3 billion for traditional accounts). Focusing on those owning traditional or Roth IRAs, 9.3 percent of the accounts received contributions, and 12.1 percent of the individuals owning these IRA types contributed to them in 2010. Among traditional IRA owners, 5.2 percent contributed, while 24.0 percent of those owning a Roth contributed to it during 2010. Of those individuals contributing to an IRA, 43.5 percent contributed the maximum amount. Of those contributing to a traditional IRA, 48.7 percent maxed out their contribution, while 39.3 percent did so with a Roth. The average and median account balances increased from $54,863 and $15,756 respectively in 2008 to $67,438 and $17,863 in 2010. This represents an increase of 22.9 percent in the average

  5. The Demand for Higher Education: A Static Structural Approach Accounting for Individual Heterogeneity and Nesting Patterns

    ERIC Educational Resources Information Center

    Flannery, Darragh; O'Donoghue, Cathal

    2013-01-01

    In this paper we estimate a structural model of higher education participation and labour choices in a static setting that accounts for individual heterogeneity and possible nesting structures in the decision process. We assume that young people that complete upper secondary education are faced with three choices, go to higher education, not go to…

  6. Saving for Success: Financial Education and Savings Goal Achievement in Individual Development Accounts

    ERIC Educational Resources Information Center

    Grinstead, Mary L.; Mauldin, Teresa; Sabia, Joseph J.; Koonce, Joan; Palmer, Lance

    2011-01-01

    Using microdata from the American Dream Demonstration, the current study examines factors associated with savings and savings goal achievement (indicated by a matched withdrawal) among participants of individual development account (IDA) programs. Multinomial logit results show that hours of participation in financial education programs, higher…

  7. Identification of Sensorimotor Components Accounting for Individual Variability in Zahlen-Verbindungs-Test (ZVT) Performance

    ERIC Educational Resources Information Center

    Rammsayer, Thomas H.; Stahl, Jutta

    2007-01-01

    The Zahlen-Verbindungs-Test (ZVT) represents a highly feasible measure of information-processing speed that correlates quite highly with standard psychometric tests of intelligence. The present study was designed to identify specific stages of the sensorimotor processing system that may account for individual differences in overall variability of…

  8. An Evaluation of the Individual Training Account/Eligible Training Provider Demonstration. Final Interim Report.

    ERIC Educational Resources Information Center

    D'Amico, Ronald; Martinez, Alexandria; Salzman, Jeffrey; Wagner, Robin

    In March 2000, thirteen grants were awarded as part of the Individual Training Account/Eligible Training Provider (ITA/ETP) Demonstration. In summer and fall of 2000, the grant recipients' activities were subjected to an interim evaluation. Site visits were made to each grantee to determine what ITA policies and practices were being formulated,…

  9. 75 FR 64909 - Fiduciary Requirements for Disclosure in Participant-Directed Individual Account Plans

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-10-20

    ...This document contains a final regulation under the Employee Retirement Income Security Act of 1974 (ERISA) that requires the disclosure of certain plan and investment-related information, including fee and expense information, to participants and beneficiaries in participant-directed individual account plans (e.g., 401(k) plans). This regulation is intended to ensure that all participants and......

  10. Effects of Individual Development Accounts (IDAs) on Household Wealth and Saving Taste

    ERIC Educational Resources Information Center

    Huang, Jin

    2010-01-01

    This study examines effects of individual development accounts (IDAs) on household wealth of low-income participants. Methods: This study uses longitudinal survey data from the American Dream Demonstration (ADD) involving experimental design (treatment group = 537, control group = 566). Results: Results from quantile regression analysis indicate…

  11. Poverty among adults with disabilities: barriers to promoting asset accumulation in individual development accounts.

    PubMed

    Soffer, Michal; McDonald, Katherine E; Blanck, Peter

    2010-12-01

    Adults with disabilities disproportionally experience poverty. We examine one novel strategy to promote economic well-being among adults with disabilities living in or near poverty, namely Individual Development Accounts (IDAs). IDAs are designed to help individuals save money and subsequently accumulate assets. Although adults with disabilities account for the majority of IDA participants, scant attention has been paid to their IDA saving performance. We describe the significance of accumulating assets, particularly as it relates to adults with disabilities. We then map the nature of IDA programs and analyze barriers to participation in IDAs and asset accumulation related to conflicting federal policies and a lack of sensitivity to disability-specific needs. We conclude by offering policy recommendations from our analysis, including the need to eliminate the means-tests used in welfare policies, de-linking participation in IDAs from employment status, and involving people with disabilities in designing and evaluating asset accumulation policies and programs.

  12. Accountability.

    ERIC Educational Resources Information Center

    Lashway, Larry

    1999-01-01

    This issue reviews publications that provide a starting point for principals looking for a way through the accountability maze. Each publication views accountability differently, but collectively these readings argue that even in an era of state-mandated assessment, principals can pursue proactive strategies that serve students' needs. James A.…

  13. Effects of low-level chronic irradiation on radiosensitivity of mammals: modeling and experimental studies

    NASA Astrophysics Data System (ADS)

    Smirnova, O. A.; Yonezawa, M.

    Effects of low dose rate chronic irradiation on radiosensitivity of mammals mice are studied by experimental and modeling methods Own and reference experiments show that priming chronic low-level short-term and long-term exposures to radiation induce respectively elevated radiosensitivity and lowered radiosensitivity radioresistance in mice The manifestation of these radiosensitization and radioprotection effects are respectively increased and decreased mortality of preirradiated specimens after challenge acute irradiation in comparison with those for previously unexposed ones Taking into account that the reason of the animal death in the experiments was the hematopoietic syndrome the biophysical models of the critical body system hematopoiesis are used to simulate the dynamics of the major hematopoietic lines in mice exposed to challenge acute irradiation following the chronic one Juxtaposition of the modeling results obtained and the relevant experimental data shows that the radiosensitization effect of chronic low-level short-term less than 1 month preirradiation on mice is due to increased radiosensitivity of lymphopoietic granulocytopoietic and erythropoietic systems accompanied by increased or close to the normal level radiosensitivity of thrombocytopoietic system which are induced by the above-indicated exposure In turn the radioprotection effect of chronic low-level long-term more than 1 month preirradiation on mice is caused by decreased radiosensitivity radioresistance of the granulocytopoietic system which

  14. Clonal cell populations unresponsive to radiosensitization induced by telomerase inhibition

    SciTech Connect

    Ju, Yeun-Jin; Shin, Hyun-Jin; Park, Jeong-Eun; Juhn, Kyoung-Mi; Woo, Seon Rang; Kim, Hee-Young; Han, Young-Hoon; Hwang, Sang-Gu; Hong, Sung-Hee; Kang, Chang-Mo; Yoo, Young-Do; Park, Won-Bong; Cho, Myung-Haing; Park, Gil Hong; Lee, Kee-Ho

    2010-11-12

    Research highlights: {yields} In our present manuscript, we have clearly showed an interesting but problematic obstacle of a radiosensitization strategy based on telomerase inhibition by showing that: Clonal population unresponsive to this radiosensitization occasionally arise. {yields} The telomere length of unsensitized clones was reduced, as was that of most sensitized clones. {yields} The unsensitized clones did not show chromosome end fusion which was noted in all sensitized clones. {yields} P53 status is not associated with the occurrence of unsensitized clone. {yields} Telomere end capping in unsensitized clone is operative even under telomerase deficiency. -- Abstract: A combination of a radiotherapeutic regimen with telomerase inhibition is valuable when tumor cells are to be sensitized to radiation. Here, we describe cell clones unresponsive to radiosensitization after telomere shortening. After extensive division of individual transformed clones of mTERC{sup -/-} cells, about 22% of clones were unresponsive to radiosensitization even though telomerase action was inhibited. The telomere lengths of unsensitized mTERC{sup -/-} clones were reduced, as were those of most sensitized clones. However, the unsensitized clones did not exhibit chromosomal end-to-end fusion to the extent noted in all sensitized clones. Thus, a defense mechanism preventing telomere erosion is operative even when telomeres become shorter under conditions of telomerase deficiency, and results in unresponsiveness to the radiosensitization generally mediated by telomere shortening.

  15. Problems and the potential direction of reforms for the current individual medical savings accounts in the Chinese health care system.

    PubMed

    Kong, Xiangjin; Yang, Yang; Gong, Fuqing; Zhao, Mingjie

    2012-12-01

    Individual health savings accounts are an important part of the current basic medical insurance system for urban workers in China. Since 1998 when the system of personal medical insurance accounts was first implemented, there has been considerable controversy over its function and significance within different social communities. This paper analyzes the main problems in the practical implementation of individual medical insurance accounts and discusses the social and cultural foundations for the establishment of family health savings accounts from the perspective of Chinese Confucian familism. Accordingly, it addresses the direction of the reform and the development of the current system of individual health insurance accounts in China.

  16. What is the role of individual accountability in patient safety? A multi-site ethnographic study.

    PubMed

    Aveling, Emma-Louise; Parker, Michael; Dixon-Woods, Mary

    2016-02-01

    An enduring debate concerns how responsibility for patient safety should be distributed between organisational systems and individual professionals. Though rule-based, calculus-like approaches intended to support a 'just culture' have become popular, they perpetuate an asocial and atomised account. In this article, we use insights from practice theory--which sees organisational phenomena as accomplished in everyday actions, with individual agency and structural conditions as a mutually constitutive, dynamic duality--along with contributions from the political science and ethics literature as a starting point for analysis. Presenting ethnographic data from five hospitals, three in one high-income country and two in low-income countries, we offer an empirically informed, normative rethinking of the role of personal accountability, identifying the collective nature of the healthcare enterprise and the extent to which patient safety depends on contributions from many hands. We show that moral responsibility for actions and behaviours is an irreducible element of professional practice, but that individuals are not somehow 'outside' and separate from 'systems': they create, modify and are subject to the social forces that are an inescapable feature of any organisational system; each element acts on the other. Our work illustrates starkly the structuring effects of the broader institutional and socioeconomic context on opportunities to 'be good'. These findings imply that one of the key responsibilities of organisations and wider institutions in relation to patient safety is the fostering of the conditions of moral community.

  17. [The mathematical modelling of population dynamics taking into account the adaptive behavior of individuals].

    PubMed

    Abakumov, A I

    2000-01-01

    The general approach for modelling of abundance dynamic of biological populations and communities is offered. The mechanisms of individual adaptation in changing environment are considered. The approach is detailed for population models without structure and with age structure. The property of solutions are investigated. As examples the author studies the concrete definitions of general models by analogy with models of Ricker and May. Theoretical analysis and calculations shows that survival of model population in extreme situation increases if adaptive behaviour is taking into account.

  18. Hypoxic radiosensitizers: substituted styryl derivatives.

    PubMed

    Nudelman, A; Falb, E; Odesa, Y; Shmueli-Broide, N

    1994-10-01

    A number of novel styryl epoxides, N-substituted-styryl-ethanolamines, N-mono and N,N'-bis-(2-hydroxyethyl)-cinnamamides--analogues to the known radiosensitizers RSU-1069, pimonidazole and etanidazole--display selective hypoxic radiosensitizing activity. The styryl group, especially when substituted by electron withdrawing groups, was found to be bioisosteric to the nitroimidazolyl functionality. The most active derivative 2-(2'-nitrophenyl)ethen-1-yl-oxirane 8a displayed a sensitizer enhancement ratio (SER) of 5 relative to misonidazole.

  19. Accounting for Linkage Disequilibrium in genome scans for selection without individual genotypes: the local score approach.

    PubMed

    Fariello, María Inés; Boitard, Simon; Mercier, Sabine; Robelin, David; Faraut, Thomas; Arnould, Cécile; Recoquillay, Julien; Bouchez, Olivier; Salin, Gérald; Dehais, Patrice; Gourichon, David; Leroux, Sophie; Pitel, Frédérique; Leterrier, Christine; SanCristobal, Magali

    2017-04-10

    Detecting genomic footprints of selection is an important step in the understanding of evolution. Accounting for linkage disequilibrium in genome scans increases detection power, but haplotype-based methods require individual genotypes and are not applicable on pool-sequenced samples. We propose to take advantage of the local score approach to account for linkage disequilibrium in genome scans for selection, cumulating (possibly small) signals from single markers over a genomic segment, to clearly pinpoint a selection signal. Using computer simulations, we demonstrate that this approach detects selection with higher power than several state-of-the-art single marker, windowing or haplotype-based approaches. We illustrate this on two benchmark data sets including individual genotypes, for which we obtain similar results with the local score and one haplotype-based approach. Finally, we apply the local score approach to Pool-Seq data obtained from a divergent selection experiment on behavior in quail, and obtain precise and biologically coherent selection signals: while competing methods fail to highlight any clear selection signature, our method detects several regions involving genes known to act on social responsiveness or autistic traits. Although we focus here on the detection of positive selection from multiple population data, the local score approach is general and can be applied to other genome scans for selection or other genome-wide analyses such as GWAS. This article is protected by copyright. All rights reserved.

  20. Radiosensitive Severe Combined Immunodeficiency Disease

    PubMed Central

    Dvorak, Christopher C.; Cowan, Morton J.

    2009-01-01

    Synopsis Inherited defects in components of the non-homologous end joining DNA repair mechanism produce a T-B-NK+ severe combined immunodeficiency disease (SCID) characterized by heightened sensitivity to ionizing radiation. Patients with the radiosensitive form of SCID may also have increased short- and long-term sensitivity to the alkylator-based chemotherapy regimens traditionally utilized for conditioning prior to allogeneic hematopoietic cell transplantation (HCT). Known etiologies of radiosensitive SCID include deficiencies of Artemis, DNA Ligase IV, DNA-dependent protein kinase catalytic subunit (DNA-PKcs), and Cernunnos-XLF, all of which have been treated with HCT. Because of their sensitivity to certain forms of chemotherapy, the approach to donor selection and type of conditioning regimen utilized for a radiosensitive SCID patient requires careful consideration. Significantly more research needs to be done in order to determine the long-term outcomes of radiosensitive SCID patients following HCT, as well as to discover novel non-toxic approaches to HCT that might benefit those with intrinsic radio- and chemo-sensitivity, as well as potentially all patients undergoing an HCT. PMID:20113890

  1. Individualism, collectivism and ethnic identity: cultural assumptions in accounting for caregiving behaviour in Britain.

    PubMed

    Willis, Rosalind

    2012-09-01

    Britain is experiencing the ageing of a large number of minority ethnic groups for the first time in its history, due to the post-war migration of people from the Caribbean and the Indian subcontinent. Stereotypes about a high level of provision of informal caregiving among minority ethnic groups are common in Britain, as in the US, despite quantitative studies refuting this assumption. This paper reports on a qualitative analysis of in-depth interviews with older people from five different ethnic groups about their conceptualisation of their ethnic identity, and their attributions of motivations of caregiving within their own ethnic group and in other groups. It is argued that ethnic identity becomes salient after migration and becoming a part of an ethnic minority group in the new country. Therefore, White British people who have never migrated do not have a great sense of ethnic identity. Further, a strong sense of ethnic identity is linked with identifying with the collective rather than the individual, which explains why the White British participants gave an individualist account of their motivations for informal care, whereas the minority ethnic participants gave a collectivist account of their motivations of care. Crucially, members of all ethnic groups were providing or receiving informal care, so it was the attribution and not the behaviour which differed.

  2. On differences in radiosensitivity estimation: TCP experiments versus survival curves. A theoretical study.

    PubMed

    Stavrev, Pavel; Stavreva, Nadejda; Ruggieri, Ruggero; Nahum, Alan

    2015-08-07

    We have compared two methods of estimating the cellular radiosensitivity of a heterogeneous tumour, namely, via cell-survival and via tumour control probability (TCP) pseudo-experiments. It is assumed that there exists intra-tumour variability in radiosensitivity and that the tumour consists predominantly of radiosensitive cells and a small number of radio-resistant cells.Using a multi-component, linear-quadratic (LQ) model of cell kill, a pseudo-experimental cell-survival versus dose curve is derived. This curve is then fitted with a mono-component LQ model describing the response of a homogeneous cell population. For the assumed variation in radiosensitivity it is shown that the composite pseudo-experimental survival curve is well approximated by the survival curve of cells with uniform radiosensitivity.For the same initial cell radiosensitivity distribution several pseudo-experimental TCP curves are simulated corresponding to different fractionation regimes. The TCP model used accounts for clonogen proliferation during a fractionated treatment. The set of simulated TCP curves is then fitted with a mono-component TCP model. As in the cell survival experiment the fit with a mono-component model assuming uniform radiosensitivity is shown to be highly acceptable.However, the best-fit values of cellular radiosensitivity produced via the two methods are very different. The cell-survival pseudo-experiment yields a high radiosensitivity value, while the TCP pseudo-experiment shows that the dose-response is dominated by the most resistant sub-population in the tumour, even when this is just a small fraction of the total.

  3. On differences in radiosensitivity estimation: TCP experiments versus survival curves. A theoretical study

    NASA Astrophysics Data System (ADS)

    Stavrev, Pavel; Stavreva, Nadejda; Ruggieri, Ruggero; Nahum, Alan

    2015-08-01

    We have compared two methods of estimating the cellular radiosensitivity of a heterogeneous tumour, namely, via cell-survival and via tumour control probability (TCP) pseudo-experiments. It is assumed that there exists intra-tumour variability in radiosensitivity and that the tumour consists predominantly of radiosensitive cells and a small number of radio-resistant cells. Using a multi-component, linear-quadratic (LQ) model of cell kill, a pseudo-experimental cell-survival versus dose curve is derived. This curve is then fitted with a mono-component LQ model describing the response of a homogeneous cell population. For the assumed variation in radiosensitivity it is shown that the composite pseudo-experimental survival curve is well approximated by the survival curve of cells with uniform radiosensitivity. For the same initial cell radiosensitivity distribution several pseudo-experimental TCP curves are simulated corresponding to different fractionation regimes. The TCP model used accounts for clonogen proliferation during a fractionated treatment. The set of simulated TCP curves is then fitted with a mono-component TCP model. As in the cell survival experiment the fit with a mono-component model assuming uniform radiosensitivity is shown to be highly acceptable. However, the best-fit values of cellular radiosensitivity produced via the two methods are very different. The cell-survival pseudo-experiment yields a high radiosensitivity value, while the TCP pseudo-experiment shows that the dose-response is dominated by the most resistant sub-population in the tumour, even when this is just a small fraction of the total.

  4. Investigating the Impact of Positive Resource Interdependence and Individual Accountability on Students' Academic Performance in Cooperative Learning

    ERIC Educational Resources Information Center

    Sarfo, Frederick Kwaku; Elen, Jan

    2011-01-01

    Introduction: This study addresses two major issues with respect to cooperative learning. The study aims at experimentally investigating the function of positive resource interdependence and individual accountability on academic performance of individuals in cooperative learning. Method: To achieve the purpose a two by two randomized post-test…

  5. 26 CFR 54.4974-1 - Excise tax on accumulations in individual retirement accounts or annuities.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... retirement account decides to begin receiving distributions from the account beginning in 1986. H's wife, W... the account over the joint life and last survivor expectancy of himself and his wife. On January 1... the joint life and last survivor expectancy of H and his wife is 22.0 years (see Table II of §...

  6. 26 CFR 54.4974-1 - Excise tax on accumulations in individual retirement accounts or annuities.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... retirement account decides to begin receiving distributions from the account beginning in 1986. H's wife, W... the account over the joint life and last survivor expectancy of himself and his wife. On January 1... the joint life and last survivor expectancy of H and his wife is 22.0 years (see Table II of §...

  7. 26 CFR 54.4974-1 - Excise tax on accumulations in individual retirement accounts or annuities.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... retirement account decides to begin receiving distributions from the account beginning in 1986. H's wife, W... the account over the joint life and last survivor expectancy of himself and his wife. On January 1... the joint life and last survivor expectancy of H and his wife is 22.0 years (see Table II of §...

  8. On the surviving fraction in irradiated multicellular tumour spheroids: calculation of overall radiosensitivity parameters, influence of hypoxia and volume effects.

    PubMed

    Horas, Jorge A; Olguin, Osvaldo R; Rizzotto, Marcos G

    2005-04-21

    We model the heterogeneous response to radiation of multicellular tumour spheroids assuming position- and volume-dependent radiosensitivity. We propose a method to calculate the overall radiosensitivity parameters to obtain the surviving fraction of tumours. A mathematical model of a spherical tumour with a hypoxic core and a viable rim which is a caricature of a real tumour is constructed. The model is embedded in a two-compartment linear-quadratic (LQ) model, assuming a mixed bivariated Gaussian distribution to attain the radiosensitivity parameters. Ergodicity, i.e., the equivalence between ensemble and volumetric averages is used to obtain the overall radiosensitivities for the two compartments. We obtain expressions for the overall radiosensitivity parameters resulting from the use of both a linear and a nonlinear dependence of the local radiosensitivity with position. The model's results are compared with experimental data of surviving fraction (SF) for multicellular spheroids of different sizes. We make one fit using only the smallest spheroid data and we are able to predict the SF for the larger spheroids. These predictions are acceptable particularly using bounded sensitivities. We conclude with the importance of taking into account the contribution of clonogenic hypoxic cells to radiosensitivity and with the convenience of using bounded local sensitivities to predict overall radiosensitivity parameters.

  9. Effects of an Individual Development Account Program on Retirement Saving: Follow-up Evidence From a Randomized Experiment.

    PubMed

    Grinstein-Weiss, Michal; Sherraden, Michael; Gale, William G; Rohe, William M; Schreiner, Mark; Key, Clinton; Oliphant, Jane E

    2015-01-01

    We examine the 10-year follow-up effects on retirement saving of an individual development account (IDA) program using data from a randomized experiment that ran from 1998 to 2003 in Tulsa, Oklahoma. The IDA program included financial education, encouragement to save, and matching funds for several qualified uses of the saving, including contributions to retirement accounts. The results indicate that as of 2009, 6 years after the program ended, the IDA program had no impact on the propensity to hold a retirement account, the account balance, or the sufficiency of retirement balances to meet retirement expenses.

  10. Superoxide dismutase levels in various radioresistant and radiosensitive tissues of irradiated rats.

    PubMed

    Krízala, J; Kovárová, H; Stoklasová, A; Ledvina, M

    1982-01-01

    The activity of superoxide dismutase (E.C. 1.15.1.1; SOD) was determined in male Wistar rats in order to evaluate the possible relationship between both the enzyme content in tissue and the resistance of this tissue to ionizing radiation (8,0 Gy, 60Co). Our results showed that some non-irradiated radioresistant organs (liver) had a high SOD activity and on the contrary, in some radiosensitive tissue (bone marrow) the SOD content was low. In spite of this observation it is not possible to generalize the statement that the radiosensitivity is directly conditioned by the SOD level without any exception. The SOD content in the spleen was higher than in the brain, but the spleen is remarkably radiosensitive, whereas the brain is not. The radiosensitivity of individual tissues probably reflected the changes of SOD activity after the irradiation.

  11. 29 CFR 2550.404a-3 - Safe harbor for distributions from terminated individual account plans.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ...) An interest-bearing federally insured bank or savings association account in the name of the... rate of return, whether or not such return is guaranteed, consistent with liquidity (except that distributions under paragraph (d)(1)(iii)(A) of this section to a bank or savings account are not required to...

  12. 78 FR 23827 - Designation of Eighteen Individuals Pursuant to the Sergei Magnitsky Rule of Law Accountability...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-04-22

    ...; POB Moscow, Russia (individual) . 15. UKHNALYOVA, Svetlana (a.k.a. UKHNALEV, Svetlana; a.k.a. UKHNALEVA, Svetlana V.); DOB 14 Mar 1973; POB Moscow, Russia (individual) . 16. VINOGRADOVA, Natalya V.;...

  13. 29 CFR 2578.1 - Termination of abandoned individual account plans.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... that the account balance will be invested in an investment product designed to preserve principal and... of such proceeds, and invest such proceeds in a product in which it (or an affiliate) has an...

  14. Low-Dose Radiation Cataract and Genetic Determinants of Radiosensitivity

    SciTech Connect

    Kleiman, Norman Jay

    2013-11-30

    The lens of the eye is one of the most radiosensitive tissues in the body. Ocular ionizing radiation exposure results in characteristic, dose related, progressive lens changes leading to cataract formation. While initial, early stages of lens opacification may not cause visual disability, the severity of such changes progressively increases with dose until vision is impaired and cataract extraction surgery may be required. Because of the transparency of the eye, radiation induced lens changes can easily be followed non-invasively over time. Thus, the lens provides a unique model system in which to study the effects of low dose ionizing radiation exposure in a complex, highly organized tissue. Despite this observation, considerable uncertainties remain surrounding the relationship between dose and risk of developing radiation cataract. For example, a growing number of human epidemiological findings suggest significant risk among various groups of occupationally and accidentally exposed individuals and confidence intervals that include zero dose. Nevertheless, questions remain concerning the relationship between lens opacities, visual disability, clinical cataract, threshold dose and/or the role of genetics in determining radiosensitivity. Experimentally, the response of the rodent eye to radiation is quite similar to that in humans and thus animal studies are well suited to examine the relationship between radiation exposure, genetic determinants of radiosensitivity and cataractogenesis. The current work has expanded our knowledge of the low-dose effects of X-irradiation or high-LET heavy ion exposure on timing and progression of radiation cataract and has provided new information on the genetic, molecular, biochemical and cell biological features which contribute to this pathology. Furthermore, findings have indicated that single and/or multiple haploinsufficiency for various genes involved in DNA repair and cell cycle checkpoint control, such as Atm, Brca1 or Rad9

  15. Pharmacological Ascorbate Radiosensitizes Pancreatic Cancer.

    PubMed

    Du, Juan; Cieslak, John A; Welsh, Jessemae L; Sibenaller, Zita A; Allen, Bryan G; Wagner, Brett A; Kalen, Amanda L; Doskey, Claire M; Strother, Robert K; Button, Anna M; Mott, Sarah L; Smith, Brian; Tsai, Susan; Mezhir, James; Goswami, Prabhat C; Spitz, Douglas R; Buettner, Garry R; Cullen, Joseph J

    2015-08-15

    The toxicity of pharmacologic ascorbate is mediated by the generation of H2O2 via the oxidation of ascorbate. Because pancreatic cancer cells are sensitive to H2O2 generated by ascorbate, they would also be expected to become sensitized to agents that increase oxidative damage such as ionizing radiation. The current study demonstrates that pharmacologic ascorbate enhances the cytotoxic effects of ionizing radiation as seen by decreased cell viability and clonogenic survival in all pancreatic cancer cell lines examined, but not in nontumorigenic pancreatic ductal epithelial cells. Ascorbate radiosensitization was associated with an increase in oxidative stress-induced DNA damage, which was reversed by catalase. In mice with established heterotopic and orthotopic pancreatic tumor xenografts, pharmacologic ascorbate combined with ionizing radiation decreased tumor growth and increased survival, without damaging the gastrointestinal tract or increasing systemic changes in parameters indicative of oxidative stress. Our results demonstrate the potential clinical utility of pharmacologic ascorbate as a radiosensitizer in the treatment of pancreatic cancer.

  16. Ethical Perceptions of Accounting Students in a Portuguese University: The Influence of Individual Factors and Personal Traits

    ERIC Educational Resources Information Center

    Costa, Alberto J.; Pinheiro, Margarida M.; Ribeiro, Mariana S.

    2016-01-01

    Our purpose is to empirically examine whether gender, age, work experience, and attendance of a course on ethics affect the ethical perceptions of Portuguese accounting students and analyze the influence of some individual factors that may affect their ethical decision-making. Additionally, we consider the degree of importance assigned to a list…

  17. Individual Learning Account Pilot Initiative: A Learning Tool for the 21st Century. Report to the OPM Director.

    ERIC Educational Resources Information Center

    President's Task Force on Federal Training Technology, Washington, DC.

    The U.S. Office of Personnel Management (OPM) evaluated the feasibility of individual learning accounts (ILAs) as an approach to workforce development. Thirteen federal agencies volunteered to participate in the initiative. Together, they conducted a total of 17 pilot tests. Some pilot tests included all employees in the agency. Others targeted…

  18. Long-Term Effects of Individual Development Accounts on Postsecondary Education: Follow-Up Evidence from a Randomized Experiment

    ERIC Educational Resources Information Center

    Grinstein-Weiss, Michal; Sherraden, Michael; Gale, William G.; Rohe, William M.; Schreiner, Mark; Key, Clinton

    2013-01-01

    This paper presents evidence from a randomized field experiment testing the impact of a 3-year matched savings program on educational outcomes 10 years after the start of the experiment. We examine the effect of an Individual Development Account (IDA) program on (1) educational enrollment, (2) degree completion, and (3) increased education level.…

  19. 26 CFR 301.6693-1 - Penalty for failure to provide reports and documents concerning individual retirement accounts or...

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... to reasonable cause. (2) Disclosure statements. The trustee of an individual retirement account... that such failure is due to reasonable cause. (b) Showing of reasonable cause. The penalty imposed by... satisfaction of the district director that such failure was due to reasonable cause. An affirmative showing...

  20. Accounting utility for determining individual usage of production level software systems

    NASA Technical Reports Server (NTRS)

    Garber, S. C.

    1984-01-01

    An accounting package was developed which determines the computer resources utilized by a user during the execution of a particular program and updates a file containing accumulated resource totals. The accounting package is divided into two separate programs. The first program determines the total amount of computer resources utilized by a user during the execution of a particular program. The second program uses these totals to update a file containing accumulated totals of computer resources utilized by a user for a particular program. This package is useful to those persons who have several other users continually accessing and running programs from their accounts. The package provides the ability to determine which users are accessing and running specified programs along with their total level of usage.

  1. Circadian rhythmometry of mammalian radiosensitivity

    NASA Technical Reports Server (NTRS)

    Haus, E.; Halberg, F.; Loken, M. K.; Kim, Y. S.

    1974-01-01

    In the case of human bone marrow, the largest number of mitoses is seen in the evening in diurnally active men, mitotic activity being at a minimum in the morning. The opposite pattern is observed for nocturnal animals such as rats and mice on a regimen of light during the daytime alternating with darkness during the night hours. The entirety of these rhythms plays an important role in the organism's responses to environmental stimuli, including its resistance to potentially harmful agents. Conditions under which circadian rhythms can be observed and validated by inferential statistical means are discussed while emphasizing how artifacts of the laboratory environment can be shown to obscure circadian periodic variations in radiosensitivity.

  2. 29 CFR 2578.1 - Termination of abandoned individual account plans.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... assets of the plan. (ii) Calculate benefits. Use reasonable care in calculating the benefits payable to.... A qualified termination administrator shall not have failed to use reasonable care in calculating... other than an individual. (i) Model notices. Appendices to this section contain model notices that...

  3. A Cognitive Processing Account of Individual Differences in Novice Logo Programmers' Conceptualisation and Use of Recursion.

    ERIC Educational Resources Information Center

    Gibbons, Pamela

    1995-01-01

    Describes a study that investigated individual differences in the construction of mental models of recursion in LOGO programming. The learning process was investigated from the perspective of Norman's mental models theory and employed diSessa's ontology regarding distributed, functional, and surrogate mental models, and the Luria model of brain…

  4. Analyzing Repeated Measures Data on Individuals Nested within Groups: Accounting for Dynamic Group Effects

    ERIC Educational Resources Information Center

    Bauer, Daniel J.; Gottfredson, Nisha C.; Dean, Danielle; Zucker, Robert A.

    2013-01-01

    Researchers commonly collect repeated measures on individuals nested within groups such as students within schools, patients within treatment groups, or siblings within families. Often, it is most appropriate to conceptualize such groups as dynamic entities, potentially undergoing stochastic structural and/or functional changes over time. For…

  5. 29 CFR 2550.404a-3 - Safe harbor for distributions from terminated individual account plans.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... funds shall be invested in an investment product designed to preserve principal and provide a reasonable... an investment product designed to preserve principal and provide a reasonable rate of return and... is less than the minimum amount required to be invested in an individual retirement plan...

  6. An Individual-Based Model of Zebrafish Population Dynamics Accounting for Energy Dynamics

    PubMed Central

    Beaudouin, Rémy; Goussen, Benoit; Piccini, Benjamin; Augustine, Starrlight; Devillers, James; Brion, François; Péry, Alexandre R. R.

    2015-01-01

    Developing population dynamics models for zebrafish is crucial in order to extrapolate from toxicity data measured at the organism level to biological levels relevant to support and enhance ecological risk assessment. To achieve this, a dynamic energy budget for individual zebrafish (DEB model) was coupled to an individual based model of zebrafish population dynamics (IBM model). Next, we fitted the DEB model to new experimental data on zebrafish growth and reproduction thus improving existing models. We further analysed the DEB-model and DEB-IBM using a sensitivity analysis. Finally, the predictions of the DEB-IBM were compared to existing observations on natural zebrafish populations and the predicted population dynamics are realistic. While our zebrafish DEB-IBM model can still be improved by acquiring new experimental data on the most uncertain processes (e.g. survival or feeding), it can already serve to predict the impact of compounds at the population level. PMID:25938409

  7. The analyst in action: an individual account of what Jungians do and why they do it.

    PubMed

    Colman, Warren

    2010-04-01

    This paper describes some similarities and differences between contemporary approaches to analysis as practised by 'Freudians' and 'Jungians' in London today. It aims to contribute to mutual understanding between different schools of analysis by showing how the analyst's interventions can only be understood in terms of the theoretical context from which they arise (cf. 'the analyst's preconscious', as discussed by Hamilton [1996]). A discussion of five key themes of Jungian theory is followed by an account of clinical work with a patient who enacted her inner world through the use of material objects brought to the consulting room, presenting difficult technical dilemmas concerning boundaries and enactment. The paper aims to shows how these Jungian themes influenced the analyst's response, particularly in relation to ideas of symbolic transformation, the unknowable nature of unconscious processes and the purposive orientation of the self towards wholeness and integration.

  8. Pesticide Environmental Accounting: a method for assessing the external costs of individual pesticide applications.

    PubMed

    Leach, A W; Mumford, J D

    2008-01-01

    The Pesticide Environmental Accounting (PEA) tool provides a monetary estimate of environmental and health impacts per hectare-application for any pesticide. The model combines the Environmental Impact Quotient method and a methodology for absolute estimates of external pesticide costs in UK, USA and Germany. For many countries resources are not available for intensive assessments of external pesticide costs. The model converts external costs of a pesticide in the UK, USA and Germany to Mediterranean countries. Economic and policy applications include estimating impacts of pesticide reduction policies or benefits from technologies replacing pesticides, such as sterile insect technique. The system integrates disparate data and approaches into a single logical method. The assumptions in the system provide transparency and consistency but at the cost of some specificity and precision, a reasonable trade-off for a method that provides both comparative estimates of pesticide impacts and area-based assessments of absolute impacts.

  9. Towards a new moral paradigm in health care delivery: accounting for individuals.

    PubMed

    Katz, Meir

    2010-01-01

    For years, commentators have debated how to most appropriately allocate scarce medical resources over large populations. In this paper, I abstract the major rationing schema into three general approaches: rationing by price, quantity, and prioritization. Each has both normative appeal and considerable weakness. After exploring them, I present what some commentators have termed the "moral paradigm" as an alternative to broader philosophies designed to encapsulate the universe of options available to allocators (often termed the market, professional, and political paradigms). While not itself an abstraction of any specific viable rationing scheme, it provides a strong basis for the development of a new scheme that offers considerable moral and political appeal often absent from traditionally employed rationing schema. As I explain, the moral paradigm, in its strong, absolute, and uncompromising version, is economically untenable. This paper articulates a modified version of the moral paradigm that is pluralist in nature rather than absolute. It appeals to the moral, emotional, and irrational sensibilities of each individual person. The moral paradigm, so articulated, can complement any health care delivery system that policy-makers adopt. It functions by granting individuals the ability to appeal to an administrative adjudicatory board designated for this purpose. The adjudicatory board would have the expertise and power to act in response to the complaints of individual aggrieved patients, including those complaints that stem from the moral, religious, ethical, emotional, irrational, or other subjective positions of the patient, and would have plenary power to affirm the denial of access to medical care or to mandate the provision of such care. The board must be designed to facilitate its intended function while creating structural limitations on abuse of power and other excess. I make some specific suggestions on matters of structure and function in the hope of

  10. Radiosensitivity of different tissues from carrot root at different phases of growth in culture

    SciTech Connect

    Degani, N.; Pickholtz, D.

    1980-09-01

    The present work compares the effect of ..gamma..-radiation dose and time in culture on the growth of cambium and phloem carrot (Daucus carota) root explants. It was found that the phloem is more radiosensitive than the cambium and that both tissues were more radiosensitive when irradiated on excision at the G/sub 1/ phase rather than at the end of the lag phase on the ninth day of growth in culture when cells were predominantly at the G/sub 2/ phase. The nuclear volumes of cells from both tissues were similar but were larger at the end of the more radioresistant lag phase than those of the G/sub 1/ phase on excision. However, nuclear volume could not account for the differences in radiosensitivity between either the tissues or irradiation times in culture.

  11. A random walk description of individual animal movement accounting for periods of rest

    PubMed Central

    Tilles, Paulo F. C.

    2016-01-01

    Animals do not move all the time but alternate the period of actual movement (foraging) with periods of rest (e.g. eating or sleeping). Although the existence of rest times is widely acknowledged in the literature and has even become a focus of increased attention recently, the theoretical approaches to describe animal movement by calculating the dispersal kernel and/or the mean squared displacement (MSD) rarely take rests into account. In this study, we aim to bridge this gap. We consider a composite stochastic process where the periods of active dispersal or ‘bouts’ (described by a certain baseline probability density function (pdf) of animal dispersal) alternate with periods of immobility. For this process, we derive a general equation that determines the pdf of this composite movement. The equation is analysed in detail in two special but important cases such as the standard Brownian motion described by a Gaussian kernel and the Levy flight described by a Cauchy distribution. For the Brownian motion, we show that in the large-time asymptotics the effect of rests results in a rescaling of the diffusion coefficient. The movement occurs as a subdiffusive transition between the two diffusive asymptotics. Interestingly, the Levy flight case shows similar properties, which indicates a certain universality of our findings. PMID:28018645

  12. A random walk description of individual animal movement accounting for periods of rest.

    PubMed

    Tilles, Paulo F C; Petrovskii, Sergei V; Natti, Paulo L

    2016-11-01

    Animals do not move all the time but alternate the period of actual movement (foraging) with periods of rest (e.g. eating or sleeping). Although the existence of rest times is widely acknowledged in the literature and has even become a focus of increased attention recently, the theoretical approaches to describe animal movement by calculating the dispersal kernel and/or the mean squared displacement (MSD) rarely take rests into account. In this study, we aim to bridge this gap. We consider a composite stochastic process where the periods of active dispersal or 'bouts' (described by a certain baseline probability density function (pdf) of animal dispersal) alternate with periods of immobility. For this process, we derive a general equation that determines the pdf of this composite movement. The equation is analysed in detail in two special but important cases such as the standard Brownian motion described by a Gaussian kernel and the Levy flight described by a Cauchy distribution. For the Brownian motion, we show that in the large-time asymptotics the effect of rests results in a rescaling of the diffusion coefficient. The movement occurs as a subdiffusive transition between the two diffusive asymptotics. Interestingly, the Levy flight case shows similar properties, which indicates a certain universality of our findings.

  13. A random walk description of individual animal movement accounting for periods of rest

    NASA Astrophysics Data System (ADS)

    Tilles, Paulo F. C.; Petrovskii, Sergei V.; Natti, Paulo L.

    2016-11-01

    Animals do not move all the time but alternate the period of actual movement (foraging) with periods of rest (e.g. eating or sleeping). Although the existence of rest times is widely acknowledged in the literature and has even become a focus of increased attention recently, the theoretical approaches to describe animal movement by calculating the dispersal kernel and/or the mean squared displacement (MSD) rarely take rests into account. In this study, we aim to bridge this gap. We consider a composite stochastic process where the periods of active dispersal or `bouts' (described by a certain baseline probability density function (pdf) of animal dispersal) alternate with periods of immobility. For this process, we derive a general equation that determines the pdf of this composite movement. The equation is analysed in detail in two special but important cases such as the standard Brownian motion described by a Gaussian kernel and the Levy flight described by a Cauchy distribution. For the Brownian motion, we show that in the large-time asymptotics the effect of rests results in a rescaling of the diffusion coefficient. The movement occurs as a subdiffusive transition between the two diffusive asymptotics. Interestingly, the Levy flight case shows similar properties, which indicates a certain universality of our findings.

  14. Individual account retirement plans: an analysis of the 2007 survey of consumer finances, with market adjustments to June 2009.

    PubMed

    Copeland, Craig

    2009-08-01

    LATEST SCF DATA: This Issue Brief assesses the current status of Americans' savings for retirement by examining the incidence of individual account plans among families, as well as the average amount of assets accumulated in these accounts. The 2007 Survey of Consumer Finances (SCF), the Federal Reserve Board's triennial survey of wealth, is the basis for this study, as it is a leading source of data on Americans' wealth, provides detailed information on retirement plan incidence and account balances among families, and is the latest available. ACCOUNTING FOR THE ECONOMIC DOWNTURN: While 2007 SCF is the most comprehensive and current survey of Americans' finances, its timing was unfortunate due to the significant downturn in the economy in 2008 just after the survey was released. To account for that change, this analysis provides estimates of the changes in asset values from the end of 2007 to mid-June 2009 for individual account plan balances. The account balances of the defined contribution plans and IRAs are adjusted based on the asset allocation reported within the plans by using equity market returns and bond market returns from January 1, 2008, to June 19, 2009. MEDIAN ASSET LEVELS FOR DEFINED CONTRIBUTION PLANS: Among all families with a defined contribution plan in 2007, the median (mid-point) plan balance was $31,800, up 16 percent from 2004. According to EBRI estimates, this dropped 16.4 percent (to $26,578) from year-end 2007 to mid-June 2009. Losses were higher for families with more than $100,000 a year in income (down 22 percent) or having a net worth in the top 10 percent (down 28 percent). MEDIAN ASSET LEVELS FOR IRA/KEOGH PLANS: Among all families with an IRA/Keogh plan, the median value of their plan was $34,000 in 2007, up 3 percent from 2004. EBRI estimates this median value dropped 15 percent (to $28,955) from year-end 2007 to mid-June 2009. LESS THAN HALF OF ALL FAMILIES HAVE A RETIREMENT PLAN THROUGH A CURRENT JOB: In 2007, 40.6 percent of

  15. Is interindividual variation of cellular radiosensitivity real or artifactual

    SciTech Connect

    Nakamura, N.; Sposto, R.; Kushiro, J.; Akiyama, M. )

    1991-03-01

    A recently developed dose-survival assay using human G0 T lymphocytes from peripheral blood was employed to assess possible interindividual variation of cellular radiosensitivity by comparing variability between a single test for different individuals and repeated tests for a single donor. The surviving fraction at each X-ray dose level fluctuated similarly between the two groups, and the X-ray dose required to kill 90% of the cells (D10) was 3.59 +/- 0.18 Gy (mean +/- SD) for 31 different individuals and 3.66 +/- 0.21 Gy for 28 repeated tests of one individual. Analysis of variance to compare the two sets of data showed that variation in the D10 value was not significantly greater in the former group. Analysis of D50 and D90 showed similar results. These results support the hypothesis that interindividual variation in cellular radiosensitivity is quite small, if it exists at all, as far as can be determined by the loss of colony-forming ability of irradiated G0 lymphocytes.

  16. 25 CFR 115.411 - What if the individual making a request regarding a minor's supervised account does not have any...

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ...'s supervised account does not have any verifiable photo identification? 115.411 Section 115.411... regarding a minor's supervised account does not have any verifiable photo identification? If the individual making a request regarding a minor's supervised account does not have any verifiable photo...

  17. 25 CFR 115.411 - What if the individual making a request regarding a minor's supervised account does not have any...

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ...'s supervised account does not have any verifiable photo identification? 115.411 Section 115.411... regarding a minor's supervised account does not have any verifiable photo identification? If the individual making a request regarding a minor's supervised account does not have any verifiable photo...

  18. 25 CFR 115.411 - What if the individual making a request regarding a minor's supervised account does not have any...

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ...'s supervised account does not have any verifiable photo identification? 115.411 Section 115.411... regarding a minor's supervised account does not have any verifiable photo identification? If the individual making a request regarding a minor's supervised account does not have any verifiable photo...

  19. 25 CFR 115.411 - What if the individual making a request regarding a minor's supervised account does not have any...

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ...'s supervised account does not have any verifiable photo identification? 115.411 Section 115.411... regarding a minor's supervised account does not have any verifiable photo identification? If the individual making a request regarding a minor's supervised account does not have any verifiable photo...

  20. 25 CFR 115.411 - What if the individual making a request regarding a minor's supervised account does not have any...

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ...'s supervised account does not have any verifiable photo identification? 115.411 Section 115.411... regarding a minor's supervised account does not have any verifiable photo identification? If the individual making a request regarding a minor's supervised account does not have any verifiable photo...

  1. All individuals are not created equal; accounting for interindividual variation in fitting life-history responses to toxicants.

    PubMed

    Jager, Tjalling

    2013-02-05

    The individuals of a species are not equal. These differences frustrate experimental biologists and ecotoxicologists who wish to study the response of a species (in general) to a treatment. In the analysis of data, differences between model predictions and observations on individual animals are usually treated as random measurement error around the true response. These deviations, however, are mainly caused by real differences between the individuals (e.g., differences in physiology and in initial conditions). Understanding these intraspecies differences, and accounting for them in the data analysis, will improve our understanding of the response to the treatment we are investigating and allow for a more powerful, less biased, statistical analysis. Here, I explore a basic scheme for statistical inference to estimate parameters governing stress that allows individuals to differ in their basic physiology. This scheme is illustrated using a simple toxicokinetic-toxicodynamic model and a data set for growth of the springtail Folsomia candida exposed to cadmium in food. This article should be seen as proof of concept; a first step in bringing more realism into the statistical inference for process-based models in ecotoxicology.

  2. Analysis of chromosomal radiosensitivity of healthy BRCA2 mutation carriers and non-carriers in BRCA families with the G2 micronucleus assay

    PubMed Central

    Baert, Annelot; Depuydt, Julie; Van Maerken, Tom; Poppe, Bruce; Malfait, Fransiska; Van Damme, Tim; De Nobele, Sylvia; Perletti, Gianpaolo; De Leeneer, Kim; Claes, Kathleen B.M.; Vral, Anne

    2017-01-01

    Breast cancer risk drastically increases in individuals with a heterozygous germline BRCA1 or BRCA2 mutation, while it is estimated to equal the population risk for relatives without the familial mutation (non-carriers). The aim of the present study was to use a G2 phase-specific micronucleus assay to investigate whether lymphocytes of healthy BRCA2 mutation carriers are characterized by increased radiosensitivity compared to controls without a family history of breast/ovarian cancer and how this relates to healthy non-carrier relatives. BRCA2 is active in homologous recombination, a DNA damage repair pathway, specifically active in the late S/G2 phase of the cell cycle. We found a significantly increased radiosensitivity in a cohort of healthy BRCA2 mutation carriers compared to individuals without a familial history of breast cancer (P=0.046; Mann-Whitney U test). At the individual level, 50% of healthy BRCA2 mutation carriers showed a radiosensitive phenotype (radiosensitivity score of 1 or 2), whereas 83% of the controls showed no radiosensitivity (P=0.038; one-tailed Fishers exact test). An odds ratio of 5 (95% CI, 1.07–23.47) indicated an association between the BRCA2 mutation and radiosensitivity in healthy mutation carriers. These results indicate the need for the gentle use of ionizing radiation for either diagnostic or therapeutic use in BRCA2 mutation carriers. We detected no increased radiosensitivity in the non-carrier relatives. PMID:28184943

  3. Accelerometer thresholds: Accounting for body mass reduces discrepancies between measures of physical activity for individuals with overweight and obesity.

    PubMed

    Raiber, Lilian; Christensen, Rebecca A G; Jamnik, Veronica K; Kuk, Jennifer L

    2017-01-01

    The objective of this study was to explore whether accelerometer thresholds that are adjusted to account for differences in body mass influence discrepancies between self-report and accelerometer-measured physical activity (PA) volume for individuals with overweight and obesity. We analyzed 6164 adults from the National Health and Nutrition Examination Survey between 2003-2006. Established accelerometer thresholds were adjusted to account for differences in body mass to produce a similar energy expenditure (EE) rate as individuals with normal weight. Moderate-, vigorous-, and moderate- to vigorous-intensity PA (MVPA) durations were measured using established and adjusted accelerometer thresholds and compared with self-report. Durations of self-report were longer than accelerometer-measured MVPA using established thresholds (normal weight: 57.8 ± 2.4 vs 9.0 ± 0.5 min/day, overweight: 56.1 ± 2.7 vs 7.4 ± 0.5 min/day, and obesity: 46.5 ± 2.2 vs 3.7 ± 0.3 min/day). Durations of subjective and objective PA were negatively associated with body mass index (BMI) (P < 0.05). Using adjusted thresholds increased MVPA durations, and reduced discrepancies between accelerometer and self-report measures for overweight and obese groups by 6.0 ± 0.3 min/day and 17.7 ± 0.8 min/day, respectively (P < 0.05). Using accelerometer thresholds that represent equal EE rates across BMI categories reduced the discrepancies between durations of subjective and objective PA for overweight and obese groups. However, accelerometer-measured PA generally remained shorter than durations of self-report within all BMI categories. Further research may be necessary to improve analytical approaches when using objective measures of PA for individuals with overweight or obesity.

  4. Educational Quality Is Measured by Individual Student Achievement Over Time. Mt. San Antonio College AB 1725 Model Accountability System Pilot Proposal.

    ERIC Educational Resources Information Center

    Mount San Antonio Coll., Walnut, CA.

    In December 1990, a project was begun at Mt. San Antonio College (MSAC) in Walnut, California, to develop a model accountability system based on the belief that educational quality is measured by individual achievement over time. This proposal for the Accountability Model (AM) presents information on project methodology and organization in four…

  5. RRx-001, A novel dinitroazetidine radiosensitizer.

    PubMed

    Oronsky, Bryan; Scicinski, Jan; Ning, Shoucheng; Peehl, Donna; Oronsky, Arnold; Cabrales, Pedro; Bednarski, Mark; Knox, Susan

    2016-06-01

    The 'holy grail' in radiation oncology is to improve the outcome of radiation therapy (RT) with a radiosensitizer-a systemic chemical/biochemical agent that additively or synergistically sensitizes tumor cells to radiation in the absence of significant toxicity. Similar to the oxygen effect, in which DNA bases modified by reactive oxygen species prevent repair of the cellular radiation damage, these compounds in general magnify free radical formation, leading to the permanent "fixation" of the resultant chemical change in the DNA structure. The purpose of this review is to present the origin story of the radiosensitizer, RRx-001, which emerged from the aerospace industry. The activity of RRx-001 as a chemosensitizer in multiple tumor types and disease states including malaria, hemorrhagic shock and sickle cell anemia, are the subject of future reviews.

  6. Daily rhythms of radiosensitivity of animals and several determining causes

    NASA Technical Reports Server (NTRS)

    Druzhinin, Y. P.; Malyutina, T. S.; Seraya, V. M.; Rodina, G. P.; Vatsek, A.; Rakova, A.

    1974-01-01

    Daily rhythms of radiosensitivity in rats and mice were determined by survival rates after acute total radiation at the same dosage at different times of the day. Radiosensitivity differed in animals of different species and varieties. Inbred mice exhibited one or two increases in radiosensitivity during the dark, active period of the day. These effects were attributed to periodic changes in the state of stem hematopoietic cells.

  7. Differential radiosensitivity among B cell subpopulations

    SciTech Connect

    Riggs, J.E.; Lussier, A.M.; Lee, S.K.; Appel, M.C.; Woodland, R.T.

    1988-09-15

    We have previously shown that low doses of ionizing radiation selectively impair a functionally defined B cell subpopulation. Normal mice, after exposure to 200 rad of ionizing radiation, have normal or near normal splenic plaque-forming cell responses to thymus-independent type 1 Ag, but reduced responses to thymus-independent type 2 Ag. Here, we confirm and extend the original findings by using hapten-specific serum RIA to demonstrate this differential radiosensitivity is systemic. We also examined splenocytes stained with a panel of lymphocyte surface Ag by FACS analysis to determine if these functional changes are accompanied by a physical alteration of the B cell pool of irradiated mice. Single-parameter FACS analyses demonstrate a diminution in both B cell number and the heterogeneity of membrane Ag expression within the surviving B cell pool after irradiation. In contrast, T cells are relatively radioresistant as the relative percentage of T cells in the irradiated splenocyte pool increases, whereas the heterogeneity of membrane Ag expression remains constant. Multiparameter FACS analyses indicate that B cells with the sIgM much greater than sIgD phenotype are more radiosensitive than B cells of the sIgM much less than sIgD phenotype. In addition, immunohistochemical analysis of splenic sections stained with anti-IgM or anti-IgD reveal the enhanced radiosensitivity of marginal zone B cells.

  8. TNFSF10/TRAIL regulates human T4 effector memory lymphocyte radiosensitivity and predicts radiation-induced acute and subacute dermatitis

    PubMed Central

    Baijer, Jan; Déchamps, Nathalie; Perdry, Hervé; Morales, Pablo; Kerns, Sarah; Vasilescu, Alexandre; Baulande, Sylvain; Azria, David; Roméo, Paul Henri; Schmitz, Annette

    2016-01-01

    Sensitivity of T4 effector-memory (T4EM) lymphocytes to radiation-induced apoptosis shows heritability compatible with a Mendelian mode of transmission. Using gene expression studies and flow cytometry, we show a higher TNF-Related Apoptosis Inducing Ligand (TRAIL/TNFSF10) mRNA level and a higher level of membrane bound TRAIL (mTRAIL) on radiosensitive compared to radioresistant T4EM lymphocytes. Functionally, we show that mTRAIL mediates a pro-apoptotic autocrine signaling after irradiation of T4EM lymphocytes linking mTRAIL expression to T4EM radiosensitivity. Using single marker and multimarker Family-Based Association Testing, we identified 3 SNPs in the TRAIL gene that are significantly associated with T4EM lymphocytes radiosensitivity. Among these 3 SNPs, two are also associated with acute and subacute dermatitis after radiotherapy in breast cancer indicating that T4EM lymphocytes radiosensitivity may be used to predict response to radiotherapy. Altogether, these results show that mTRAIL level regulates the response of T4EM lymphocytes to ionizing radiation and suggest that TRAIL/TNFSF10 genetic variants hold promise as markers of individual radiosensitivity. PMID:26982083

  9. Assessment of Correlation between Chromosomal Radiosensitivity of Peripheral Blood Lymphocytes after In vitro Irradiation and Normal Tissue Side Effects for Cancer Patients Undergoing Radiotherapy

    PubMed Central

    Guogytė, Kamilė; Plieskienė, Aista; Ladygienė, Rima; Vaisiūnas, Žygimantas; Sevriukova, Olga; Janušonis, Vinsas; Žiliukas, Julius

    2017-01-01

    Patients receiving identical radiation treatments experience different effects, from undetectable to severe, on normal tissues. A crucial factor of radiotherapy related side effects is individual radiosensitivity. It is difficult to spare surrounding normal tissues delivering radiation to cancer cells during radiotherapy. Therefore, it may be useful to develop a simple routine cytogenetic assay which would allow the screening of a large number of individuals for radiosensitivity optimizing tumor control rates and minimizing severe radiotherapy effects with possibility to predict risk level for developing more severe early normal tissue adverse events after irradiation. This study was conducted to assess the correlation between in vitro radiosensitivity of peripheral blood lymphocytes from cancer patients who are undergoing radiotherapy using the cytokinesis-block micronucleus (CBMN), G2 chromosomal radiosensitivity assays, and normal tissue acute side effects. The CBMN and G2 chromosomal radiosensitivity assays were performed on blood samples taken from cancer patients before radiotherapy, after first fractionation, and after radiotherapy. Acute normal tissue reactions were graded according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer. This study suggests that there is a correlation between higher frequency of micronuclei after in vitro irradiation of blood samples and higher degree of normal tissue reactions. In addition, higher number of chromatid breaks was observed in patients with more severe normal tissue reactions. This pilot study included only 5 cancer patients, and therefore, further studies with a bigger cohort are required to identify radiosensitive patients. PMID:28250908

  10. Relating Intercellular Variability in Nanoparticle Uptake with Biological Consequence: A Quantitative X-ray Fluorescence Study for Radiosensitization of Cells.

    PubMed

    Turnbull, Tyron; Douglass, Michael; Paterson, David; Bezak, Eva; Thierry, Benjamin; Kempson, Ivan

    2015-11-03

    Internalized gold nanoparticles were quantified in large numbers of individual prostate cancer cells using large area synchrotron X-ray fluorescence microscopy. Cells were also irradiated with a 6 MV linear accelerator to assess the biological consequence of radiosensitization with gold nanoparticles. A large degree of heterogeneity in nanoparticle uptake between cells resulted in influenced biological effect.

  11. Association Between Genetic Polymorphisms in the XRCC1, XRCC3, XPD, GSTM1, GSTT1, MSH2, MLH1, MSH3, and MGMT Genes and Radiosensitivity in Breast Cancer Patients

    SciTech Connect

    Mangoni, Monica; Bisanzi, Simonetta; Carozzi, Francesca; Sani, Cristina; Biti, Giampaolo; Livi, Lorenzo; Barletta, Emanuela; Costantini, Adele Seniori; Gorini, Giuseppe

    2011-09-01

    Purpose: Clinical radiosensitivity varies considerably among patients, and radiation-induced side effects developing in normal tissue can be therapy limiting. Some single nucleotide polymorphisms (SNPs) have been shown to correlate with hypersensitivity to radiotherapy. We conducted a prospective study of 87 female patients with breast cancer who received radiotherapy after breast surgery. We evaluated the association between acute skin reaction following radiotherapy and 11 genetic polymorphisms in DNA repair genes: XRCC1 (Arg399Gln and Arg194Trp), XRCC3 (Thr241Met), XPD (Asp312Asn and Lys751Gln), MSH2 (gIVS12-6T>C), MLH1 (Ile219Val), MSH3 (Ala1045Thr), MGMT (Leu84Phe), and in damage-detoxification GSTM1 and GSTT1 genes (allele deletion). Methods and Materials: Individual genetic polymorphisms were determined by polymerase chain reaction and single nucleotide primer extension for single nucleotide polymorphisms or by a multiplex polymerase chain reaction assay for deletion polymorphisms. The development of severe acute skin reaction (moist desquamation or interruption of radiotherapy due to toxicity) associated with genetic polymorphisms was modeled using Cox proportional hazards, accounting for cumulative biologically effective radiation dose. Results: Radiosensitivity developed in eight patients and was increased in carriers of variants XRCC3-241Met allele (hazard ratio [HR] unquantifiably high), MSH2 gIVS12-6nt-C allele (HR = 53.36; 95% confidence intervals [95% CI], 3.56-798.98), and MSH3-1045Ala allele (HR unquantifiably high). Carriers of XRCC1-Arg194Trp variant allele in combination with XRCC1-Arg399Gln wild-type allele had a significant risk of radiosensitivity (HR = 38.26; 95% CI, 1.19-1232.52). Conclusions: To our knowledge, this is the first report to find an association between MSH2 and MSH3 genetic variants and the development of radiosensitivity in breast cancer patients. Our findings suggest the hypothesis that mismatch repair mechanisms may be

  12. On the mechanism of salivary gland radiosensitivity

    SciTech Connect

    Konings, Antonius W.T. . E-mail: a.w.t.konings@med.rug.nl; Coppes, Rob P.; Vissink, Arjan

    2005-07-15

    Purpose: To contribute to the understanding of the enigmatic radiosensitivity of the salivary glands by analysis of appropriate literature, especially with respect to mechanisms of action of early radiation damage, and to supply information on the possibilities of amelioration of radiation damage to the salivary glands after radiotherapy of head-and-neck cancer. Methods and Materials: Selected published data on the mechanism of salivary gland radiosensitivity and radioprotection were studied and analyzed. Results: From a classical point of view, the salivary glands should not respond as rapidly to radiation as they appear to do. Next to the suggestion of massive apoptosis, the leakage of granules and subsequent lysis of acinar cells was suggested to be responsible for the acute radiation-induced function loss of the salivary glands. The main problem with these hypotheses is that recently performed assays show no cell loss during the first days after irradiation, while saliva flow is dramatically diminished. The water secretion is selectively hampered during the first days after single-dose irradiation. Literature is discussed that shows that the compromised cells suffer selective radiation damage to the plasma membrane, disturbing signal transduction primarily affecting watery secretion. Although the cellular composition of the submandibular gland and the parotid gland are different, the damage response is very alike. The acute radiation-induced function loss in both salivary glands can be ameliorated by prophylactic treatment with specific receptor agonists. Conclusions: The most probable mechanism of action, explaining the enigmatic high radiosensitivity for early effects, is selective radiation damage to the plasma membrane of the secretory cells, disturbing muscarinic receptor stimulated watery secretion. Later damage is mainly due to classical mitotic cell death of progenitor cells, leading to a hampered replacement capacity of the gland for secretory cells

  13. Taxonomic and developmental aspects of radiosensitivity

    SciTech Connect

    Harrison, F.L.; Anderson, S.L.

    1996-11-01

    Considerable information is available on the effects of radioactivity on adult and early life stages of organisms. The preponderance of data is on mortality after a single irradiation with relatively high doses. Unfortunately, because experiments were carried out under different conditions and for different time periods, the validity of comparing the results from different laxonomic groups is questionable. In general, the conclusions are that there is a relationship (1) between radioresistance to high doses of acute radiation and taxonomy of the organism, primitive forms being more radioresistant than complex vertebrates and (2) between radiosensitivity and developmental stage, early life stages being more sensitive than later stages. The first conclusion may be related to the capability of the organism to repopulate cells and to differentiate and redifferentiate them; the second to the rate of cellular division and to the degree of differentiation. In question, however, is the relevance of the responses from high levels of acute radiation to that of the responses to long-term exposure to low levels of radiation, which are ecologically of more interest. Data from studies of the effects of acute and chronic exposure on development of gametes and zygotes indicate that, for some fishes and invertebrates, responses at the cellular and molecular levels show effect levels comparable to those observed in some mammals. Acute doses between 0,05 and 0.5Cy and dose rates between 0.02 to 0.2mCy/h appear to define critical ranges in which detrimental effects on fertility are first observed in a variety of radiosensitive organisms. To better understand inherent radiosensitivity, we need more information on the ability of cells to repopulate and differentiate and to prevent or repair damage to biological critical molecules, such as DNA, because these factors may alter significantly organisms` responses to radiation.

  14. Chromosomal Radiosensitivity in Lymphocytes of Cervix Cancer Patients—Correlation with Side Effect after Radiotherapy

    NASA Astrophysics Data System (ADS)

    Wegierek-Ciuk, Aneta; Lankoff, Anna; Lisowska, Halina; Banasik-Nowak, Anna; Arabski, Michał; Kedzierawski, Piotr; Florek, Agnieszka; Wojcik, Andrzej

    2010-01-01

    It is well known that cancer patients receiving similar radiotherapy treatments differ widely in normal tissue reactions ranging from undetectable to unacceptably severe levels. Therefore, an important goal of radiobiological research is to establish a test which would allow identifying individual radiosensitivity of patients prior to radiotherapy. The aim of the presented study is to assess the relationship between lymphocyte intrinsic radiosensitivity in vitro and early reaction of normal tissue in cervix cancer patients treated by radiotherapy. The following endpoints are analyzed in vitro: frequency of micronuclei, the kinetics of DNA repair and apoptosis. Acute normal tissue reaction to radiotherapy in the skin, bladder and rectum are scored according to the EORTC/RTOG scale. Our results show a wide inter-individual variability in chromosomal radiosensitivity in vitro. The majority of patients show a Grade 0, 1 or 2 reaction for all organs studied. No statistically significant correlation has been observed between the in vitro results in lymphocytes and the degree of early normal tissue and organ reaction.

  15. Customer Choice or Business as Usual?: Promoting Innovation in the Design of WIA Training Programs Through the Individual Training Account Experiment.

    ERIC Educational Resources Information Center

    Perez-Johnson, Irma; Decker, Paul

    The Workforce Investment Act (WIA) of 1998 requires that workforce investment areas establish individual training accounts (ITAs) that provide vouchers customers can use to pay for training. The United States Department of Labor is supporting the ITA experiment, during which new customers determined to be eligible for training will be randomly…

  16. Hypoxic radiosensitization: adored and ignored.

    PubMed

    Overgaard, Jens

    2007-09-10

    Since observations from the beginning of the last century, it has become well established that solid tumors may contain oxygen-deficient hypoxic areas and that cells in such areas may cause tumors to become radioresistant. Identifying hypoxic cells in human tumors has improved by the help of new imaging and physiologic techniques, and a substantial amount of data indicates the presence of hypoxia in many types of human tumors, although with a considerable heterogeneity among individual tumors. Controlled clinical trials during the last 40 years have indicated that this source of radiation resistance can be eliminated or modified by normobaric or hyperbaric oxygen or by the use of nitroimidazoles as hypoxic radiation sensitizers. More recently, attention has been given to hypoxic cytotoxins, a group of drugs that selectively or preferably destroys cells in a hypoxic environment. An updated systematic review identified 10,108 patients in 86 randomized trials designed to modify tumor hypoxia in patients treated with curative attempted primary radiation therapy alone. Overall modification of tumor hypoxia significantly improved the effect of radiotherapy, with an odds ratio of 0.77 (95% CI, 0.71 to 0.86) for the outcome of locoregional control and with an associated significant overall survival benefit (odds ratio = 0.87; 95% CI, 0.80 to 0.95). No significant influence was found on the incidence of distant metastases or on the risk of radiation-related complications. Ample data exist to support a high level of evidence for the benefit of hypoxic modification. However, hypoxic modification still has no impact on general clinical practice.

  17. Radiosensitization in prostate cancer: mechanisms and targets

    PubMed Central

    2013-01-01

    Prostate cancer is the second most commonly diagnosed cancer in American men over the age of 45 years and is the third most common cause of cancer related deaths in American men. In 2012 it is estimated that 241,740 men will be diagnosed with prostate cancer and 28,170 men will succumb to prostate cancer. Currently, radiation therapy is one of the most common definitive treatment options for localized prostate cancer. However, significant number of patients undergoing radiation therapy will develop locally persistent/recurrent tumours. The varying response rates to radiation may be due to 1) tumor microenvironment, 2) tumor stage/grade, 3) modality used to deliver radiation, and 4) dose of radiation. Higher doses of radiation has not always proved to be effective and have been associated with increased morbidity. Compounds designed to enhance the killing effects of radiation, radiosensitizers, have been extensively investigated over the past decade. The development of radiosensitizing agents could improve survival, improve quality of life and reduce costs, thus benefiting both patients and healthcare systems. Herin, we shall review the role and mechanisms of various agents that can sensitize tumours, specifically prostate cancer. PMID:23351141

  18. Actual questions raised by nanoparticle radiosensitization

    NASA Astrophysics Data System (ADS)

    Brun, Emilie; Sicard-Roselli, Cécile

    2016-11-01

    Radiosensitization by metallic nanoparticles (NP) has been explored for more than a decade with promising results in vitro and in cellulo reported in a vast number of publications. Yet, few clinical trials are on-going. This could be related to the lack of selectivity of NP leading to massive quantities to be injected to observe an effect but also to the higher degree of complexity than first thought leading to an absence of consensus probably caused by the lack of standardization in pre-clinical studies. Given the wide panel of NP used, in terms of core nature, size, coating, not to mention of cell lines and irradiation modalities, cross-comparison of data is not a walk in the park. But only a thorough examination could help identifying the key parameters and the possible mechanisms involved. This step is crucial as it should provide guidance for designing the most efficient combination NP/radiation and rationally establishing clinical protocols. In this review, we will combine and confront cellular radiosensitization results with in vitro and numerical experiments in order to give the more recent vision of this complex phenomenon. We decided to address a few hot topics such as the influence of the incident radiation energy, the localization of NP or the so-called ;biological; effect. We will highlight that among the barriers to break down, some are not restricted to the ;nano; community: an incontestable support could be offered by the ;radiation; community in the broadest sense.

  19. Differential radiosensitivity among B cell subpopulations

    SciTech Connect

    Riggs, J.E.

    1988-01-01

    The selective radiosensitivity of sIgM >> sIgD marginal zone B cells is associated with the selective loss of B cell function. The simultaneous restoration of impaired function and recovery of these cells with time supports this premise. B cell recovery, delayed one week after irradiation, is in progress at two weeks, and virtually complete by three weeks. XID mice reveal similar recovery kinetics although there are fewer recovering cells and these bear reduced levels of Ia. This observation represents additional evidence that xid B cells are distinct from those of normal mice. The simultaneous loss, and concurrent recovery, of sIgM >> sIgD B cells and TI-2 responsiveness in irradiated mice suggests the existence of a unique B cell subpopulation possessing both phenotypes. Additional support for this hypothesis is provided by demonstrating that splenocytes, depleted of IgD{sup +} cells adoptively reconstitute this response in XID mice. The peritoneal B cell pool, which, compared to the spleen, consist of increased numbers of sIgM >> sIgD B cells, is shown to be a source of radiosensitive B cells that are TI-2 responsive. These observations represent additional evidence for an association between sIgM >> sIgD B cells and TI-2 responsiveness.

  20. Evaluation of nitrobenzimidazoles as hypoxic cell radiosensitizers

    SciTech Connect

    Wright, J.; Frank, L.R.; Bush, D.; Harrison, G.H.

    1983-07-01

    Radiobiological and pharmacokinetic assays were performed to determine the potential of 2-nitrobenzimidazole (NBI) as a hypoxic cell radiosensitizing agent. As judged by comparing survival curve slopes of Serratia marcescens irradiated under aerated and hypoxic conditions, the NBI enhancement ratio (ER) at 2 mM concentration was 2.4 +/- 0.2, compared with an oxygen enhancement ratio of 3.3 +/- 0.3. 2,5-Dinitrobenzimidazole (DNBI) was investigated in vitro; its ER was 3.0 +/- 0.3 at 4 mM concentration. Very poor tissue penetration of DNBI precluded further testing in vivo. Acute toxic signs appeared in C3H/HeJ mice following ip injection of NBI at 100 mg/kg. These would be partly attributable to the stress caused by the high pH of the injection vehicle. The LD50 was estimated to be 125-150 mg/kg. Mammary adenocarcinoma tumors grown in the flanks of these mice exhibited maximum NBI levels at 5 min postinjection (ip). Peak tumor radiosensitization occurred in the interval between 5 and 10 min postinjection. The ER for tumor regrowth delay was 2.1 +/- 0.3 following 50 mg/kg injected into mice 5 min before irradiation. Functional evaluation up to 40 days after treatment revealed no evidence of neurological deficit.

  1. Individual Genetic Susceptibility

    SciTech Connect

    Eric J. Hall

    2008-12-08

    Risk estimates derived from epidemiological studies of exposed populations, as well as the maximum permissible doses allowed for occupational exposure and exposure of the public to ionizing radiation are all based on the assumption that the human population is uniform in its radiosensitivity, except for a small number of individuals, such as ATM homozygotes who are easily identified by their clinical symptoms. The hypothesis upon which this proposal is based is that the human population is not homogeneous in radiosensitiviry, but that radiosensitive sub-groups exist which are not easy to identify. These individuals would suffer an increased incidence of detrimental radiation effects, and distort the shape of the dose response relationship. The radiosensitivity of these groups depend on the expression levels of specific proteins. The plan was to investigate the effect of 3 relatively rare, high penetrate genes available in mice, namely Atm, mRad9 & Brca1. The purpose of radiation protection is to prevent! deterministic effects of clinical significance and limit stochastic effects to acceptable levels. We plan, therefore to compare with wild type animals the radiosensitivity of mice heterozygous for each of the genes mentioned above, as well as double heterozygotes for pairs of genes, using two biological endpoints: a) Ocular cataracts as an important and relevant deterministic effect, and b) Oncogenic transformation in cultured embryo fibroblasts, as a surrogate for carcinogenesis, the most relevant stochastic effect.

  2. Change in radiosensitivity of rats during hypokinetic stress

    NASA Technical Reports Server (NTRS)

    Chernov, I. P.

    1980-01-01

    The laws governing stress modification of radiation sickness in relation to hypokinetic stress were investigated. It was found that gamma irradiation (800 rad) of rats on the third day of exposure to hypokinesia increased the radiosensitivity of the animals which was determined by the survival rate and the dynamics of body weight and the weight of some internal organs. The same radiation dose was given on the 20th day of hypokinesia and on the third day of recovery from the 20 day hypokinesia decreased the radiosensitivity of rats. It is concluded that the variations in the radiosensitivity observed may be due to a stress effect of hypokinesia.

  3. Radiosensitivity of Human Fibroblasts is Associated With Amino Acid Substitution Variants in Susceptible Genes And Correlates With The Number of Risk Alleles

    SciTech Connect

    Alsbeih, Ghazi . E-mail: galsbeih@kfshrc.edu.sa; El-Sebaie, Medhat; Al-Harbi, Najla; Al-Buhairi, Muneera; Al-Hadyan, Khaled; Al-Rajhi, Nasser

    2007-05-01

    Purpose: Genetic predictive markers of radiosensitivity are being sought for stratifying radiotherapy for cancer patients and risk assessment of radiation exposure. We hypothesized that single nucleotide polymorphisms in susceptible genes are associated with, and the number of risk alleles has incremental effect on, individual radiosensitivity. Methods and Materials: Six amino acid substitution variants (ATM 1853 Asp/Asn G>A, p53 72 Arg/Pro G>C, p21 31 Ser/Arg C>A, XRCC1 399 Arg/Gln G>A, XRCC3 241 Thr/Met C>T, and TGF{beta}1 10 Leu/Pro T>C) were genotyped by direct sequencing in 54 fibroblast strains of different radiosensitivity. Results: The clonogenic survival fraction at 2 Gy range was 0.15-0.50 (mean, 0.34, standard deviation, 0.08). The mean survival fraction at 2 Gy divided the cell strains into radiosensitive (26 cases) and normal (28 controls). A significant association was observed between the survival fraction at 2 Gy and ATM 1853 Asn, XRCC3 241 Met, and TGF{beta}1 10 Leu alleles (p = 0.05, p = 0.02, and p = 0.02, respectively). The p53 72 Arg allele showed a borderline association (p = 0.07). The number of risk alleles increased with increasing radiosensitivity, and the group comparison showed a statistically significant difference between the radiosensitive and control groups (p {<=}0.001). Conclusion: The results of our study have shown that single nucleotide polymorphisms in susceptible genes influence cellular radiation response and that the number of risk alleles has a combined effect on radiosensitivity. Individuals with multiple risk alleles could be more susceptible to radiation effects than those with fewer risk alleles. These results may have implications in predicting normal tissue reactions to radiotherapy and risk assessment of radiation exposure.

  4. Standing Out and Fitting In: A Report on a Support Group for Individuals with Asperger Syndrome Using a Personal Account

    ERIC Educational Resources Information Center

    MacLeod, Andrea; Johnston, Paula

    2007-01-01

    In this article, Andrea MacLeod, lecturer in autism studies at the University of Birmingham, and Paula Johnston, a woman with Asperger syndrome who now focuses on writing and speaking about her condition, consider the function of specialist group interventions for individuals with Asperger syndrome. These authors report on one model--a discussion…

  5. 20 CFR 903.4 - Procedures for access to records and accountings of disclosures from records, regarding individuals.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... BOARD FOR THE ENROLLMENT OF ACTUARIES ACCESS TO RECORDS Records Pertaining to Individuals § 903.4... addressed to the Executive Director, Joint Board for the Enrollment of Actuaries, c/o U.S. Department of the... Board for the Enrollment of Actuaries, 2401 E Street, NW., suite 1537, Washington, DC, between the...

  6. Radiosensitivity of cultured insect cells: II. Diptera

    SciTech Connect

    Koval, T.M.

    1983-10-01

    The radiosensitivity of five dipteran cell lines representing three mosquito genera and one fruit fly genus were examined. These lines are: (1) ATC-10, Aedes aegypti; (2) RU-TAE-14, Toxorhynchites amboinensis; (3) RU-ASE-2A, Anopheles stephensi; (4) WR69-DM-1, Drosophila melanogaster; and (5) WR69-DM-2, Drosophila melanogaster. Population doubling times for these lines range from approximately 16 to 48 hr. Diploid chromosome numbers are six for the mosquito cells and eight for the fruit fly cells D/sub 0/ values are 5.1 and 6.5 Gy for the Drosophila cell lines and 3.6, 6.2, and 10.2 Gy for the mosquito cell lines. The results of this study demonstrate that dipteran insect cells are a few times more resistant to radiation than mammalian cells, but not nearly as radioresistant as lepidopteran cells.

  7. Ganetespib radiosensitization for liver cancer therapy

    PubMed Central

    Chettiar, Sivarajan T.; Malek, Reem; Annadanam, Anvesh; Nugent, Katriana M.; Kato, Yoshinori; Wang, Hailun; Cades, Jessica A.; Taparra, Kekoa; Belcaid, Zineb; Ballew, Matthew; Manmiller, Sarah; Proia, David; Lim, Michael; Anders, Robert A.; Herman, Joseph M.; Tran, Phuoc T.

    2016-01-01

    ABSTRACT Therapies for liver cancer particularly those including radiation are still inadequate. Inhibiting the stress response machinery is an appealing anti-cancer and radiosensitizing therapeutic strategy. Heat-shock-protein-90 (HSP90) is a molecular chaperone that is a prominent effector of the stress response machinery and is overexpressed in liver cancer cells. HSP90 client proteins include critical components of pathways implicated in liver cancer cell survival and radioresistance. The effects of a novel non-geldanamycin HSP90 inhibitor, ganetespib, combined with radiation were examined on 3 liver cancer cell lines, Hep3b, HepG2 and HUH7, using in vitro assays for clonogenic survival, apoptosis, cell cycle distribution, γH2AX foci kinetics and client protein expression in pathways important for liver cancer survival and radioresistance. We then evaluated tumor growth delay and effects of the combined ganetespib-radiation treatment on tumor cell proliferation in a HepG2 hind-flank tumor graft model. Nanomolar levels of ganetespib alone exhibited liver cancer cell anti-cancer activity in vitro as shown by decreased clonogenic survival that was associated with increased apoptotic cell death, prominent G2-M arrest and marked changes in PI3K/AKT/mTOR and RAS/MAPK client protein activity. Ganetespib caused a supra-additive radiosensitization in all liver cancer cell lines at low nanomolar doses with enhancement ratios between 1.33–1.78. These results were confirmed in vivo, where the ganetespib-radiation combination therapy produced supra-additive tumor growth delay compared with either therapy by itself in HepG2 tumor grafts. Our data suggest that combined ganetespib-radiation therapy exhibits promising activity against liver cancer cells, which should be investigated in clinical studies. PMID:26980196

  8. Prediction of cellular radiosensitivity from DNA damage induced by gamma-rays and carbon ion irradiation in canine tumor cells.

    PubMed

    Wada, Seiichi; Van Khoa, Tran; Kobayashi, Yasuhiko; Funayama, Tomoo; Ogihara, Kikumi; Ueno, Shunji; Ito, Nobuhiko

    2005-11-01

    Diseases of companion animals are shifting from infectious diseases to neoplasms (cancer), and since radiation therapy is one of the effective choices available for cancer treatment, the application of radiotherapy in veterinary medicine is likely to increase. However tumor tissues have different radiosensitivities, and therefore it is important to determine the intrinsic radiosensitivity of tumors in individual patients in advance of radiotherapy. We have studied the relationship between the surviving cell fraction measured by a clonogenic assay and DNA double strand breaks detected by a comet assay under neutral conditions in three canine tumor cell lines, after gamma-ray and carbon ion irradiation. In all the cell lines, cell death assessed by the clonogenic assay was much higher following irradiation with carbon ions than with gamma-rays. The initial and residual (4 hr) DNA damage due to gamma-ray and carbon ion irradiation were higher in a radiosensitive cell line than in a radioresistant cell line. The surviving cell fraction at 2 Gy (SF2) showed a tendency for correlation with both the initial and residual DNA damage. In particular, the residual damage per Gy was significantly correlated with SF2, regardless of the type of radiation. This indicates that cellular radiosensitivity can be predicted by detection of radiation-induced residual DNA damage.

  9. Metalloporphyrins and their uses as radiosensitizers for radiation therapy

    DOEpatents

    Miura, Michiko; Slatkin, Daniel N.

    2004-07-06

    The present invention covers radiosensitizers containing as an active ingredient halogenated derivatives of boronated porphyrins containing multiple carborane cages having the structure ##STR1## which selectively accumulate in neoplastic tissue within the irradiation volume and thus can be used in cancer therapies including, but not limited to, boron neutron--capture therapy and photodynamic therapy. The present invention also covers methods for using these radiosensitizers in tumor imaging and cancer treatment.

  10. Inhibitors of Histone Deacetylases for Radiosensitization of Prostate Cancer

    DTIC Science & Technology

    2005-02-01

    AD Award Number: W81XWH-04-1-0170 TITLE: Inhibitors of Histone Deacetylases for Radiosensitization of Prostate Cancer PRINCIPAL INVESTIGATOR: Mira 0...of Histone Deacetylases for Radiosensitization W81XWH-04-1-0170 of Prostate Cancer 6. AUTHOR(S) Mira 0. Jung, Ph.D. 7. PERFORMING ORGANIZA TION NAME(S...cellular radiation sensitivity. 14. SUBJECT TERMS 15. NUMBER OF PA GES Radiation sensitivity, histone deacetylase , cytotoxicity 13 16. PRICE CODE 17

  11. Evolving systems of care: Individuals found not criminally responsible on account of mental disorder in custody of civil and forensic psychiatric services.

    PubMed

    Crocker, A G; Côté, G

    2009-09-01

    Following psychiatric deinstitutionalization and changes in involuntary civil commitment laws, many individuals with severe mental disorders have been receiving mental health services through the back door, that is, the criminal justice system. Significant changes to the section of Criminal Code of Canada dealing with individuals with mental disorders have led to significant annual increases in the number of individuals declared Not criminally responsible on account of mental disorder (NCRMD), many of whom are directed to civil psychiatric settings. The goal of the present study was to describe the psychosociocriminological and risk characteristics of individuals found NCRMD remanded to civil psychiatric hospitals (CPH) compared to a forensic psychiatric hospital (FPH). This study was conducted between October 2004 and August 2006 in the sole FPH of the province of Québec and two large CPH in the Montréal metropolitan area. The final sample for the current study consisted of 96 men: 60 from the FPH and 36 from the two CPH. Results indicate that individuals in both settings have similar psychosociocriminal profiles, including PCL-R scores, but that individuals in CPH have higher scores in the Risk subscale of the HCR-20 than do their counterparts in the FPH. This difference is due to a higher score on two items: exposure to destabilizing factors and noncompliance with remediation attempts. Results are discussed in terms of the need for civil psychiatric settings to implement risk assessment and management programs into their services, and the need for further research into forensic mental health services.

  12. Evolution of aging: individual life history trade-offs and population heterogeneity account for mortality patterns across species.

    PubMed

    Le Cunff, Y; Baudisch, A; Pakdaman, K

    2014-08-01

    A broad range of mortality patterns has been documented across species, some even including decreasing mortality over age. Whether there exist a common denominator to explain both similarities and differences in these mortality patterns remains an open question. The disposable soma theory, an evolutionary theory of aging, proposes that universal intracellular trade-offs between maintenance/lifespan and reproduction would drive aging across species. The disposable soma theory has provided numerous insights concerning aging processes in single individuals. Yet, which specific population mortality patterns it can lead to is still largely unexplored. In this article, we propose a model exploring the mortality patterns which emerge from an evolutionary process including only the disposable soma theory core principles. We adapt a well-known model of genomic evolution to show that mortality curves producing a kink or mid-life plateaus derive from a common minimal evolutionary framework. These mortality shapes qualitatively correspond to those of Drosophila melanogaster, Caenorhabditis elegans, medflies, yeasts and humans. Species evolved in silico especially differ in their population diversity of maintenance strategies, which itself emerges as an adaptation to the environment over generations. Based on this integrative framework, we also derive predictions and interpretations concerning the effects of diet changes and heat-shock treatments on mortality patterns.

  13. N-methylformamide: cytotoxic, radiosensitizer, or chemosensitizer

    SciTech Connect

    Clagett-Carr, K.; Sarosy, G.; Plowman, J.; Hoth, D.F.; Leyland-Jones, B.

    1988-05-01

    N-methylformamide (NMF), a polar solvent, is currently being evaluated by the National Cancer Institute (NCI) as an antineoplastic agent because of its activity against colon, mammary, and lung tumor xenografts. Results from preclinical studies suggest that it has radiosensitizing, chemosensitizing, and differentiating activity. Its mechanism of action remains unknown, but may involve cellular depletion of glutathione, cell membrane changes, or modulation of proto-oncogene expression. Preclinical toxicology studies conducted in mice, rats, and beagle dogs showed reversible hepatotoxicity to be dose-limiting. Clinically, NMF is administered both orally and by intravenous (IV) injection. The bioavailability with oral administration is 90% to 95%. The highest reported plasma concentration of NMF is approximately 4 mmol/L in a patient who received a dose of 2,000 mg/m2 of IV NMF. Biphasic elimination with IV NMF is seen on both the daily for five days and weekly for 3 weeks schedule. Approximately 5% to 7% of the total administered IV dose is excreted in the urine. In phase I studies, dose-limiting toxicities included reversible hepatotoxicity, a generalized malaise syndrome, and nausea and vomiting. One partial response has been reported in the 111 patients treated on phase II trials in colorectal, head and neck, and renal carcinomas. Suggestions for the future development of this drug are presented. 82 references.

  14. Lanthanum fluoride nanoparticles for radiosensitization of tumors

    NASA Astrophysics Data System (ADS)

    Kudinov, Konstantin; Bekah, Devesh; Cooper, Daniel; Shastry, Sathvik; Hill, Colin; Bradforth, Stephen; Nadeau, Jay

    2016-03-01

    Dense inorganic nanoparticles have recently been identified as promising radiosensitizers. In addition to dose enhancement through increased attenuation of ionizing radiation relative to biological tissue, scintillating nanoparticles can transfer energy to coupled photosensitizers to amplify production of reactive oxygen species, as well as provide UVvisible emission for optical imaging. Lanthanum fluoride is a transparent material that is easily prepared as nanocrystals, and which can provide radioluminescence at a number of wavelengths through simple substitution of lanthanum ions with other luminescent lanthanides. We have prepared lanthanum fluoride nanoparticles doped with cerium, terbium, or both, that have good spectral overlap with chlorine6 or Rose Bengal photosensitizer molecules. We have also developed a strategy for stable conjugation of the photosensitizers to the nanoparticle surface, allowing for high energy transfer efficiencies on a per molecule basis. Additionally, we have succeeded in making our conjugates colloidally stable under physiological conditions. Here we present our latest results, using nanoparticles and nanoparticle-photosensitizer conjugates to demonstrate radiation dose enhancement in B16 melanoma cells. The effects of nanoparticle treatment prior to 250 kVp x-ray irradiation were investigated through clonogenic survival assays and cell cycle analysis. Using a custom apparatus, we have also observed scintillation of the nanoparticles and conjugates under the same conditions that the cell samples are irradiated.

  15. Molecular Parameters of Hyperthermia for Radiosensitization

    PubMed Central

    Pandita, Tej K.; Pandita, Shruti; Bhaumik, Sukesh R.

    2011-01-01

    Hyperthermia is a potent sensitizer of cell killing by ionizing radiation (IR), however, the precise mechanism of heat-induced cell death is not yet clear. Radiosensitization can be attributed to the fact that heat is a pleiotropic damaging agent, affecting multiple cell components to varying degrees by altering protein structures, thus influencing the DNA damage response. Hyperthermia alone induces several steps associated with IR signaling in cells. For example, hyperthermia enhances ATM kinase activity and increases cellular ATM autophosphorylation. This prior activation of ATM or other components of the IR-induced signaling pathway by heat interferes with the normal IR-induced signaling required for chromosomal DNA double-strand break repair, thus resulting in increased cell killing post irradiation. Hyperthermia also induces heat shock protein 70 (HSP70) synthesis and enhances telomerase activity. HSP70 expression is associated with radioresistance. Inactivation of HSP70 and telomerase increases residual DNA DSBs post IR exposure, which correlates with increased cell killing, supporting the role of HSP70 and telomerase in IR-induced DNA damage repair. Thus, hyperthermia influences several molecular parameters involved in sensitizing tumor cells to radiation and can enhance the potential of targeted radiotherapy. PMID:19883367

  16. Homologous recombination as a potential target for caffeine radiosensitization in mammalian cells: reduced caffeine radiosensitization in XRCC2 and XRCC3 mutants.

    PubMed

    Asaad, N A; Zeng, Z C; Guan, J; Thacker, J; Iliakis, G

    2000-11-23

    The radiosensitizing effect of caffeine has been associated with the disruption of multiple DNA damage-responsive cell cycle checkpoints, but several lines of evidence also implicate inhibition of DNA repair. The role of DNA repair inhibition in caffeine radiosensitization remains uncharacterized, and it is unknown which repair process, or lesion, is affected. We show that a radiosensitive cell line, mutant for the RAD51 homolog XRCC2 and defective in homologous recombination repair (HRR), displays significantly diminished caffeine radiosensitization that can be restored by expression of XRCC2. Despite the reduced radiosensitization, caffeine effectively abrogates checkpoints in S and G2 phases in XRCC2 mutant cells indicating that checkpoint abrogation is not sufficient for radiosensitization. Another radiosensitive line, mutant for XRCC3 and defective in HRR, similarly shows reduced caffeine radiosensitization. On the other hand, a radiosensitive mutant (irs-20) of DNA-PKcs with a defect in non-homologous end-joining (NHEJ) is radiosensitized by caffeine to an extent comparable to wild-type cells. In addition, rejoining of radiation-induced DNA DSBs, that mainly reflects NHEJ, remains unaffected by caffeine in XRCC2 and XRCC3 mutants, or their wild-type counterparts. These observations suggest that caffeine targets steps in HRR but not in NHEJ and that abrogation of checkpoint response is not sufficient to explain radiosensitization. Indeed, immortalized fibroblasts from AT patients show caffeine radiosensitization despite the checkpoint defects associated with ATM mutation. We propose that caffeine radiosensitization is mediated by inhibition of stages in DNA DSB repair requiring HRR and that checkpoint disruption contributes by allowing these DSBs to transit into irreparable states. Thus, checkpoints may contribute to genomic stability by promoting error-free HRR.

  17. Homologous recombination as a potential target for caffeine radiosensitization in mammalian cells: reduced caffeine radiosensitization in XRCC2 and XRCC3 mutants

    NASA Technical Reports Server (NTRS)

    Asaad, N. A.; Zeng, Z. C.; Guan, J.; Thacker, J.; Iliakis, G.

    2000-01-01

    The radiosensitizing effect of caffeine has been associated with the disruption of multiple DNA damage-responsive cell cycle checkpoints, but several lines of evidence also implicate inhibition of DNA repair. The role of DNA repair inhibition in caffeine radiosensitization remains uncharacterized, and it is unknown which repair process, or lesion, is affected. We show that a radiosensitive cell line, mutant for the RAD51 homolog XRCC2 and defective in homologous recombination repair (HRR), displays significantly diminished caffeine radiosensitization that can be restored by expression of XRCC2. Despite the reduced radiosensitization, caffeine effectively abrogates checkpoints in S and G2 phases in XRCC2 mutant cells indicating that checkpoint abrogation is not sufficient for radiosensitization. Another radiosensitive line, mutant for XRCC3 and defective in HRR, similarly shows reduced caffeine radiosensitization. On the other hand, a radiosensitive mutant (irs-20) of DNA-PKcs with a defect in non-homologous end-joining (NHEJ) is radiosensitized by caffeine to an extent comparable to wild-type cells. In addition, rejoining of radiation-induced DNA DSBs, that mainly reflects NHEJ, remains unaffected by caffeine in XRCC2 and XRCC3 mutants, or their wild-type counterparts. These observations suggest that caffeine targets steps in HRR but not in NHEJ and that abrogation of checkpoint response is not sufficient to explain radiosensitization. Indeed, immortalized fibroblasts from AT patients show caffeine radiosensitization despite the checkpoint defects associated with ATM mutation. We propose that caffeine radiosensitization is mediated by inhibition of stages in DNA DSB repair requiring HRR and that checkpoint disruption contributes by allowing these DSBs to transit into irreparable states. Thus, checkpoints may contribute to genomic stability by promoting error-free HRR.

  18. Coculture with astrocytes reduces the radiosensitivity of glioblastoma stem-like cells and identifies additional targets for radiosensitization.

    PubMed

    Rath, Barbara H; Wahba, Amy; Camphausen, Kevin; Tofilon, Philip J

    2015-11-01

    Toward developing a model system for investigating the role of the microenvironment in the radioresistance of glioblastoma (GBM), human glioblastoma stem-like cells (GSCs) were grown in coculture with human astrocytes. Using a trans-well assay, survival analyses showed that astrocytes significantly decreased the radiosensitivity of GSCs compared to standard culture conditions. In addition, when irradiated in coculture, the initial level of radiation-induced γH2AX foci in GSCs was reduced and foci dispersal was enhanced suggesting that the presence of astrocytes influenced the induction and repair of DNA double-strand breaks. These data indicate that astrocytes can decrease the radiosensitivity of GSCs in vitro via a paracrine-based mechanism and further support a role for the microenvironment as a determinant of GBM radioresponse. Chemokine profiling of coculture media identified a number of bioactive molecules not present under standard culture conditions. The gene expression profiles of GSCs grown in coculture were significantly different as compared to GSCs grown alone. These analyses were consistent with an astrocyte-mediated modification in GSC phenotype and, moreover, suggested a number of potential targets for GSC radiosensitization that were unique to coculture conditions. Along these lines, STAT3 was activated in GSCs grown with astrocytes; the JAK/STAT3 inhibitor WP1066 enhanced the radiosensitivity of GSCs under coculture conditions and when grown as orthotopic xenografts. Further, this coculture system may also provide an approach for identifying additional targets for GBM radiosensitization.

  19. The temporal organization of processes of cell reproduction and its connection with rhythms of radiosensitivity of the body

    NASA Technical Reports Server (NTRS)

    Druzhinin, Y. P.; Romanov, Y. A.; Vatsek, A.

    1974-01-01

    Radiosensitivity of individual phases of the mitotic cycle was studied in synchronous cell cultures and in several biological objects. It was found that radiosensitivity changed essentially according to phases of the mitotic cycle, depending on the kind of cells, evaluation criteria and the radiation dosage. Tests on partially synchronized HeLa cell populations, according to the criterion of survival, showed them most sensitive during mitosis, as well as in later G sub 1- or early DNA-synthesizing stages. With radiation in doses of 300 rad, the proportion of surviving cells showed a sensitivity directly before DNA synthesis of approximately 4 times higher than the later S-phase and during the major portion of G sub 1- and G sub 2-periods. Sensitivity of cells in mitosis was approximately 3 times higher than in late G sub 1- and early S-phases.

  20. Differences in DNA Repair Capacity, Cell Death and Transcriptional Response after Irradiation between a Radiosensitive and a Radioresistant Cell Line

    PubMed Central

    Borràs-Fresneda, Mireia; Barquinero, Joan-Francesc; Gomolka, Maria; Hornhardt, Sabine; Rössler, Ute; Armengol, Gemma; Barrios, Leonardo

    2016-01-01

    Normal tissue toxicity after radiotherapy shows variability between patients, indicating inter-individual differences in radiosensitivity. Genetic variation probably contributes to these differences. The aim of the present study was to determine if two cell lines, one radiosensitive (RS) and another radioresistant (RR), showed differences in DNA repair capacity, cell viability, cell cycle progression and, in turn, if this response could be characterised by a differential gene expression profile at different post-irradiation times. After irradiation, the RS cell line showed a slower rate of γ-H2AX foci disappearance, a higher frequency of incomplete chromosomal aberrations, a reduced cell viability and a longer disturbance of the cell cycle when compared to the RR cell line. Moreover, a greater and prolonged transcriptional response after irradiation was induced in the RS cell line. Functional analysis showed that 24 h after irradiation genes involved in “DNA damage response”, “direct p53 effectors” and apoptosis were still differentially up-regulated in the RS cell line but not in the RR cell line. The two cell lines showed different response to IR and can be distinguished with cell-based assays and differential gene expression analysis. The results emphasise the importance to identify biomarkers of radiosensitivity for tailoring individualized radiotherapy protocols. PMID:27245205

  1. Differences in DNA Repair Capacity, Cell Death and Transcriptional Response after Irradiation between a Radiosensitive and a Radioresistant Cell Line.

    PubMed

    Borràs-Fresneda, Mireia; Barquinero, Joan-Francesc; Gomolka, Maria; Hornhardt, Sabine; Rössler, Ute; Armengol, Gemma; Barrios, Leonardo

    2016-06-01

    Normal tissue toxicity after radiotherapy shows variability between patients, indicating inter-individual differences in radiosensitivity. Genetic variation probably contributes to these differences. The aim of the present study was to determine if two cell lines, one radiosensitive (RS) and another radioresistant (RR), showed differences in DNA repair capacity, cell viability, cell cycle progression and, in turn, if this response could be characterised by a differential gene expression profile at different post-irradiation times. After irradiation, the RS cell line showed a slower rate of γ-H2AX foci disappearance, a higher frequency of incomplete chromosomal aberrations, a reduced cell viability and a longer disturbance of the cell cycle when compared to the RR cell line. Moreover, a greater and prolonged transcriptional response after irradiation was induced in the RS cell line. Functional analysis showed that 24 h after irradiation genes involved in "DNA damage response", "direct p53 effectors" and apoptosis were still differentially up-regulated in the RS cell line but not in the RR cell line. The two cell lines showed different response to IR and can be distinguished with cell-based assays and differential gene expression analysis. The results emphasise the importance to identify biomarkers of radiosensitivity for tailoring individualized radiotherapy protocols.

  2. TGF{beta}1 polymorphisms and late clinical radiosensitivity in patients treated for gynecologic tumors

    SciTech Connect

    Ruyck, Kim de . E-mail: kim.deruyck@UGent.be; Van Eijkeren, Marc; Claes, Kathleen; Bacher, Klaus; Vral, Anne; Neve, Wilfried de; Thierens, Hubert

    2006-07-15

    Purpose: To investigate the association between six transforming growth factor {beta}1 gene (TGF{beta}1) polymorphisms (-1.552delAGG, -800G>A, -509C>T, Leu10Pro, Arg25Pro, Thr263Ile) and the occurrence of late normal tissue reactions after gynecologic radiotherapy (RT). Methods and Materials: Seventy-eight women with cervical or endometrial cancer and 140 control individuals were included in the study. According to the Common Terminology Criteria for Adverse Events version 3.0 (CTCAEv3.0) scale, 25 patients showed late adverse RT reactions (CTC2+), of whom 11 had severe complications (CTC3+). Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), single base extension and genotyping assays were performed to examine the polymorphic sites in TGF{beta}1. Results: Homozygous variant -1.552delAGG, -509TT, and 10Pro genotypes were associated with the risk of developing late severe RT reactions. Triple (variant) homozygous patients had a 3.6 times increased risk to develop severe RT reactions (p = 0.26). Neither the -800A allele, nor the 25Pro allele or the 263Ile allele were associated with clinical radiosensitivity. There was perfect linkage disequilibrium (LD) between the -1.552delAGG and the -509C>T polymorphisms, and tight LD between the -1.552/-509 and the Leu10Pro polymorphisms. Haplotype analysis revealed two major haplotypes but could not distinguish radiosensitive from nonradiosensitive patients. Conclusions: The present study shows that homozygous variant TGF{beta}1 -1.552delAGG, -509TT, and 10Pro genotypes may be associated with severe clinical radiosensitivity after gynecologic RT.

  3. Modification of radiosensitivity by the so-called tissue recovery stimulator. I. Radiosensitizing effects of solcoseryl.

    PubMed

    Kumar, A; Kimura, H; Aoyama, T; Sugahara, T

    1992-12-01

    The effect of solcoseryl on the growth, radiosensitization and ability of V79 cells to recover from X-ray-induced damage has been observed. Solcoseryl at 0.8 mg/ml was the optimal concentration for the stimulation of cell growth. Increased sensitivity to X-irradiation was found in the shoulder region of V79 cells treated before and after irradiation with solcoseryl (0.8 mg/ml). The Dq and extrapolation number (n) decreased. Solcoseryl treatment apparently does not reduce split dose recovery or inhibit the repair of potentially lethal damage. Flow cytofluorometry studies of the cell cycle distribution and mitotic index show that solcoseryl inhibits the expression of radiation-induced cell arrest in the G2 phase of the cell cycle. Although this action increases radiation sensitization, additional mechanisms probably exist.

  4. Platinum complexes with one radiosensitizing ligand (PtCl2(NH3) (sensitizer)): radiosensitization and toxicity studies in vitro

    SciTech Connect

    Skov, K.A.; Farrell, N.P.; Adomat, H.

    1987-11-01

    Complexes of general formula (PtCl2(NH3)L) with one radiosensitizing ligand per platinum are compared with ligand L alone, complexes with two radiosensitizers per platinum (PtCl2L2), and their analogs with NH3 ligands, with respect to radiosensitizing properties and toxicity in CHO cells. Radiosensitizing ligands, L, were misonidazole, metronidazole, 4(5)-nitroimidazole, and 2-amino-5-nitrothiazole, and the ammine analogs were cis- and trans-DDP (diamminedichloroplatinum(II)) and the monoammine, K(PtCl3(NH3)). Results are related to a previous study on plasmid DNA binding by these series. The toxicity of the mono series (PtCl2(NH3)L), attributable to DNA binding, is much higher than the corresponding bis complexes, (PtCl2L2). For L = misonidazole, toxicity is similar to the monoammine, but higher in hypoxic than in aerobic cells. trans-(PtCl2(NH3)-(misonidazole)) is more toxic than the cis isomer. Except for L = 4(5)-nitroimidazole, the complexes (PtCl2(NH3)L) are more toxic than L in air and hypoxia. Hypoxic radiosensitization by the mono complexes is comparable to the monoammine and is not better than free sensitizers, again except for L = 4(5)-nitroimidazole. Significantly lower sensitization is observed in oxic cells. The bis complexes (PtCl2L2), which do not bind to DNA as well as the mono complexes, are less effective radiosensitizers and less toxic than the (PtCl2(NH3)L) series.

  5. Roadmap to clinical use of gold nanoparticles for radiosensitization

    PubMed Central

    Schuemann, J.; Berbeco, R.; Chithrani, B. D.; Cho, S.; Kumar, R.; McMahon, S.; Sridhar, S.; Krishnan, S.

    2015-01-01

    The past decade has seen a dramatic increase in interest in the use of Gold Nanoparticles (GNPs) as radiation sensitizers for radiotherapy. This interest was initially driven by their strong absorption of ionizing radiation and the resulting ability to increase dose deposited within target volumes even at relatively low concentrations. These early observations are supported by extensive experimental validation, showing GNPs’ efficacy at sensitizing tumors in both in vitro and in vivo systems to a range of types of ionizing radiation, including kilovoltage and megavoltage X-rays as well as charged particles. Despite this experimental validation, there has been limited translation of GNP-mediated radiosensitization to a clinical setting. One of the key challenges in this area is the wide range of experimental systems that have been investigated, spanning a range of particle sizes, shapes and preparations. As a result, mechanisms of uptake and radiosensitization have remained difficult to clearly identify. This has proven a significant impediment to the identification of optimal GNP formulations which strike a balance among their radiosensitizing properties, their specificity to the tumors, their biocompatibility, and their imageability in vivo. This white paper reviews the current state of knowledge in each of the areas concerning the use of GNPs as radiosensitizers, and outlines the steps which will be required to advance GNP-enhanced radiation therapy from their current pre-clinical setting to clinical trials and eventual routine usage. PMID:26700713

  6. Histone Deacetylation Critically Determines T-cell Subset Radiosensitivity1

    PubMed Central

    Pugh, Jason L.; Sukhina, Alona S.; Seed, Thomas M.; Manley, Nancy R.; Sempowski, Gregory A.; van den Brink, Marcel R.M.; Smithey, Megan J.; Nikolich-Zugich, Janko

    2014-01-01

    Lymphocytes are sensitive to ionizing radiation and naïve lymphocytes are more radiosensitive than their memory counterparts. Less is known about radiosensitivity of memory cell subsets. We examined the radiosensitivity of naïve (TN), effector memory (TEM), and central memory (TCM) T cell subsets in C57BL/6 mice, and found TEM to be more resistant to radiation-induced apoptosis than either TN or TCM. Surprisingly, we found no correlation between the extent of radiation-induced apoptosis in T cell subsets and : (i) levels of pro- and anti-apoptotic Bcl-2 family members; or (ii) the H2-AX content and maximal γH2-AX fold change. Rather, TEM cell survival correlated with higher levels of immediate γH2-AX marking, immediate break binding and genome-wide open chromatin structure. T cells were able to mark DNA damage seemingly instantly (30 s), even if kept on ice. Relaxing chromatin with the histone deacetylase inhibitor valproic acid following radiation or etoposide treatment, improved the survival of TCM and TN cells up to levels seen in the resistant TEM cells, but did not improve survival from caspase-mediated apoptosis. We conclude that an open genome-wide chromatin state is the key determinant of efficient immediate repair of DNA damage in T cells, explaining the observed T cell subset radiosensitivity differences. PMID:24990082

  7. Disturbance of redox status enhances radiosensitivity of hepatocellular carcinoma

    PubMed Central

    Sun, Chao; Wang, Zhen-hua; Liu, Xiong-xiong; Yang, Li-na; Wang, Yali; Liu, Yang; Mao, Ai-hong; Liu, Yuan-yuan; Zhou, Xin; Di, Cui-xia; Gan, Lu; Zhang, Hong

    2015-01-01

    Aims: High constitutive expression of Nrf2 has been found in many types of cancers, and this high level of Nrf2 also favors resistance to drugs and radiation. Here we investigate how isoliquiritigenin (ISL), a natural antioxidant, inhibits the Nrf2-dependent antioxidant pathway and enhances the radiosensitivity of HepG2 cells and HepG2 xenografts. Results: Treatment of HepG2 cells with ISL for 6 h selectively enhanced transcription and expression of Keap1. Keap1 effectively induced ubiquitination and degradation of Nrf2, and inhibited translocation of Nrf2 to the nucleus. Consequently, expression of Nrf2 downstream genes was reduced, and the Nrf2-dependent antioxidant system was suppressed. Endogenous ROS was higher than before ISL treatment, causing redox imbalance and oxidative stress in HepG2 cells. Moreover, pretreatment with ISL for 6 h followed by X-ray irradiation significantly increased γ-H2AX foci and cell apoptosis, and reduced clonogenic potential compared with cells irradiated with X-rays alone. In addition, HepG2 xenografts, ISL, and X-ray co-treatments induced greater apoptosis and tumor growth inhibition, when compared with X-ray treatments alone. Additionally, HepG2 xenografts, in which Nrf2 was expressed at very low levels due to ectopic expression of Keap1, showed that ISL-mediated radiosensitization was Keap1 dependent. Innovation and Conclusions: ISL inhibited the Nrf2-antioxidant pathway by increasing the levels of Keap1 and ultimately inducing oxidative stress via disturbance of the redox status. The antioxidant ISL possessed pro-oxidative properties, and enhanced the radiosensitivity of liver cancer cells, both in vivo and in vitro. Taken together, these results demonstrated the effectiveness of using ISL to decrease radioresistance, suggesting that ISL could be developed as an adjuvant radiosensitization drug. Disturbance of redox status could be a potential target for radiosensitization. PMID:26101703

  8. WE-G-BRE-08: Radiosensitization by Olaparib Eluting Nanospheres

    SciTech Connect

    Tangutoori, S; Kumar, R; Sridhar, S; Korideck, H; Makrigiorgos, G; Cormack, R

    2014-06-15

    Purpose: Permanent prostate brachytherapy often uses inert bio-absorbable spacers to achieve the desired geometric distribution of sources within the prostate. Transforming these spacers into implantable nanoplatforms for chemo-radiation therapy (INCeRT) provides a means of providing sustained in-situ release of radiosensitizers in the prostate to enhance the therapeutic ratio of the procedure. Olaparib, a PARP inhibitor, suppresses DNA repair processes present during low dose rate continuous irradiation. This work investigates the radiosensitizing/DNA damage repair inhibition by NanoOlaparib eluting nanospheres. Methods: Human cell line PC3 (from ATCC), was maintained in F12-k medium supplemented with fetal bovine serum. Clonogenic assay kit (from Fischer Scientific) was used to fix and stain the cells to determine the long term effects of irradiation. Nanoparticle size and zeta potential of nanospheres were determined using a Zeta particle size analyzer. The incorporation of Olaparib in nanospheres was evaluated by HPLC. Irradiation was performed in a small animal irradiator operating at 220 KeV.The long term effects of radio-sensitization with olaparib and nanoolaparib was determined using the clonogenic assay at 2 Gy and 4 Gy doses. The cells were allowed to grow for around 10 doubling cycles, The colonies were fixed and stained using clonogenic assay kit. The excess stain was washed off using DI water and the images were taken using a digital camera. Results: Radiosensitization studies were carried out in prostate cancer cell line, PC3 radiation at 0, 2 and 4Gy doses. Strongest dose response was observed with nanoolaparib treated cells compared to untreated cells. Conclusion: A two stage drug release of drug eluting nanospheres from a biodegradable spacer has been suggested for sustained in-situ release of Olaparib to suppress DNA repair processes during prostate brachytherapy. The Olaparib eluting nanospheres had the same in-vitro radiosensitizing effect as

  9. Enhanced chromosomal radiosensitivity in peripheral blood lymphocytes of larynx cancer patients

    SciTech Connect

    Lisowska, Halina; Lankoff, Anna; Wieczorek, Andrzej; Florek, Agnieszka; Kuszewski, Tomasz; Gozdz, Stanislaw; Wojcik, Andrzej . E-mail: awojcik@pu.kielce.pl

    2006-11-15

    Purpose: The chromosomal radiosensitivity in peripheral blood lymphocytes of cancer patients was reported to be higher than that of healthy donors. This effect is especially prominent when aberrations induced in the G{sub 2} phase of the cell cycle are analyzed. The aim of our study was to investigate if the G{sub 2} aberration frequencies in lymphocytes of patients with larynx cancer are higher than in the case of control individuals. Also, we tested if the frequencies of G{sub 2} aberrations correlate with side effects of radiotherapy. Methods and Materials: Peripheral blood of 38 patients was collected before the onset of radiotherapy, cultured for 72 h, and irradiated with 2 Gy after 67 h. Lymphocytes of 40 healthy donors were treated in the same way. Results: The spontaneous and radiation-induced aberration frequencies in lymphocytes of patients were on average higher than in those of healthy donors. No statistically significant correlation was observed between aberration frequencies in lymphocytes and the degree of both early and late normal tissue reactions. Conclusions: The chromosomal radiosensitivity of lymphocytes of patients with larynx cancer may be a marker of cancer predisposition; however, it does not appear to have a predictive value for the risk of developing side effects to radiotherapy.

  10. Clinical, Molecular- and Cytogenetic Analysis of a Case of Severe Radio-Sensitivity

    PubMed Central

    Greulich-Bode, K.M.; Zimmermann, F.; Müller, W.-U.; Pakisch, B.; Molls, M.; Würschmidt, F.

    2012-01-01

    In radiotherapy the normal tissue reaction is often a limiting factor for radiation treatment. Still there is no screening method, which predicts normal tissue reaction on radiotherapy, especially in comparison to tumor tissue, and therefore allows tailoring of the radiation dose to each patient. Here, we present a case of severe radiation-related side effects. We applied classical cytogenetic techniques (Giemsa-banding and staining of centromeric regions), the comet assay as well as multicolor fluorescence in situ hybridization on peripheral blood lymphocytes of this patient in order to determine the radio-sensitivity on the DNA level and to correlate these findings with the clinical outcome. Our investigations revealed abnormalities on chromosome 9, deficiencies in the DNA-repair capacity after radiation exposure and a high number of radiation induced chromosomal aberrations. A detected high amount of residual damage two or three hours after radiation exposure and repair as well as the high number of chromosomal aberrations (ChAs) suggests a correlation between repair capacity and radiation induced ChAs. We concluded that the detected abnormalities might serve as a genetic basis for the radio-sensitive phenotype of this patient. Taken together this report strengthens the idea that intensive DNA genomic analysis of individual patients can serve as the basis for more favourable treatment of cancer patients. PMID:23450188

  11. Radiosensitivity to high energy iron ions is influenced by heterozygosity for Atm, Rad9 and Brca1

    NASA Astrophysics Data System (ADS)

    Zhou, G.; Smilenov, L. B.; Lieberman, H. B.; Ludwig, T.; Hall, E. J.

    2010-09-01

    Loss of function of DNA repair genes has been implicated in the development of many types of cancer. In the last several years, heterozygosity leading to haploinsufficiency for proteins involved in DNA repair was shown to play a role in genomic instability and carcinogenesis after DNA damage is induced, for example by ionizing radiation. Since the effect of heterozygosity for one gene is relatively small, we hypothesize that predisposition to cancer could be a result of the additive effect of heterozygosity for two or more genes critical to pathways that control DNA damage signaling, repair or apoptosis. We investigated the role of heterozygosity for Atm, Rad9 and Brca1 on cell oncogenic transformation and cell survival induced by 1 GeV/ n56Fe ions. Our results show that cells heterozygous for both Atm and Rad9 or Atm and Brca1 have high survival rates and are more sensitive to transformation by high energy iron ions when compared with wild-type controls or cells haploinsufficient for only one of these proteins. Since mutations or polymorphisms for similar genes exist in a small percentage of the human population, we have identified a radiosensitive sub-population. This finding has several implications. First, the existence of a radiosensitive sub-population may distort the shape of the dose-response relationship. Second, it would not be ethical to put exceptionally radiosensitive individuals into a setting where they may potentially be exposed to substantial doses of radiation.

  12. RADIOSENSITIVITY TO HIGH ENERGY IRON IONS IS INFLUENCED BY HETEROZYGOSITY for ATM, RAD9 and BRCA1

    PubMed Central

    Zhou, G.; Smilenov, L. B.; Lieberman, H. B.; Ludwig, T.; Hall, E. J.

    2013-01-01

    Loss of function of DNA repair genes has been implicated in the development of many types of cancer. In the last several years, heterozygosity leading to haploinsufficiency for proteins involved in DNA repair was shown to play a role in genomic instability and carcinogenesis after DNA damage is induced, for example by ionizing radiation. Since the effect of heterozygosity for one gene is relatively small, we hypothesize that predisposition to cancer could be a result of the additive effect of heterozygosity for two or more genes critical to pathways that control DNA damage signaling, repair or apoptosis. We investigated the role of heterozygosity for Atm, Rad9 and Brca1 on cell oncogenic transformation and cell survival induced by 1GeV/n 56Fe ions. Our results show that cells heterozygous for both Atm and Rad9 or Atm and Brca1 have high survival rates and are more sensitive to transformation by high energy Iron ions when compared with wild-type controls or cells haploinsufficient for only one of these proteins. Since mutations or polymorphisms for similar genes exist in a small percentage of the human population, we have identified a radiosensitive sub-population. This finding has several implications. First, the existence of a radiosensitive sub-population may distort the shape of the dose-response relationship. Second, it would not be ethical to put exceptionally radiosensitive individuals into a setting where they may potentially be exposed to substantial doses of radiation. PMID:24431481

  13. Factors Affecting the Radiosensitivity of Hexaploid Wheat to γ-Irradiation: Radiosensitivity of Hexaploid Wheat (Triticum aestivum L.)

    PubMed Central

    Zhao, Linshu; Guo, Huijun; Xie, Yongdun; Zhao, Shirong; Song, Xiyun; Han, Longzhi; Liu, Luxiang

    2016-01-01

    Understanding the radiosensitivity of plants, an important factor in crop mutation breeding programs, requires a thorough investigation of the factors that contribute to this trait. In this study, we used the highly radiosensitive wheat (Triticum aestivum L.) variety HY1 and J411, a γ-irradiation-insensitive control, which were screened from a natural population, to examine the factors affecting radiosensitivity, including free radical content and total antioxidant capacity, as well as the expression of TaKu70 and TaKu80 (DNA repair-related genes) as measured by real-time PCR. We also investigated the alternative splicing of this gene in the wild-type wheat ecotype by sequence analysis. Free radical contents and total antioxidant capacity significantly increased upon exposure of HY1 wheat to γ-irradiation in a dose-dependent manner. By contrast, in J411, the free radical contents exhibited a similar trend, but the total antioxidant capacity exhibited a downward trend upon increasing γ-irradiation. Additionally, we detected dose-dependent increases in TaKu70 and TaKu80 expression levels in γ-irradiated HY1, while in J411, TaKu70 expression levels increased, followed by a decline. We also detected alternative splicing of TaKu70 mRNA, namely, intron retention, in HY1 but not in J411. Our findings indicate that γ-irradiation induces oxidative stress and DNA damage in hexaploid wheat, resulting in growth retardation of seedlings, and they suggest that TaKu70 may play a causal role in radiosensitivity in HY1. Further studies are required to exploit these factors to improve radiosensitivity in other wheat varieties. PMID:27551965

  14. The National Trajectory Project of Individuals Found Not Criminally Responsible on Account of Mental Disorder. Part 5: How Essential Are Gender-Specific Forensic Psychiatric Services?

    PubMed Central

    Nicholls, Tonia L; Crocker, Anne G; Seto, Michael C; Wilson, Catherine M; Charette, Yanick; Côté, Gilles

    2015-01-01

    Objective: To state the sociodemographic characteristics, mental health histories, index offence characteristics, and criminal histories of male and female forensic psychiatric patients. Clinicians and researchers advocate that mental health and criminal justice organizations implement gender-specific services; however, few studies have sampled forensic patients to evaluate the extent to which men’s and women’s treatment and management needs are different. Method: Data were collected from Review Board files from May 2000 to April 2005 in the 3 largest Canadian provinces. Using official criminal records, participants were followed for 3 to 8 years, until December 2008. The final sample comprised 1800 individuals: 15.6% were women and 84.4% were men. Results: There were few demographic differences, but women had higher psychosocial functioning than men. Both men and women had extensive mental health histories; women were more likely diagnosed with mood disorders and PDs and men were more likely diagnosed with schizophrenia spectrum disorders and SUDs. The nature of the index offence did not differ by gender, except women were more likely to have perpetrated murders and attempted murders. For offences against a person, women were more likely to offend against offspring and partners and less likely to offend against strangers, compared with men. Women had significantly less extensive criminal histories than men. Conclusions: Not criminally responsible on account of mental disorder–accused women have a distinct psychosocial, clinical, and criminological profile from their male counterparts, which may suggest gender-specific assessment, risk management, and treatment in forensic services could benefit patients. The findings are also consistent with traditional models (Risk-Need-Responsivity) and ultimately demonstrate the importance of individual assessment and client-centred services. PMID:25886689

  15. Assessment of the intrinsic radiosensitivity of glioma cells and monitoring of metabolite ratio changes after irradiation by 14.7-T high-resolution ¹H MRS.

    PubMed

    Zhang, Zhaotao; Zeng, Qingshi; Liu, Yun; Li, Chuanfu; Feng, Dechao; Wang, Jianzheng

    2014-05-01

    Gliomas are the most common type of primary brain tumor. Radiation therapy (RT) is the primary adjuvant treatment to eliminate residual tumor tissue after surgery. However, the current RT guided by conventional imaging is unsatisfactory. A fundamental question is whether it is possible to further enhance the effectiveness and efficiency of RT based on individual radiosensitivity. In this research, to probe the correlation between radiosensitivity and the metabolite characteristics of glioma cells in vitro, a perchloric acid (PCA) extracting method was used to obtain water-soluble metabolites [such as N-acetylaspartate (NAA), choline (Cho), creatine (Cr) and succinate (Suc)]. Spectral patterns from these processed water-soluble metabolite samples were acquired by in vitro 14.7-T high-resolution ¹H MRS. Survival fraction analysis was performed to test the intrinsic radiosensitivity of glioma cell lines. Good ¹H MRS of PCA extracts from glioma cells was obtained. The radiosensitivity of glioma cells correlated positively with the Cho/Cr and Cho/NAA ratios, but negatively with the Suc/Cr ratio. Irradiation of the C6 cell line at different X-ray dosages led to changes in metabolite ratios and apoptotic rates. A plateau phase of metabolite ratio change and a decrease in apoptotic rate were found in the C6 cell line. We conclude that in vitro high-resolution ¹H MRS possesses the sensitivity required to detect subtle biochemical changes at the cellular level. ¹H MRS may aid in the assessment of the individual radiosensitivity of brain tumors, which is pivotal in the identification of the biological target volume.

  16. Monte Carlo simulations guided by imaging to predict the in vitro ranking of radiosensitizing nanoparticles

    PubMed Central

    Retif, Paul; Reinhard, Aurélie; Paquot, Héna; Jouan-Hureaux, Valérie; Chateau, Alicia; Sancey, Lucie; Barberi-Heyob, Muriel; Pinel, Sophie; Bastogne, Thierry

    2016-01-01

    This article addresses the in silico–in vitro prediction issue of organometallic nanoparticles (NPs)-based radiosensitization enhancement. The goal was to carry out computational experiments to quickly identify efficient nanostructures and then to preferentially select the most promising ones for the subsequent in vivo studies. To this aim, this interdisciplinary article introduces a new theoretical Monte Carlo computational ranking method and tests it using 3 different organometallic NPs in terms of size and composition. While the ranking predicted in a classical theoretical scenario did not fit the reference results at all, in contrast, we showed for the first time how our accelerated in silico virtual screening method, based on basic in vitro experimental data (which takes into account the NPs cell biodistribution), was able to predict a relevant ranking in accordance with in vitro clonogenic efficiency. This corroborates the pertinence of such a prior ranking method that could speed up the preclinical development of NPs in radiation therapy. PMID:27920524

  17. Monte Carlo simulations guided by imaging to predict the in vitro ranking of radiosensitizing nanoparticles.

    PubMed

    Retif, Paul; Reinhard, Aurélie; Paquot, Héna; Jouan-Hureaux, Valérie; Chateau, Alicia; Sancey, Lucie; Barberi-Heyob, Muriel; Pinel, Sophie; Bastogne, Thierry

    This article addresses the in silico-in vitro prediction issue of organometallic nanoparticles (NPs)-based radiosensitization enhancement. The goal was to carry out computational experiments to quickly identify efficient nanostructures and then to preferentially select the most promising ones for the subsequent in vivo studies. To this aim, this interdisciplinary article introduces a new theoretical Monte Carlo computational ranking method and tests it using 3 different organometallic NPs in terms of size and composition. While the ranking predicted in a classical theoretical scenario did not fit the reference results at all, in contrast, we showed for the first time how our accelerated in silico virtual screening method, based on basic in vitro experimental data (which takes into account the NPs cell biodistribution), was able to predict a relevant ranking in accordance with in vitro clonogenic efficiency. This corroborates the pertinence of such a prior ranking method that could speed up the preclinical development of NPs in radiation therapy.

  18. Non-homologous end-joining protein expression screen from radiosensitive cancer patients yields a novel DNA double strand break repair phenotype

    PubMed Central

    Goh, Su Kak; McKay, Jeremy N.; Chao, Michael; McKay, Timothy M.

    2017-01-01

    Background Clinical radiosensitivity is a significant impediment to tumour control and cure, in that it restricts the total doses which can safely be delivered to the whole radiotherapy population, within the tissue tolerance of potentially radiosensitive (RS) individuals. Understanding its causes could lead to personalization of radiotherapy. Methods We screened tissues from a unique bank of RS cancer patients for expression defects in major DNA double-strand break repair proteins, using Western blot analysis and subsequently reverse-transcriptase polymerase chain reaction and pulsed-field gel electrophoresis. Results We hypothesized that abnormalities in expression of these proteins may explain the radiosensitivity of some of our cancer patients. The cells from one patient showed a reproducibly consistent expression reduction in two complex-forming DNA double-strand break repair protein components (DNA Ligase IV and XRCC4). We also showed a corresponding reduction in both gene products at the mRNA level. Additionally, the mRNA inducibility by ionizing radiation was increased for one of the proteins in the patient’s cells. We confirmed the likely functional significance of the non-homologous end-joining (NHEJ) expression abnormalities with a DNA double strand break (DNA DSB) repair assay. Conclusions We have identified a novel biological phenotype linked to clinical radiosensitivity. This is important in that very few molecular defects are known in human radiotherapy subjects. Such knowledge may contribute to the understanding of radiation response mechanisms in cancer patients and to personalization of radiotherapy. PMID:28361061

  19. Gay-Straight Alliances Vary on Dimensions of Youth Socializing and Advocacy: Factors Accounting for Individual and Setting-Level Differences

    PubMed Central

    Poteat, V. Paul; Scheer, Jillian R.; Marx, Robert A.; Calzo, Jerel P.; Yoshikawa, Hiro

    2016-01-01

    Gay-Straight Alliances (GSAs) are school-based youth settings that could promote health. Yet, GSAs have been treated as homogenous without attention to variability in how they operate or to how youth are involved in different capacities. Using a systems perspective, we considered two primary dimensions along which GSAs function to promote health: providing socializing and advocacy opportunities. Among 448 students in 48 GSAs who attended six regional conferences in Massachusetts (59.8% LGBQ; 69.9% White; 70.1% cisgender female), we found substantial variation among GSAs and youth in levels of socializing and advocacy. GSAs were more distinct from one another on advocacy than socializing. Using multilevel modeling, we identified group and individual factors accounting for this variability. In the socializing model, youth and GSAs that did more socializing activities did more advocacy. In the advocacy model, youth who were more actively engaged in the GSA as well as GSAs whose youth collectively perceived greater school hostility and reported greater social justice efficacy did more advocacy. Findings suggest potential reasons why GSAs vary in how they function in ways ranging from internal provisions of support, to visibility raising, to collective social change. The findings are further relevant for settings supporting youth from other marginalized backgrounds and that include advocacy in their mission. PMID:25855133

  20. Construction and validation of a dose-response curve using the comet assay to determine human radiosensitivity to ionizing radiation.

    PubMed

    Güerci, A; Zúñiga, L; Marcos, R

    2011-01-01

    Individual radiosensitivity is an individual characteristic associated with an increased reaction to ionizing radiation. The purpose of our work is to establish a dose-response curve useful to classify individuals as radiosensitive or radioresistant. Thus, a dose-response curve was constructed by measuring in vitro responses to increasing doses (0 to 8 Gy) of gamma radiation in the comet assay. The obtained curve fit well with a linear equation in the range of 0 to 8 Gy. The overall dose-response curve was constructed for percent DNA in tail, as a measure of the genetic damage induced by irradiation. To probe the goodness of the constructed curve, a validation study was carried out with whole blood from two donors in a blind study. Results show that, for the two applied doses (2 and 6 Gy), the obtained values fit well inside the interval of confidence of the curve. In conclusion, our results demonstrate the usefulness of the comet assay in determining individual responses to defined doses of gamma radiation. The standard dose-response curve constructed may be used to detect individuals departing from reference values.

  1. Rockets, radiosensitizers, and RRx-001: an origin story part I.

    PubMed

    Oronsky, Bryan; Scicinski, Jan; Ning, Shoucheng; Peehl, Donna; Oronsky, Arnold; Cabrales, Pedro; Bednarski, Mark; Knox, Susan

    2016-03-01

    From Adam and Eve, to Darwinism, origin stories attempt to fill in the blanks, connect the dots, and define the turning points that are fundamental to subsequent developments. The purpose of this review is to present the origin story of a one-of-a-kind anticancer agent, RRx-001, which emerged from the aerospace industry as a putative radiosensitizer; not since the dynamite-to-dilator transformation of nitroglycerin in 1878 or the post-World War II explosive-to-elixir conversion of hydralazine, an ingredient in rocket fuel, to an antihypertensive, an antidepressant and an antituberculant, has energetic chemistry been harnessed for therapeutic purposes. This is Part 1 of the radiosensitization story; Parts 2 and 3, which detail the crossover activity of RRx-001 as a chemosensitizer in multiple tumor types and disease states including malaria, hemorrhagic shock and sickle cell anemia, are the subject of future reviews.

  2. Low-Dose Hyper-Radiosensitivity: Past, Present, and Future

    SciTech Connect

    Marples, Brian Collis, Spencer J.

    2008-04-01

    This review article discusses the biology of low-dose hyper-radiosensitivity (HRS) with reference to the molecular regulation of DNA repair and cell cycle control processes. Particular attention is paid to the significance of G2-phase cell cycle checkpoints in overcoming low-dose hyper-radiosensitivity and the impact of HRS on low-dose rate radiobiology. The history of HRS from the original in vivo discovery to the most recent in vitro and clinical data are examined to present a unifying hypothesis concerning the molecular control and regulation of this important low dose radiation response. Finally, preclinical and clinical data are discussed, from a molecular viewpoint, to provide theoretical approaches to exploit HRS biology for clinical gain.

  3. Autophagy Inhibition to Increase Radiosensitization in Breast Cancer

    PubMed Central

    Liang, Diana Hwang; El-Zein, Randa; Dave, Bhuvanesh

    2015-01-01

    Currently, many breast cancer patients with localized breast cancer undergo breast-conserving therapy, consisting of local excision followed by radiation therapy. Following radiation therapy, breast cancer cells are noted to undergo induction of autophagy, development of radioresistance, and enrichment of breast cancer stem cell subpopulations. It is hypothesized that inhibition of the cytoprotective autophagy that arises following radiation therapy increases radiosensitivity and confers longer relapse-free survival by eliminating tumor-initiating breast cancer stem cells. Therefore, we reviewed the controversial role of autophagy in breast cancer tumorigenesis and progression, autophagy induction by radiotherapy, and utilization of autophagy inhibitors to increase radiosensitivity of breast cancer and to target radioresistant breast cancer stem cells. PMID:26613064

  4. Accounting: Accountants Need Verbal Skill Training

    ERIC Educational Resources Information Center

    Whitaker, Bruce L.

    1978-01-01

    Verbal skills training is one aspect of accounting education not usually included in secondary and postsecondary accounting courses. The author discusses the need for verbal competency and methods of incorporating it into accounting courses, particularly a variation of the Keller plan of individualized instruction. (MF)

  5. Radiosensitization of EMT6 cells by four platinum complexes

    SciTech Connect

    Teicher, B.A.; Rockwell, S.; Lee, J.B.

    1985-05-01

    The compounds described here are dichloro complexes of bivalent platinum with one or two potentially radiosensitizing ligands. The radiosensitization of oxygenated and hypoxic exponentially growing EMT6 cells in vitro was measured. The dose modifying factors obtained with 200 ..mu..M and 400 ..mu..M trans-bis(2-nitroimidazole)dichloroplatinum II (NIPt) in hypoxic cells were 1.5 and 2.1, respectively. For trans-bis(2-amino-5-nitrothiazole)dichloroplatinum II (Plant) under the same conditions, the dose modifying factor was 1.5 at 200 ..mu..M and 1.8 at 400 ..mu..M. Neither compound sensitized oxygenated cells when tested similar protocols. Unlike the trans complexes (1,2-diamino-4-nitrobenzene)dichloroplatinum II (Plato) was cytotoxic toward the hypoxic cells in the absence of X rays. The time course of cytotoxicity for 100 ..mu..M Plato in exponentially growing cells showed rapid killing of hypoxic cells, and much less toxicity toward oxygenated cells. In radiosensitization studies, dose modifying factors of 1.6 and 2.0 were found with 200 ..mu..M and 400 ..mu..M Plato in hypoxic cells. The compound did not sensitize aerobic cells. The well-known platinum complex cis-dipyridinedichloroplatinum II (PyPt) represents a cis-platinum heterocyclic aromatic complex that does not have a nitro-functionality. The dose modifying factor obtained with 400 ..mu..M PyPt in hypoxic cells was 1.7. On a molar basis, the nitro-functional platinum complexes appear to be more effective as hypoxic cell radiosensitizers than the corresponding free ligands.

  6. Potential biomarkers for radiosensitivity in head and neck cancers

    PubMed Central

    Pardo-Reoyo, Sherly; Roig-Lopez, J. L.

    2016-01-01

    Radiotherapy is a mainstay of treatment for head and neck cancer. However, the morbidity of treatment remains a clinical challenge. Molecular profiling has provided further insight into tumor biology and tumor sensitivity to radiation, and this information could be used to personalize treatment. In this review, we discuss published signatures of radiosensitivity and discuss the pathways that may be important in dictating radiation sensitivity. Applications of these signatures could result in less morbidity if dose de-escalation efforts are successful. PMID:28149885

  7. Radiosensitization: enhancing the radiation inactivation of foodborne bacteria

    NASA Astrophysics Data System (ADS)

    Borsa, J.; Lacroix, M.; Ouattara, B.; Chiasson, F.

    2004-09-01

    Irradiation of meat products to kill pathogens can be limited by radiation-induced detriment of sensory quality. Since such detriment is directly related to dose, one approach to reduce it is by devising means to lower the dose of radiation required for processing. Increasing the radiation sensitivity of the target microorganisms would lower the dose required for a given level of microbial kill. In this work, the radiation sensitivities of inoculated Escherichia coli and Salmonella typhi in ground beef were examined under a variety of conditions. Results showed that specific manipulations of treatment conditions significantly increased the radiation sensitivity of the test organisms, ranging from a few percent to several-fold reduction in D10. In particular, radiation sensitization could be effected by certain additives, including carvacrol, thymol and trans-cinnamaldehyde, and also by certain compositions of modified atmosphere in the package headspace. A combination of additives and modified atmosphere effected a greater radiosensitization effect than could be achieved by either factor applied alone. Radiosensitization could be demonstrated with irradiation of either fresh or frozen ground meat. The radiosensitization phenomenon may be of practical utility in enhancing the technical effectiveness and feasibility of irradiation of a variety of meat and other food products.

  8. The HSP90 Inhibitor Ganetespib Radiosensitizes Human Lung Adenocarcinoma Cells

    PubMed Central

    Gomez-Casal, Roberto; Bhattacharya, Chitralekha; Epperly, Michael W.; Basse, Per H.; Wang, Hong; Wang, Xinhui; Proia, David A.; Greenberger, Joel S.; Socinski, Mark A.; Levina, Vera

    2015-01-01

    The molecular chaperone HSP90 is involved in stabilization and function of multiple client proteins, many of which represent important oncogenic drivers in NSCLC. Utilization of HSP90 inhibitors as radiosensitizing agents is a promising approach. The antitumor activity of ganetespib, HSP90 inhibitor, was evaluated in human lung adenocarcinoma (AC) cells for its ability to potentiate the effects of IR treatment in both in vitro and in vivo. The cytotoxic effects of ganetespib included; G2/M cell cycle arrest, inhibition of DNA repair, apoptosis induction, and promotion of senescence. All of these antitumor effects were both concentration- and time-dependent. Both pretreatment and post-radiation treatment with ganetespib at low nanomolar concentrations induced radiosensitization in lung AC cells in vitro. Ganetespib may impart radiosensitization through multiple mechanisms: such as down regulation of the PI3K/Akt pathway; diminished DNA repair capacity and promotion of cellular senescence. In vivo, ganetespib reduced growth of T2821 tumor xenografts in mice and sensitized tumors to IR. Tumor irradiation led to dramatic upregulation of β-catenin expression in tumor tissues, an effect that was mitigated in T2821 xenografts when ganetespib was combined with IR treatments. These data highlight the promise of combining ganetespib with IR therapies in the treatment of AC lung tumors. PMID:26010604

  9. Radiosensitization of non-small cell lung cancer by kaempferol.

    PubMed

    Kuo, Wei-Ting; Tsai, Yuan-Chung; Wu, His-Chin; Ho, Yung-Jen; Chen, Yueh-Sheng; Yao, Chen-Han; Yao, Chun-Hsu

    2015-11-01

    The aim of the present study was to determine whether kaempferol has a radiosensitization potential for lung cancer in vitro and in vivo. The in vitro radio-sensitization activity of kaempferol was elucidated in A-549 lung cancer cells by using an MTT (3-(4 5-dimethylthiazol-2-yl)-25-diphenyl-tetrazolium bromide) assay, cell cycle analysis and clonogenic assay. The in vivo activity was evaluated in the BALB/c nude mouse xenograft model of A-549 cells by hematoxylin and eosin staining and immunohistochemistry, and the tumor volume was recorded. Protein levels of the apoptotic pathway were detected by western blot analysis. Treatment with kaempferol inhibited the growth of A-549 cells through activation of apoptotic pathway. However, the same doses did not affect HFL1 normal lung cell growth. Kaempferol induced G2/M cell cycle arrest and the enhancement of radiation-induced death and clonogenic survival inhibition. The in vivo data showed that kaempferol increased tumor cell apoptosis and killing of radiation. In conclusion, the findings demonstrated that kaempferol increased tumor cell killing by radiation in vitro and in vivo through inhibition of the AKT/PI3K and ERK pathways and activation of the mitochondria apoptosis pathway. The results of the present study provided solid evidence that kaempferol is a safe and potential radiosensitizer.

  10. Preclinical evaluation of radiosensitizing activity of Pluronic block copolymers

    PubMed Central

    Perera, Reshani H.; Patel, Ravi; Wu, Hanping; Gangolli, Mihika; Traughber, Bryan; Oleinick, Nancy; Exner, Agata A.

    2014-01-01

    Purpose Pluronic block copolymers are non-ionic surfactants with demonstrated sensitizing activity in chemotherapy and hyperthermia in various tumor cell lines. In the current study we investigated the potential activity of Pluronic as a radiosensitizing agent. Materials and methods As a possible mechanism, the effect of Pluronic on Hsp70 and Hsp90 was examined. Gli36 human glioma cells were treated with radiation alone as well as with a combination treatment of Pluronic and radiation. Results Clonogenic cell survival assays show that Pluronic has an elevated effect on radiosensitization (50% high, p < 0.01), even with radiation doses as low as 2 Gy. The Hsp90 level was reduced 24 h after the combined treatment in both in vitro and in vivo. Similarly, Hsp70 levels were also decreased 24 h post treatment. When Gli36 cells were exposed to Pluronic before and during irradiation, DNA DSB: double-strand breaks repair was reduced, and elevated apoptosis was also seen in tumor xenografts. Conclusion Data suggest the potential use of L10 as a radiosensitizer. While the mechanism of sensitization requires additional investigation, the presented results indicate that the effect may be due, in part, to a decrease in Hsp90 and 70 levels and increased DNA damage. PMID:23631609

  11. Keeping Accountability Systems Accountable

    ERIC Educational Resources Information Center

    Foote, Martha

    2007-01-01

    The standards and accountability movement in education has undeniably transformed schooling throughout the United States. Even before President Bush signed the No Child Left Behind (NCLB) Act into law in January 2002, mandating annual public school testing in English and math for grades 3-8 and once in high school, most states had already…

  12. Antisense inhibition of cyclin D1 expression is equivalent to flavopiridol for radiosensitization of zebrafish embryos

    SciTech Connect

    McAleer, Mary Frances; Duffy, Kevin T.; Davidson, William R.; Kari, Gabor; Dicker, Adam P.; Rodeck, Ulrich; Wickstrom, Eric . E-mail: eric@tesla.jci.tju.edu

    2006-10-01

    Purpose: Flavopiridol, a small molecule pan-cyclin inhibitor, has been shown to enhance Radiation response of tumor cells both in vitro and in vivo. The clinical utility of flavopiridol, however, is limited by toxicity, previously attributed to pleiotropic inhibitory effects on several targets affecting multiple signal transduction pathways. Here we used zebrafish embryos to investigate radiosensitizing effects of flavopiridol in normal tissues. Methods and Materials: Zebrafish embryos at the 1- to 4-cell stage were treated with 500 nM flavopiridol or injected with 0.5 pmol antisense hydroxylprolyl-phosphono nucleic acid oligomers to reduce cyclin D1 expression, then subjected to ionizing radiation (IR) or no radiation. Results: Flavopiridol-treated embryos demonstrated a twofold increase in mortality after exposure to 40 Gy by 96 hpf and developed distinct radiation-induced defects in midline development (designated as the 'curly up' phenotype) at higher rates when compared with embryos receiving IR only. Cyclin D1-deficient embryos had virtually identical IR sensitivity profiles when compared with embryos treated with flavopiridol. This was particularly evident for the IR-induced curly up phenotype, which was greatly exacerbated by both flavopriridol and cyclin D1 downregulation. Conclusions: Treatment of zebrafish embryos with flavopiridol enhanced radiation sensitivity of zebrafish embryos to a degree that was very similar to that associated with downregulation of cyclin D1 expression. These results are consistent with the hypothesis that inhibition of cyclin D1 is sufficient to account for the radiosensitizing action of flavopiridol in the zebrafish embryo vertebrate model.

  13. Combined inhibition of Wee1 and PARP1/2 for radiosensitization in pancreatic cancer

    PubMed Central

    Karnak, David; Engelke, Carl G.; Parsels, Leslie A.; Kausar, Tasneem; Wei, Dongping; Robertson, Jordan R.; Marsh, Katherine B.; Davis, Mary A.; Zhao, Lili; Maybaum, Jonathan; Lawrence, Theodore S.; Morgan, Meredith A.

    2014-01-01

    Purpose While the addition of radiation to chemotherapy improves survival in patients with locally advanced pancreatic cancer, more effective therapies are urgently needed. Thus, we investigated the radiosensitizing efficacy of the novel drug combination of Wee1 and PARP1/2 [poly (ADP-ribose) polymerase 1/2] inhibitors (AZD1775 and olaparib, respectively) in pancreatic cancer. Experimental Design Radiosensitization of AsPC-1 or MiaPaCa-2 human pancreatic cancer cells was assessed by clonogenic survival and tumor growth assays. Mechanistically, the effects of AZD1775, olaparib, and radiation on cell cycle, DNA damage (γH2AX) and HRR (homologous recombination repair) were determined. Results Treatment of AsPC-1 and MiaPaCa-2 cells with either AZD1775 or olaparib caused modest radiosensitization while treatment with the combination significantly increased radiosensitization. Radiosensitization by the combination of AZD1775 and olaparib was associated with G2 checkpoint abrogation and persistent DNA damage. In addition, AZD1775 inhibited HRR activity and prevented radiation-induced Rad51 focus formation. Finally, in vivo, in MiaPaCa-2-derived xenografts, olaparib did not radiosensitize, while AZD1775 produced moderate, yet significant, radiosensitization (P<0.05). Importantly, the combination of AZD1775 and olaparib produced highly significant radiosensitization (P<0.0001) evidenced by a 13-day delay in tumor volume doubling (vs radiation alone) and complete eradication of 20% of tumors. Conclusions Taken together, these results demonstrate the efficacy of combined inhibition of Wee1 and PARP inhibitors for radiosensitizing pancreatic cancers and support the model that Wee1 inhibition sensitizes cells to PARP inhibitor-mediated radiosensitization through inhibition of HRR and abrogation of the G2 checkpoint, ultimately resulting in unrepaired, lethal DNA damage and radiosensitization. PMID:25117293

  14. Synthesis and radiosensitization properties of hydrogen peroxide and sodium hyaluronate complex

    SciTech Connect

    Rosli, Nur Ratasha Alia Md.; Mohamed, Faizal; Heng, Cheong Kai; Rahman, Irman Abdul; Ahmad, Ainee Fatimah; Mohamad, Hur Munawar Kabir

    2014-09-03

    Cancer cells which are large in size are resistant towards radiation therapy due to the presence of large amount of anti-oxidative enzymes and hypoxic cancer cells. Thus radiosensitizer agents have been developed to enhance the therapeutic effect of radiotherapy by increasing the sensitivity of these cancer cells towards radiation. This study is conducted to investigate the radiosensitization properties of radiosensitizer complex containing hydrogen peroxide and sodium hyaluronate. Combination with sodium hyaluronate may decrease reactivity of hydrogen peroxide but maintain the oxygen concentration needed for radiosensitizing effect. HepG2 cancer cells are cultured as the mean of test subject. Cancer cell samples which are targeted and not targeted with these radiosensitizers are irradiated with 2Gy single fractionated dose. Results obtained shows that the cancer cells which are not targeted with radiosensitizers has a cell viability of 98.80±0.37% after a time interval of 48 hours and has even repopulated over 100% after a 72 hour time interval. This shows that the cancer cells are resistant towards radiation. However, when the cancer cells are targeted with radiosensitizers prior to irradiation, there is a reduction of cell viability by 25.50±10.81% and 10.30±5.10% at time intervals of 48 and 72 hours respectively. This indicates that through the use of these radiosensitizers, cancer cells are more sensitive towards radiation.

  15. Neuropathy of nitroimidazole radiosensitizers: clinical and pathological description

    SciTech Connect

    Wasserman, T.H.; Nelson, J.S.; VonGerichten, D.

    1984-09-01

    The dose limiting toxicity of the nitroimidazole radiosensitizers is peripherial neuropathy. Improved pharmacology of newer drugs has eliminated the encephalopathy. Peripheral neuropathies are predominently mild to moderate paresthesias of both hands and feet. Subjective changes occur with or without minimal objective changes on neurologic exam. All of the neuropathies occurred within 30 days of the last drug dose and are of varible duration. Sural nerve biopsies from patients indicate progressive axonal degeneration affecting both large and small caliber myelinated fibers. Axonal damage appears to be more severe in the distal portion of the nerves. More data are needed for correlation of clinical and pathological changes.

  16. Gadolinium-based nanoparticles for theranostic MRI-radiosensitization.

    PubMed

    Lux, François; Sancey, Lucie; Bianchi, Andrea; Crémillieux, Yannick; Roux, Stéphane; Tillement, Olivier

    2015-01-01

    A rapid development of gadolinium-based nanoparticles is observed due to their attractive properties as MRI-positive contrast agents. Indeed, they display high relaxivity, adapted biodistribution and passive uptake in the tumor thanks to enhanced permeability and retention effect. In addition to these imaging properties, it has been recently shown that they can act as effective radiosensitizers under different types of irradiation (radiotherapy, neutron therapy or hadron therapy). These new therapeutic modalities pave the way to therapy guided by imaging and to personalized medicine.

  17. Mechanism of binding of the radiosensitizers metronidazole and misonidazole (RO-07-0582) to bovine and human serum albumin: a proton NMR study

    SciTech Connect

    Sulkowska, A.; Lubas, B.; Wilczok, T.

    1981-01-01

    High-resolution proton NMR spectra of the radiosensitizer metronidazole and its derivative misonidazole (RO-07-0582) were measured in D/sub 2/O at resonance frequency 60 MHz and interpreted in the aliphatic and aromatic regions. The linewidths of the NMR peaks attributed to individual fragments of nitroimidazole molecules were then analyzed in the presence of bovine and human serum albumin. With increasing concentration of serum albumin, a selectively larger broadening of the lines attributable to the protons of the aliphatic moieties than of those of the imidazole rings was observed for both compounds. This broadening for misonidazole strongly depends on the ionic strength of the solution. The results indicate a specific immobilization of the molecules of both radiosensitizers during their interaction with serum albumin and the involvement of the aliphatic chains of misonidazole and metronidazole as the primary binding sites.

  18. SU11657 Enhances Radiosensitivity of Human Meningioma Cells

    SciTech Connect

    Milker-Zabel, Stefanie Bois, Angelika Zabel-du; Ranai, Gholamreza; Trinh, Thuy; Unterberg, Andreas; Debus, Juergen; Lipson, Kenneth E.; Abdollahi, Amir; Huber, Peter E.

    2008-03-15

    Purpose: To analyze the effect of the multireceptor tyrosine kinase inhibitor SU11657 (primarily vascular endothelial growth factor, platelet-derived growth factor) in combination with irradiation in freshly isolated primary human meningioma cells. Methods and Materials: Tumor specimens were obtained from meningioma patients undergoing surgery at the Department of Neurosurgery, University of Heidelberg, Germany. For the present study only cells up to passage 6 were used. Benign and atypical meningioma cells and human umbilical vein endothelial cells (HUVEC) were treated with SU11657 alone and in combination with 6-MV photons (0-10 Gy). Clonogenic survival and cell proliferation were determined alone and in coculture assays to determine direct and paracrine effects. Results: Radiation and SU11657 alone reduced cell proliferation in atypical and benign meningioma cells as well as in HUVEC in a dose-dependent manner. SU11657 alone also reduced clonogenic survival of benign and atypical meningioma cells. SU11657 increased radiosensitivity of human meningioma cells in clonogenic survival and cell number/proliferation assays. The anticlonogenic and antiproliferative effects alone and the radiosensitization effects of SU11657 were more pronounced in atypical meningioma cells compared with benign meningioma cells. Conclusion: Small-molecule tyrosine kinase inhibitors like SU11657 are capable of amplifying the growth inhibitory effects of irradiation in meningioma cells. These data provide a rationale for further clinical evaluation of this combination concept, especially in atypical and malignant meningioma patients.

  19. Role of Natural Radiosensitizers and Cancer Cell Radioresistance: An Update

    PubMed Central

    Sultana, Misbah; Qazi, Aamer; Qazi, Mahmood Husain; Parveen, Gulshan; Waquar, Sulayman; Ashraf, Abdul Basit; Rasool, Mahmood

    2016-01-01

    Cancer originates from genetic mutations accumulation. Cancer stem cells have been depicted as tumorigenic cells that can differentiate and self-renew. Cancer stem cells are thought to be resistant to conventional therapy like chemotherapy and radiation therapy. Radiation therapy and chemotherapy damage carcinomic DNA cells. Because of the ability of cancer stem cells to self-renew and reproduce malignant tumors, they are the subject of intensive research. In this review, CSCs radioresistant mechanisms which include DNA damage response and natural radiosensitizers have been summed up. Reactive oxygen species play an important role in different physiological processes. ROS scavenging is responsible for regulation of reactive oxygen species generation. A researcher has proved that microRNAs regulate tumor radiation resistance. Ionizing radiation does not kill the cancer cells; rather, IR just slows down the signs and symptoms. Ionizing radiation damages DNA directly/indirectly. IR is given mostly in combination with other chemo/radiotherapies. We briefly described here the behavior of cancer stem cells and radioresistance therapies in cancer treatment. To overcome radioresistance in treatment of cancer, strategies like fractionation modification, treatment in combination, inflammation modification, and overcoming hypoxic tumor have been practiced. Natural radiosensitizers, for example, curcumin, genistein, and quercetin, are more beneficial than synthetic compounds. PMID:26998418

  20. The radiosensitivity index predicts for overall survival in glioblastoma

    PubMed Central

    Ahmed, Kamran A.; Chinnaiyan, Prakash; Fulp, William J.; Eschrich, Steven; Torres-Roca, Javier F.; Caudell, Jimmy J.

    2015-01-01

    We have previously developed a multigene expression model of tumor radiosensitivity (RSI) with clinical validation in multiple cohorts and disease sites. We hypothesized RSI would identify glioblastoma patients who would respond to radiation and predict treatment outcomes. Clinical and array based gene expression (Affymetrix HT Human Genome U133 Array Plate Set) level 2 data was downloaded from the cancer genome atlas (TCGA). A total of 270 patients were identified for the analysis: 214 who underwent radiotherapy and temozolomide and 56 who did not undergo radiotherapy. Median follow-up for the entire cohort was 9.1 months (range: 0.04–92.2 months). Patients who did not receive radiotherapy were more likely to be older (p < 0.001) and of poorer performance status (p < 0.001). On multivariate analysis, RSI is an independent predictor of OS (HR = 1.64, 95% CI 1.08–2.5; p = 0.02). Furthermore, on subset analysis, radiosensitive patients had significantly improved OS in the patients with high MGMT expression (unmethylated MGMT), 1 year OS 84.1% vs. 53.7% (p = 0.005). This observation held on MVA (HR = 1.94, 95% CI 1.19–3.31; p = 0.008), suggesting that RT has a larger therapeutic impact in these patients. In conclusion, RSI predicts for OS in glioblastoma. These data further confirm the value of RSI as a disease-site independent biomarker. PMID:26451615

  1. The radiosensitivity index predicts for overall survival in glioblastoma.

    PubMed

    Ahmed, Kamran A; Chinnaiyan, Prakash; Fulp, William J; Eschrich, Steven; Torres-Roca, Javier F; Caudell, Jimmy J

    2015-10-27

    We have previously developed a multigene expression model of tumor radiosensitivity (RSI) with clinical validation in multiple cohorts and disease sites. We hypothesized RSI would identify glioblastoma patients who would respond to radiation and predict treatment outcomes. Clinical and array based gene expression (Affymetrix HT Human Genome U133 Array Plate Set) level 2 data was downloaded from the cancer genome atlas (TCGA). A total of 270 patients were identified for the analysis: 214 who underwent radiotherapy and temozolomide and 56 who did not undergo radiotherapy. Median follow-up for the entire cohort was 9.1 months (range: 0.04-92.2 months). Patients who did not receive radiotherapy were more likely to be older (p < 0.001) and of poorer performance status (p < 0.001). On multivariate analysis, RSI is an independent predictor of OS (HR = 1.64, 95% CI 1.08-2.5; p = 0.02). Furthermore, on subset analysis, radiosensitive patients had significantly improved OS in the patients with high MGMT expression (unmethylated MGMT), 1 year OS 84.1% vs. 53.7% (p = 0.005). This observation held on MVA (HR = 1.94, 95% CI 1.19-3.31; p = 0.008), suggesting that RT has a larger therapeutic impact in these patients. In conclusion, RSI predicts for OS in glioblastoma. These data further confirm the value of RSI as a disease-site independent biomarker.

  2. Accounting Curriculum.

    ERIC Educational Resources Information Center

    Prickett, Charlotte

    This curriculum guide describes the accounting curriculum in the following three areas: accounting clerk, bookkeeper, and nondegreed accountant. The competencies and tasks complement the Arizona validated listing in these areas. The guide lists 24 competencies for nondegreed accountants, 10 competencies for accounting clerks, and 11 competencies…

  3. Anti-tubulin drugs conjugated to anti-ErbB antibodies selectively radiosensitize

    PubMed Central

    Adams, Stephen R.; Yang, Howard C.; Savariar, Elamprakash N.; Aguilera, Joe; Crisp, Jessica L.; Jones, Karra A.; Whitney, Michael A.; Lippman, Scott M.; Cohen, Ezra E. W.; Tsien, Roger Y.; Advani, Sunil J.

    2016-01-01

    Tumour resistance to radiotherapy remains a barrier to improving cancer patient outcomes. To overcome radioresistance, certain drugs have been found to sensitize cells to ionizing radiation (IR). In theory, more potent radiosensitizing drugs should increase tumour kill and improve patient outcomes. In practice, clinical utility of potent radiosensitizing drugs is curtailed by off-target side effects. Here we report potent anti-tubulin drugs conjugated to anti-ErbB antibodies selectively radiosensitize to tumours based on surface receptor expression. While two classes of potent anti-tubulins, auristatins and maytansinoids, indiscriminately radiosensitize tumour cells, conjugating these potent anti-tubulins to anti-ErbB antibodies restrict their radiosensitizing capacity. Of translational significance, we report that a clinically used maytansinoid ADC, ado-trastuzumab emtansine (T-DM1), with IR prolongs tumour control in target expressing HER2+ tumours but not target negative tumours. In contrast to ErbB signal inhibition, our findings establish an alternative therapeutic paradigm for ErbB-based radiosensitization using antibodies to restrict radiosensitizer delivery. PMID:27698471

  4. Radiosensitization by the histone deacetylase inhibitor vorinostat under hypoxia and with capecitabine in experimental colorectal carcinoma

    PubMed Central

    2012-01-01

    Background The histone deacetylase inhibitor vorinostat is a candidate radiosensitizer in locally advanced rectal cancer (LARC). Radiosensitivity is critically influenced by hypoxia; hence, it is important to evaluate the efficacy of potential radiosensitizers under variable tissue oxygenation. Since fluoropyrimidine-based chemoradiotherapy (CRT) is the only clinically validated regimen in LARC, efficacy in combination with this established regimen should be assessed in preclinical models before a candidate drug enters clinical trials. Methods Radiosensitization by vorinostat under hypoxia was studied in four colorectal carcinoma cell lines and in one colorectal carcinoma xenograft model by analysis of clonogenic survival and tumor growth delay, respectively. Radiosensitizing effects of vorinostat in combination with capecitabine were assessed by evaluation of tumor growth delay in two colorectal carcinoma xenografts models. Results Under hypoxia, radiosensitization by vorinostat was demonstrated in vitro in terms of decreased clonogenicity and in vivo as inhibition of tumor growth. Adding vorinostat to capecitabine-based CRT increased radiosensitivity of xenografts in terms of inhibited tumor growth. Conclusions Vorinostat sensitized colorectal carcinoma cells to radiation under hypoxia in vitro and in vivo and improved therapeutic efficacy in combination with capecitabine-based CRT in vivo. The results encourage implementation of vorinostat into CRT in LARC trials. PMID:23017053

  5. Life Experiences of People Who Stutter, and the Perceived Impact of Stuttering on Quality of Life: Personal Accounts of South African Individuals

    ERIC Educational Resources Information Center

    Klompas, Michelle; Ross, Eleanor

    2004-01-01

    The purpose of the study was to investigate the life experiences of a group of South African adults who stutter and the impact of stuttering on their quality of life. Participants were 16 adults with a mean age of 28.9 and ranging from 20 to 59 years. Methods involved individual interviews designed to explore the life domains of education; social…

  6. Differentiation and radiosensitivity of hemopoietic stem cells of mice during hypokinesia

    NASA Technical Reports Server (NTRS)

    Shvets, V. N.

    1980-01-01

    The potential for differentiation and radiosensitivity of the stem hemopoietic cells (KOE) under conditions of initial and later hypokinesia is examined. It is established that in the initial period of hypokinesia (3 days) when a stress reaction prevails, changes occur in the erythroid differentiation and radiosensitivity of KOE. This effect is associated with redistribution of T-lymphocytes that increase in number in the bone marrow of mice during hypokinesia. At later periods of hypokinesia (30 days) when changes in the organism are related to hypokinesia proper, differentiation and radiosensitivity of KOE were normalized.

  7. DNA Damage Response Assessments in Human Tumor Samples Provide Functional Biomarkers of Radiosensitivity

    PubMed Central

    Willers, Henning; Gheorghiu, Liliana; Liu, Qi; Efstathiou, Jason A.; Wirth, Lori J.; Krause, Mechthild; von Neubeck, Cläre

    2015-01-01

    Predictive biomarkers are urgently needed for individualization of radiation therapy and treatment with radiosensitizing anti-cancer agents. Genomic profiling of human cancers will provide us with unprecedented insight into the mutational landscape of genes directly or indirectly involved in the response to radiation-induced DNA damage. However, to what extent this wealth of structural information about the cancer genome will produce biomarkers of sensitivity to radiation remains to be seen. Investigators are increasingly studying the subnuclear accumulation (i.e., foci) of proteins in the DNA damage response (DDR), such as γ-H2AX, 53BP1, or RAD51, as a surrogate of treatment sensitivity. Recent findings from preclinical studies have demonstrated the predictive potential of DDR foci by correlating foci with clinically relevant endpoints such as tumor control probability. Therefore, pre-clinical investigations of DDR foci responses are increasingly moving into cells and tissues from patients, which is the major focus of this review. The advantage of using DDR foci as functional biomarkers is that they can detect alterations in DNA repair due to various mechanisms. Moreover, they provide a global measurement of DDR network function without needing to know the identities of all the components, many of which remain unknown. Foci assays are thus expected to yield functional insight that may complement or supersede genomic information, thereby giving radiation oncologists unique opportunities to individualize cancer treatments in the near future. PMID:26384272

  8. The National Trajectory Project of Individuals Found Not Criminally Responsible on Account of Mental Disorder in Canada. Part 1: Context and Methods

    PubMed Central

    Crocker, Anne G; Nicholls, Tonia L; Seto, Michael C; Côté, Gilles; Charette, Yanick; Caulet, Malijai

    2015-01-01

    The National Trajectory Project examined longitudinal data from a large sample of people found not criminally responsible on account of mental disorder (NCRMD) to assess the presence of provincial differences in the application of the law, to examine the characteristics of people with serious mental illness who come into conflict with the law and receive this verdict, and to investigate the trajectories of NCRMD–accused people as they traverse the mental health and criminal justice systems. Our paper describes the rationale for the National Trajectory Project and the methods used to collect data in Quebec, Ontario, and British Columbia, the 3 most populous provinces in Canada and the 3 provinces with the most people found NCRMD. PMID:25886685

  9. Potential radiosensitizing agents. 5. 2-Substituted benzimidazole derivatives

    SciTech Connect

    Gupta, R.P.; Larroquette, C.A.; Agrawal, K.C.

    1982-11-01

    A series of 2-substituted benzimidazoles and their derivatives have been synthesized and tested for their ability to selectively sensitize hypoxic Chinese hamster cells (V-79) toward the lethal effect of ionizing radiation. These compounds were prepared by reacting the 2-substituted benzimidazoles with 1,2-epoxy-3-methoxypropane in the presence of potassium carbonate. Reaction of the 2-nitro and 2-methylfonyl analogue with the epoxide also yielded a cyclized material, which was confirmed to be a benzimidazo(2,1-b)oxazole. In an attempt to increase the electron affinity, 5- or 6-nitro-2-substituted-benzimidazoles were also synthesized and then reacted with the epoxide to yield the corresponding 1-substituted derivatives. The results of the biological tests for the radiosensitizing activity of these agents against Chinese hamster cells (V-79) in culture indicated that the 2-nitro-substituted analogues were the most effective sensitizers in this series.

  10. Dissociative electron attachment to the radiosensitizing chemotherapeutic agent hydroxyurea

    NASA Astrophysics Data System (ADS)

    Huber, S. E.; Śmiałek, M. A.; Tanzer, K.; Denifl, S.

    2016-06-01

    Dissociative electron attachment to hydroxyurea was studied in the gas phase for electron energies ranging from zero to 9 eV in order to probe its radiosensitizing capabilities. The experiments were carried out using a hemispherical electron monochromator coupled with a quadrupole mass spectrometer. Diversified fragmentation of hydroxyurea was observed upon low energy electron attachment and here we highlight the major dissociation channels. Moreover, thermodynamic thresholds for various fragmentation reactions are reported to support the discussion of the experimental findings. The dominant dissociation channel, which was observed over a broad range of energies, is associated with formation of NCO-, water, and the amidogen (NH2) radical. The second and third most dominant dissociation channels are associated with formation of NCNH- and NHCONH2-, respectively, which are both directly related to formation of the highly reactive hydroxyl radical. Other ions observed with significant abundance in the mass spectra were NH2-/O-, OH-, CN-, HNOH-, NCONH2-, and ONHCONH2-.

  11. Effect of medroxyprogesterone acetate (Provera) on ovarian radiosensitivity

    SciTech Connect

    Jarrell, J.; YoungLai, E.V.; McMahon, A.; Barr, R.; O'Connell, G.; Belbec, L.

    1989-04-01

    Medroxyprogesterone acetate (Provera) is a drug that is commonly given to young women with cancer during chemotherapy and radiation to control heavy bleeding associated with anovulation. Because hypothalamic-pituitary-ovarian suppression has been associated with ovarian protection from the effects of chemotherapy and medroxyprogesterone acetate has been identified as a radiosensitizing agent, we explored the effects of medroxyprogesterone acetate on a rat model with known radiation injury characteristics. Sprague-Dawley rats were treated with medroxyprogesterone acetate or vehicle from day 22 to day 37 of life and were either irradiated or sham-irradiated on day 30 of life and then killed on day 44. Radiation with medroxyprogesterone acetate administration produced a greater loss in preantral and healthy control follicles than in control follicles. No suppression of luteinizing hormone or follicle-stimulating hormone had occurred by day 30 but ovarian glutathione content was reduced. These findings indicate that the administration of medroxyprogesterone acetate with radiotherapy may enhance ovarian injury.

  12. Expression of hPNAS-4 Radiosensitizes Lewis Lung Cancer

    SciTech Connect

    Zeng Hui; Yuan Zhu; Zhu Hong; Li Lei; Shi Huashan; Wang Zi; Fan Yu; Deng Qian; Zeng Jianshuang; He Yinbo; Xiao Jianghong; Li Zhiping

    2012-11-15

    Purpose: This study aimed to transfer the hPNAS-4 gene, a novel apoptosis-related human gene, into Lewis lung cancer (LL2) and observe its radiosensitive effect on radiation therapy in vitro and in vivo. Methods and Materials: The hPNAS-4 gene was transfected into LL2 cells, and its expression was detected via western blot. Colony formation assay and flow cytometry were used to detect the growth and apoptosis of cells treated with irradiation/PNAS-4 in vitro. The hPNAS-4 gene was transferred into LL2-bearing mice through tail vein injection of the liposome/gene complex. The tumor volumes were recorded after radiation therapy. Proliferating cell nuclear antigen (PCNA) immunohistochemistry staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay were performed to detect the tumor cell growth and apoptosis in vivo. Results: The hPNAS-4 gene was successfully transferred into LL2 cells and tumor tissue, and its overexpressions were confirmed via western blot analysis. Compared with the control, empty plasmid, hPNAS-4, radiation, and empty plasmid plus radiation groups, the hPNAS-4 plus radiation group more significantly inhibited growth and enhanced apoptosis of LL2 cells in vitro and in vivo (P<.05). Conclusions: The hPNAS-4 gene was successfully transferred into LL2 cells and tumor tissue and was expressed in both LL2 cell and tumor tissue. The hPNAS-4 gene therapy significantly enhanced growth inhibition and apoptosis of LL2 tumor cells by radiation therapy in vitro and in vivo. Therefore, it may be a potential radiosensitive treatment of radiation therapy for lung cancer.

  13. Karenitecin (bnp1350) and flavopridol as radiosensitizers in malignant glioma

    PubMed Central

    Rajesh, Deepika; Robins, H. Ian; Howard, Steven P.

    2016-01-01

    The poor prognosis of malignant glioma patients highlights the need to develop low toxicity, tumor specific agents with the ability to synergize with proven efficacious treatment modalities, e.g., ionizing irradiation. This paper investigates the potential of BNP1350 (karenitecin), a topoisomerase I-targeting anticancer agent, and flavopridol a cyclin-dependent kinase inhibitor as radiosensitizers at clinically relevant doses in glioblastoma cell lines. A clonogenic survival and apoptosis assays were performed to test the effect of karenitecin (0.1 nM to 10 nM), flavopridol, (50 nM to 500 nM), radiation (1 Gy to 5.5 Gy) and a combination of radiation and karenitecin or radiation and flavopridol on the glioma cell lines T986 and M059K. Cells were stained for cyclins B and D using antibodies followed by flow cytometry. Propidium Iodide staining was used to reveal the various phases of the cell cycle; cyclin staining in the G0/G1 and G2/M phase of the cell cycle was estimated as the Mean Fluorescence Intensity (MFI) after subtracting the MFI recorded by the isotype controls. Results demonstrated that in irradiated cells, pretreatment with karenitecin induced apoptosis, a transient arrest in the G2/M phase of the cell cycle and increased the expression of cyclin B1. Flavopridol treatment also induced apoptosis and a transient block in the G2/M phase of the cell cycle. The combined effects of karenitecin and flavopridol displayed synergistic effects. The unique radiosensitizing activity of orally administrable karenitecin and flavopridol is consistent with continued investigation of these compounds preclinically, as well as in the clinical setting. PMID:28111642

  14. Radiosensitization by Inhibiting STAT1 in Renal Cell Carcinoma

    SciTech Connect

    Hui Zhouguang; Tretiakova, Maria; Zhang Zhongfa; Li Yan; Wang Xiaozhen; Zhu, Julie Xiaohong; Gao Yuanhong; Mai Weiyuan; Furge, Kyle; Qian Chaonan; Amato, Robert; Butler, E. Brian

    2009-01-01

    Purpose: Renal cell carcinoma (RCC) has been historically regarded as a radioresistant malignancy, but the molecular mechanism underlying its radioresistance is not understood. This study investigated the role of signal transducer and activator of transcription 1 (STAT1), a transcription factor downstream of the interferon-signaling pathway, in radioresistant RCC. Methods and Materials: The expressions of STAT1 and STAT3 in 164 human clear cell RCC samples, 47 papillary RCC samples, and 15 normal kidney tissue samples were examined by microarray expression profiling and immunohistochemistry. Western blotting was performed to evaluate the total and phosphorylated STAT1 expression in CRL-1932 (786-O) (human clear cell RCC), SKRC-39 (human papillary RCC), CCL-116 (human fibroblast), and CRL-1441 (G-401) (human Wilms tumor). STAT1 was reduced or inhibited by fludarabine and siRNA, respectively, and the effects on radiation-induced cell death were investigated using clonogenic assays. Results: STAT1 expression, but not STAT3 expression, was significantly greater in human RCC samples (p = 1.5 x 10{sup -8} for clear cell; and p = 3.6 x 10{sup -4} for papillary). Similarly, the expression of STAT1 was relatively greater in the two RCC cell lines. STAT1 expression was reduced by both fludarabine and siRNA, significantly increasing the radiosensitivity in both RCC cell lines. Conclusion: This is the first study reporting the overexpression of STAT1 in human clear cell and papillary RCC tissues. Radiosensitization in RCC cell lines was observed by a reduction or inhibition of STAT1 signaling, using fludarabine or siRNA. Our data suggest that STAT1 may play a key role in RCC radioresistance and manipulation of this pathway may enhance the efficacy of radiotherapy.

  15. miR-424 acts as a tumor radiosensitizer by targeting aprataxin in cervical cancer

    PubMed Central

    Jin, Hua; Zou, Hua; Xia, Wei; Dai, Nan; Dai, Xiao-Yan; Wang, Dong; Xu, Cheng-Xiong; Qing, Yi

    2016-01-01

    Previous studies have shown that some dysregulated miRNAs are involved in radioresistance of tumor cells. Here, we identified significantly decreased miR-424 expression in radioresistant cervical cancer cells and specimens from cervical cancer patients with radioresistance compared to their radiosensitive parental cells and specimens from radiosensitive patients, respectively. Ectopic expression of miR-424 significantly increased radiation-induced DNA damage, cell apoptosis and G2/M cell cycle arrest in radioresistant cervical cancer cells. Notably, miR-424 agomiR treatment can sensitize radioresistant cervical cancer cells to radiation in a xenograft model. Furthermore, we demonstrated that miR-424 regulated radiosensitivity by directly targeting aprataxin. Taken together, these findings suggest that miR-424 acts as a radiosensitizing miRNA and reveal a new therapeutic strategy for radioresistant cervical cancers. PMID:27769049

  16. Suppression of autophagy augments the radiosensitizing effects of STAT3 inhibition on human glioma cells

    SciTech Connect

    Yuan, Xiaopeng; Du, Jie; Hua, Song; Zhang, Haowen; Gu, Cheng; Wang, Jie; Yang, Lei; Huang, Jianfeng; Yu, Jiahua Liu, Fenju

    2015-01-15

    Radiotherapy is an essential component of the standard therapy for newly diagnosed glioblastoma. To increase the radiosensitivity of glioma cells is a feasible solution to improve the therapeutic effects. It has been suggested that inhibition of signal transducer and activator of transcription 3 (STAT3) can radiosensitize glioma cells, probably via the activation of mitochondrial apoptotic pathway. In this study, human malignant glioma cells, U251 and A172, were treated with an STAT3 inhibitor, WP1066, or a short hairpin RNA plasmid targeting STAT3 to suppress the activation of STAT3 signaling. The radiosensitizing effects of STAT3 inhibition were confirmed in glioma cells. Intriguingly, combination of ionizing radiation exposure and STAT3 inhibition triggered a pronounced increase of autophagy flux. To explore the role of autophagy, glioma cells were treated with 3-methyladenine or siRNA for autophagy-related gene 5, and it was demonstrated that inhibition of autophagy further strengthened the radiosensitizing effects of STAT3 inhibition. Accordingly, more apoptotic cells were induced by the dual inhibition of autophagy and STAT3 signaling. In conclusion, our data revealed a protective role of autophagy in the radiosensitizing effects of STAT3 inhibition, and inhibition of both autophagy and STAT3 might be a potential therapeutic strategy to increase the radiosensitivity of glioma cells. - Highlights: • Inactivation of STAT3 signaling radiosensitizes malignant glioma cells. • STAT3 inhibition triggers a significant increase of autophagy flux induced by ionizing radiation in glioma cells. • Suppression of autophagy further strengthens the radiosensitizing effects of STAT3 inhibition in glioma cells. • Dual inhibition of autophagy and STAT3 induce massive apoptotic cells upon exposure to ionizing radiation.

  17. Dietary Restraint Partially Mediates the Relationship between Impulsivity and Binge Eating Only in Lean Individuals: The Importance of Accounting for Body Mass in Studies of Restraint

    PubMed Central

    Coffino, Jaime A.; Orloff, Natalia C.; Hormes, Julia M.

    2016-01-01

    Binge eating is characteristic of eating and weight-related disorders such as binge eating disorder, bulimia nervosa, and obesity. In light of data suggest impulsivity is associated with overeating specifically in restrained eaters, this study sought to elucidate the exact nature of the associations between these variables, hypothesizing that the relationship between impulsivity and binge eating is mediated by restrained eating. We further hypothesized that the role of dietary restraint as a mediator would be moderated by body mass index (BMI). Study participants (n = 506, 50.6% female) were categorized based on self-reported BMI as under- and normal-weight (BMI < 25, 65.8%, n = 333) or overweight and obese (BMI ≥ 25, 34.2%, n = 173) and completed the “restrained eating” subscale of the Dutch Eating Behavior Questionnaire, the “impulse control difficulties” subscale of the Difficulties with Emotion Regulation Scale, and the Binge Eating Scale. Findings provide initial evidence for the hypothesized moderated mediation model, with dietary restraint partially mediating the relationship between impulsivity and binge eating severity only in lean respondents. In respondents with overweight or obesity, impulsivity was significantly correlated with binge eating severity, but not with dietary restraint. Findings inform our conceptualization of dietary restraint as a possible risk factor for binge eating and highlight the importance of accounting for body mass in research on the impact of dietary restraint on eating behaviors. PMID:27757092

  18. The National Trajectory Project of Individuals Found Not Criminally Responsible on Account of Mental Disorder in Canada. Part 3: Trajectories and Outcomes Through the Forensic System

    PubMed Central

    Crocker, Anne G; Charette, Yanick; Seto, Michael C; Nicholls, Tonia L; Côté, Gilles; Caulet, Malijai

    2015-01-01

    Objective: To examine the processing and Review Board (RB) disposition outcomes of people found not criminally responsible on account of mental disorder (NCRMD) across the 3 most populous provinces in Canada. Although the Criminal Code is federally legislated, criminal justice is administered by provinces and territories. It follows that a person with mental illness who comes into conflict with the law and subsequently comes under the management of a legally mandated RB may experience different trajectories across jurisdictions. Method: The National Trajectory Project examined 1800 men and women found NCRMD in British Columbia (n = 222), Quebec (n = 1094), and Ontario (n = 484) between May 2000 and April 2005, followed until December 2008. Results: We found significant interprovincial differences in the trajectories of people found NCRMD, including time detained in hospital and time under the supervision of an RB. The odds of being conditionally or absolutely discharged by the RB varied across provinces, even after number of past offences, diagnosis at verdict, and most severe index offence (all covariates decreased likelihood of discharge) were considered. Conclusions: Considerable discrepancies in the application of NCRMD legislation and the processing of NCRMD cases through the forensic system across the provinces suggests that fair and equitable treatment under the law could be enhanced by increased national integration and collaboration. PMID:25886687

  19. Is Nitric Oxide (NO) the Last Word in Radiosensitization? A Review

    PubMed Central

    Oronsky, Bryan T; Knox, Susan J; Scicinski, Jan J

    2012-01-01

    As a short-lived radical that diffuses across membranes, rather than interacting with membrane-bound receptors, nitric oxide (NO) represents a significant departure from synthetically derived radiosensitizers. An endogenous compound, NO may equal or surpass its molecular cousin, oxygen, as a hypoxic radiosensitizer, through pleiotropic phenotypic effects on tumor perfusion, cell signaling, mitochondrial respiration, the fixation of radiation-induced damage, and the radioprotection of normal tissue. However, unlike oxygen, in the context of radiosensitization, the clinical role and utility of NO are poorly understood, with often contradictory and controversial reported effects: whether NO functions as a radiosensitizer may ultimately be contextual to the tumor microenvironment. This may make NO manipulation an ideal candidate for a personalized radiosensitization approach tailored to specific patient and tumor types/microenvironmental characteristics. Effective delivery of NO both systemically and directly to the tumor may be critical to the success of this approach. Compounds that release NO or NO precursors have the potential to drive innovation and result in a new fertile branch of the radiosensitizer tree. PMID:22496921

  20. The National Trajectory Project of Individuals Found Not Criminally Responsible on Account of Mental Disorder in Canada. Part 2: The People Behind the Label

    PubMed Central

    Crocker, Anne G; Nicholls, Tonia L; Seto, Michael C; Charette, Yanick; Côté, Gilles; Caulet, Malijai

    2015-01-01

    Objective: To examine the psychosocio-criminological characteristics of not criminally responsible on account of mental disorder (NCRMD)–accused people and compare them across the 3 most populous provinces. In Canada, the number of people found NCRMD has risen during the past 20 years. The Criminal Code is federally legislated but provincially administered, and mental health services are provincially governed. Our study offers a rare opportunity to observe the characteristics and trajectories of NCRMD–accused people. Method: The National Trajectory Project examined 1800 men and women found NCRMD in British Columbia (n = 222), Quebec (n = 1094), and Ontario (n = 484) between May 2000 to April 2005, followed until December 2008. Results: The most common primary diagnosis was a psychotic spectrum disorder. One-third of NCRMD–accused people had a severe mental illness and a concomitant substance use disorder, with British Columbia having the highest rate of dually diagnosed NCRMD–accused people. Most accused people (72.4%) had at least 1 prior psychiatric hospitalization. Two-thirds of index NCRMD offences were against the person, with a wide range of severity. Family members, followed by professionals, such as police and mental health care workers, were the most frequent victims. Quebec had the highest proportion of people with a mood disorder and the lowest median offence severity. There were both interprovincial differences and similarities in the characteristics of NCRMD–accused people. Conclusions: Contrary to public perception, severe violent offenses such as murder, attempted murder or sexual offences represent a small proportion of all NCRMD verdict offences. The results reveal a heterogeneous population regarding mental health and criminological characteristics in need of hierarchically organized forensic mental health services and levels of security. NCRMD–accused people were well known to civil psychiatric services prior to being found NCRMD

  1. Randomly Accountable

    ERIC Educational Resources Information Center

    Kane, Thomas J.; Staiger, Douglas O.; Geppert, Jeffrey

    2002-01-01

    The accountability debate tends to devolve into a battle between the pro-testing and anti-testing crowds. When it comes to the design of a school accountability system, the devil is truly in the details. A well-designed accountability plan may go a long way toward giving school personnel the kinds of signals they need to improve performance.…

  2. c-MYC is a radiosensitive locus in human breast cells

    PubMed Central

    Wade, M A; Sunter, N J; Fordham, S E; Long, A; Masic, D; Russell, L J; Harrison, C J; Rand, V; Elstob, C; Bown, N; Rowe, D; Lowe, C; Cuthbert, G; Bennett, S; Crosier, S; Bacon, C M; Onel, K; Scott, K; Scott, D; Travis, L B; May, F E B; Allan, J M

    2015-01-01

    Ionising radiation is a potent human carcinogen. Epidemiological studies have shown that adolescent and young women are at increased risk of developing breast cancer following exposure to ionising radiation compared with older women, and that risk is dose-dependent. Although it is well understood which individuals are at risk of radiation-induced breast carcinogenesis, the molecular genetic mechanisms that underlie cell transformation are less clear. To identify genetic alterations potentially responsible for driving radiogenic breast transformation, we exposed the human breast epithelial cell line MCF-10A to fractionated doses of X-rays and examined the copy number and cytogenetic alterations. We identified numerous alterations of c-MYC that included high-level focal amplification associated with increased protein expression. c-MYC amplification was also observed in primary human mammary epithelial cells following exposure to radiation. We also demonstrate that the frequency and magnitude of c-MYC amplification and c-MYC protein expression is significantly higher in breast cancer with antecedent radiation exposure compared with breast cancer without a radiation aetiology. Our data also demonstrate extensive intratumor heterogeneity with respect to c-MYC copy number in radiogenic breast cancer, suggesting continuous evolution at this locus during disease development and progression. Taken together, these data identify c-MYC as a radiosensitive locus, implicating this oncogenic transcription factor in the aetiology of radiogenic breast cancer. PMID:25531321

  3. Increased radiosensitivity of a subpopulation of T-lymphocyte progenitors from patients with Fanconi's anemia

    SciTech Connect

    Knox, S.J.; Wilson, F.D.; Greenberg, B.R.; Shifrine, M.; Rosenblatt, L.S.; Reeves, J.D.; Misra, H.

    1981-06-01

    In vitro radiation survival of peripheral blood T lymphocytes was studied in 15 clinically normal adults and 4 patients with Fanconi's anemia. Tritiated thymidine incorporation in a whole blood lymphocyte stimulation test (LST) and a newly developed whole blood T-lymphocyte colony assay were used to measure lymphocyte blastogenesis and colony formation in response to phytohemagglutinin (PHA) or concanavalin-A (Con-A) stimulation. Lymphocyte colony formation was found to be consistently more sensitive than the LST for detection of low-level radiation effects using both normal cells and lymphocytes from Fanconi's anemia patients. Lymphocytes from patients with Fanconi's anemia were significantly more sensitive to in vitro x irradiation than lymphocytes from clinically normal individuals as measured by their ability to divide when stimulated by PHA in the LST and colony formation assay. No significant difference in the radiosensitivity of the Con-A response was observed between the two groups. The PHA-responsive T-lymphocyte subpopulation in Fanconi's anemia patients appears to be intrinsically defective. The nature of this defect, significance in the disease process, and relevancy of these findings to the establishment of radiation protection standards are discussed.

  4. Increased radiosensitivity of a subpopulation ot T-lymphocyte progenitors from patients with Fanconi's anemia

    SciTech Connect

    Knox, S.J.; Wilson, F.D.; Greenberg, B.R.; Shifrine, M.; Rosenblatt, L.S.; Reeves, J.D.; Misra, H.

    1981-06-01

    In vitro radiation survival of peripheral blood T lymphocytes was studied in 15 clinically normal adults and 4 patients with Fanconi's anemia. Tritiated thymidine incorporation in a whole blood lymphocyte stimulation test (LST) and a newly developed whole blood T-lymphocyte colony assay were used to measure lymphocyte blastogenesis and colony formation in response to phytohemagglutinin (PHA) or concanavalin-A (Con-A) stimulation. Lymphocyte colony formation was found to be consistently more sensitive than the LST for detection of low-level radiation effects using both normal cells and lymphocytes from Fanconi's anemia patients. Lymphocytes from patients with Fanconi's anemia were significantly more sensitive to in vitro x-irradiation than lymphocytes from clinically normal individuals as measured by their ability to divide when stimulated by PHA in the LST (patients, D37 . 198 R; normals, D37 . 309 R, p . 0.057) and colony formation assay (patients, D37 . 53 R; normals, D37 . 109 R, p . 0.016). No significant difference in the radiosensitivity of the Con-A response was observed between the two groups. The PHA-responsive T-lymphocyte subpopulation in Fanconi's anemia patients appears to be intrinsically defective. The nature of this defect, significance in the disease process, and relevancy of these findings to the establishment of radiation protection standards are discussed.

  5. Fulvestrant radiosensitizes human estrogen receptor-positive breast cancer cells

    SciTech Connect

    Wang, Jing; Yang, Qifeng; Haffty, Bruce G.; Li, Xiaoyan; Moran, Meena S.

    2013-02-08

    Highlights: ► Fulvestrant radiosensitizes MCF-7 cells. ► Fulvestrant increases G1 arrest and decreases S phase in MCF-7 cells. ► Fulvestrant down-regulates DNA-PKcs and RAD51 in MCF-7 cells. -- Abstract: The optimal sequencing for hormonal therapy and radiation are yet to be determined. We utilized fulvestrant, which is showing promise as an alternative to other agents in the clinical setting of hormonal therapy, to assess the cellular effects of concomitant anti-estrogen therapy (fulvestrant) with radiation (F + RT). This study was conducted to assess the effects of fulvestrant alone vs. F + RT on hormone-receptor positive breast cancer to determine if any positive or negative combined effects exist. The effects of F + RT on human breast cancer cells were assessed using MCF-7 clonogenic and tetrazolium salt colorimetric (MTT) assays. The assays were irradiated with a dose of 0, 2, 4, 6 Gy ± fulvestrant. The effects of F + RT vs. single adjuvant treatment alone on cell-cycle distribution were assessed using flow cytometry; relative expression of repair proteins (Ku70, Ku80, DNA-PKcs, Rad51) was assessed using Western Blot analysis. Cell growth for radiation alone vs. F + RT was 0.885 ± 0.013 vs. 0.622 ± 0.029 @2 Gy, 0.599 ± 0.045 vs. 0.475 ± 0.054 @4 Gy, and 0.472 ± 0.021 vs. 0.380 ± 0.018 @6 Gy RT (p = 0.003). While irradiation alone induced G2/M cell cycle arrest, the combination of F + RT induced cell redistribution in the G1 phase and produced a significant decrease in the proportion of cells in G2 phase arrest and in the S phase in breast cancer cells (p < 0.01). Furthermore, levels of repair proteins DNA-PKcs and Rad51 were significantly decreased in the cells treated with F + RT compared with irradiation alone. F + RT leads to a decrease in the surviving fraction, increased cell cycle arrest, down regulating of nonhomologous repair protein DNA-PKcs and homologous recombination repair protein RAD51. Thus, our findings suggest that F + RT

  6. Revamping High School Accounting Courses.

    ERIC Educational Resources Information Center

    Bittner, Joseph

    2002-01-01

    Provides ideas for updating accounting courses: convert to semester length; focus on financial reporting/analysis, financial statements, the accounting cycle; turn textbook exercises into practice sets for the accounting cycle; teach about corporate accounting; and address individual line items on financial statements. (SK)

  7. DNA-PKcs-Dependent Modulation of Cellular Radiosensitivity by a Selective Cyclooxygenase-2 Inhibitor

    SciTech Connect

    Kodym, Elisabeth; Kodym, Reinhard; Chen, Benjamin P.; Chen, David J.; Morotomi-Yano, Keiko; Choy, Hak; Saha, Debabrata

    2007-09-01

    Purpose: Inhibition of cyclooxygenase-2 has been shown to increase radiosensitivity. Recently, the suppression of radiation-induced DNA-dependant protein kinase (DNA-PK) activity by the selective cyclooxygenase-2 inhibitor celecoxib was reported. Given the importance of DNA-PK for repair of radiation-induced DNA double-strand breaks by nonhomologous end-joining and the clinical use of the substance, we investigated the relevance of the DNA-PK catalytic subunit (DNA-PKcs) for the modulation of cellular radiosensitivity by celecoxib. Methods and Materials: We used a syngeneic model of Chinese hamster ovarian cell lines: AA8, possessing a wild-type DNK-PKcs; V3, lacking a functional DNA-PKcs; and V3/WT11, V3 stably transfected with the DNA-PKcs. The cells were treated with celecoxib (50 {mu}M) for 24 h before irradiation. The modulation of radiosensitivity was determined using the colony formation assay. Results: Treatment with celecoxib increased the cellular radiosensitivity in the DNA-PKcs-deficient cell line V3 with a dose-enhancement ratio of 1.3 for a surviving fraction of 0.5. In contrast, clonogenic survival was increased in DNA-PKcs wild-type-expressing AA8 cells and in V3 cells transfected with DNA-PKcs (V3/WT11). The decrease in radiosensitivity was comparable to the radiosensitization in V3 cells, with a dose-enhancement ratio of 0.76 (AA8) and 0.80 (V3/WT11) for a survival of 0.5. Conclusions: We have demonstrated a DNA-PKcs-dependent differential modulation of cellular radiosensitivity by celecoxib. These effects might be attributed to alterations in signaling cascades downstream of DNA-PK toward cell survival. These findings offer an explanation for the poor outcomes in some recently published clinical trials.

  8. Inhibiting CD146 by its Monoclonal Antibody AA98 Improves Radiosensitivity of Cervical Cancer Cells

    PubMed Central

    Cheng, Huawen

    2016-01-01

    Background Cervical cancer is one of the major causes of cancer death of females worldwide. Radiotherapy is considered effective for cervical cancer treatment, but the low radiosensitivity found in some cases severely affects therapeutic outcomes. This study aimed to reveal the role of CD146, an important adhesion molecule facilitating tumor angiogenesis, in regulating radiosensitivity of cervical cancer cells. Material/Methods CD146 protein expression was compared in normal cells, cervical cancer cells with lower radiosensitivity, and cervical cancer cells with higher sensitivity from cervical squamous cell carcinoma patients. Anti-CD146 monoclonal antibody AA98 was used to inhibit CD146 in human cervical cancer SiHa cells with relatively low radiosensitivity, and then the cell survival and apoptosis changes after radiation were detected by colony formation assay and flow cytometry. Results CD146 protein was significantly up-regulated in cervical cancer cells (P<0.001), especially in cancer cells with lower radiosensitivity. The SiHa cells treated with AA98 showed more obvious inhibition in cell survival (P<0.05) and promotion in cell apoptosis (P<0.01) after radiation, compared to the untreated cells. More dramatic changes in apoptotic factors Caspase 3 and Bcl-XL were also detected in AA98-treated cells. Conclusions These results indicate that inhibiting CD146 improves the effect of radiation in suppressing SiHa cells. This study shows the potential of CD146 as a target for increasing radiosensitivity of cervical cancer cells, which might allow improvement in treatment outcome in cervical cancer. Further studies are necessary for understanding the detailed mechanism of CD146 in regulating radiosensitivity. PMID:27647179

  9. Radiosensitization Effect of STI-571 on Pancreatic Cancer Cells In Vitro

    SciTech Connect

    Chung, Hye Won; Wen, Jing; Lim, Jong-Baeck; Bang, Seung Min; Park, Seung Woo; Song, Si Young

    2009-11-01

    Purpose: To examine STI-571-induced radiosensitivity in human pancreatic cancer cells in vitro. Methods and Materials: Three human pancreatic cancer cell lines (Bxpc-3, Capan-1, and MiaPaCa-2) exhibiting different expression levels of c-Kit and platelet-derived growth factor receptor beta (PDGFRbeta) and showing different K-ras mutation types were used. For evaluation of the antitumor activity of STI-571 in combination with radiation, clonogenic survival assays, Western blot analysis, and the annexin V/propidium iodide assay with microscopic evaluation by 4',6-diamidino-2-phenylindole were conducted. Results: Dramatic phosphorylated (p)-c-Kit and p-PDGFRbeta attenuation, a modest dose- and time-dependent growth inhibition, and significant radiosensitization were observed after STI-571 treatment in view of apoptosis, although the levels of growth inhibition and increased radiosensitization were different according to cell lines. The grades of radiosensitivity corresponded to the attenuation levels of p-c-Kit and p-PDGFRbeta by STI-571, particularly to those of p-c-Kit, and the radiosensitivity was partially affected by K-ras mutation in pancreatic cancer cells. Among downstream pathways associated with c-Kit or PDGFRbeta, p-PLCgamma was more closely related to radiosensitivity compared with p-Akt1 or p-extracellular signal-regulated kinase 1. Conclusion: STI-571 enhances radiation response in pancreatic cancer cells. This effect is affected by the attenuation levels of p-c-Kit or p-PDGFRbeta, and K-ras mutation status. Among them, p-c-Kit plays more important roles in the radiosensitivity in pancreatic cancer compared with p-PDGFRbeta or K-ras mutation status.

  10. Accounting: "Balancing Out" the Accounting Program.

    ERIC Educational Resources Information Center

    Babcock, Coleen

    1979-01-01

    The vocational accounting laboratory is a viable, meaningful educational experience for high school seniors, due to the uniqueness of its educational approach and the direct involvement of the professional and business community. A balance of experiences is provided to match individual needs and goals of students. (CT)

  11. Radiosensitization of two murine fibrosarcomas with 6-thioguanine.

    PubMed

    Kim, J H; Alfieri, A A; Kim, S H; Hong, S S

    1990-03-01

    In Vivo murine tumor experiments were carried out to determine whether 6-thioguanine (6-TG) could enhance the cytotoxic effects of radiation on tumors. The combined effects of single and fractionated x-irradiation were evaluated on the transplanted methylcholanthrene induced fibrosarcoma (Meth-A) in BALB/c mice, a moderately radioresponsive tumor and on the radiation induced fibrosarcoma (RIF) in C3H/He mice, a highly radioresistant tumor. The combined treatment of single administration of 6-TG (25 mg/kg) and of x-irradiation (20 Gy) on Meth-A tumors produced more than 90% tumor control, whereas the radiation alone resulted in less than 5% tumor control. The radiosensitizing effect by 6-TG was higher when the drug was administered either 1 to 8 hr prior to or 24 hr after x-irradiation. The dose modification factor of single dose 6-TG (10 mg/kg) is estimated to be 1.47 for Meth-A tumor and 1.25 for RIF tumor. The tumor control rates of fractionated irradiation alone and with concomitant 6-TG in Meth-A tumors were 14% and 59%, respectively. Based on the studies reported here and well documented pharmacokinetics in humans, it is suggested that combined radiation therapy and 6-TG may provide an enhanced therapeutic effect even in tumor varieties where the drug has no apparent anti-tumor activity on non-irradiated cells.

  12. Targeted Radiosensitization by the Chk1 Inhibitor SAR-020106

    SciTech Connect

    Borst, Gerben R.; McLaughlin, Martin; Kyula, Joan N.; Neijenhuis, Sari; Khan, Aadil; Good, James; Zaidi, Shane; Powell, Ned G.; Meier, Pascal; Collins, Ian; Garrett, Michelle D.; Verheij, Marcel; Harrington, Kevin J.

    2013-03-15

    Purpose: To explore the activity of a potent Chk1 inhibitor (SAR-020106) in combination with radiation. Methods and Materials: Colony and mechanistic in vitro assays and a xenograft in vivo model. Results: SAR-020106 suppressed-radiation-induced G{sub 2}/M arrest and reduced clonogenic survival only in p53-deficient tumor cells. SAR-020106 promoted mitotic entry following irradiation in all cell lines, but p53-deficient cells were likely to undergo apoptosis or become aneuploid, while p53 wild-type cells underwent a postmitotic G{sub 1} arrest followed by subsequent normal cell cycle re-entry. Following combined treatment with SAR-020106 and radiation, homologous-recombination-mediated DNA damage repair was inhibited in all cell lines. A significant increase in the number of pan-γH2AX-staining apoptotic cells was observed only in p53-deficient cell lines. Efficacy was confirmed in vivo in a clinically relevant human head-and-neck cell carcinoma xenograft model. Conclusion: The Chk1 inhibitor SAR-020106 is a potent radiosensitizer in tumor cell lines defective in p53 signaling.

  13. Targeting the AKT pathway: Repositioning HIV protease inhibitors as radiosensitizers.

    PubMed

    Goda, Jayant S; Pachpor, Tejaswini; Basu, Trinanjan; Chopra, Supriya; Gota, Vikram

    2016-02-01

    Cellular resistance in tumour cells to different therapeutic approaches has been a limiting factor in the curative treatment of cancer. Resistance to therapeutic radiation is a common phenomenon which significantly reduces treatment options and impacts survival. One of the mechanisms of acquiring resistance to ionizing radiation is the overexpression or activation of various oncogenes like the EGFR (epidermal growth factor receptor), RAS (rat sarcoma) oncogene or loss of PTEN (phosphatase and tensin homologue) which in turn activates the phosphatidyl inositol 3-kinase/protein kinase B (PI3-K)/AKT pathway responsible for radiation resistance in various tumours. Blocking the pathway enhances the radiation response both in vitro and in vivo. Due to the differential activation of this pathway (constitutively activated in tumour cells and not in the normal host cells), it is an excellent candidate target for molecular targeted therapy to enhance radiation sensitivity. In this regard, HIV protease inhibitors (HPIs) known to interfere with PI3-K/AKT signaling in tumour cells, have been shown to sensitize various tumour cells to radiation both in vitro and in vivo. As a result, HPIs are now being investigated as possible radiosensitizers along with various chemotherapeutic drugs. This review describes the mechanisms by which PI3-K/AKT pathway causes radioresistance and the role of HIV protease inhibitors especially nelfinavir as a potential candidate drug to target the AKT pathway for overcoming radioresistance and its use in various clinical trials for different malignancies.

  14. Targeting the AKT pathway: Repositioning HIV protease inhibitors as radiosensitizers

    PubMed Central

    Goda, Jayant S.; Pachpor, Tejaswini; Basu, Trinanjan; Chopra, Supriya; Gota, Vikram

    2016-01-01

    Cellular resistance in tumour cells to different therapeutic approaches has been a limiting factor in the curative treatment of cancer. Resistance to therapeutic radiation is a common phenomenon which significantly reduces treatment options and impacts survival. One of the mechanisms of acquiring resistance to ionizing radiation is the overexpression or activation of various oncogenes like the EGFR (epidermal growth factor receptor), RAS (rat sarcoma) oncogene or loss of PTEN (phosphatase and tensin homologue) which in turn activates the phosphatidyl inositol 3-kinase/protein kinase B (PI3-K)/AKT pathway responsible for radiation resistance in various tumours. Blocking the pathway enhances the radiation response both in vitro and in vivo. Due to the differential activation of this pathway (constitutively activated in tumour cells and not in the normal host cells), it is an excellent candidate target for molecular targeted therapy to enhance radiation sensitivity. In this regard, HIV protease inhibitors (HPIs) known to interfere with PI3-K/AKT signaling in tumour cells, have been shown to sensitize various tumour cells to radiation both in vitro and in vivo. As a result, HPIs are now being investigated as possible radiosensitizers along with various chemotherapeutic drugs. This review describes the mechanisms by which PI3-K/AKT pathway causes radioresistance and the role of HIV protease inhibitors especially nelfinavir as a potential candidate drug to target the AKT pathway for overcoming radioresistance and its use in various clinical trials for different malignancies. PMID:27121513

  15. The inherent cellular radiosensitivity of epithelial ovarian carcinoma

    SciTech Connect

    Rotmensch, J.; Schwartz, J.L.; Atcher, R.W.; Grdina, D.J.; Toohill, M.; Weichselbaum, R.W. )

    1989-12-01

    Ovarian carcinomas of similar histology have variable responses to radiation therapy. It has been suggested that inherent cellular resistance to radiation may in part underlie radiotherapy failure. To determine in vitro radiobiological parameters of papillary serous adenocarcinoma of the ovary, we investigated the cellular responses of 16 early-passage ovarian carcinoma cell lines to radiation. The radiosensitivity, as measured by D0, ranged from 1.05 to 2.40 Gy (mean 1.70 Gy), and, as measured by D, ranged from 1.65 to 3.54 Gy (mean 2.38 Gy). The extrapolation number -n ranged from 1.1 to 2.0 (mean 1.5). The cells had a 1.3- to 5.4-fold (mean 2.8) ability to recover from potential lethal damage (PLDR) 24 hr after irradiation and subculture from plateau-phase cultures. Their inherent radioresistance may be one factor in the failure of some ovarian cancers to be sterilized by radiation.

  16. Oxidized silicon nanoparticles for radiosensitization of cancer and tissue cells.

    PubMed

    Klein, Stefanie; Dell'Arciprete, Maria L; Wegmann, Marc; Distel, Luitpold V R; Neuhuber, Winfried; Gonzalez, Mónica C; Kryschi, Carola

    2013-05-03

    The applicability of ultrasmall uncapped and aminosilanized oxidized silicon nanoparticles (SiNPs and NH2-SiNPs) as radiosensitizer was studied by internalizing these nanoparticles into human breast cancer (MCF-7) and mouse fibroblast cells (3T3) that were exposed to X-rays at a single dose of 3 Gy. While SiNPs did not increase the production of reactive oxygen species (ROS) in X-ray treated cells, the NH2-SiNPs significantly enhanced the ROS formation. This is due to the amino functionality as providing positive surface charges in aqueous environment. The NH2-SiNPs were observed to penetrate into the mitochondrial membrane, wherein these nanoparticles provoked oxidative stress. The NH2-SiNPs induced mitochondrial ROS production was confirmed by the determination of an increased malondialdehyde level as representing a gauge for the extent of membrane lipid peroxidation. X-ray exposure of NH2-SiNPs incubated MCF-7 and 3T3 cells increased the ROS concentration for 180%, and 120%, respectively. Complementary cytotoxicity studies demonstrate that these silicon nanoparticles are more cytotoxic for MCF-7 than for 3T3 cells.

  17. MK-8776, a novel chk1 kinase inhibitor, radiosensitizes p53-defective human tumor cells

    PubMed Central

    Bridges, Kathleen A.; Chen, Xingxing; Liu, Huifeng; Rock, Crosby; Buchholz, Thomas A.; Shumway, Stuart D.; Skinner, Heath D.; Meyn, Raymond E.

    2016-01-01

    Radiotherapy is commonly used to treat a variety of solid tumors but improvements in the therapeutic ratio are sorely needed. The aim of this study was to assess the Chk1 kinase inhibitor, MK-8776, for its ability to radiosensitize human tumor cells. Cells derived from NSCLC and HNSCC cancers were tested for radiosensitization by MK-8776. The ability of MK-8776 to abrogate the radiation-induced G2 block was determined using flow cytometry. Effects on repair of radiation-induced DNA double strand breaks (DSBs) were determined on the basis of rad51, γ-H2AX and 53BP1 foci. Clonogenic survival analyses indicated that MK-8776 radiosensitized p53-defective tumor cells but not lines with wild-type p53. Abrogation of the G2 block was evident in both p53-defective cells and p53 wild-type lines indicating no correlation with radiosensitization. However, only p53-defective cells entered mitosis harboring unrepaired DSBs. MK-8776 appeared to inhibit repair of radiation-induced DSBs at early times after irradiation. A comparison of MK-8776 to the wee1 inhibitor, MK-1775, suggested both similarities and differences in their activities. In conclusion, MK-8776 radiosensitizes tumor cells by mechanisms that include abrogation of the G2 block and inhibition of DSB repair. Our findings support the clinical evaluation of MK-8776 in combination with radiation. PMID:27690219

  18. Radiosensitizing effect of the histone acetyltransferase inhibitor anacardic acid on various mammalian cell lines

    PubMed Central

    CATE, ROSEMARIE TEN; KRAWCZYK, PRZEMEK; STAP, JAN; ATEN, JACOB A.; FRANKEN, NICOLAAS A.P.

    2010-01-01

    Agents that enhance the effectiveness of ionizing radiation have been investigated over many decades. A relatively new group of potential radiosensitizers consists of agents that inhibit histone acetyltransferases (HATs). This study evaluated the radiosensitizing properties of the HAT inhibitor anacardic acid (AA), used at a low-toxic concentration of 100 μM in V79, SW1573 and U2OS cells. Radiation survival curves were analyzed according to the linear quadratic model. Significant radiosensitization by AA was only obtained in U2OS cells. AA significantly increased the value of the linear parameter α, but not of the quadratic parameter β, indicating fixation of potentially lethal damage and an intact repair function of sublethal damage. The increase of the α value was also observed in SW1573 cells, but was not accompanied by a significant radiosensitization. A likely explanation for the enhancement of the α value may be an increase in the amount of lethal lesions due to the compacted chromatin structure. Despite the conflicting results of the radiosensitizing effect of AA in the three cell lines tested, the ability of AA to increase the α value suggests potential advantages for clinical application. PMID:22966377

  19. Clofarabine Acts as Radiosensitizer In Vitro and In Vivo by Interfering With DNA Damage Response

    SciTech Connect

    Cariveau, Mickael J.; Stackhouse, Murray; Cui Xiaoli; Tiwari, Kamal; Waud, William; Secrist, John A.; Xu Bo

    2008-01-01

    Purpose: Combination treatment with radiotherapy and chemotherapy has emerged as the dominant form of cancer adjuvant regimens in recent years. Clofarabine, a newly approved drug for pediatric leukemia, is a second-generation purine nucleoside analogue that can block DNA synthesis and inhibit DNA repair. Therefore, we hypothesized that clofarabine could work synergistically with radiotherapy to increase the tumor cell response. Methods and Materials: The effects of clofarabine on radiosensitivity have been established in several tumor cell lines in vitro and in vivo using colony-forming assays and tumor xenografts. The effect of clofarabine on the DNA damage response was also studied in vitro by measuring {gamma}-H2AX focus formation. Results: Clonogenic survival was significantly reduced in irradiated cells treated with clofarabine, demonstrating the strong radiosensitizing effect of clofarabine. Furthermore, clofarabine displayed a radiosensitizing effect that was greater than gemcitabine or 5-fluorouracil. We also found that low doses of clofarabine can prolong the presence of radiation-induced {gamma}-H2AX nuclear focus formation, and high doses of clofarabine can induce DNA double-strand breaks, suggesting that clofarabine can interfere with DNA damage response pathways. In addition, clofarabine-induced radiosensitization was also established in vivo using a colorectal cancer model, DLD-1, in athymic nude mice. When combined with fractionated radiotherapy, a moderate dose of clofarabine led to a significant increase in tumor growth inhibition. Conclusion: Clofarabine acts as a powerful radiosensitizer both in vitro and in vivo by interfering with the DNA damage response.

  20. Tetrandrine Exerts a Radiosensitization Effect on Human Glioma through Inhibiting Proliferation by Attenuating ERK Phosphorylation

    PubMed Central

    Ma, Ji-wei; Zhang, Yong; Ye, Ji-cheng; Li, Ru; Wen, Yu-Lin; Huang, Jian-xian; Zhong, Xue-yun

    2017-01-01

    Tetrandrine (Tet), a bisbenzylisoquinoline alkaloid, has been reported to have a radiosensitization effect on tumors. However, its effects on human glioma and the specific molecular mechanisms of these effects remain unknown. In this study, we demonstrated that Tet has a radiosensitization effect on human glioma cells. It has been hypothesized that Tet has a radiosensitization effect on glioma cells by affecting the glioma cell cycle and DNA repair mechanism and that ERK mediates these activities. Therefore, we conducted detailed analyses of the effects of Tet on the cell cycle by performing flow cytometric analysis and on DNA repair by detecting the expression of phosphorylated H2AX by immunofluorescence. We used western blot analysis to investigate the role of ERK in the effect of Tet on the cell cycle and DNA repair. The results revealed that Tet exerts its radiosensitization effect on glioma cells by inhibiting proliferation and decreasing the expression of phosphorylated ERK and its downstream proteins. In summary, our data indicate that ERK is involved in Tet-induced radiosensitization of glioma cells via inhibition of glioma cell proliferation or of the cell cycle at G0/G1 phase. PMID:27829269

  1. Youth Individual Development Accounts: Retirement Planning Initiatives

    ERIC Educational Resources Information Center

    Shobe, Marcia A.; Sturm, Stephanie L.

    2007-01-01

    Given the growing interest in a privatized Social Security system and the lack of adequate retirement planning among many people in the United States, many households are often ill prepared for retirement. The outlook for low-income populations is even bleaker because they are often not privy to the same financial education and asset-building…

  2. MiR-122 Induces Radiosensitization in Non-Small Cell Lung Cancer Cell Line

    PubMed Central

    Ma, Debin; Jia, Hui; Qin, Mengmeng; Dai, Wenjie; Wang, Tao; Liang, Erguang; Dong, Guofu; Wang, Zuojun; Zhang, Zhiyuan; Feng, Fan

    2015-01-01

    MiR-122 is a novel tumor suppresser and its expression induces cell cycle arrest, or apoptosis, and inhibits cell proliferation in multiple cancer cells, including non-small cell lung cancer (NSCLC) cells. Radioresistance of cancer cell leads to the major drawback of radiotherapy for NSCLC and the induction of radiosensitization could be a useful strategy to fix this problem. The present work investigates the function of miR-122 in inducing radiosensitization in A549 cell, a type of NSCLC cells. MiR-122 induces the radiosensitization of A549 cells. MiR-122 also boosts the inhibitory activity of ionizing radiation (IR) on cancer cell anchor-independent growth and invasion. Moreover, miR-122 reduced the expression of its targeted genes related to tumor-survival or cellular stress response. These results indicate that miR-122 would be a novel strategy for NSCLC radiation-therapy. PMID:26389880

  3. Radiosensitization of Human Colorectal Cancer Cells by MLN4924: An Inhibitor of NEDD8-Activating Enzyme.

    PubMed

    Wan, Juefeng; Zhu, Ji; Li, Guichao; Zhang, Zhen

    2016-08-01

    Colorectal cancer is the third most frequently diagnosed cancer and the combination of radiation with capecitabine has been shown to achieve only 15% to 25% of pathologic complete response. This study aimed to investigate the effect of MLN4924, a potent small molecule inhibitor of SKP1-Cullin-F-box proteins E3 ubiquitin ligases, as a novel radiosensitizing agent in colorectal cancer cells. Indeed, we found that MLN4924 effectively sensitized colorectal cancer cells to radiation with a sensitivity-enhancement ratio of 1.61 for HT-29 cells and 1.35 for HCT-116 cells. Mechanistically, MLN4924 significantly enhanced radiation-induced G2/M arrest, apoptosis, and DNA damage response through accumulation of p27. Knockdown of p27 via small interfering RNA partially inhibited MLN4924-induced radiosensitization, indicating a causal role played by p27. Our study suggested that MLN4924 could be further developed as a novel radiosensitizing agent against colorectal cancer.

  4. Radiosensitization of DNA in presence of Pt(II)-based compounds

    NASA Astrophysics Data System (ADS)

    Śmiałek, Małgorzata A.; Ptasińska, Sylwia; Gow, Jason; Pieve, Chiara Da; Mason, Nigel J.

    2014-04-01

    X-ray irradiation of plasmid DNA in presence of platinum (II)-based compounds was carried out in order to assess the radiosensitization capabilities of these drugs. In present investigations pBR322 plasmid DNA was used to monitor the effectiveness of chosen compounds in inducing strand breaks. Samples were incubated in the presence of potential radiosensitisers: platinum (II) bromide and cis-diamminedibromoplatinum (II). The results were examined against a common cancer chemotherapy drug cis-diamminedichloroplatinum (II). It was found that platinum (II) bromide can greatly increase the levels of single- and double-strand break formation observed in the irradiated samples with respect to the samples containing platinum as a radiosensitizer only, possessing very little chemotherapeutic activity. The suggested drugs exhibit much higher level of radiosensitivity than widely used cisplatin and thus may be good candidates for cancer treatment.

  5. Chitooligosaccharides promote radiosensitivity in colon cancer line SW480

    PubMed Central

    Han, Fu-Shi; Yang, Shi-Jie; Lin, Mou-Bin; Chen, Ying-Qun; Yang, Ping; Xu, Jin-Ming

    2016-01-01

    AIM: To investigate the anti-proliferation and radiosensitization effect of chitooligosaccharides (COS) on human colon cancer cell line SW480. METHODS: SW480 cells were treated with 0, 1.0, 2.0, 3.0, 4.0 and 5.0 mg/mL of COS for 48 h. CCK-8 assay was employed to obtain the cell survival ratio of SW480 cells, and the anti-proliferation curve was observed with the inhibition ratio of COS on SW480 cells. The RAY + COS group was treated with 1.0 mg/mL of COS for 48 h, while both the RAY and RAY+COS groups were exposed to X-ray at 0, 1, 2, 4, 6 and 8 Gy, respectively. Clonogenic assay was used to analyze cell viability in the two groups at 10 d after treatment, and a cell survival curve was used to analyze the sensitization ratio of COS. The RAY group was exposed to X-ray at 6 Gy, while the RAY+COS group was treated with 1.0 mg/mL of COS for 48 h in advance and exposed to X-ray at 6 Gy. Flow cytometry was employed to detect cell cycle and apoptosis rate in the non-treatment group, as well as in the RAY and RAY + COS groups after 24 h of treatment. RESULTS: COS inhibited the proliferation of SW480 cells, and the inhibition rate positively correlated with the concentration of COS (P < 0.01). Cell viability decreased as radiation dose increased in the RAY and RAY+COS groups (P < 0.01). Cell viabilities in the RAY+COS group were lower than in the RAY group at all doses of X-ray exposure (P < 0.01), and the sensitization ratio of COS on SW480 cells was 1.39. Compared with the non-treatment group, there was a significant increase in apoptosis rate in both the RAY and RAY + COS groups; while the apoptosis rate in the RAY+COS group was significantly higher than in the RAY group (P < 0.01). In comparing these three groups, the percentage of G2/M phase in both the RAY and RAY + COS groups significantly increased, and the percentage of the S phase and G0/G1 phase was downregulated. Furthermore, the percentage in the G2/M phase was higher, and the percentage in the S phase and G0/G

  6. Nanoscale Dynamics of Radiosensitivity: Role of Low Energy Electrons

    NASA Astrophysics Data System (ADS)

    Sanche, Léon

    This chapter addresses the nanoscale dynamics involved in the sensitization of biological cells to ionizing radiation. More specifically, it describes the role of low energy electrons (LEE) in radiosensitization by gold nanoparticles and chemotherapeutic agents, as well as potential applications to radiotherapy. The basic mechanisms of action of the LEE generated within nanoscopic volumes by ionizing radiation are described in solid water ice and various forms of DNA. These latter include the subunits (i.e., a base, a sugar or the phosphate group), short single strands (i.e., oligonucleotides) and plasmid and linear DNA. By comparing the results from experiments with the different forms of the DNA molecule and theory, it is possible to determine fundamental mechanisms that are involved in the dissociation of the subunits, base release and the production of single, double-strand breaks and cross-links. Below 15 eV, LEE localize on DNA subunits to form transient negative ions. Such states can damage DNA by dissociating into a stable anion and radical fragment(s), via dissociative electron attachment, or by decaying into dissociative electronically excited states. LEE can also transfer from one DNA subunit to another, particularly from a base to the phosphate group, where they can induce cleavage of the C-O bond (i.e., break a strand). DNA damage and the corresponding nanoscale dynamics are found to be modified in the presence of other cellular constituents. For example, condensing on DNA the most abundant cellular molecule, H2O, induces the formation of a new type of transient anion whose parent is a H2O-DNA complex.

  7. Hedgehog Pathway Inhibition Radiosensitizes Non-Small Cell Lung Cancers

    SciTech Connect

    Zeng, Jing; Aziz, Khaled; Chettiar, Sivarajan T.; Aftab, Blake T.; Armour, Michael; Gajula, Rajendra; Gandhi, Nishant; Salih, Tarek; Herman, Joseph M.; Wong, John; Rudin, Charles M.; Tran, Phuoc T.; Hales, Russell K.

    2013-05-01

    Purpose: Despite improvements in chemoradiation, local control remains a major clinical problem in locally advanced non-small cell lung cancer. The Hedgehog pathway has been implicated in tumor recurrence by promoting survival of tumorigenic precursors and through effects on tumor-associated stroma. Whether Hedgehog inhibition can affect radiation efficacy in vivo has not been reported. Methods and Materials: We evaluated the effects of a targeted Hedgehog inhibitor (HhAntag) and radiation on clonogenic survival of human non-small cell lung cancer lines in vitro. Using an A549 cell line xenograft model, we examined tumor growth, proliferation, apoptosis, and gene expression changes after concomitant HhAntag and radiation. In a transgenic mouse model of Kras{sup G12D}-induced and Twist1-induced lung adenocarcinoma, we assessed tumor response to radiation and HhAntag by serial micro-computed tomography (CT) scanning. Results: In 4 human lung cancer lines in vitro, HhAntag showed little or no effect on radiosensitivity. By contrast, in both the human tumor xenograft and murine inducible transgenic models, HhAntag enhanced radiation efficacy and delayed tumor growth. By use of the human xenograft model to differentiate tumor and stromal effects, mouse stromal cells, but not human tumor cells, showed significant and consistent downregulation of Hedgehog pathway gene expression. This was associated with increased tumor cell apoptosis. Conclusions: Targeted Hedgehog pathway inhibition can increase in vivo radiation efficacy in lung cancer preclinical models. This effect is associated with pathway suppression in tumor-associated stroma. These data support clinical testing of Hedgehog inhibitors as a component of multimodality therapy for locally advanced non-small cell lung cancer.

  8. Intra-arterial bromodeoxyuridine radiosensitization of malignant gliomas

    SciTech Connect

    Hegarty, T.J.; Thornton, A.F.; Diaz, R.F.; Chandler, W.F.; Ensminger, W.D.; Junck, L.; Page, M.A.; Gebarski, S.S.; Hood, T.W.; Stetson, P.L. )

    1990-08-01

    In the 1950's it was first observed that mammalian cells exposed to the halogenated deoxyuridines were more sensitive to ultraviolet light and radiation than untreated cells. This prompted early clinical trials with bromodeoxyuridine (BUdR) which showed mixed results. More recently, several Phase I studies, while establishing the feasibility of continuous intravenous (IV) infusion of BUdR, have reported significant dose limiting skin and bone marrow toxicities and have questioned the optimal method of BUdR delivery. To exploit the high mitotic activity of malignant gliomas relative to surrounding normal brain tissue, we have developed a permanently implantable infusion pump system for safe, continuous intraarterial (IA) internal carotid BUdR delivery. Since July 1985, 23 patients with malignant brain tumors (18 grade 4, 5 grade 3) have been treated in a Phase I clinical trial using IA BUdR (400-600 mg/m2/day X 8 1/2 weeks) and focal external beam radiotherapy (59.4 Gy at 1.8 Gy/day in 6 1/2 weeks). Following initial biopsy/surgery the infusion pump system was implanted; BUdR infusion began 2 weeks prior to and continued throughout the 6 1/2 week course of radiotherapy. There have been no vascular complications. Side-effects in all patients have included varying degrees of anorexia, fatigue, ipsilateral forehead dermatitis, blepharitis, and conjunctivitis. Myelosuppression requiring dose reduction occurred in one patient. An overall Kaplan-Meier estimated median survival of 20 months has been achieved. As in larger controlled series, histologic grade and age are prognostically significant. We have shown in a Phase I study that IA BUdR radiosensitization is safe, tolerable, may lead to improved survival, and appears to be an efficacious primary treatment of malignant gliomas.

  9. Radiosensitivity of testicular cells in the fetal mouse

    SciTech Connect

    Vergouwen, R.P.F.A.; Roepers-Gajadien, H.L.; Rooij, D.G. de; Huiskamp, R.; Bas, R.J.; Davids, J.A.G.

    1995-01-01

    The effects of prenatal X irradiation on postnatal development of the CBA/P mouse testis was studied. At days 14, 15 and 18 post coitus pregnant female mice were exposed to single doses of X rays ranging from 0.25-1.5 Gy. Higher doses resulted in extensive loss of fetal mice. In the male offspring, at days 3 and 31 post partum, the numbers of gonocytes, type A spermatogonia and Sertoli cells per testis were determined using the disector method. Furthermore, after irradiation at day 15 post coitus, the numbers of Leydig cells, mesenchymal cells, macrophages, myoid cells, lymphatic endothelial cells, endothelial cells and perivascular cells per testis were also determined at days 3 and 31 post partum. At day 3 post partum, the number of germ cells was decreased after irradiation at days 14 and 15 post coitus. A D{sub o} value of 0.7 Gy was determined for the radiosensitivity of the gonocytes at day 14 post coitus. A D{sub o} value of 0.8 Gy was determined for the gonocytes at day 15 post coitus which, however, seems to be less accurate. No accurate D{sub o} value could be determined for the gonocytes at day 18 post coitus. At day 31 post partum, the repopulation of the seminiferous epithelium as well as testis weights and tubular diameters were more affected by irradiation with increasing age of the mice at the time of irradiation. The percentage of tubular cross sections showing spermatids decreased with increasing dose after irradiation at days 15 and 18 post coitus, but not after irradiation at day 14 post coitus. Furthermore, in tubular cross sections showing spermatids, exposure of testes to 1.25 and 1.5 Gy at day 18 post coitus resulted in significantly lower numbers of spermatids per cross section when compared to those testes exposed to the same doses at day 15 post coitus. 30 refs., 7 figs., 1 tab.

  10. Continuous intravenous infusions of bromodeoxyuridine as a clinical radiosensitizer

    SciTech Connect

    Kinsella, T.J.; Mitchell, J.B.; Russo, A.; Aiken, M.; Morstyn, G.; Hsu, S.M.; Rowland, J.; Glatstein, E.

    1984-10-01

    Twelve patients were treated with continuous intravenous (24-hour) infusions of bromodeoxyuridine (BUdR) at 650 or 1000 mg/m2/d for up to two weeks. Myelosuppression, especially thrombocytopenia, was the major systemic toxicity and limited the infusion period to nine to 14 days. However, bone marrow recovery occurred within seven to ten days, allowing for a second infusion in most patients. Local toxicity (within the radiation field) was minimal, with the exception of one of four patients, who underwent abdominal irradiation. Pharmacology studies revealed a steady-state arterial plasma level of 6 x 10(-7) mol/L and 1 x 10(-6) mol/L during infusion of 650 and 1000 mg/m2/d, respectively. In vivo BUdR uptake into normal bone marrow was evaluated in two patients by comparison of preinfusion and postinfusion in vitro radiation survival curves of marrow CFUc with enhancement ratios (D0-pre/D0-post) of 1.8 (with 650 mg/m2/d) and 2.5 (with 1000 mg/m2/d). In vivo BUdR incorporation into normal skin and tumor cells using an anti-BUdR monoclonal antibody and immunohistochemistry was demonstrated in biopsies from three patients revealing substantially less cellular incorporation into normal skin (less than 10%) compared with tumor (up to 50% to 70%). The authors conclude that local and systemic toxicity of continuous infusion of BUdR at 1000 mg/m2/d for approximately two weeks is tolerable. The observed normal tissue toxicity is comparable with previous clinical experience with intermittent (12 hours every day for two weeks) infusions of BUdR. Theoretically, a constant infusion should allow for greater incorporation of BUdR into cycling tumor cells and thus, for further enhancement of radiosensitization.

  11. Enhanced radiosensitization of p53 mutant cells by oleamide

    SciTech Connect

    Lee, Yoon-Jin; Chung, Da Yeon; Lee, Su-Jae; Ja Jhon, Gil; Lee, Yun-Sil . E-mail: yslee@kcch.re.kr

    2006-04-01

    Purpose: Effect of oleamide, an endogenous fatty-acid primary amide, on tumor cells exposed to ionizing radiation (IR) has never before been explored. Methods and Materials: NCI H460, human lung cancer cells, and human astrocytoma cell lines, U87 and U251, were used. The cytotoxicity of oleamide alone or in combination with IR was determined by clonogenic survival assay, and induction of apoptosis was estimated by FACS analysis. Protein expressions were confirmed by Western blotting, and immunofluorescence analysis of Bax by use of confocal microscopy was also performed. The combined effect of IR and oleamide to suppress tumor growth was studied by use of xenografts in the thighs of nude mice. Results: Oleamide in combination with IR had a synergistic effect that decreased clonogenic survival of lung-carcinoma cell lines and also sensitized xenografts in nude mice. Enhanced induction of apoptosis of the cells by the combined treatment was mediated by loss of mitochondrial membrane potential, which resulted in the activation of caspase-8, caspase-9, and caspase-3 accompanied by cytochrome c release and Bid cleavage. The synergistic effects of the combined treatment were more enhanced in p53 mutant cells than in p53 wild-type cells. In p53 wild-type cells, both oleamide and radiation induced Bax translocation to mitochondria. On the other hand, in p53 mutant cells, radiation alone slightly induced Bax translocation to mitochondria, whereas oleamide induced a larger translocation. Conclusions: Oleamide may exhibit synergistic radiosensitization in p53 mutant cells through p53-independent Bax translocation to mitochondria.

  12. Effect of anemia on tumor radiosensitivity under normo and hyperbaric conditions

    SciTech Connect

    Rojas, A.; Stewart, F.A.; Smith, K.A.; Soranson, J.A.; Randhawa, V.S.; Stratford, M.R.; Denekamp, J.

    1987-11-01

    The effect of chronic anemia on tumor radiosensitivity in a murine tumor has been investigated. Anemia was induced by bilateral kidney irradiation given several months before tumor implantation. Anemic, anemic transfused, and normal non-anemic age-matched tumor bearing animals were irradiated with X rays (2 F/24 hr) either in air, air plus misonidazole, or under hyperbaric oxygen. The most resistant response was that of tumors grown in normal mice treated in air. Anemia produced an increase in radiosensitivity which was further enhanced by red blood cell replacement. The most sensitive overall response was seen in the anemic-transfused group treated with HBO.

  13. Differential radiosensitivity in cultured B-16 melanoma cells following interrupted melanogenesis induced by glucosamine

    SciTech Connect

    Mileo, A.M.; Mattei, E.; Fanuele, M.; Delpino, A.; Ferrini, U. )

    1989-05-01

    The relationship between cell pigmentation and radiosensitivity was investigated in a cell model in which melanogenesis was suppressed by a glycosylation inhibitor. It was found that X-irradiation of melanotic B-16 melanoma cells and their amelanotic counterparts, obtained by glucosamine treatment, showed an inverse correlation between radiosensitivity and melanin contents. Since melanogenesis interruption by glucosamine does not affect the DNA repair capacity of nonpigmented cells, it is likely that intracellular melanins play a role in the relative resistance of pigmented cells to X-irradiation.

  14. Radiosensitizing activity of 1-alkyl-3-nitropyrrolo-(2,3-b)-pyridine derivative

    SciTech Connect

    Jin, Y.Z.; Stratford, I.J.

    1989-02-01

    Radiosensitization characteristics of a newly synthesized N-(3,N'-morpholinpropyl)-2-(3-nitropyrrolo-(2,3-b)-pyridine -1-yl) ethanoic acid amide and the chemical basis of the action were studied. Partition coefficient, redox potentials for the one electron reduction of the compound were determined. This was confirmed by studies on the radiosensitization effect and cytotoxicity of the compound tested in vitro using Chinese hamster V79 cells. The results show that the sensitizing efficiency for this compound is C1.6 at a concentration of 0.5 mmol dm-3, which is similar to MISO. Its toxicity was not lower than that of MISO or metronidazole.

  15. TAS-116, a Novel Hsp90 Inhibitor, Selectively Enhances Radiosensitivity of Human Cancer Cells to X-rays and Carbon Ion Radiation.

    PubMed

    Lee, Younghyun; Sunada, Shigeaki; Hirakawa, Hirokazu; Fujimori, Akira; Nickoloff, Jac A; Okayasu, Ryuichi

    2017-01-01

    Hsp90 inhibitors have been investigated as cancer therapeutics in monotherapy and to augment radiotherapy; however, serious adverse effects of early-generation Hsp90 inhibitors limited their development. TAS-116 is a novel Hsp90 inhibitor with lower adverse effects than other Hsp90 inhibitors, and here, we investigated the radiosensitizing effects of TAS-116 in low linear energy transfer (LET) X-ray and high LET carbon ion-irradiated human cancer cells and mouse tumor xenografts. TAS-116 decreased cell survival of both X-ray and carbon ion-irradiated human cancer cell lines (HeLa and H1299 cells), and similar to other Hsp90 inhibitors, it did not affect radiosensitivity of noncancerous human fibroblasts. TAS-116 increased the number of radiation-induced γ-H2AX foci and delayed the repair of DNA double-strand breaks (DSB). TAS-116 reduced the expression of proteins that mediate repair of DSBs by homologous recombination (RAD51) and nonhomologous end joining (Ku, DNA-PKcs), and suppressed formation of RAD51 foci and phosphorylation/activation of DNA-PKcs. TAS-116 also decreased expression of the cdc25 cell-cycle progression marker, markedly increasing G2-M arrest. Combined treatment of mouse tumor xenografts with carbon ions and TAS-116 showed promising delay in tumor growth compared with either individual treatment. These results demonstrate that TAS-116 radiosensitizes human cancer cells to both X-rays and carbon ions by inhibiting the two major DSB repair pathways, and these effects were accompanied by marked cell-cycle arrest. The promising results of combination TAS-116 + carbon ion radiotherapy of tumor xenografts justify further exploration of TAS-116 as an adjunct to radiotherapy using low or high LET radiation. Mol Cancer Ther; 16(1); 16-24. ©2016 AACR.

  16. Mastering the Vocabulary of Accounting.

    ERIC Educational Resources Information Center

    Tischler, Helene

    Developed for use by students in an introductory accounting course, these learning modules deal with mastering the vocabulary of accounting. Focus of the modules is on vocabulary appearing in the first six chapters of the text, "Accounting Principles" by Niswonger and Fess. Covered in the individual modules are the following topics:…

  17. Standardized Testing and School Accountability

    ERIC Educational Resources Information Center

    Wiliam, Dylan

    2010-01-01

    This article explores the use of standardized tests to hold schools accountable. The history of testing for accountability is reviewed, and it is shown that currently between-school differences account for less than 10% of the variance in student scores, in part because the progress of individuals is small compared to the spread of achievement…

  18. Accounting Specialist.

    ERIC Educational Resources Information Center

    Ohio State Univ., Columbus. Center on Education and Training for Employment.

    This publication identifies 20 subjects appropriate for use in a competency list for the occupation of accounting specialist, 1 of 12 occupations within the business/computer technologies cluster. Each unit consists of a number of competencies; a list of competency builders is provided for each competency. Titles of the 20 units are as follows:…

  19. Painless Accountability.

    ERIC Educational Resources Information Center

    Brown, R. W.; And Others

    The computerized Painless Accountability System is a performance objective system from which instructional programs are developed. Three main simplified behavioral response levels characterize this system: (1) cognitive, (2) psychomotor, and (3) affective domains. Each of these objectives are classified by one of 16 descriptors. The second major…

  20. Accountability Overboard

    ERIC Educational Resources Information Center

    Chieppo, Charles D.; Gass, James T.

    2009-01-01

    This article reports that special interest groups opposed to charter schools and high-stakes testing have hijacked Massachusetts's once-independent board of education and stand poised to water down the Massachusetts Comprehensive Assessment System (MCAS) tests and the accountability system they support. President Barack Obama and Massachusetts…

  1. Fulvestrant radiosensitizes human estrogen receptor-positive breast cancer cells.

    PubMed

    Wang, Jing; Yang, Qifeng; Haffty, Bruce G; Li, Xiaoyan; Moran, Meena S

    2013-02-08

    The optimal sequencing for hormonal therapy and radiation are yet to be determined. We utilized fulvestrant, which is showing promise as an alternative to other agents in the clinical setting of hormonal therapy, to assess the cellular effects of concomitant anti-estrogen therapy (fulvestrant) with radiation (F+RT). This study was conducted to assess the effects of fulvestrant alone vs. F+RT on hormone-receptor positive breast cancer to determine if any positive or negative combined effects exist. The effects of F+RT on human breast cancer cells were assessed using MCF-7 clonogenic and tetrazolium salt colorimetric (MTT) assays. The assays were irradiated with a dose of 0, 2, 4, 6 Gy ± fulvestrant. The effects of F+RT vs. single adjuvant treatment alone on cell-cycle distribution were assessed using flow cytometry; relative expression of repair proteins (Ku70, Ku80, DNA-PKcs, Rad51) was assessed using Western Blot analysis. Cell growth for radiation alone vs. F+RT was 0.885±0.013 vs. 0.622±0.029 @2 Gy, 0.599±0.045 vs. 0.475±0.054 @4 Gy, and 0.472±0.021 vs. 0.380±0.018 @6 Gy RT (p=0.003). While irradiation alone induced G2/M cell cycle arrest, the combination of F+RT induced cell redistribution in the G1 phase and produced a significant decrease in the proportion of cells in G2 phase arrest and in the S phase in breast cancer cells (p<0.01). Furthermore, levels of repair proteins DNA-PKcs and Rad51 were significantly decreased in the cells treated with F+RT compared with irradiation alone. F+RT leads to a decrease in the surviving fraction, increased cell cycle arrest, down regulating of nonhomologous repair protein DNA-PKcs and homologous recombination repair protein RAD51. Thus, our findings suggest that F+RT increases breast cancer cell radiosensitivity compared with radiation alone. These findings have salient implications for designing clinical trials using fulvestrant and radiation therapy.

  2. Individual-based model for radiation risk assessment

    NASA Astrophysics Data System (ADS)

    Smirnova, O.

    A mathematical model is developed which enables one to predict the life span probability for mammals exposed to radiation. It relates statistical biometric functions with statistical and dynamic characteristics of an organism's critical system. To calculate the dynamics of the latter, the respective mathematical model is used too. This approach is applied to describe the effects of low level chronic irradiation on mice when the hematopoietic system (namely, thrombocytopoiesis) is the critical one. For identification of the joint model, experimental data on hematopoiesis in nonirradiated and irradiated mice, as well as on mortality dynamics of those in the absence of radiation are utilized. The life span probability and life span shortening predicted by the model agree with corresponding experimental data. Modeling results show the significance of ac- counting the variability of the individual radiosensitivity of critical system cells when estimating the radiation risk. These findings are corroborated by clinical data on persons involved in the elimination of the Chernobyl catastrophe after- effects. All this makes it feasible to use the model for radiation risk assessments for cosmonauts and astronauts on long-term missions such as a voyage to Mars or a lunar colony. In this case the model coefficients have to be determined by making use of the available data for humans. Scenarios for the dynamics of dose accumulation during space flights should also be taken into account.

  3. Chromosomal radiosensitivity of human immunodeficiency virus positive/negative cervical cancer patients in South Africa

    PubMed Central

    HERD, OLIVIA; FRANCIES, FLAVIA; KOTZEN, JEFFREY; SMITH, TRUDY; NXUMALO, ZWIDE; MULLER, XANTHENE; SLABBERT, JACOBUS; VRAL, ANNE; BAEYENS, ANS

    2016-01-01

    Cervical cancer is the second most common cancer amongst South African women and is the leading cause of cancer-associated mortality in this region. Several international studies on radiation-induced DNA damage in lymphocytes of cervical cancer patients have remained inconclusive. Despite the high incidence of cervical cancer in South Africa, and the extensive use of radiotherapy to treat it, the chromosomal radiosensitivity of South African cervical cancer patients has not been studied to date. Since a high number of these patients are human immunodeficiency virus (HIV)-positive, the effect of HIV infection on chromosomal radiosensitivity was also investigated. Blood samples from 35 cervical cancer patients (20 HIV-negative and 15 HIV-positive) and 20 healthy controls were exposed to X-rays at doses of 6 MV of 2 and 4 Gy in vitro. Chromosomal radiosensitivity was assessed using the micronucleus (MN) assay. MN scores were obtained using the Metafer 4 platform, an automated microscopic system. Three scoring methods of the MNScore module of Metafer were applied and compared. Cervical cancer patients had higher MN values than healthy controls, with HIV-positive patients having the highest MN values. Differences between groups were significant when using a scoring method that corrects for false positive and false negative MN. The present study suggested increased chromosomal radiosensitivity in HIV-positive South African cervical cancer patients. PMID:26549042

  4. Different radiosensitivities of mast-cell precursors in the bone marrow and skin of mice

    SciTech Connect

    Kitamura, Y.; Yokoyama, M.; Sonoda, T.; Mori, K.J.

    1983-01-01

    Although tissue mast cells are derived from the bone marrow, some descendants of bone marrow-derived precursors retain the ability to proliferate and differentiate into mast cells even after localization in the skin. The purpose of the present study was to determine the D0 values for mast-cell precursors in the bone marrow and those localized in the skin. Bone marrow cells were removed from (WB X C57BL/6)F1-+/+ mice after various doses of irradiation and injected into the skin of the congenic W/Wv mice which were genetically without mast cells. Radiosensitivity of mast-cell precursors in the bone marrow was evaluated by determining the proportion of the injection sites at which mast cells did not appear. For the assay of the radiosensitivity of mast-cell precursors localized in the skin, pieces of skin were removed from beige C57BL/6 (bgJ/bgJ. Chediak-Higashi syndrome) mice after various doses of irradiation and grafted onto the back of the normal C57BL/6 mice. Radiosensitivity of mast-cell precursors in the skin was evaluated by determining the decrease of beige-type mast cells which possessed giant granules. Mast-cell precursors in the bone marrow were much more radiosensitive than those localized in the skin. D0 value was about 100 rad for the former and about 800 rad for the latter.

  5. In vitro 3-dimensional tumor model for radiosensitivity of HPV positive OSCC cell lines.

    PubMed

    Zhang, Mei; Rose, Barbara; Lee, C Soon; Hong, Angela M

    2015-01-01

    The incidence of oropharyngeal squamous cell carcinoma (OSCC) is increasing due to the rising prevalence of human papillomavirus (HPV) positive OSCC. HPV positive OSCC is associated with better outcomes than HPV negative OSCC. Our aim was to explore the possibility that this favorable prognosis is due to the enhanced radiosensitivity of HPV positive OSCC. HPV positive OSCC cell lines were generated from the primary OSCCs of 2 patients, and corresponding HPV positive cell lines generated from nodal metastases following xenografting in nude mice. Monolayer and 3 dimensional (3D) culture techniques were used to compare the radiosensitivity of HPV positive lines with that of 2 HPV negative OSCC lines. Clonogenic and protein assays were used to measure survival post radiation. Radiation induced cell cycle changes were studied using flow cytometry. In both monolayer and 3D culture, HPV positive cells exhibited a heterogeneous appearance whereas HPV negative cells tended to be homogeneous. After irradiation, HPV positive cells had a lower survival in clonogenic assays and lower total protein levels in 3D cultures than HPV negative cells. Irradiated HPV positive cells showed a high proportion of cells in G1/S phase, increased apoptosis, an increased proliferation rate, and an inability to form 3D tumor clumps. In conclusion, HPV positive OSCC cells are more radiosensitive than HPV negative OSCC cells in vitro, supporting a more radiosensitive nature of HPV positive OSCC.

  6. Homozygous mutation of MTPAP causes cellular radiosensitivity and persistent DNA double-strand breaks

    PubMed Central

    Martin, N T; Nakamura, K; Paila, U; Woo, J; Brown, C; Wright, J A; Teraoka, S N; Haghayegh, S; McCurdy, D; Schneider, M; Hu, H; Quinlan, A R; Gatti, R A; Concannon, P

    2014-01-01

    The study of rare human syndromes characterized by radiosensitivity has been instrumental in identifying novel proteins and pathways involved in DNA damage responses to ionizing radiation. In the present study, a mutation in mitochondrial poly-A-polymerase (MTPAP), not previously recognized for its role in the DNA damage response, was identified by exome sequencing and subsequently associated with cellular radiosensitivity. Cell lines derived from two patients with the homozygous MTPAP missense mutation were radiosensitive, and this radiosensitivity could be abrogated by transfection of wild-type mtPAP cDNA into mtPAP-deficient cell lines. Further analysis of the cellular phenotype revealed delayed DNA repair, increased levels of DNA double-strand breaks, increased reactive oxygen species (ROS), and increased cell death after irradiation (IR). Pre-IR treatment of cells with the potent anti-oxidants, α-lipoic acid and n-acetylcysteine, was sufficient to abrogate the DNA repair and clonogenic survival defects. Our results firmly establish that mutation of the MTPAP gene results in a cellular phenotype of increased DNA damage, reduced repair kinetics, increased cell death by apoptosis, and reduced clonogenic survival after exposure to ionizing radiation, suggesting a pathogenesis that involves the disruption of ROS homeostasis. PMID:24651433

  7. Activating PTEN by COX-2 inhibitors antagonizes radiation-induced AKT activation contributing to radiosensitization

    SciTech Connect

    Meng, Zhen; Gan, Ye-Hua

    2015-05-01

    Radiotherapy is still one of the most effective nonsurgical treatments for many tumors. However, radioresistance remains a major impediment to radiotherapy. Although COX-2 inhibitors can induce radiosensitization, the underlying mechanism is not fully understood. In this study, we showed that COX-2 selective inhibitor celecoxib enhanced the radiation-induced inhibition of cell proliferation and apoptosis in HeLa and SACC-83 cells. Treatment with celecoxib alone dephosphorylated phosphatase and tensin homolog deleted on chromosome ten (PTEN), promoted PTEN membrane translocation or activation, and correspondingly dephosphorylated or inactivated protein kinase B (AKT). By contrast, treatment with radiation alone increased PTEN phosphorylation, inhibited PTEN membrane translocation and correspondingly activated AKT in the two cell lines. However, treatment with celecoxib or another COX-2 selective inhibitor (valdecoxib) completely blocked radiation-induced increase of PTEN phosphorylation, rescued radiation-induced decrease in PTEN membrane translocation, and correspondingly inactivated AKT. Moreover, celecoxib could also upregulate PTEN protein expression by downregulating Sp1 expression, thereby leading to the activation of PTEN transcription. Our results suggested that COX-2 inhibitors could enhance radiosensitization at least partially by activating PTEN to antagonize radiation-induced AKT activation. - Highlights: • COX-2 inhibitor, celecoxib, could enhance radiosensitization. • Radiation induced PTEN inactivation (phosphorylation) and AKT activation. • COX-2 inhibitor induced PTEN expression and activation, and inactivated AKT. • COX-2 inhibitor enhanced radiosensitization through activating PTEN.

  8. [Radiosensitivity curve of different stages of spermatogenesis of Anopheles atroparvus (Diptera:Nematocera)].

    PubMed

    Lecis, A R; Figus, V; Santarini, C

    1975-01-01

    In order to obtain a dose-hatchability curve for irradiated spermatogenetic stages of Anopheles atroparvus, we have irradiated with the same dose "4500 r" young fourth larval stages, old fourth larval stages, nymphae and adult males. Those different stages represent different phases of spermatogenesis. The peak of radiosensitivity for embryonic mortality, was found in spermatids, lowest appeared in spermatogonies.

  9. Radiosensitization of human pancreatic cancer cells by MLN4924, an investigational NEDD8-activating enzyme inhibitor.

    PubMed

    Wei, Dongping; Li, Hua; Yu, Jie; Sebolt, Jonathan T; Zhao, Lili; Lawrence, Theodore S; Smith, Peter G; Morgan, Meredith A; Sun, Yi

    2012-01-01

    Radiotherapy is used in locally advanced pancreatic cancers in which it can improve survival in combination with gemcitabine. However, prognosis is still poor in this setting in which more effective therapies remain needed. MLN4924 is an investigational small molecule currently in phase I clinical trials. MLN4924 inhibits NAE (NEDD8 Activating Enzyme), a pivotal regulator of the E3 ubiquitin ligase SCF (SKP1, Cullins, and F-box protein), that has been implicated recently in DNA damage and repair. In this study, we provide evidence that MLN4924 can be used as an effective radiosensitizer in pancreatic cancer. Specifically, MLN4924 (20-100 nmol/L) effectively inhibited cullin neddylation and sensitized pancreatic cancer cells to ionizing radiation in vitro with a sensitivity enhancement ratio of approximately 1.5. Mechanistically, MLN4924 treatment stimulated an accumulation of several SCF substrates, including CDT1, WEE1, and NOXA, in parallel with an enhancement of radiation-induced DNA damage, aneuploidy, G(2)/M phase cell-cycle arrest, and apoptosis. RNAi-mediated knockdown of CDT1 and WEE1 partially abrogated MLN4924-induced aneuploidy, G(2)/M arrest, and radiosensitization, indicating a causal effect. Furthermore, MLN4924 was an effective radiosensitizer in a mouse xenograft model of human pancreatic cancer. Our findings offer proof-of-concept for use of MLN4924 as a novel class of radiosensitizer for the treatment of pancreatic cancer.

  10. Differential Radiosensitizing Effect of Valproic Acid in Differentiation Versus Self-Renewal Promoting Culture Conditions

    SciTech Connect

    Debeb, Bisrat G.; Xu Wei; Mok, Henry; Li Li; Robertson, Fredika; Ueno, Naoto T.; Reuben, Jim; Lucci, Anthony; Cristofanilli, Massimo; Woodward, Wendy A.

    2010-03-01

    Purpose: It has been shown that valproic acid (VA) enhances the proliferation and self-renewal of normal hematopoietic stem cells and that breast cancer stem/progenitor cells can be resistant to radiation. From these data, we hypothesized that VA would fail to radiosensitize breast cancer stem/progenitor cells grown to three-dimensional (3D) mammospheres. Methods and Materials: We used the MCF7 breast cancer cell line grown under stem cell-promoting culture conditions (3D mammosphere) and standard nonstem cell monolayer culture conditions (two-dimensional) to examine the effect of pretreatment with VA on radiation sensitivity in clonogenic survival assays and on the expression of embryonic stem cell transcription factors. Results: 3D-cultured MCF-7 cells expressed higher levels of Oct4, Nanog, and Sox2. The 3D passage enriched self-renewal and increased radioresistance in the 3D mammosphere formation assays. VA radiosensitized adherent cells but radioprotected 3D cells in single-fraction clonogenic assays. Moreover, fractionated radiation sensitized VA-treated adherent MCF7 cells but did not have a significant effect on VA-treated single cells grown to mammospheres. Conclusion: We have concluded that VA might preferentially radiosensitize differentiated cells compared with those expressing stem cell surrogates and that stem cell-promoting culture is a useful tool for in vitro evaluation of novel cancer therapeutic agents and radiosensitizers.

  11. [Modification of the radiosensitivity of cultured "Vero" cells by cumene hydroperoxide].

    PubMed

    Drancourt, N; Waultier, S; Paulin, R; Feugeas, C

    1993-12-01

    Cumene-hydroperoxide is a radical reaction promoter. Vero cells monolayers treated with this compound were irradiated with gamma-rays and their radiosensitization was compared with that of irradiated, non-treated control cells. Cumene-hydroperoxide treated cells showed a paradoxal radioresistance. We propose a possible buffer-like effect of cumene-hydroperoxide to explain these results.

  12. Downregulation of a novel human gene, ROGDI, increases radiosensitivity in cervical cancer cells

    PubMed Central

    Chen, Yi-Fan; Cho, Jonathan J.; Huang, Tsai-Hua; Tseng, Chao-Neng; Huang, Eng-Yen; Cho, Chung-Lung

    2016-01-01

    ABSTRACT ROGDI is a protein that contains a leucine zipper domain and may be involved in cell proliferation. In addition, ROGDI is associated with genome stability by regulating the activity of a DNA damage marker, γ-H2AX. The role of ROGDI in tumor radiosensitization has not been investigated. Previous studies have indicated that radiosensitivity is associated with DNA repair and the cell cycle. In general, the G2/M DNA damage checkpoint is more sensitive to radiation, whereas the G1/S phase transition is more resistant to radiation. Inhibition of cyclin-dependent kinases (CDKs) can lead to a halt of cell cycle progression and a stay at different phases or checkpoints. Our data show that the downregulation of ROGDI led to a decreased expression of CDK 1, 2, cyclin A, B and resulted in a G2/M phase transition block. In addition, the downregulation of ROGDI increased cell accumulation at the G2 phase as detected using flow cytometry and decreased cell survival as revealed by clonogenic assay in HeLa and C33A cells following irradiation. These findings suggest that the downregulation of ROGDI can mediate radiosensitivity by blocking cells at G2/M, the most radiosensitive phase of the cell cycle, as well as exerting deleterious effects in the form of DNA damage, as shown by increased γ-H2AX activation. PMID:27636029

  13. Regulatory mechanisms and clinical perspectives of miRNA in tumor radiosensitivity

    PubMed Central

    Cao, Ya; Dong, Zigang

    2012-01-01

    MicroRNA (miRNA) influences carcinogenesis at multiple stages and it can effectively control tumor radiosensitivity by affecting DNA damage repair, cell cycle checkpoint, apoptosis, radio-related signal transduction pathways and tumor microenvironment. MiRNA also efficiently modulates tumor radiosensitivity at multiple levels by blocking the two essential non-homologous end-joining repair and homologous recombination repair pathways in the DNA damage response. It interferes with four radio-related pathways in ionizing radiation, including the PI3-K/Akt, NF-κB, MAPK and TGFβ signaling pathways. Moreover, the regulatory effect of miRNA in radiosensitivity can be enhanced when interacting with various key molecules, including H2AX, BRCA1, ATM, DNA-PK, RAD51, Chk1, Cdc25A, p53, PLK1, HIF-1 and VEGF, which are involved in these processes. Therefore, thoroughly understanding the mechanism of miRNA in tumor radiosensitivity could assist in finding novel targets to improve the radiotherapeutic effects and provide new clinical perspectives and insights for developing effective cancer treatments. PMID:22798379

  14. Influence of some methodological factors on the radiosensitivity of the mouse zygote

    SciTech Connect

    Jacquet, P.; Grinfeld, S. )

    1990-10-01

    The experiments reported here were undertaken to investigate the influence of some methodological factors on the radiosensitivity of the mouse zygote. The following factors were studied: (1) the use of natural or hormone-stimulated ovulation; (2) the procedure followed for fertilization:mating overnight, or only during a short period in the morning after all oocytes have been ovulated, in vitro fertilization; (3) the type of irradiation, i.e., in vivo or in vitro irradiation. The radiosensitivity of the zygotes was estimated under the different experimental conditions by measuring the ability of the irradiated embryos to cleave and to develop further to the blastocyst stage. Our results suggest that the protocols used for mating and fertilization probably have a greater influence on embryonic survival following irradiation than the use of gonadotropins to stimulate ovulation. The highest degree of synchrony in the development of the embryos is achieved by restricting mating to a short period or by using in vitro fertilization. The very low LD50s obtained under such synchronous conditions confirm the high radiosensitivity of the mouse zygote at the early pronuclear stage. Comparison between the effects of in vivo and in vitro irradiation does not indicate a greater radiosensitivity of the embryo irradiated in vitro in comparison to the embryo irradiated in vivo.

  15. Radiosensitization of EGFR/HER2 positive pancreatic cancer is mediated by inhibition of Akt independent of Ras mutational status

    PubMed Central

    Kimple, Randall J.; Vaseva, Angelina V.; Cox, Adrienne D.; Baerman, Kathryn M.; Calvo, Benjamin F.; Tepper, Joel E.; Shields, Janiel M.; Sartor, Carolyn I.

    2009-01-01

    Purpose Epidermal growth factor receptor family members (e.g., EGFR, HER2, HER3, and HER4) are commonly overexpressed in pancreatic cancer. We investigated the effects of inhibition of EGFR/HER2 signaling on pancreatic cancer to elucidate the role(s) of EGFR/HER2 in radiosensitization and to provide evidence in support of further clinical investigations. Experimental Design Expression of EGFR family members in pancreatic cancer lines was assessed by qRT-PCR. Cell growth inhibition was determined by MTS assay. The effects of inhibition of EGFR family receptors and downstream signaling pathways on in vitro radiosensitivity were evaluated using clonogenic assays. Growth delay was used to evaluate the effects of nelfinavir on in vivo tumor radiosensitivity. Results Lapatinib inhibited cell growth in four pancreatic cancer cell lines, but radiosensitized only wild-type K-ras-expressing T3M4 cells. Akt activation was blocked in a wild-type K-ras cell line, whereas constitutive phosphorylation of Akt and ERK was seen in lines expressing mutant K-ras. Overexpression of constitutively-active K-ras(G12V) abrogated lapatinib-mediated inhibition of both Akt phosphorylation and radiosensitization. Inhibition of MEK/ERK signaling with U0126 had no effect on radiosensitization, whereas inhibition of activated Akt with LY294002 (enhancement ratio 1.2–1.8) or nelfinavir (enhancement ratio 1.2–1.4) radiosensitized cells regardless of K-ras mutation status. Oral nelfinavir administration to mice bearing mutant K-ras-containing Capan-2 xenografts resulted in a greater than additive increase in radiation-mediated tumor growth delay (synergy assessment ratio of 1.5). Conclusions Inhibition of EGFR/HER2 enhances radiosensitivity in wild-type K-ras pancreatic cancer. Nelfinavir, and other PI3K/Akt inhibitors, are effective pancreatic radiosensitizers regardless of K-ras mutation status. PMID:20103665

  16. Numb/Notch signaling pathway modulation enhances human pancreatic cancer cell radiosensitivity.

    PubMed

    Bi, Yi-Liang; Min, Min; Shen, Wei; Liu, Yan

    2016-11-01

    The present study aims to evaluate whether repression of the Numb/Notch signaling pathway affects the radiosensitivity of human pancreatic cancer cell lines. Different doses of X-rays (0, 2, 3, 4, and 5 Gy) were applied to the PANC-1, SW1990, and MIA PaCa-2 human pancreatic cancer cell lines, and the Numb/Notch pathway inhibitor DAPT was added at different doses (0, 1, 3, and 5 μmol/l). MTT assay, colony formation assay, flow cytometry, scratch assay, and Transwell experiments were performed, and qRT-PCR and Western blot were conducted for the detection of Numb expression. Tumorigenicity assay in nude mice was carried out to verify the influence of blocker of the Numb/Notch signaling pathway on the radiosensitivity of xenograft tumors. The MTT assay, colony formation assay and flow cytometry experiments revealed that proliferation decreased as radiation dose increased. The viability of PANC-1 cells at 5 Gy, SW 1990 cells at 4 Gy and 5 Gy, and MIA PaCa-2 cells at 2-5 Gy was significantly lower than that of non-irradiated cells (all P < 0.05). The migration and invasion assays indicated that the PANC-1 cell line was least radiosensitive, while the MIA PaCa-2 cell line was the most radiosensitive. Numb expression significantly increased with increasing radiation dose, whereas the expression of Hes1, Notch1, and Hes5 significantly decreased compared to non-irradiated cells (P < 0.05). Compared to untreated control cells, DAPT dose dependently increased Numb expression and inhibited Notch1, Hes1, and Hes5 expressions at 2 Gy (P < 0.05). Subcutaneous tumorigenicity assay in nude mice demonstrated that DAPT increased the radiosensitivity of PANC-1, SW 1990, and MIA PaCa-2 cells. These findings suggest that Numb/Notch signaling in pancreatic cancer cells is associated with X-ray radiation and that inhibition of the Numb/Notch signaling pathway can enhance radiosensitivity, suggesting that inhibition of the Numb/Notch signaling pathway may serve as a potential

  17. Short Hairpin RNA Suppression of Thymidylate Synthase Produces DNA Mismatches and Results in Excellent Radiosensitization

    SciTech Connect

    Flanagan, Sheryl A.; Cooper, Kristin S.; Mannava, Sudha; Nikiforov, Mikhail A.; Shewach, Donna S.

    2012-12-01

    Purpose: To determine the effect of short hairpin ribonucleic acid (shRNA)-mediated suppression of thymidylate synthase (TS) on cytotoxicity and radiosensitization and the mechanism by which these events occur. Methods and Materials: shRNA suppression of TS was compared with 5-fluoro-2 Prime -deoxyuridine (FdUrd) inactivation of TS with or without ionizing radiation in HCT116 and HT29 colon cancer cells. Cytotoxicity and radiosensitization were measured by clonogenic assay. Cell cycle effects were measured by flow cytometry. The effects of FdUrd or shRNA suppression of TS on dNTP deoxynucleotide triphosphate imbalances and consequent nucleotide misincorporations into deoxyribonucleic acid (DNA) were analyzed by high-pressure liquid chromatography and as pSP189 plasmid mutations, respectively. Results: TS shRNA produced profound ({>=}90%) and prolonged ({>=}8 days) suppression of TS in HCT116 and HT29 cells, whereas FdUrd increased TS expression. TS shRNA also produced more specific and prolonged effects on dNTPs deoxynucleotide triphosphates compared with FdUrd. TS shRNA suppression allowed accumulation of cells in S-phase, although its effects were not as long-lasting as those of FdUrd. Both treatments resulted in phosphorylation of Chk1. TS shRNA alone was less cytotoxic than FdUrd but was equally effective as FdUrd in eliciting radiosensitization (radiation enhancement ratio: TS shRNA, 1.5-1.7; FdUrd, 1.4-1.6). TS shRNA and FdUrd produced a similar increase in the number and type of pSP189 mutations. Conclusions: TS shRNA produced less cytotoxicity than FdUrd but was equally effective at radiosensitizing tumor cells. Thus, the inhibitory effect of FdUrd on TS alone is sufficient to elicit radiosensitization with FdUrd, but it only partially explains FdUrd-mediated cytotoxicity and cell cycle inhibition. The increase in DNA mismatches after TS shRNA or FdUrd supports a causal and sufficient role for the depletion of dTTP thymidine triphosphate and consequent DNA

  18. Garcinol, a Histone Acetyltransferase Inhibitor, Radiosensitizes Cancer Cells by Inhibiting Non-Homologous End Joining

    SciTech Connect

    Oike, Takahiro; Ogiwara, Hideaki; Torikai, Kohta; Nakano, Takashi; Yokota, Jun; Kohno, Takashi

    2012-11-01

    Purpose: Non-homologous end joining (NHEJ), a major pathway used to repair DNA double-strand breaks (DSBs) generated by ionizing radiation (IR), requires chromatin remodeling at DSB sites through the acetylation of histones by histone acetyltransferases (HATs). However, the effect of compounds with HAT inhibitory activities on the DNA damage response (DDR), including the NHEJ and cell cycle checkpoint, as well as on the radiosensitivity of cancer cells, remains largely unclear. Here, we investigated whether garcinol, a HAT inhibitor found in the rinds of Garcinia indica fruit (called mangosteens), has effects on DDR, and whether it can be used for radiosensitization. Methods and Materials: The following assays were used to examine the effect of garcinol on the inhibition of DSB repair, including the following: a conventional neutral comet assay; a cell-based assay recently developed by us, in which NHEJ repair of DSBs on chromosomal DNA was evaluated; the micrococcal nuclease sensitivity assay; and immunoblotting for autophosphorylation of DNA-dependent protein kinase catalytic subunit (DNA-PKcs). We assessed the effect of garcinol on the cell cycle checkpoint after IR treatment by analyzing the phosphorylation levels of checkpoint kinases CHK1 and CHK2 and histone H3, and by cell cycle profile analysis using flow cytometry. The radiosensitizing effect of garcinol was assessed by a clonogenic survival assay, whereas its effects on apoptosis and senescence were examined by annexin V and senescence-associated {beta}-galactosidase (SA-{beta}-Gal) staining, respectively. Results: We found that garcinol inhibits DSB repair, including NHEJ, without affecting cell cycle checkpoint. Garcinol radiosensitized A549 lung and HeLa cervical carcinoma cells with dose enhancement ratios (at 10% surviving fraction) of 1.6 and 1.5, respectively. Cellular senescence induced by IR was enhanced by garcinol. Conclusion: These results suggest that garcinol is a radiosensitizer that

  19. DNA-Dependent Protein Kinase As Molecular Target for Radiosensitization of Neuroblastoma Cells.

    PubMed

    Dolman, M Emmy M; van der Ploeg, Ida; Koster, Jan; Bate-Eya, Laurel Tabe; Versteeg, Rogier; Caron, Huib N; Molenaar, Jan J

    2015-01-01

    Tumor cells might resist therapy with ionizing radiation (IR) by non-homologous end-joining (NHEJ) of IR-induced double-strand breaks. One of the key players in NHEJ is DNA-dependent protein kinase (DNA-PK). The catalytic subunit of DNA-PK, i.e. DNA-PKcs, can be inhibited with the small-molecule inhibitor NU7026. In the current study, the in vitro potential of NU7026 to radiosensitize neuroblastoma cells was investigated. DNA-PKcs is encoded by the PRKDC (protein kinase, DNA-activated, catalytic polypeptide) gene. We showed that PRKDC levels were enhanced in neuroblastoma patients and correlated with a more advanced tumor stage and poor prognosis, making DNA-PKcs an interesting target for radiosensitization of neuroblastoma tumors. Optimal dose finding for combination treatment with NU7026 and IR was performed using NGP cells. One hour pre-treatment with 10 μM NU7026 synergistically sensitized NGP cells to 0.63 Gy IR. Radiosensitizing effects of NU7026 increased in time, with maximum effects observed from 96 h after IR-exposure on. Combined treatment of NGP cells with 10 μM NU7026 and 0.63 Gy IR resulted in apoptosis, while no apoptotic response was observed for either of the therapies alone. Inhibition of IR-induced DNA-PK activation by NU7026 confirmed the capability of NGP cells to, at least partially, resist IR by NHEJ. NU7026 also synergistically radiosensitized other neuroblastoma cell lines, while no synergistic effect was observed for low DNA-PKcs-expressing non-cancerous fibroblasts. Results obtained for NU7026 were confirmed by PRKDC knockdown in NGP cells. Taken together, the current study shows that DNA-PKcs is a promising target for neuroblastoma radiosensitization.

  20. Enhancement of P53-Mutant Human Colorectal Cancer Cells Radiosensitivity by Flavonoid Fisetin

    SciTech Connect

    Chen Wenshu; Lee Yijang; Yu Yichu; Hsaio Chinghui

    2010-08-01

    Purpose: The aim of this study was to investigate whether fisetin is a potential radiosensitizer for human colorectal cancer cells, which are relatively resistant to radiotherapy. Methods and Materials: Cell survival was examined by clonogenic survival assay, and DNA fragmentation was assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay. The effects of treatments on cell cycle distribution and apoptosis were examined by flow cytometry. Western blot analysis was performed to ascertain the protein levels of {gamma}-H2AX, phospho-Chk2, active caspase-3, PARP cleavage, phospho-p38, phospho-AKT, and phospho-ERK1/2. Results: Fisetin pretreatment enhanced the radiosensitivity of p53-mutant HT-29 human colorectal cancer cells but not human keratocyte HaCaT cells; it also prolonged radiation-induced G{sub 2}/M arrest, enhanced radiation-induced cell growth arrest in HT-29 cells, and suppressed radiation-induced phospho-H2AX (Ser-139) and phospho-Chk2 (Thr-68) in p53-mutant HT-29 cells. Pretreatment with fisetin enhanced radiation-induced caspase-dependent apoptosis in HT-29 cells. Fisetin pretreatment augmented radiation-induced phosphorylation of p38 mitogen-activated protein kinase, which is involved in caspase-mediated apoptosis, and SB202190 significantly reduced apoptosis and radiosensitivity in fisetin-pretreated HT-29 cells. By contrast, both phospho-AKT and phospho-ERK1/2, which are involved in cell proliferation and antiapoptotic pathways, were suppressed after irradiation combined with fisetin pretreatment. Conclusions: To our knowledge, this study is the first to provide evidence that fisetin exerts a radiosensitizing effect in p53-mutant HT-29 cells. Fisetin could potentially be developed as a novel radiosensitizer against radioresistant human cancer cells.

  1. Celecoxib Enhances the Radiosensitizing Effect of 7-Hydroxystaurosporine (UCN-01) in Human Lung Cancer Cell Lines

    SciTech Connect

    Kim, Young-Mee; Jeong, In-Hye; Pyo, Hongryull

    2012-07-01

    Purpose: 7-Hydroxystaurosporine (UCN-01), a Chk1-specific inhibitor, showed promising in vitro and in vivo chemo- or radiosensitizing activity. However, there have been concerns about its limited therapeutic efficacy and risk of side effects. A method of enhancing the treatment efficacy of UCN-01 while not increasing its side effects on normal tissue may therefore be required to apply this drug in clinical settings. Celecoxib is a cyclooxygenase-2 (COX-2)-specific inhibitor that downregulates ataxia telangiectasia and rad3-related (ATR) protein, an upstream kinase of Chk1. In this study, we investigated whether the addition of celecoxib can potentiate the radiosensitizing effect of UCN-01. Methods and Materials: The cooperative radiosensitizing effects and the underlying molecular mechanisms of UCN-01 plus celecoxib were determined by clonogenic assay, tumor growth delay assay, flow cytometry, and Western blotting. Synergism of the three agents combined (UCN-01 plus celecoxib plus radiation) were evaluated using median drug effect analysis and drug-independent action model analysis. Results: The combination of UCN-01 and celecoxib could induce synergistic cytotoxicity and radiosensitizing effects in in vitro and in vivo systems. The combination of both drugs also cooperatively inhibited IR-induced G{sub 2}/M arrest, and increased the G{sub 2} to mitotic transition. Conclusions: Combined treatment with UCN-01 and celecoxib can exert synergistically enhanced radiosensitizing effects via cooperative inhibition of the ionizing radiation-activated G{sub 2} checkpoint. We propose that this combination strategy may be useful in clinical applications of UCN-01 for radiotherapy of cancer patients.

  2. Iodine-125-labeled cRGD-gold nanoparticles as tumor-targeted radiosensitizer and imaging agent

    NASA Astrophysics Data System (ADS)

    Su, Ning; Dang, Yajie; Liang, Guangli; Liu, Guizhi

    2015-04-01

    Research interests on radiosensitive property of gold nanoparticles (GNPs) are rapidly raised because of the extensively proved in vitro effectiveness and clinical necessity. However, the issue of targeted accumulation of GNPs in tumor tissues hindered the transference to in vivo applications. In this study, hybrid nano-sized cyclic Arg-Gly-Asp-conjugated GNPs (cRGD-GNPs) integrated with radioactive iodine-125 was fabricated as tumor-targeted radiosensitizer. Therapeutic effects, including acute apoptosis (2 days post treatment) and long-term influence (up to 21 days), were investigated on NCI-H446 tumor-bearing mice via Tc-99 m-Annexin V SPECT and volume measurements, respectively. Apoptosis and volume loss were consistent in showing that tumor growth was effectively suppressed via the treatment of 125I-cRGD-GNP sensitized radiotherapy (RT), a more significantly radiosensitive effect than the treatment of non-targeted GNPs with RT, RT treatment alone, and no treatment. SPECT/CT images showed that the uptake of cRGD-GNPs by tumor tissues reached the peak target/non-target value of 4.76 at around 2 h post injection, and dynamic radioactivity monitoring showed that 125I-cRGD-GNPs maintained about 2.5% of injected dosage at 55 h post injection. For long-term influence, a significant radiosensitized RT-induced volume loss was observed. Hence, cyclic RGD conjugation makes the GNP-based radiosensitizer tumor targeting, offering a new modality for enhancing radiotherapeutic efficacy. Additionally, the introduction of I-125 serves as both a therapeutic factor and a radiotracer for in vivo tracking of GNPs.

  3. Simulation on the molecular radiosensitization effect of gold nanoparticles in cells irradiated by x-rays

    NASA Astrophysics Data System (ADS)

    Xie, W. Z.; Friedland, W.; Li, W. B.; Li, C. Y.; Oeh, U.; Qiu, R.; Li, J. L.; Hoeschen, C.

    2015-08-01

    Abundant studies have focused on the radiosensitization effect of gold nanoparticles (GNPs) in the cellular environment with x-ray irradiation. To better understand the physical foundation and to initially study the molecular radiosensitization effect within the nucleus, a simple cell model with detailed DNA structure in the central nucleus was set up and complemented with different distributions of single and multiple GNPs in this work. With the biophysical Monte Carlo simulation code PARTRAC, the radiosensitization effects on both physical quantities and primary biological responses (DNA strand breaks) were simulated. The ratios of results under situations with GNPs compared to those without GNPs were defined as the enhancement factors (EFs). The simulation results show that the presence of GNP can cause a notable enhancement effect on the energy deposition within a few micrometers from the border of GNP. The greatest upshot appears around the border and is mostly dominated by Auger electrons. The enhancement effect on the DNA strand breakage becomes smaller because of the DNA distribution inside the nucleus, and the corresponding EFs are between 1 and 1.5. In the present simulation, multiple GNPs on the nucleus surface, the 60 kVp x-ray spectrum and the diameter of 100 nm are relatively more effective conditions for both physical and biological radiosensitization effects. These results preliminarily indicate that GNP can be a good radiosensitizer in x-ray radiotherapy. Nevertheless, further biological responses (repair process, cell survival, etc) need to be studied to give more accurate evaluation and practical proposal on GNP’s application in clinical treatment.

  4. Optimal energy for cell radiosensitivity enhancement by gold nanoparticles using synchrotron-based monoenergetic photon beams.

    PubMed

    Rahman, Wan Nordiana; Corde, Stéphanie; Yagi, Naoto; Abdul Aziz, Siti Aishah; Annabell, Nathan; Geso, Moshi

    2014-01-01

    Gold nanoparticles have been shown to enhance radiation doses delivered to biological targets due to the high absorption coefficient of gold atoms, stemming from their high atomic number (Z) and physical density. These properties significantly increase the likelihood of photoelectric effects and Compton scattering interactions. Gold nanoparticles are a novel radiosensitizing agent that can potentially be used to increase the effectiveness of current radiation therapy techniques and improve the diagnosis and treatment of cancer. However, the optimum radiosensitization effect of gold nanoparticles is strongly dependent on photon energy, which theoretically is predicted to occur in the kilovoltage range of energy. In this research, synchrotron-generated monoenergetic X-rays in the 30-100 keV range were used to investigate the energy dependence of radiosensitization by gold nanoparticles and also to determine the photon energy that produces optimum effects. This investigation was conducted using cells in culture to measure dose enhancement. Bovine aortic endothelial cells with and without gold nanoparticles were irradiated with X-rays at energies of 30, 40, 50, 60, 70, 81, and 100 keV. Trypan blue exclusion assays were performed after irradiation to determine cell viability. Cell radiosensitivity enhancement was indicated by the dose enhancement factor which was found to be maximum at 40 keV with a value of 3.47. The dose enhancement factor obtained at other energy levels followed the same direction as the theoretical calculations based on the ratio of the mass energy absorption coefficients of gold and water. This experimental evidence shows that the radiosensitization effect of gold nanoparticles varies with photon energy as predicted from theoretical calculations. However, prediction based on theoretical assumptions is sometimes difficult due to the complexity of biological systems, so further study at the cellular level is required to fully characterize the effects

  5. Simulation on the molecular radiosensitization effect of gold nanoparticles in cells irradiated by x-rays.

    PubMed

    Xie, W Z; Friedland, W; Li, W B; Li, C Y; Oeh, U; Qiu, R; Li, J L; Hoeschen, C

    2015-08-21

    Abundant studies have focused on the radiosensitization effect of gold nanoparticles (GNPs) in the cellular environment with x-ray irradiation. To better understand the physical foundation and to initially study the molecular radiosensitization effect within the nucleus, a simple cell model with detailed DNA structure in the central nucleus was set up and complemented with different distributions of single and multiple GNPs in this work. With the biophysical Monte Carlo simulation code PARTRAC, the radiosensitization effects on both physical quantities and primary biological responses (DNA strand breaks) were simulated. The ratios of results under situations with GNPs compared to those without GNPs were defined as the enhancement factors (EFs). The simulation results show that the presence of GNP can cause a notable enhancement effect on the energy deposition within a few micrometers from the border of GNP. The greatest upshot appears around the border and is mostly dominated by Auger electrons. The enhancement effect on the DNA strand breakage becomes smaller because of the DNA distribution inside the nucleus, and the corresponding EFs are between 1 and 1.5. In the present simulation, multiple GNPs on the nucleus surface, the 60 kVp x-ray spectrum and the diameter of 100 nm are relatively more effective conditions for both physical and biological radiosensitization effects. These results preliminarily indicate that GNP can be a good radiosensitizer in x-ray radiotherapy. Nevertheless, further biological responses (repair process, cell survival, etc) need to be studied to give more accurate evaluation and practical proposal on GNP's application in clinical treatment.

  6. Arkansas' Curriculum Guide. Competency Based Computerized Accounting.

    ERIC Educational Resources Information Center

    Arkansas State Dept. of Education, Little Rock. Div. of Vocational, Technical and Adult Education.

    This guide contains the essential parts of a total curriculum for a one-year secondary-level course in computerized accounting. Addressed in the individual sections of the guide are the following topics: the complete accounting cycle, computer operations for accounting, computerized accounting and general ledgers, computerized accounts payable,…

  7. TU-F-CAMPUS-T-03: Enhancing the Tumor Specific Radiosensitization Using Molecular Targeted Gold Nanorods

    SciTech Connect

    Diagaradjane, P; Deorukhkar, A; Sankaranarayanapillai, M; Singh, P; Manohar, N; Tailor, R; Cho, S; Goodrich, G; Krishnan, S

    2015-06-15

    Purpose: Gold nanoparticle (GNP) mediated radiosensitization has gained significant attention in recent years. However, the widely used passive targeting strategy requires high concentration of GNPs to induce the desired therapeutic effect, thus dampening the enthusiasm for clinical translation. The purpose of this study is to utilize a molecular targeting strategy to minimize the concentration of GNPs injected while simultaneously enhancing the tumor specific radiosensitization for an improved therapeutic outcome. Methods: Cetuximab (antibody specific to the epidermal growth factor receptor that is over-expressed in tumors) conjugated gold nanorods (cGNRs) was used for the tumor targeting. The binding affinity, internalization, and in vitro radiosensitization were evaluated using dark field microscopy, transmission electron microscopy, and clonogenic cell survival assay, respectively. In vivo biodistribution in tumor (HCT116-colorectal cancer cells) bearing mice were quantified using inductively coupled plasma mass spectrometry. In vivo radiosensitization potential was tested using 250-kVp x-rays and clinically relevant 6-MV radiation beams. Results: cGNRs displayed excellent cell-surface binding and internalization (∼31,000 vs 12,000/cell) when compared to unconjugated GNRs (pGNRs). In vitro, the dose enhancement factor at 10% survival (DEF10) was estimated as 1.06 and 1.17, respectively for both 250-kVp and 6-MV beams. In vivo biodistribution analysis revealed enhanced uptake of cGNRs in tumor (1.3 µg/g of tumor tissue), which is ∼1000-fold less than the reported values using passive targeting strategy. Nonetheless, significant radiosensitization was observed in vivo with cGNRs when compared to pGNRs, when irradiated with 250-kVp (tumor volume doubling time 35 days vs 25 days; p=0.002) and 6 MV (17 days vs 13 days; p=0.0052) beams. Conclusion: The enhanced radiosensitization effect observed with very low intratumoral concentrations of gold and megavoltage x

  8. The Hsp70 inhibiting peptide aptamer A17 potentiates radiosensitization of tumor cells by Hsp90 inhibition.

    PubMed

    Schilling, Daniela; Garrido, Carmen; Combs, Stephanie E; Multhoff, Gabriele

    2017-04-01

    The inhibition of heat shock protein 90 (Hsp90) is a promising strategy to increase the radiosensitivity of tumor cells. However, Hsp90 inhibition induces the expression of Hsp70 which is a prominent cytoprotective protein. Therefore, dual targeting of Hsp70 and Hsp90 might be beneficial to increase the radiosensitivity of tumor cells. Hsp70 inhibiting peptide aptamers have been shown to increase the sensitivity of tumor cells to apoptosis induced by different anticancer drugs. Herein, we studied the radiosensitizing activity of the Hsp70 inhibiting peptide aptamer A17 in combination with the Hsp90 inhibitor NVP-AUY922. Whereas A17 significantly increased apoptosis induction by NVP-AUY922 it did not significantly affect the radiosensitivity of human lung and breast cancer cells. However, Hsp70 inhibition by the aptamer A17 potentiated the radiosensitizing effects of the Hsp90 inhibitor NVP-AUY922. Mechanistically we speculate that an increased number of DNA double strand breaks and an enhanced G2/M arrest might be responsible for the increased radiosensitization in A17 expressing tumor cells. Therefore, the simultaneous inhibition of Hsp90 and Hsp70 combined with radiotherapy might provide a promising anti-cancer strategy.

  9. Radiosensitization by the investigational NEDD8-activating enzyme inhibitor MLN4924 (pevonedistat) in hormone-resistant prostate cancer cells.

    PubMed

    Wang, Xiaofang; Zhang, Wenjuan; Yan, Zi; Liang, Yupei; Li, Lihui; Yu, Xiaoli; Feng, Yan; Fu, Shen; Zhang, Yanmei; Zhao, Hu; Yu, Jinha; Jeong, Lak Shin; Guo, Xiaomao; Jia, Lijun

    2016-06-21

    Salvage radiotherapy (SRT) is the first-line treatment for prostate cancer patients with biochemical recurrence following radical prostatectomy, and new specific radiosensitizers are in urgent need to enhance SRT effect. MLN4924 (also known as Pevonedistat), a specific inhibitor of NEDD8-activating enzyme, has recently entered phase I/II clinical trials in several malignancies. By inhibiting cullin neddylation, MLN4924 inactivates Cullin-RING ligases (CRL), which have been validated as an attractive radiosensitizing target. In our study, we demonstrate that MLN4924 can be used as a potent radiosensitizer in hormone-resistant prostate cancer cells. We found that MLN4924 inhibited cullin neddylation and sensitized prostate cancer cells to irradiation (IR). Mechanistically, MLN4924 enhanced IR-induced G2 cell-cycle arrest, by inducing accumulation of WEE1/p21/p27, three well-known CRL substrates. Importantly, siRNA knockdown of WEE1/p21/p27 partially abrogated MLN4924-induced G2 cell-cycle arrest, indicating a causal role of WEE1/p21/p27 in MLN4924-induced radiosensitization. Further mechanistic studies revealed that induction of DNA damage and apoptosis also contributed to MLN4924 radiosensitization in hormone-resistant prostate cancer cells. Our findings lay the foundation for future application of MLN4924 as a potential radiosensitizer in hormone refractory prostate cancer (HRPC).

  10. Macrophages enhance the radiosensitizing activity of lipid A: A novel role for immune cells in tumor cell radioresponse

    SciTech Connect

    Ridder, Mark de . E-mail: Mark.De.Ridder@vub.ac.be; Verovski, Valeri N.; Darville, Martine I.; Berge, Dirk L. van den; Monsaert, Christinne; Eizirik, Decio L.; Storme, Guy A.

    2004-10-01

    Purpose: This study examines whether activated macrophages may radiosensitize tumor cells through the release of proinflammatory mediators. Methods and materials: RAW 264.7 macrophages were activated by lipid A, and the conditioned medium (CM) was analyzed for the secretion of cytokines and the production of nitric oxide (NO) through inducible nitric oxide synthase (iNOS). EMT-6 tumor cells were exposed to CM and analyzed for hypoxic cell radiosensitivity. The role of nuclear factor (NF)-{kappa}B in the transcriptional activation of iNOS was examined by luciferase reporter gene assay. Results: Clinical immunomodulator lipid A, at a plasma-relevant concentration of 3 {mu}g/mL, stimulated RAW 264.7 macrophages to release NO, tumor necrosis factor (TNF)-{alpha}, and other cytokines. This in turn activated iNOS-mediated NO production in EMT-6 tumor cells and drastically enhanced their radiosensitivity. Radiosensitization was abrogated by the iNOS inhibitor aminoguanidine but not by a neutralizing anti-TNF-{alpha} antibody. The mechanism of iNOS induction was linked to NF-{kappa}B but not to JAK/STAT signaling. Interferon-{gamma} further increased the NO production by macrophages to a level that caused radiosensitization of EMT-6 cells through the bystanding effect of diffused NO. Conclusions: We demonstrate for the first time that activated macrophages may radiosensitize tumor cells through the induction of NO synthesis, which occurs in both tumor and immune cells.

  11. Toward Reflective Accountability: Using NSSE for Accountability and Transparency

    ERIC Educational Resources Information Center

    McCormick, Alexander C.

    2009-01-01

    Accountability pressures in higher education are not new; they are part of an enduring public policy discourse about the costs and benefits, both individual and social, of higher education. What is relatively new, however, is the prominent place that issues of accountability now occupy on the nation's higher education agenda. There is an important…

  12. First-Person Accounts.

    ERIC Educational Resources Information Center

    Gribs, H.; And Others

    1995-01-01

    Personal accounts describe the lives of 2 individuals with deaf-blindness, one an 87-year-old woman who was deaf from birth and became totally blind over a 50-year period and the other of a woman who became deaf-blind as a result of a fever at the age of 7. Managing activities of daily life and experiencing sensory hallucinations are among topics…

  13. The High Radiosensitizing Efficiency of a Trace of Gadolinium-Based Nanoparticles in Tumors

    NASA Astrophysics Data System (ADS)

    Dufort, Sandrine; Le Duc, Géraldine; Salomé, Murielle; Bentivegna, Valerie; Sancey, Lucie; Bräuer-Krisch, Elke; Requardt, Herwig; Lux, François; Coll, Jean-Luc; Perriat, Pascal; Roux, Stéphane; Tillement, Olivier

    2016-07-01

    We recently developed the synthesis of ultrasmall gadolinium-based nanoparticles (GBN), (hydrodynamic diameter <5 nm) characterized by a safe behavior after intravenous injection (renal clearance, preferential accumulation in tumors). Owing to the presence of gadolinium ions, GBN can be used as contrast agents for magnetic resonance imaging (MRI) and as radiosensitizers. The attempt to determine the most opportune delay between the intravenous injection of GBN and the irradiation showed that a very low content of radiosensitizing nanoparticles in the tumor area is sufficient (0.1 μg/g of particles, i.e. 15 ppb of gadolinium) for an important increase of the therapeutic effect of irradiation. Such a promising and unexpected result is assigned to a suited distribution of GBN within the tumor, as revealed by the X-ray fluorescence (XRF) maps.

  14. Cellular Pathways in Response to Ionizing Radiation and Their Targetability for Tumor Radiosensitization

    PubMed Central

    Maier, Patrick; Hartmann, Linda; Wenz, Frederik; Herskind, Carsten

    2016-01-01

    During the last few decades, improvements in the planning and application of radiotherapy in combination with surgery and chemotherapy resulted in increased survival rates of tumor patients. However, the success of radiotherapy is impaired by two reasons: firstly, the radioresistance of tumor cells and, secondly, the radiation-induced damage of normal tissue cells located in the field of ionizing radiation. These limitations demand the development of drugs for either radiosensitization of tumor cells or radioprotection of normal tissue cells. In order to identify potential targets, a detailed understanding of the cellular pathways involved in radiation response is an absolute requirement. This review describes the most important pathways of radioresponse and several key target proteins for radiosensitization. PMID:26784176

  15. Cellular Pathways in Response to Ionizing Radiation and Their Targetability for Tumor Radiosensitization.

    PubMed

    Maier, Patrick; Hartmann, Linda; Wenz, Frederik; Herskind, Carsten

    2016-01-14

    During the last few decades, improvements in the planning and application of radiotherapy in combination with surgery and chemotherapy resulted in increased survival rates of tumor patients. However, the success of radiotherapy is impaired by two reasons: firstly, the radioresistance of tumor cells and, secondly, the radiation-induced damage of normal tissue cells located in the field of ionizing radiation. These limitations demand the development of drugs for either radiosensitization of tumor cells or radioprotection of normal tissue cells. In order to identify potential targets, a detailed understanding of the cellular pathways involved in radiation response is an absolute requirement. This review describes the most important pathways of radioresponse and several key target proteins for radiosensitization.

  16. The High Radiosensitizing Efficiency of a Trace of Gadolinium-Based Nanoparticles in Tumors

    PubMed Central

    Dufort, Sandrine; Le Duc, Géraldine; Salomé, Murielle; Bentivegna, Valerie; Sancey, Lucie; Bräuer-Krisch, Elke; Requardt, Herwig; Lux, François; Coll, Jean-Luc; Perriat, Pascal; Roux, Stéphane; Tillement, Olivier

    2016-01-01

    We recently developed the synthesis of ultrasmall gadolinium-based nanoparticles (GBN), (hydrodynamic diameter <5 nm) characterized by a safe behavior after intravenous injection (renal clearance, preferential accumulation in tumors). Owing to the presence of gadolinium ions, GBN can be used as contrast agents for magnetic resonance imaging (MRI) and as radiosensitizers. The attempt to determine the most opportune delay between the intravenous injection of GBN and the irradiation showed that a very low content of radiosensitizing nanoparticles in the tumor area is sufficient (0.1 μg/g of particles, i.e. 15 ppb of gadolinium) for an important increase of the therapeutic effect of irradiation. Such a promising and unexpected result is assigned to a suited distribution of GBN within the tumor, as revealed by the X-ray fluorescence (XRF) maps. PMID:27411781

  17. Radiosensitizing Effect of P2X7 Receptor Antagonist on Melanoma in vitro and in vivo.

    PubMed

    Tanamachi, Keisuke; Nishino, Keisuke; Mori, Natsuki; Suzuki, Toshihiro; Tanuma, Sei-Ichi; Abe, Ryo; Tsukimoto, Mitsutoshi

    2017-03-24

    Melanoma is highly malignant, and generally exhibits radioresistance, responding poorly to radiation therapy. We previously reported that activation of P2X7, P2Y6, and P2Y12 receptors is involved in the DNA damage response after γ-irradiation of human lung adenocarcinoma A549 cells. However, it is not clear whether these receptors are also involved in the case of melanoma cells, although P2X7 receptor is highly expressed in various cancers, including melanoma. Here, we show that P2X7 receptor antagonist enhances radiation-induced cytotoxicity in B16 melanoma cells in vitro and in vivo. We confirmed that these cells express P2X7 receptor mRNA and exhibit P2X7 receptor-mediated activities, such as ATP-induced pore formation and cytotoxicity. We further examined the radiosensitizing effect of P2X7 receptor antagonist Brilliant Blue G (BBG) in vitro by colony formation assay of B16 cells. γ-Irradiation dose-dependently reduced cell survival, and pretreatment with BBG enhanced the radiation-induced cytotoxicity. BBG pretreatment also decreased the number of DNA repair foci in nuclei, supporting involvement of P2X7 receptor in the DNA damage response. Finally, we investigated the radiosensitizing effect of BBG on B16 melanoma cells inoculated into the hind footpad of C57BL/6 mice. Neither 1 Gy γ-irradiation alone nor BBG alone suppressed the increase of tumor volume, but the combination of irradiation and BBG significantly suppressed tumor growth. Our results suggest that P2X7 receptor antagonist BBG has a radiosensitizing effect in melanoma in vitro and in vivo. BBG, which is used as a food coloring agent, appears to be a promising candidate as a radiosensitizer.

  18. HAP1 gene expression is associated with radiosensitivity in breast cancer cells

    SciTech Connect

    Wu, Jing; Zhang, Jun-ying; Yin, Li; Wu, Jian-zhong; Guo, Wen-jie; Wu, Jian-feng; Chen, Meng; Xia, You-you; Tang, Jin-hai; Ma, Yong-chao; He, Xia

    2015-01-02

    Highlights: • Overexpression of HAP1 gene promotes apoptosis in MCF-7 cells after irradiation. • HAP1 reduces tumor volume in nude mice xenograft models after irradiation. • HAP1 increases radiosensitivity of breast cancer cells in vitro and vivo. - Abstract: Objectives: The purpose of this study was to investigate the relationship between huntingtin-associated protein1 (HAP1) gene and radiation therapy of breast cancer cells. Methods: HAP1 gene was transfected into breast cancer MCF-7 cells, which was confirmed by quantitative reverse transcription-polymerase chain reaction analysis (qRT-PCR) and Western blot in vitro. The changes of cell radiosensitivity were assessed by colony formation assay. Apoptosis were examined by flow cytometry. The expressions of two radiation-induced genes were evaluated by Western blot. Tumor growth was investigated in nude mice xenograft models in vivo. Results: Our data showed that HAP1 gene expression was significantly increased in HAP1-transfected MCF-7 cells in comparison with the parental cells or negative control cells. The survival rate in MCF-7/HAP1 cells was significantly decreased after irradiation (0, 2, 4, 6, 8 Gy), compared to cells in MCF-7 and MCF-7/Pb groups in vitro. HAP1 gene increased apoptosis in MCF-7 cells after irradiation. Additionally, the tumor volume and weight in MCF-7/HAP1 + RT group were observably lower than in MCF-7/HAP1 group and MCF-7/Pb + RT group. Conclusion: The present study indicated that HAP1 gene expression was related to the radiosensitivity of breast cancer cells and may play an important role in the regulation of cellular radiosensitivity.

  19. Rosiglitazone enhances the radiosensitivity of p53-mutant HT-29 human colorectal cancer cells

    SciTech Connect

    Chiu, Shu-Jun; Hsaio, Ching-Hui; Tseng, Ho-Hsing; Su, Yu-Han; Shih, Wen-Ling; Lee, Jeng-Woei; Chuah, Jennifer Qiu-Yu

    2010-04-09

    Combined-modality treatment has improved the outcome in cases of various solid tumors, and radiosensitizers are used to enhance the radiotherapeutic efficiency. Rosiglitazone, a synthetic ligand of peroxisome proliferator-activated receptors {gamma} used in the treatment of type-2 diabetes, has been shown to reduce tumor growth and metastasis in human cancer cells, and may have the potential to be used as a radiosensitizer in radiotherapy for human colorectal cancer cells. In this study, rosiglitazone treatment significantly reduced the cell viability of p53-wild type HCT116 cells but not p53-mutant HT-29 cells. Interestingly, rosiglitazone pretreatment enhanced radiosensitivity in p53-mutant HT-29 cells but not HCT116 cells, and prolonged radiation-induced G{sub 2}/M arrest and enhanced radiation-induced cell growth inhibition in HT-29 cells. Pretreatment with rosiglitazone also suppressed radiation-induced H2AX phosphorylation in response to DNA damage and AKT activation for cell survival; on the contrary, rosiglitazone pretreatment enhanced radiation-induced caspase-8, -9, and -3 activation and PARP cleavage in HT-29 cells. In addition, pretreatment with a pan-caspase inhibitor, zVAD-fmk, attenuated the levels of caspase-3 activation and PARP cleavage in radiation-exposed cancer cells in combination with rosiglitazone pretreatment. Our results provide proof for the first time that rosiglitazone suppresses radiation-induced survival signals and DNA damage response, and enhances the radiation-induced apoptosis signaling cascade. These findings can assist in the development of rosiglitazone as a novel radiosensitizer.

  20. Cell-Specific Radiosensitization by Gold Nanoparticles at Megavoltage Radiation Energies

    SciTech Connect

    Jain, Suneil; Coulter, Jonathan A.; Hounsell, Alan R.; Butterworth, Karl T.; McMahon, Stephen J.; Hyland, Wendy B.; Muir, Mark F.; Dickson, Glenn R.; Prise, Kevin M.; Currell, Fred J.; O'Sullivan, Joe M.; Hirst, David G.

    2011-02-01

    Purpose: Gold nanoparticles (GNPs) have been shown to cause sensitization with kilovoltage (kV) radiation. Differences in the absorption coefficient between gold and soft tissue, as a function of photon energy, predict that maximum enhancement should occur in the kilovoltage (kV) range, with almost no enhancement at megavoltage (MV) energies. Recent studies have shown that GNPs are not biologically inert, causing oxidative stress and even cell death, suggesting a possible biological mechanism for sensitization. The purpose of this study was to assess GNP radiosensitization at clinically relevant MV X-ray energies. Methods and Materials: Cellular uptake, intracellular localization, and cytotoxicity of GNPs were assessed in normal L132, prostate cancer DU145, and breast cancer MDA-MB-231 cells. Radiosensitization was measured by clonogenic survival at kV and MV photon energies and MV electron energies. Intracellular DNA double-strand break (DSB) induction and DNA repair were determined and GNP chemosensitization was assessed using the radiomimetic agent bleomycin. Results: GNP uptake occurred in all cell lines and was greatest in MDA-MB-231 cells with nanoparticles accumulating in cytoplasmic lysosomes. In MDA-MB-231 cells, radiation sensitizer enhancement ratios (SERs) of 1.41, 1.29, and 1.16 were achieved using 160 kVp, 6 MV, and 15 MV X-ray energies, respectively. No significant effect was observed in L132 or DU145 cells at kV or MV energies (SER 0.97-1.08). GNP exposure did not increase radiation-induced DSB formation or inhibit DNA repair; however, GNP chemosensitization was observed in MDA-MB-231 cells treated with bleomycin (SER 1.38). Conclusions: We have demonstrated radiosensitization in MDA-MB-231 cells at MV X-ray energies. The sensitization was cell-specific with comparable effects at kV and MV energies, no increase in DSB formation, and GNP chemopotentiation with bleomycin, suggesting a possible biological mechanism of radiosensitization.

  1. Cytosine Deaminase/5-Fluorocytosine Exposure Induces Bystander and Radiosensitization Effects in Hypoxic Glioblastoma Cells in vitro

    SciTech Connect

    Chen, Jennifer K.; Hu, Lily J.; Wang Dongfang; Lamborn, Kathleen R.; Deen, Dennis F. . E-mail: dennisdeen@juno.com

    2007-04-01

    Purpose: Treatment of glioblastoma (GBM) is limited by therapeutic ratio; therefore, successful therapy must be specifically cytotoxic to cancer cells. Hypoxic cells are ubiquitous in GBM, and resistant to radiation and chemotherapy, and, thus, are logical targets for gene therapy. In this study, we investigated whether cytosine deaminase (CD)/5-fluorocytosine (5-FC) enzyme/prodrug treatment induced a bystander effect (BE) and/or radiosensitization in hypoxic GBM cells. Methods and Materials: We stably transfected cells with a gene construct consisting of the SV40 minimal promoter, nine copies of a hypoxia-responsive element, and the yeast CD gene. During hypoxia, a hypoxia-responsive element regulates expression of the CD gene and facilitates the conversion of 5-FC to 5-fluorouracil, a highly toxic antimetabolite. We used colony-forming efficiency (CFE) and immunofluorescence assays to assess for BE in co-cultures of CD-expressing clone cells and parent, pNeo- or green fluorescent protein-stably transfected GBM cells. We also investigated the radiosensitivity of CD clone cells treated with 5-FC under hypoxic conditions, and we used flow cytometry to investigate treatment-induced cell cycle changes. Results: Both a large BE and radiosensitization occurred in GBM cells under hypoxic conditions. The magnitude of the BE depended on the number of transfected cells producing CD, the functionality of the CD, the administered concentration of 5-FC, and the sensitivity of cell type to 5-fluorouracil. Conclusion: Hypoxia-inducible CD/5-FC therapy in combination with radiation therapy shows both a pronounced BE and a radiosensitizing effect under hypoxic conditions.

  2. Comparison of microwave and magnetic nanoparticle hyperthermia radiosensitization in murine breast tumors

    NASA Astrophysics Data System (ADS)

    Giustini, Andrew J.; Petryk, Alicia A.; Hoopes, Paul J.

    2011-03-01

    Hyperthermia has been shown to be an effective radiosensitizer. Its utility as a clinical modality has been limited by a minimally selective tumor sensitivity and the inability to be delivered in a tumor-specific manner. Recent in vivo studies (rodent and human) have shown that cancer cell-specific cytotoxicity can be effectively and safely delivered via iron oxide magnetic nanoparticles (mNP) and an appropriately matched noninvasive alternating magnetic field (AMF). To explore the tumor radiosensitization potential of mNP hyperthermia we used a syngeneic mouse breast cancer model, dextran-coated 110 nm hydrodynamic diameter mNP and a 169 kHz / 450 Oe (35.8 kA/m) AMF. Intradermally implanted (flank) tumors (150 +/- 40 mm3) were treated by injection of 0.04 ml mNP (7.5 mg Fe) / cm3 into the tumor and an AMF (35.8 kA/m and 169 kHz) exposure necessary to achieve a CEM (cumulative equivalent minute) thermal dose of 60 (CEM 60). Tumors were treated with mNP hyperthermia (CEM 60), radiation alone (15 Gy, single dose) and in combination. Compared to the radiation and heat alone treatments, the combined treatment resulted in a greater than two-fold increase in tumor regrowth tripling time (tumor treatment efficacy). None of the treatments resulted in significant normal tissue toxicity or morbidity. Studies were also conducted to compare the radiosensitization effect of mNP hyperthermia with that of microwave-induced hyperthermia. The effects of incubation of nanoparticles within tumors (to allow nanoparticles to be endocytosed) before application of AMF and radiation were determined. This preliminary information suggests cancer cell specific hyperthermia (i.e. antibody-directed or anatomically-directed mNP) is capable of providing significantly greater radiosensitization / therapeutic ratio enhancement than other forms of hyperthermia delivery.

  3. Histone deacetylase enzyme silencing using shRNAs enhances radiosensitivity of SW579 thyroid cancer cells

    PubMed Central

    Wang, Ye; Jin, Tao; Dai, Xueming; Yan, Dongwang; Peng, Zhihai

    2016-01-01

    The aim of the present study was to screen the enzymes that are associated with the radiosensitivity of SW579 thyroid cancer cells, and investigate whether radiation, combined with specific RNA interference on the screened enzymes, enhances radiosensitivity of SW579 thyroid cancer cells. Quantitative polymerase chain reaction (qPCR) was used to analyze epigenetic enzyme expression changes before and after radiotherapy, and four enzymes, histone deacetylase 1 (HDAC1), HDAC2, HDAC4 and HDAC6 were screened. Western blot analysis was performed to analyze the change in HDAC1, HDAC2, HDAC4 and HDAC6 protein expression following radiotherapy. Short hairpin RNA (ShRNA)-HDAC1, shRNA-HDAC2, shRNA-HDAC4 and shRNA-HDAC6 plasmids were constructed and SW579 cells were transfected with corresponding shRNA-HDACs. Reverse transcription-qPCR was used to detect whether downregulation of HDAC mRNAs had been effective. In addition, shRNA and shRNA negative control (NC) pools were established and transfected into the SW579 cells. The samples were divided into four groups; control, trichostatin A, shRNA pool and shRNA NC pool, to analyze the effective enhancement of specific shRNA on radiosensitivity in thyroid cancer cells. The morphological changes were observed in the SW579 cells, and the number of tumor cells decreased markedly in the shRNA pool group compared with that of the other three groups. Therefore, it was concluded that HDACs present a potential target for increasing the sensitivity of thyroid cancer cells to radiotherapy, and shRNA-HDAC interference combined with radiotherapy promotes the radiosensitivity of tumors. PMID:27600599

  4. Metronidazole as a radiosensitizer: a preliminary report on estimation in serum and saliva

    SciTech Connect

    Karim, A.B.M.F.; Faber, D.B.; Haas, R.E.; Hoekstra, F.H.; Njo, K.H.

    1980-09-01

    Some studies indicate the clinical benefit of hypoxic radiosensitizers in patients who are undergoing radiotherapy. Serum level of sensitizers are usualy advised; however they are very demanding on the patient. Saliva level of the sensitizers may be an alternative method. This study correlated serum level of metronidazole to the saliva level in 10 patients who were undergoing radiotherapy with the sensitizer. A change to the saliva level method appears to relieve the patients.

  5. Inhibition of Hsp27 Radiosensitizes Head-and-Neck Cancer by Modulating Deoxyribonucleic Acid Repair

    SciTech Connect

    Guttmann, David M.; Hart, Lori; Du, Kevin; Seletsky, Andrew; Koumenis, Constantinos

    2013-09-01

    Purpose: To present a novel method of tumor radiosensitization through Hsp27 knockdown using locked nucleic acid (LNA) and to investigate the role of Hsp27 in DNA double strand break (DSB) repair. Methods and Materials: Clonogenic survival assays, immunoblotting, the proximity ligation assay, and γH2AX foci analysis were conducted in SQ20B and FaDu human head-and-neck cancer cell lines treated with Hsp27 LNA and Hsp27 short hairpin RNA (shRNA). Additionally, nude mice with FaDu flank tumors were treated with fractionated radiation therapy after pretreatment with Hsp27 LNA and monitored for tumor growth. Results: Hsp27 LNA and Hsp27 shRNA radiosensitized head-and-neck cancer cell lines in an Hsp27-dependent manner. Ataxia-Telangectasia Mutated-mediated DNA repair signaling was impaired in irradiated cells with Hsp27 knockdown. ATM kinase inhibition abrogated the radiosensitizing effect of Hsp27. Furthermore, Hsp27 LNA and shRNA both attenuated DNA repair kinetics after radiation, and Hsp27 was found to colocalize with ATM in both untreated and irradiated cells. Last, combined radiation and Hsp27 LNA treatment in tumor xenografts in nude mice suppressed tumor growth compared with either treatment alone. Conclusions: These results support a radiosensitizing property of Hsp27 LNA in vitro and in vivo, implicate Hsp27 in double strand break repair, and suggest that Hsp27 LNA might eventually serve as an effective clinical agent in the radiotherapy of head-and-neck cancer.

  6. Differential Radiosensitizing Potential of Temozolomide in MGMT Promoter Methylated Glioblastoma Multiforme Cell Lines

    SciTech Connect

    Nifterik, Krista A. van; Berg, Jaap van den; Stalpers, Lukas J.A.; Lafleur, M. Vincent M.; Leenstra, Sieger; Slotman, Ben J.; Hulsebos, Theo J.M.; Sminia, Peter

    2007-11-15

    Purpose: To investigate the radiosensitizing potential of temozolomide (TMZ) for human glioblastoma multiforme (GBM) cell lines using single-dose and fractionated {gamma}-irradiation. Methods and Materials: Three genetically characterized human GBM cell lines (AMC-3046, VU-109, and VU-122) were exposed to various single (0-6 Gy) and daily fractionated doses (2 Gy per fraction) of {gamma}-irradiation. Repeated TMZ doses were given before and concurrent with irradiation treatment. Immediately plated clonogenic cell-survival curves were determined for both the single-dose and the fractionated irradiation experiments. To establish the net effect of clonogenic cell survival and cell proliferation, growth curves were determined, expressed as the number of surviving cells. Results: All three cell lines showed MGMT promoter methylation, lacked MGMT protein expression, and were sensitive to TMZ. The isotoxic TMZ concentrations used were in a clinically feasible range of 10 {mu}mol/L (AMC-3046), 3 {mu}mol/L (VU-109), and 2.5 {mu}mol/L (VU-122). Temozolomide was able to radiosensitize two cell lines (AMC 3046 and VU-122) using single-dose irradiation. A reduction in the number of surviving cells after treatment with the combination of TMZ and fractionated irradiation was seen in all three cell lines, but only AMC 3046 showed a radiosensitizing effect. Conclusions: This study on TMZ-sensitive GBM cell lines shows that TMZ can act as a radiosensitizer and is at least additive to {gamma}-irradiation. Enhancement of the radiation response by TMZ seems to be independent of the epigenetically silenced MGMT gen000.

  7. Training within the Accounting Firm.

    ERIC Educational Resources Information Center

    Finch, Beth; And Others

    1991-01-01

    A survey received 509 responses from 2,000 randomly selected accounting employees about which training topics are receiving the most attention and who is receiving the training. Results prove that training has become an integral part of a certified public accountant's job; topics most often covered were tax related--individual and corporate income…

  8. Zidovudine, abacavir and lamivudine increase the radiosensitivity of human esophageal squamous cancer cell lines.

    PubMed

    Chen, Xuan; Wang, Cong; Guan, Shanghui; Liu, Yuan; Han, Lihui; Cheng, Yufeng

    2016-07-01

    Telomerase is a type of reverse transcriptase that is overexpressed in almost all human tumor cells, but not in normal tissues, which provides an opportunity for radiosensitization targeting telomerase. Zidovudine, abacavir and lamivudine are reverse transcriptase inhibitors that have been applied in clinical practice for several years. We sought to explore the radiosensitization effect of these three drugs on human esophageal cancer cell lines. Eca109 and Eca9706 cells were treated with zidovudine, abacavir and lamivudine for 48 h before irradiation was administered. Samples were collected 1 h after irradiation. Clonal efficiency assay was used to evaluate the effect of the combination of these drugs with radiation doses of 2, 4, 6 and 8 Gy. DNA damage was measured by comet assay. Telomerase activity (TA) and relative telomere length (TL) were detected and evaluated by real-time PCR. Apoptosis rates were assessed by flow cytometric analysis. The results showed that all the drugs tested sensitized the esophageal squamous cell carcinoma (ESCC) cell lines to radiation through an increase in radiation-induced DNA damage and cell apoptosis, deregulation of TA and decreasing the shortened TL caused by radiation. Each of the drugs investigated (zidovudine, abacavir and lamivudine) could be used for sensitizing human esophageal cancer cell lines to radiation. Consequently, the present study supports the potential of these three drugs as therapeutic agents for the radiosensitization of esophageal squamous cell cancer.

  9. Effect of downregulation of survivin expression on radiosensitivity of human epidermoid carcinoma cells

    SciTech Connect

    Sah, Nand K.; Munshi, Anupama; Hobbs, Marvette B.A.; Carter, Bing Z.; Andreeff, Michael; Meyn, Raymond E. . E-mail: rmeyn@mdanderson.org

    2006-11-01

    Purpose: The expression of survivin, a member of the inhibitor-of-apoptosis protein family, is elevated in many types of human cancer. High survivin expression has been associated with poor patient prognosis and tumor resistance to chemotherapy and radiotherapy. The purpose of this study was to compare the radiosensitizing effects of five agents that target survivin on their relative ability to downregulate survivin expression. Methods and Materials: The human epidermoid carcinoma cell line A431 was treated with adenoviral-mediated wild-type p53, antisense to survivin, the mitogen-activated protein kinase inhibitor PD98059, the cyclin-dependent kinase inhibitor Purvalanol A, or the histone deacetylase inhibitor trichostatin A. The radiosensitizing effects of these treatments were determined by clonogenic survival curve analysis and their abilities to suppress survivin expression by Western blot analysis. Results: All the strategies were shown to radiosensitize A431 cells. This effect correlated with their abilities to downregulate survivin. Conclusion: Expression of survivin appears to confer a radioresistant phenotype that can be overcome using several clinically achievable strategies that target survivin either specifically or nonspecifically.

  10. A chemical screen for medulloblastoma identifies quercetin as a putative radiosensitizer

    PubMed Central

    Biesmans, Dennis; Crommentuijn, Matheus H.W.; Cloos, Jacqueline; Li, Xiao-Nan; Kogiso, Mari; Tannous, Bakhos A.; Vandertop, W. Peter; Noske, David P.; Kaspers, Gertjan J.L.; Würdinger, Tom; Hulleman, Esther

    2016-01-01

    Treatment of medulloblastoma in children fails in approximately 30% of patients, and is often accompanied by severe late sequelae. Therefore, more effective drugs are needed that spare normal tissue and diminish long-term side effects. Since radiotherapy plays a pivotal role in the treatment of medulloblastoma, we set out to identify novel drugs that could potentiate the effect of ionizing radiation. Thereto, a small molecule library, consisting of 960 chemical compounds, was screened for its ability to sensitize towards irradiation. This small molecule screen identified the flavonoid quercetin as a novel radiosensitizer for the medulloblastoma cell lines DAOY, D283-med, and, to a lesser extent, D458-med at low micromolar concentrations and irradiation doses used in fractionated radiation schemes. Quercetin did not affect the proliferation of neural precursor cells or normal human fibroblasts. Importantly, in vivo experiments confirmed the radiosensitizing properties of quercetin. Administration of this flavonoid at the time of irradiation significantly prolonged survival in orthotopically xenografted mice. Together, these findings indicate that quercetin is a potent radiosensitizer for medulloblastoma cells that may be a promising lead for the treatment of medulloblastoma in patients. PMID:26967057

  11. The Effect of Metformin and GANT61 Combinations on the Radiosensitivity of Prostate Cancer Cells

    PubMed Central

    Gonnissen, Annelies; Isebaert, Sofie; McKee, Chad M.; Muschel, Ruth J.; Haustermans, Karin

    2017-01-01

    The anti-diabetes drug metformin has been shown to have anti-neoplastic effects in several tumor models through its effects on energy metabolism and protein synthesis. Recent studies show that metformin also targets Hedgehog (Hh) signaling, a developmental pathway re-activated in several tumor types, including prostate cancer (PCa). Furthermore, we and others have shown that Hh signaling is an important target for radiosensitization. Here, we evaluated the combination of metformin and the Hh inhibitor GANT61 (GLI-ANTagonist 61) with or without ionizing radiation in three PCa cell lines (PC3, DU145, 22Rv1). The effect on proliferation, radiosensitivity, apoptosis, cell cycle distribution, reactive oxygen species production, DNA repair, gene and protein expression was investigated. Furthermore, this treatment combination was also assessed in vivo. Metformin was shown to interact with Hh signaling by inhibiting the effector protein glioma-associated oncogene homolog 1 (GLI1) in PCa cells both in vitro and in vivo. The combination of metformin and GANT61 significantly inhibited PCa cell growth in vitro and enhanced the radiation response of 22Rv1 cells compared to either single agent. Nevertheless, neither the growth inhibitory effect nor the radiosensitization effect of the combination treatment observed in vitro was seen in vivo. Although the interaction between metformin and Hh signaling seems to be promising from a therapeutic point of view in vitro, more research is needed when implementing this combination strategy in vivo. PMID:28208838

  12. Different radiosensitivities of mast-cell precursors in the bone marrow and skin of mice

    SciTech Connect

    Kitamura, Y.; Yokoyama, M.; Sonoda, T.; Mori, K.J.

    1983-01-01

    Although tissue mast cells are derived from the bone marrow, some descendants of bone marrow-derived precursors retain the ability to proliferate and differentiate into mast cells even after localization in the skin. The purpose of the present study was to determine the D/sub 0/ values for mast-cell precursors in the bone marrow and those localized in the skin. Bone marrow cells were removed from (WB X C57BL/6)F/sub 1/+/+ mice after various doses of irradiation and injected into the skin of the congenic W/W/sup v/ mice which were genetically without mast cells. Radiosensitivity of mast-cell precursors in the bone marrow was evaluated by determining the proportion of the injection sites at which mast cells did not appear. For the assay of the radiosensitivity of mast-cell precursors localized in the skin, pieces of skin were removed from beige C57BL/6 (bg/sup J//bg/sup J/, Chediak-Higashi syndrome) mice after various doses of irradiation and grafted onto the backs of the normal C57BL/6 mice. Radiosensitivity of mast-cell precursors in the skin was evaluated by determining the decrease of beige-type mast cells which possessed giant granules. Mast-cell precursors in the bone marrow were much more radiosenitive than those localized in the skin. D/sup 0/ value was about 100 rad for the former and about 800 rad for the latter.

  13. Fundamental mechanisms of DNA radiosensitization: damage induced by low-energy electrons in brominated oligonucleotide trimers.

    PubMed

    Park, Yeunsoo; Polska, Katarzyna; Rak, Janusz; Wagner, J Richard; Sanche, Léon

    2012-08-16

    The replacement of nucleobases with brominated analogs enhances DNA radiosensitivity. We examine the chemistry of low-energy electrons (LEEs) in this sensitization process by experiments with thin films of the oligonucleotide trimers TBrXT, where BrX = 5-BrU (5-bromouracil), 5-BrC (5-bromocytosine), 8-BrA (8-bromoadenine), or 8-BrG (8-bromoguanine). The products induced from irradiation of thin (∼ 2.5 nm) oligonucleotide films, with 10 eV electrons, under ultrahigh vacuum (UHV) are analyzed by HPLC-UV. The number of damaged brominated trimers ranges from about 12 to 15 × 10(-3) molecules per incident electron, whereas under the identical conditions, these numbers drop to 4-7 × 10(-3) for the same, but nonbrominated oligonucleotides. The results of HPLC analysis show that the main degradation pathway of trinucleotides containing brominated bases involve debromination (i.e., loss of the bromine atom and its replacement with a hydrogen atom). The electron-induced sum of products upon bromination increases by factors of 2.1 for the pyrimidines and 3.2 for the purines. Thus, substitution of any native nucleobase with a brominated one in simple models of DNA increases LEE-induced damage to DNA and hence its radiosensitivity. Furthermore, besides the brominated pyrimidines that have already been tested in clinical trials, brominated purines not only appear to be promising sensitizers for radiotherapy, but could provide a higher degree of radiosensitization.

  14. Lin28-let7 Modulates Radiosensitivity of Human Cancer Cells With Activation of K-Ras

    SciTech Connect

    Oh, Jee-Sun.; Kim, Jae-Jin; Byun, Ju-Yeon; Kim, In-Ah

    2010-01-15

    Purpose: To evaluate the potential of targeting Lin28-let7 microRNA regulatory network for overcoming the radioresistance of cancer cells having activated K-Ras signaling. Methods and Materials: A549 lung carcinoma cells and ASPC1 pancreatic cancer cells possessing K-RAS mutation were transfected with pre-let7a microRNA or Lin28 siRNA, respectively. Clonogenic assay, quantitative reverse transcription polymerase chain reaction, and Western analysis were performed. The effects of Lin28 on SQ20B cells having wild-type K-RAS, and a normal fibroblast were also assessed. Results: The overexpression of let-7a decreased expression of K-Ras and radiosensitized A549 cells. Inhibition of Lin28, a repressor of let-7, attenuated K-Ras expression and radiosensitized A549 and ASPC1 cells. Neither SQ20B cells expressing wild-type K-RAS nor HDF, the normal human fibroblasts, were radiosensitized by this approach. Conclusions: The Lin28-let7 regulatory network may be a potentially useful therapeutic target for overcoming the radioresistance of human cancers having activated K-Ras signaling.

  15. Salinomycin radiosensitizes human nasopharyngeal carcinoma cell line CNE-2 to radiation.

    PubMed

    Zhang, Yongqin; Zuo, Yun; Guan, Zhifeng; Lu, Weidong; Xu, Zheng; Zhang, Hao; Yang, Yan; Yang, Meilin; Zhu, Hongcheng; Chen, Xiaochen

    2016-01-01

    Nasopharyngeal carcinoma (NPC) is primarily treated by chemoradiation. However, how to promote radiation sensitivity in NPC remains a challenge. Salinomycin is potentially useful for the treatment of cancer. This study aimed to explore the radiosensitivity of salinomycin on human nasopharyngeal carcinoma cell line CNE-2. CNE-2 were treated with salinomycin or irradiation, alone or in combination. The cytotoxicity effects of salinomycin were measured using CCK-8 assay. Clonogenic survival assay was used to evaluate the effects of salinomycin on the radiosensitivity of CNE-2. The changes of cell cycle distribution and apoptosis were assayed using flow cytometry. The expression of Caspase3/Bax/Bal-2 was detected by Western blotting. DNA damage was detected via γ-H2AX foci counting. The results showed that salinomycin induced apoptosis and G2/M arrest, increased Bax and cleaved Caspase3, decreased Bcl-2 expression, and increased the formation of γ-H2AX nuclear foci. These data suggest that salinomycin may be a radiosensitizer for NPC radiotherapy.

  16. Bacillus calmette-guerin cell wall cytoskeleton enhances colon cancer radiosensitivity through autophagy.

    PubMed

    Yuk, Jae-Min; Shin, Dong-Min; Song, Kyoung-Sub; Lim, Kyu; Kim, Ki-Hye; Lee, Sang-Hee; Kim, Jin-Man; Lee, Ji-Sook; Paik, Tae-Hyun; Kim, Jun-Sang; Jo, Eun-Kyeong

    2010-01-01

    The cell wall skeleton of Mycobacterium bovis Bacillus Calmette-Guerin (BCG/CWS) is an effective antitumor immunotherapy agent. Here, we demonstrate that BCG/CWS has a radiosensitizing effect on colon cancer cells through the induction of autophagic cell death. Exposure of HCT116 colon cancer cells to BCG/CWS before ionizing radiation (IR) resulted in increased cell death in a caspase-independent manner. Treatment with BCG/CWS plus IR resulted in the induction of autophagy in colon cancer cells. Either the autophagy inhibitor 3-methyladenine or knockdown of beclin 1 or Atg7 significantly reduced tumor cell death induced by BCG/CWS plus IR, whereas the caspase inhibitor z-VAD-fmk failed to do so. BCG/CWS plus IR-mediated autophagy and cell death was mediated predominantly by the generation of reactive oxygen species (ROS). The c-Jun NH(2)-terminal kinase pathway functioned upstream of ROS generation in the induction of autophagy and cell death in HCT116 cells after co-treatment with BCG/CWS and IR. Furthermore, toll-like receptor (TLR) 2, and in part, TLR4, were responsible for BCG/CWS-induced radiosensitization. In vivo studies revealed that BCG/CWS-mediated radiosensitization of HCT116 xenograft growth is accompanied predominantly by autophagy. Our data suggest that BCG/CWS in combination with IR is a promising therapeutic strategy for enhancing radiation therapy in colon cancer cells through the induction of autophagy.

  17. Radiosensitization by the ATR Inhibitor AZD6738 through Generation of Acentric Micronuclei

    PubMed Central

    Dillon, Magnus T.; Barker, Holly E.; Pedersen, Malin; Hafsi, Hind; Bhide, Shreerang A.; Newbold, Kate L.; Nutting, Christopher M.

    2017-01-01

    AZD6738 is an orally active ATR inhibitor (ATRi) currently in phase I clinical trials. We found in vitro growth inhibitory activity of this ATRi in a panel of human cancer cell lines. We demonstrated radiosensitization by AZD6738 to single radiation fractions in multiple cancer cell lines independent of both p53 and BRCA2 status by the clonogenic assay. Radiosensitization by AZD6738 to clinically relevant doses of fractionated radiation was demonstrated in vitro using a 3D tumor spheroid model and, in vivo, AZD6738 radiosensitized by abrogating the radiation-induced G2 cell-cycle checkpoint and inhibiting homologous recombination. Mitosis with damaged DNA resulted in mitotic catastrophe as measured by micronucleus formation by live-cell fluorescent-ubiquitination cell-cycle imaging of cell-cycle progression and nuclear morphology. Induction of micronuclei was significantly more prominent for AZD6738 compared with inhibition of the downstream kinase CHK1 alone at isoeffective doses. Micronuclei were characterized as acentric chromosomal fragments, which displayed characteristics of increased DNA damage and cell-cycle dyssynchrony when compared with the primary nucleus. PMID:28062704

  18. Radiosensitivity and relative biological effectiveness based on a generalized target model

    PubMed Central

    Zhao, Lei; Wu, Di; Mi, Dong; Sun, Yeqing

    2017-01-01

    By considering both cellular repair effects and indirect effects of radiation, we have generalized the traditional target model, and made it have a linear–quadratic–linear characteristic. To assess the repair capacity–dependent radiosensitivity and relative biological effectiveness (RBE), the generalized target model was used to fit the survival of human normal embryonic lung fibroblast MRC-5 cells in the G0 and G1 phases after various types of radiations. The fitting results indicate that the generalized target model works well in the dose ranges considered. The resulting calculations qualitatively show that the parameter ratio (a/V) in the model could represent the cellular repair capacity. In particular, the significant linear correlations between radiosensitivity/RBE and cellular repair capacity are observed for different slopes of the linear regression curves. These results show that the radiosensitivity and RBE depend on the cellular repair capacity and can be regulated by linear energy transfer. These analyses suggest that the ratio a/V in the generalized target model can also be used for radiation damage assessment in radiotherapy. PMID:27422933

  19. Low Dose Rate Radiosensitization of Hepatocellular Carcinoma In Vitro and in Patients1

    PubMed Central

    Cuneo, Kyle C.; Davis, Mary A.; Feng, Mary U.; Novelli, Paula M.; Ensminger, William D.; Lawrence, Theodore S.

    2014-01-01

    Transarterial radioembolization (TARE) with 90Y microspheres delivers low dose rate radiation (LDR) to intrahepatic tumors. In the current study, we examined clonogenic survival, DNA damage, and cell cycle distribution in hepatocellular carcinoma (HCC) cell lines treated with LDR in combination with varying doses and schedules of 5-fluorouracil (5-FU), gemcitabine, and sorafenib. Radiosensitization was seen with 1 to 3 μM 5-FU (enhancement ratio 2.2–13.9) and 30 to 100 nM gemcitabine (enhancement ratio 1.9–2.9) administered 24 hours before LDR (0.26 Gy/h to 4.2 Gy). Sorafenib radiosensitized only at high concentrations (3–10 μM) when administered after LDR. For a given radiation dose, greater enhancement was seen with LDR compared to standard dose rate therapy. Summarizing our clinical experience with low dose rate radiosensitization, 13 patients (5 with HCC, 8 with liver metastases) were treated a total of 16 times with TARE and concurrent gemcitabine. Six partial responses and one complete response were observed with a median time to local failure of 7.1 months for all patients and 9.9 months for patients with HCC. In summary, HCC is sensitized to LDR with clinically achievable concentrations of gemcitabine and 5-FU in vitro. Encouraging responses were seen in a small cohort of patients treated with TARE and concurrent gemcitabine. Future studies are needed to validate the safety and efficacy of this approach. PMID:24956939

  20. 14 CFR 152.305 - Accounting records.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 14 Aeronautics and Space 3 2014-01-01 2014-01-01 false Accounting records. 152.305 Section 152.305... AIRPORT AID PROGRAM Accounting and Reporting Requirements § 152.305 Accounting records. (a) Airport... individual project, an accounting record satisfactory to the Administrator which segregates cost...

  1. 14 CFR 152.305 - Accounting records.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 14 Aeronautics and Space 3 2013-01-01 2013-01-01 false Accounting records. 152.305 Section 152.305... AIRPORT AID PROGRAM Accounting and Reporting Requirements § 152.305 Accounting records. (a) Airport... individual project, an accounting record satisfactory to the Administrator which segregates cost...

  2. 14 CFR 152.305 - Accounting records.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 14 Aeronautics and Space 3 2012-01-01 2012-01-01 false Accounting records. 152.305 Section 152.305... AIRPORT AID PROGRAM Accounting and Reporting Requirements § 152.305 Accounting records. (a) Airport... individual project, an accounting record satisfactory to the Administrator which segregates cost...

  3. 32 CFR 310.25 - Disclosure accounting.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 2 2013-07-01 2013-07-01 false Disclosure accounting. 310.25 Section 310.25....25 Disclosure accounting. (a) Disclosure accountings. (1) Keep an accurate record of all disclosures... accounting is required even if the individual has consented to the disclosure of the information....

  4. 32 CFR 310.25 - Disclosure accounting.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 32 National Defense 2 2012-07-01 2012-07-01 false Disclosure accounting. 310.25 Section 310.25....25 Disclosure accounting. (a) Disclosure accountings. (1) Keep an accurate record of all disclosures... accounting is required even if the individual has consented to the disclosure of the information....

  5. 32 CFR 310.25 - Disclosure accounting.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 32 National Defense 2 2014-07-01 2014-07-01 false Disclosure accounting. 310.25 Section 310.25....25 Disclosure accounting. (a) Disclosure accountings. (1) Keep an accurate record of all disclosures... accounting is required even if the individual has consented to the disclosure of the information....

  6. 32 CFR 310.25 - Disclosure accounting.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 2 2011-07-01 2011-07-01 false Disclosure accounting. 310.25 Section 310.25....25 Disclosure accounting. (a) Disclosure accountings. (1) Keep an accurate record of all disclosures... accounting is required even if the individual has consented to the disclosure of the information....

  7. 14 CFR 152.305 - Accounting records.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 3 2010-01-01 2010-01-01 false Accounting records. 152.305 Section 152.305... AIRPORT AID PROGRAM Accounting and Reporting Requirements § 152.305 Accounting records. (a) Airport... individual project, an accounting record satisfactory to the Administrator which segregates cost...

  8. Folate-targeted Polymeric Nanoparticle Formulation of Docetaxel is an Effective Molecularly Targeted Radiosensitizer with Efficacy Dependent on the Timing of Radiotherapy

    PubMed Central

    Werner, Michael E.; Copp, Jonathan A.; Karve, Shrirang; Cummings, Natalie D.; Sukumar, Rohit; Li, Chenxi; Napier, Mary E.; Chen, Ronald C.; Cox, Adrienne D.; Wang, Andrew Z.

    2011-01-01

    Nanoparticle (NP) chemotherapeutics hold great potential as radiosensitizers. Their unique properties, such as preferential accumulation in tumors and their ability to target tumors through molecular targeting ligands, are ideally suited for radiosensitization. We aimed to develop a molecularly targeted nanoparticle formulation of docetaxel (Dtxl) and evaluate its property as a radiosensitizer. Using a biodegradable and biocompatible lipid-polymer NP platform and folate as a molecular targeting ligand, we engineered a folate-targeted nanoparticle (FT-NP) formulation of Dtxl. These NPs have sizes of 72±4 nm and surface charges of −42±8 mV. Using folate receptor over-expressing KB cells and folate receptor low HTB-43 cells, we showed folate-mediated intracellular uptake of NPs. In vitro radiosensitization studies initially showed FT-NP is less effective than Dtxl as a radiosensitizer. However, the radiosensitization efficacy is dependent on the timing of radiotherapy. In vitro radiosensitization conducted with irradiation given at the optimal time (24 hours) showed FT-NP Dtxl is as effective as Dtxl. When FT-NP Dtxl is compared to Dtxl and non-targeted nanoparticle (NT-NP) Dtxl in vivo, FT-NP was found to be significantly more effective than Dtxl or NT-NP Dtxl as a radiosensitizer. We also confirmed that radiosensitization is dependent on timing of irradiation in vivo. In summary, FT-NP Dtxl is an effective radiosensitizer in folate-receptor over-expressing tumor cells. Time of irradiation is critical in achieving maximal efficacy with this nanoparticle platform. To the best of our knowledge, our report is the first to demonstrate the potential of molecularly targeted NPs as a promising new class of radiosensitizers. PMID:22011071

  9. Relationship between genetic polymorphisms of DNA ligase 1 and non-small cell lung cancer susceptibility and radiosensitivity.

    PubMed

    Tian, H; He, X; Yin, L; Guo, W J; Xia, Y Y; Jiang, Z X

    2015-06-26

    The aim of this study was to examine the relationship between genetic polymorphisms in DNA ligase 1 (LIG1) and non-small cell lung cancer (NSCLC) susceptibility and radiosensitivity in a Chinese population. This was a case-control study that included 352 NSCLC patients and 448 healthy controls. Polymerase chain reaction-restriction fragment length polymorphism analysis was conducted to detect HaeIII polymorphisms in exon 6 of the LIG1 gene in this popula-tion. This information was used to observe the effects of radiation in pa-tients with different genotypes in order to determine the genotypes as-sociated with radiosensitivity. The CC genotype and C allele frequency were significantly higher in the NSCLC group than in the control group (P = 0.012 and P = 0.023, respectively). The relative risk of experienc-ing NSCLC was 2.55 [95% confidence interval (CI), 1.12-3.98] for CC homozygous patients and 0.87 (95%CI, 0.46-1.88) for AA homozygous patients. Analysis of LIG1 genetic polymorphisms and radiosensitiv-ity of NSCLC patients showed that AA homozygous patients were sig-nificantly more radiosensitive than the control group (AA vs AC, P = 0.014; AA vs CC, P < 0.001; AC vs CC, P = 0.023). Therefore, the LIG1 CC genotype was associated with susceptibility to NSCLC, and the AA genotype demonstrated increased radiosensitivity compared to the AC and CC genotypes.

  10. Increased Chromosomal Radiosensitivity in Women Carrying BRCA1/BRCA2 Mutations Assessed With the G2 Assay

    SciTech Connect

    Ernestos, Beroukas; Nikolaos, Pandis; Koulis, Giannoukakos; Eleni, Rizou; Konstantinos, Beroukas; Alexandra, Giatromanolaki; Michael, Koukourakis

    2010-03-15

    Purpose: Several in vitro studies suggest that BRCA1 and BRCA2 mutation carriers present increased sensitivity to ionizing radiation. Different assays for the assessment of deoxyribonucleic acid double-strand break repair capacity have been used, but results are rather inconsistent. Given the concerns about the possible risks of breast screening with mammography in mutation carrier women and the potentially damaging effects of radiotherapy, the purpose of this study was to further investigate the radiosensitivity of this population. Methods and Materials: The G2 chromosomal radiosensitivity assay was used to assess chromosomal breaks in lymphocyte cultures after exposure to 1 Gy. A group of familiar breast cancer patients carrying a mutation in the BRCA1 or BRCA2 gene (n = 15) and a group of healthy mutation carriers (n = 5) were investigated and compared with a reference group of healthy women carrying no mutation (n = 21). Results: BRCA1 and BRCA2 mutation carriers had a significantly higher number of mean chromatid breaks per cell (p = 0.006) and a higher maximum number of breaks (p = 0.0001) as compared with their matched controls. Both healthy carriers and carriers with a cancer history were more radiosensitive than controls (p = 0.002 and p = 0.025, respectively). Age was not associated with increased radiosensitivity (p = 0.868). Conclusions: Our results indicate that BRCA1 and BRCA2 mutation carriers show enhanced radiosensitivity, presumably because of the involvement of the BRCA genes in deoxyribonucleic acid repair and cell cycle control mechanisms.

  11. Radiosensitization by SAHA in Experimental Colorectal Carcinoma Models-In Vivo Effects and Relevance of Histone Acetylation Status

    SciTech Connect

    Folkvord, Sigurd; Ree, Anne Hansen; Furre, Torbjorn; Halvorsen, Thomas; Flatmark, Kjersti

    2009-06-01

    Purpose: Histone deacetylase inhibitors are being evaluated as antitumor agents in ongoing clinical trials, and promising preclinical results, combined with favorable toxicity profiles, have rendered the drugs as interesting candidates for combination with other treatment modalities, such as radiotherapy. The aim of the present study was to evaluate the radiosensitizing properties of suberoylanilide hydroxamic acid (SAHA) and the possible requirement of histone hyperacetylation at radiation exposure. Methods and materials: Radiosensitization by SAHA was assessed in a colorectal carcinoma cell line and in two colorectal xenograft models by analysis of clonogenic survival and tumor growth delay, respectively. Histone acetylation status at radiation exposure was evaluated by Western blot. Results: In vitro, radiosensitization was demonstrated when cells were preincubated with SAHA, and, in the xenografts, tumor growth was delayed when the mice were treated with fractionated radiation combined with daily SAHA injections compared with radiation alone. Surprisingly, the SAHA-dependent growth delay was still present when radiation was delivered at restored baseline acetylation levels compared with maximal histone hyperacetylation. Conclusion: SAHA was an effective radiosensitizer in experimental colorectal carcinoma models, suggesting that histone deacetylase inhibition might constitute a valuable supplement to current multimodal treatment strategies in rectal cancer. The presence of histone hyperacetylation at radiation was not required to obtain an increased radiation response, questioning the validity of using histone hyperacetylation as a molecular marker for radiosensitivity.

  12. Tat-SmacN7 induces radiosensitization in cancer cells through the activation of caspases and induction of apoptosis.

    PubMed

    Chen, Fenghua; Xu, Chang; Du, Liqing; Wang, Yan; Cao, Jia; Fu, Yue; Guo, Yanting; Liu, Qiang; Fan, Feiyue

    2013-03-01

    A major concern in cancer therapy is resistance of tumors such as human non-small cell lung cancer and esophageal cancer to radiotherapy. Intrinsic radioresistance of these cancer cells limits therapeutic efficiency. Here, we determined in two cancer cell lines the potential radiosensitizing activity of Tat-SmacN7, a small molecule compound, which mimics the activity of Smac, a mitochondrial protein released during apoptosis. We found that Tat-SmacN7 can enter the cells and promote RNA expression and the activity of caspase-3, -8 and -9 and sensitized the cancer cells to radiation with a sensitization enhancement ratio (SER) of 1.5-1.6. Tat-SmacN7 radiosensitization was mediated by both extrinsic and intrinsic apoptosis pathways through activation of caspases. Consistently, blockage of caspase activation, through treatment with a caspase inhibitor, z-VAD-fmk, inhibited apoptosis and abrogated Tat-SmacN7 radiosensitization. Our study demonstrates that Tat-SmacN7 also has radiosensitization effects in vivo, so it could be further developed as a novel class of radiosensitizers for the treatment of radioresistant human non-small cell lung cancer and esophageal cancer.

  13. TIGAR knockdown radiosensitizes TrxR1-overexpressing glioma in vitro and in vivo via inhibiting Trx1 nuclear transport

    PubMed Central

    Zhang, Yushuo; Chen, Fei; Tai, Guomei; Wang, Jiaojiao; Shang, Jun; Zhang, Bing; Wang, Ping; Huang, Baoxing; Du, Jie; Yu, Jiahua; Zhang, Haowen; Liu, Fenju

    2017-01-01

    The up-regulation of thioredoxin reductase-1 (TrxR1) is detected in more than half of gliomas, which is significantly associated with increased malignancy grade and recurrence rate. The biological functions of NADPH-dependent TrxR1 are mainly associated with reduced thioredoxin-1 (Trx1) which plays critical roles in cellular redox signaling and tumour radio-resistance. Our previous work has proved that TP53 induced glycolysis and apoptosis regulator (TIGAR) knockdown could notably radiosensitize glioma cells. However, whether TrxR1-overexpressing glioma cells could be re-radiosensitized by TIGAR silence is still far from clear. In the present study, TrxR1 was stably over-expressed in U-87MG and T98G glioma cells. Both in vitro and in vivo data demonstrated that the radiosensitivity of glioma cells was considerably diminished by TrxR1 overexpression. TIGAR abrogation was able to radiosensitize TrxR1-overexpressing gliomas by inhibiting IR-induced Trx1 nuclear transport. Post-radiotherapy, TIGAR low-expression predicted significant longer survival time for animals suffering from TrxR1-overexpessing xenografts, which suggested that TIGAR abrogation might be a promising strategy for radiosensitizing TrxR1-overexpressing glial tumours. PMID:28338004

  14. TIGAR knockdown radiosensitizes TrxR1-overexpressing glioma in vitro and in vivo via inhibiting Trx1 nuclear transport.

    PubMed

    Zhang, Yushuo; Chen, Fei; Tai, Guomei; Wang, Jiaojiao; Shang, Jun; Zhang, Bing; Wang, Ping; Huang, Baoxing; Du, Jie; Yu, Jiahua; Zhang, Haowen; Liu, Fenju

    2017-03-24

    The up-regulation of thioredoxin reductase-1 (TrxR1) is detected in more than half of gliomas, which is significantly associated with increased malignancy grade and recurrence rate. The biological functions of NADPH-dependent TrxR1 are mainly associated with reduced thioredoxin-1 (Trx1) which plays critical roles in cellular redox signaling and tumour radio-resistance. Our previous work has proved that TP53 induced glycolysis and apoptosis regulator (TIGAR) knockdown could notably radiosensitize glioma cells. However, whether TrxR1-overexpressing glioma cells could be re-radiosensitized by TIGAR silence is still far from clear. In the present study, TrxR1 was stably over-expressed in U-87MG and T98G glioma cells. Both in vitro and in vivo data demonstrated that the radiosensitivity of glioma cells was considerably diminished by TrxR1 overexpression. TIGAR abrogation was able to radiosensitize TrxR1-overexpressing gliomas by inhibiting IR-induced Trx1 nuclear transport. Post-radiotherapy, TIGAR low-expression predicted significant longer survival time for animals suffering from TrxR1-overexpessing xenografts, which suggested that TIGAR abrogation might be a promising strategy for radiosensitizing TrxR1-overexpressing glial tumours.

  15. Radiosensitivity of human tumour cells is correlated with the induction but not with the repair of DNA double-strand breaks.

    PubMed

    El-Awady, R A; Dikomey, E; Dahm-Daphi, J

    2003-08-04

    Nine human tumour cell lines (four mammary, one bladder, two prostate, one cervical, and one squamous cell carcinoma) were studied as to whether cellular radiosensitivity is related to the number of initial or residual double-strand breaks (dsb). Cellular sensitivity was measured by colony assay and dsb by means of constant- and graded-field gel electrophoresis (CFGE and GFGE, respectively). The nine tumour cell lines showed a broad variation in cellular sensitivity (SF2 0.17-0.63). The number of initial dsb as measured by GFGE ranged between 14 and 27 dsb/Gy/diploid DNA content. In contrast, normal fibroblasts raised from skin biopsies of seven individuals showed only a marginal variation with 18-20 dsb/Gy/diploid DNA content. For eight of the nine tumour cell lines, there was a significant correlation between the number of initial dsb and the cellular radiosensitivity. The tumour cells showed a broad variation in the amount of dsb measured 24 h after irradiation by CFGE, which, however, was not correlated with the cellular sensitivity. This residual damage was found to be influenced not only by the actual number of residual dsb, but also by apoptosis and cell cycle progression which had impact on CFGE measurements. Some cell line strains were able to proliferate even after exposure to 150 Gy while others were found to degrade their DNA. Our results suggest that for tumour cells, in contrast to normal cells, the variation in sensitivity is mainly determined by differences in the initial number of dsb induced.

  16. HLF/miR-132/TTK axis regulates cell proliferation, metastasis and radiosensitivity of glioma cells.

    PubMed

    Chen, Shu; Wang, Yang; Ni, Chunxia; Meng, Ge; Sheng, Xiaofang

    2016-10-01

    Glioma is a malignant cancer with high mortality. A key prognostic factor of glioma is radiosensitivity. It has also been known that microRNAs (miR) significantly contribute to the development of glioma. miR-132 has been previously reported to inhibit tumor growth in some cancers, but not well studied in glioma. It is necessary to understand the association between miR-132 and glioma, including miR-132 expression in glioma, effects of miR-132 on cancer metastasis and radiosensitivity, and the involved molecular mechanism. We first explored the expression levels of miR-132 in human normal and glioma tissues, then correlated the expression levels with different stages of glioma. Utilizing human glioma U87 cells, lentiviral transduction technique, luciferase reporter assay, wound healing assay, transwell invasion assay and clonogenic assay, we investigated the effects of hepatic leukemia factor (HLF), miR-132 and TTK protein kinase (TTK) on cancer cell viability, proliferation, migration, invasion and radiosensitivity. The expression of miR-132 was low in human glioma tissues, and the downregulated expression was associated with advanced glioma grades. HLF directly bound to the BS1 site of miR-132 promoter to enhance the expression of miR-132. HLF-mediated miR-132 was able to directly target and inhibit a downstream factor TTK, which had an oncogenic role. Overexpression of TTK could reverse the inhibitory effects of either miR-132 or HLF on cancer cell proliferation, metastasis and radioresistance. TTK acts as an oncogene in glioma. HLF-mediated miR-132 directly suppresses TTK expression, thus exerting inhibitory effects on cancer cell proliferation, metastasis and radioresistance.

  17. Radiosensitivity in HeLa cervical cancer cells overexpressing glutathione S-transferase π 1

    PubMed Central

    YANG, LIANG; LIU, REN; MA, HONG-BIN; YING, MING-ZHEN; WANG, YA-JIE

    2015-01-01

    The aims of the present study were to investigate the effect of overexpressed exogenous glutathione S-transferase π 1 (GSTP1) gene on the radiosensitivity of the HeLa human cervical cancer cell line and conduct a preliminarily investigation into the underlying mechanisms of the effect. The full-length sequence of human GSTP1 was obtained by performing a polymerase chain reaction (PCR) using primers based on the GenBank sequence of GSTP1. Subsequently, the gene was cloned into a recombinant eukaryotic expression plasmid, and the resulting construct was confirmed by restriction analysis and DNA sequencing. A HeLa cell line that was stably expressing high levels of GSTP1 was obtained through stable transfection of the constructed plasmids using lipofectamine and screening for G418 resistance, as demonstrated by reverse transcription-PCR. Using the transfected HeLa cells, a colony formation assay was conducted to detect the influence of GSTP1 overexpression on the cell radiosensitivity. Furthermore, flow cytometry was used to investigate the effect of GSTP1 overexpression on cell cycle progression, with the protein expression levels of the cell cycle regulating factor cyclin B1 detected using western blot analysis. Colony formation and G2/M phase arrest in the GSTP1-expressing cells were significantly increased compared with the control group (P<0.01). In addition, the expression of cyclin B1 was significantly reduced in the GSTP1-expressing cells. These results demonstrated that increased expression of GSTP1 inhibits radiosensitivity in HeLa cells. The mechanism underlying this effect may be associated with the ability of the GSTP1 protein to reduce cyclin B1 expression, resulting in significant G2/M phase arrest. PMID:26622693

  18. Radiosensitizing activity and pharmacokinetics of multiple dose administered KU-2285 in peripheral nerve tissue in mice

    SciTech Connect

    Iwai, Hiroyuki; Matsuno, Etsuko ); Sasai, Keisuke; Abe, Mitsuyuki; Shibamoto, Yuta )

    1994-06-15

    In a clinical trial in which a 2-nitroimidazole radiosensitizer was administered repeatedly, the dose-limiting toxicity was found to be peripheral neuropathy. In the present study, the in vivo radiosensitizing activity of KU-2285 in combination with radiation dose fractionation, and the pharmacokinetics of cumulative dosing of KU-2285 in the peripheral nerves were examined. The ability of three nitroimidazoles, misonidazole (MISO), etanidazole (SR-2508) and KU-2285, to sensitize SCCVII tumors to radiation treatment has been compared for drug doses in the range 0-200 mg/kg. Single radiation doses or two different fractionation schedules (6 Gy/fractions [times] three fractions/48 h or 5 Gy/fractions [times] five fractions/48 h) were used; the tumor cell survival was determined using an in vivo/in vitro colony assay. The pharmacokinetics in the sciatic nerves were undertaken, when KU-2285 or etanidazole were injected at a dose of 200 mg/kg intravenously one, two, three, or four times at 2-h intervals. At less than 100 mg/kg, KU-2285 sensitized SCCVII tumors more than MISO and SR-2508 by fractionated irradiation. Evaluation of pharmacokinetics in the peripheral nerves showed that the apparent biological half-life of SR-2508 increased with the increases in the number of administrations, whereas that of KU-2285 became shorter. Since most clinical radiotherapy is given in small multiple fractions, KU-2285 appears to be a hypoxic cell radiosensitizer that could be useful in such regimens, and that poses no risk of chronic peripheral neurotoxicity. 12 refs., 5 figs., 1 tab.

  19. Partition coefficient as a guide to the development of radiosensitizers which are less toxic than misonidazole

    SciTech Connect

    Brown, J.M.; Workman, P.

    1980-04-01

    Ten 2-nitroimidazole radiosensitizers of electron affinity equal to that of misonidazole, but differing in their octanol:water partition coefficient over a 100-fold range, were chosen to examine the effect of lipophilicity on the pharmacokinetics of these drugs in BALB/c mice bearing EMT6 tumors. Plasma, tumor, and brain concentrations were assayed, using high performance liquid chromatography (HPLC), as a function of time after a single ip injection of each drug. Peak concentrations in the tumor declined with decreasing lipophilicity. This was due to declining peak plasma concentrations resulting from slower drug absorption and could be overcome by iv injection. The tumor plasma ratio, once sufficient time had elapsed for it to reach its equilibrium value, was independent of partition coefficient (P) over the range 0.026 to 1.5 but showed a 50% reduction in this ratio for the most hydrophilic compound studied (P = 0.014). (This compound was also the one drug in the series which was significantly poorer than misonidazole in its radiosensitization as a function of drug concentration). The brain/plasma ratio, on the other hand, showed a marked dependence on lipophilicity. For misonidazole and more lipophilic compounds, the brain/plasma ratio was 1.0, but as the lipophilicity decreased below that of misonidazole, the compounds showed an increasing difficulty in penetration into the brain, and brain/plasma levels of less than 0.1 were found for the most hydrophilic drugs. These low brain/plasma ratios correlated with an increased acute LD/sub 50/ of the drugs. Bilateral nephrectomy was used to increase the apparent plasma half-life of SR-2508 from 0.8 to 15 hr. This change, however, did not affect the tumor/brain ratio of approximately 10 for this drug. The significance of these pharmacokinetic data is discussed in terms of the development of a radiosensitizer superior to misonidazole for clinical use.

  20. Optical isomers of a new 2-nitroimidazole nucleoside analog (PR-350 series): Radiosensitization efficiency and toxicity

    SciTech Connect

    Oya, Natsuo; Sasai, Keisuke; Shibata, Toru

    1995-08-30

    A new 2-nitroimidazole nucleoside radiosensitizer, PR-350 (1-[1{prime},3{prime},4{prime}-trihydroxy-2{prime}-butoxy]-methyl-2-nitroimidazole), has been reported to be as efficient as and less toxic than etanidazole. This compound is racemic, and it was recently optically resolved into two isomers, PR-68 (2{prime}R,3{prime}S type) and PR-69 (2{prime}S,3{prime}R type). The other two isomers, PR-28 (2{prime}S,3{prime}S type) and PR-44 (2{prime}R,3{prime}R type), were asymmetrically synthesized. In the present study, we investigated the properties, sensitizing activity, and toxicity of PR-350 and the four optical isomers in comparison with those of other 2-nitroimidazole hypoxic cell radiosensitizers, etanidazole, KU-2285, KIN-804, and RP-170. Because PR-350 and PR-28 can be industrially synthesized, we evaluated whether either of these two drugs are suitable for further investigation. In vivo radiosensitizing activity differed among the four optical isomers, which appeared to be due, at least in part, to differences in lipophilicity. Although PR-28 was the least toxic, its low sensitization efficiency does not warrant clinical trials. Among the PR compounds, PR-68 appears to be most efficient, but optical resolution of PR-68 from PR-350 is expensive, and asymmetrical synthesis of PR-68 is not established. Therefore, PR-350 seems to be most suitable for further investigation among the PR-350 series compounds, considering its higher efficiency compared with PR-28 and PR-44, and established synthesis. 28 refs., 7 figs., 1 tab.

  1. The influence of blood storage time and general anaesthesia on chromosomal radiosensitivity assessment.

    PubMed

    Baeyens, Ans; Herd, Olivia; Francies, Flavia Zita; Cairns, Alan; Katzman, Gary; Murdoch, Marshall; Padiachy, Dineshree; Morford, Mike; Vral, Anne; Slabbert, Jacobus P

    2016-03-01

    The micronucleus assay (MN assay) is a well-established assay in genetic toxicology, biomonitoring of mutagen-exposed populations and chromosomal radiosensitivity testing. To evaluate the effect of storage time on the chromosomal radiosensitivity assessment in lymphocytes, micronuclei (MN) yields in blood samples received and processed on the same day were compared with MN yields obtained when blood cultures were set up 24 and 48h after blood sampling. Furthermore, the influence of general anaesthesia on MN and binucleated cells (BN) yields in the MN assay was considered. Blood samples of 10 healthy donors were irradiated and blood cultures were set up during the same day of blood sampling or with a delay of 24 or 48h. The MN assay was also performed on two blood samples from 60 women undergoing breast surgery. The first blood sample was taken before general anaesthesia and the second sample, 2h after anaesthesia induction. Fifty percent of the blood samples were transported to the cytogenetics lab within 2h while the other 50% reached the lab after 24h. The results of this study show a decrease in BN and an increase in MN yields with increasing storage time before irradiation and setting up of the MN assay for both healthy controls and patients. The administration of general anaesthesia in patients resulted in lower BN yields, higher spontaneous MN yields but no differences in radiation-induced MN yields. In conclusion, this study indicates that the time between blood sampling and the in vitro irradiation of the samples for the MN assay influences the MN yields. Delays of more than 24h should be avoided. To assess chromosomal radiosensitivity in patients, blood samples should be taken before induction of general anaesthesia as anaesthesia can have an impact on the reliability of the MN results.

  2. Can Radiosensitivity Associated with Defects in DNA Repair be Overcome by Mitochondrial-Targeted Antioxidant Radioprotectors

    PubMed Central

    Greenberger, Joel S.; Berhane, Hebist; Shinde, Ashwin; Han Rhieu, Byung; Bernard, Mark; Wipf, Peter; Skoda, Erin M.; Epperly, Michael W.

    2014-01-01

    Radiation oncologists have observed variation in normal tissue responses between patients in many instances with no apparent explanation. The association of clinical tissue radiosensitivity with specific genetic repair defects (Wegner’s syndrome, Ataxia telangiectasia, Bloom’s syndrome, and Fanconi anemia) has been well established, but there are unexplained differences between patients in the general population with respect to the intensity and rapidity of appearance of normal tissue toxicity including radiation dermatitis, oral cavity mucositis, esophagitis, as well as differences in response of normal tissues to standard analgesic or other palliative measures. Strategies for the use of clinical radioprotectors have included modalities designed to either prevent and/or palliate the consequences of radiosensitivity. Most prominently, modification of total dose, fraction size, or total time of treatment delivery has been necessary in many patients, but such modifications may reduce the likelihood of local control and/or radiocurability. As a model system in which to study potential radioprotection by mitochondrial-targeted antioxidant small molecules, we have studied cell lines and tissues from Fanconi anemia (Fancd2−/−) mice of two background strains (C57BL/6NHsd and FVB/N). Both were shown to be radiosensitive with respect to clonogenic survival curves of bone marrow stromal cells in culture and severity of oral cavity mucositis during single fraction or fractionated radiotherapy. Oral administration of the antioxidant GS-nitroxide, JP4-039, provided significant radioprotection, and also ameliorated distant bone marrow suppression (abscopal effect of irradiation) in Fancd2−/− mice. These data suggest that radiation protection by targeting the mitochondria may be of therapeutic benefit even in the setting of defects in the DNA repair process for irradiation-induced DNA double strand breaks. PMID:24596683

  3. Rapid fluorescence-based assay for radiosensitivity and chemosensitivity testing in mammalian cells in vitro

    SciTech Connect

    Begg, A.C.; Mooren, E.

    1989-02-01

    An efficient and rapid cytotoxicity assay has been developed, particularly for radiobiological studies, utilizing 96-well microtiter plates. Several days after treatment, cell numbers per well were measured by fluorescent intensity using an automatic reader after staining with the DNA specific dye Hoechst 33258. For radiobiological applications, a microtiter plate irradiation box was designed and built which allowed a variable number of wells (minimum 4, maximum 16) to be irradiated at one time. In this manner, complete dose-response curves could be obtained from one plate. The assay depends on the growth of surviving and untreated cells, and by appropriate choice of conditions (cell numbers plated, time of assay), cell survival curves for this quick fluorescence assay were in reasonable agreement with those from a clonogenic assay for cisplatin and X-ray-induced cell killing. The assay can span 1.5-2 decades of cell survival and is suitable for any cell line which grows as a monolayer. Radiobiological applications were tested using agents or conditions which modified radiation damage. Firstly, sublethal damage repair could be demonstrated in RIF1 mouse tumor cells by comparing the survival curve for a single X-ray dose with that for two fractions separated by 4 h. Secondly, incorporation of 5-iodo-2'-deoxyuridine into cellular DNA was shown to radiosensitize Chinese Hamster cells, with similar enhancement ratios obtained from the fluorescence and clonogenic assays. Thirdly, radiosensitization by cisplatin and radioprotection by cysteamine could be readily measured using the quick fluorescence assay. The ability to have multiple dose groups per plate makes it an efficient assay for both radiosensitivity and chemosensitivity testing.

  4. Retrospective growth kinetics and radiosensitivity analysis of various human xenograft models

    PubMed Central

    Lee, Ji Young; Kim, Eun Ho; Chung, Namhyun

    2016-01-01

    The purpose of this study was to delineate the various factors that affect the growth characteristics of human cancer xenografts in nude mice and to reveal the relationship between the growth characteristics and radiosensitivity. We retrospectively analyzed 390 xenografts comprising nine different human cancer lines grown in nude mice used in our institute between 2009 and 2015. Tumor growth rate (TGR) was calculated using exponential growth equations. The relationship between the TGR of xenografts and the proliferation of the cells in vitro was examined. Additionally, we examined the correlations between the surviving fractions of cells after 2 Gy irradiation in vitro and the response of the xenograft to radiation. The TGR of xenografts was positively related to the proliferation of the cells in vitro (rP=0.9714, p<0.0001), whereas it was independent of the histological type of the xenografts. Radiation-induced suppression of the growth rate (T/C%) of xenografts was positively related to the radiosensitivity of the cells in vitro (SF2; rP=0.8684, p=0.0284) and TGR (rP=0.7623, p=0.0780). The proliferation of human cancer cells in vitro and the growth rate of xenografts were positively related. The radiosensitivity of cancer cells, as judged from the SF2 values in vitro, and the radiation-induced suppression of xenograft growth were positively related. In conclusion, the growth rate of human xenografts was independent of histological type and origin of the cancer cells, and was positively related to the proliferation of the cancer cells in vitro. PMID:28053611

  5. Increased radiosensitivity of colorectal tumors with intra-tumoral injection of low dose of gold nanoparticles

    PubMed Central

    Shi, Minghan; Paquette, Benoit; Thippayamontri, Thititip; Gendron, Louis; Guérin, Brigitte; Sanche, Léon

    2016-01-01

    The potential of gold nanoparticles (GNPs) as radiosensitizers for the treatment of malignant tumors has been limited by the large quantities of GNPs that must be administered and the requirement for low-energy X-ray irradiation to optimize radiosensitization. In this study, we enhance the radiosensitivity of HCT116 human colorectal cells with tiopronin-coated GNPs (Tio-GNPs) combined with a low-energy X-ray (26 keV effective energy) source, similar to the Papillon 50 clinical irradiator used for topical irradiation of rectal tumors. Sensitizer enhancement ratios of 1.48 and 1.69 were measured in vitro, when the HCT116 cells were incubated with 0.1 mg/mL and 0.25 mg/mL of Tio-GNPs, respectively. In nude mice bearing the HCT116 tumor, intra-tumoral (IT) injection of Tio-GNPs allowed a 94 times higher quantity of Tio-GNPs to accumulate than was possible by intravenous injection and facilitated a significant tumor response. The time following irradiation, for tumors growing to four times their initial tumor volume (4Td) was 54 days for the IT injection of 366.3 μg of Tio-GNPs plus 10 Gy, compared to 37 days with radiation alone (P=0.0018). Conversely, no significant improvement was obtained when GNPs were injected intravenously before tumor irradiation (P=0.6547). In conclusion, IT injection of Tio-GNPs combined with low-energy X-rays can significantly reduce the growth of colorectal tumors. PMID:27789945

  6. Accounting Instruction in a Business Learning Center.

    ERIC Educational Resources Information Center

    Polisky, Mildred K.

    1981-01-01

    Describes the individualized audiovisual approach to teaching beginning accounting at a Wisconsin technical college. Discusses how it began as a remedial lab, its theories of individualized instruction, how the pilot project worked, and why this method is used. (CT)

  7. Identification of Novel Radiosensitizers in a High-Throughput, Cell-Based Screen for DSB Repair Inhibitors

    PubMed Central

    Goglia, Alexander G.; Delsite, Robert; Luz, Antonio N.; Shahbazian, David; Salem, Ahmed F.; Sundaram, Ranjini K.; Chiaravalli, Jeanne; Hendrikx, Petrus J.; Wilshire, Jennifer A.; Jasin, Maria; Kluger, Harriet; Glickman, J. Fraser; Powell, Simon N.; Bindra, Ranjit S.

    2014-01-01

    Most cancer therapies involve a component of treatment which inflicts DNA damage in tumor cells, such as double-strand breaks (DSBs), which are considered the most serious threat to genomic integrity. Complex systems have evolved to repair these lesions, and successful DSB repair is essential for tumor cell survival after exposure to ionizing radiation (IR) and other DNA damaging agents. As such, inhibition of DNA repair is a potentially efficacious strategy for chemo- and radio-sensitization. Homologous recombination (HR) and nonhomologous end-joining (NHEJ) represent the two major pathways by DSBs are repaired in mammalian cells. Here, we report the design and execution of a high-throughput, cell-based small molecule screen for novel DSB repair inhibitors. We miniaturized our recently developed dual NHEJ and HR reporter system into a 384-well plate-based format and interrogated a diverse library of 20,000 compounds for molecules which selectively modulate NHEJ and HR repair in tumor cells. We identified a collection of novel hits which potently inhibit DSB repair, and we have validated their functional activity in comprehensive panel of orthogonal secondary assays. A selection of these inhibitors were found to radiosensitize cancer cell lines in vitro, which suggests they may be useful as novel chemo- and radio-sensitizers. Surprisingly, we identified several FDA-approved drugs, including the calcium channel blocker, mibefradil dihydrochloride, which demonstrated activity as DSB repair inhibitors and radiosensitizers. These findings suggest the possibility for repurposing them as tumor cell radiosensitizers in the future. Accordingly, we recently initiated a Phase I clinical trial testing mibefradil as glioma radiosensitizer. PMID:25512618

  8. Celecoxib enhances the radiosensitivity of HCT116 cells in a COX-2 independent manner by up-regulating BCCIP

    PubMed Central

    Xu, Xiao-Ting; Hu, Wen-Tao; Zhou, Ju-Ying; Tu, Yu

    2017-01-01

    It has been reported that celecoxib, a cyclooxygenase-2 (COX-2)-selective nonsteroidal anti-inflammatory drug (NSAID), regulates the radiosensitivity of several cancer cells. BCCIP (BRCA2 and CDKN1A interacting protein) plays a critical role in maintaining the critical functions of p53 in tumor suppression and response to therapy. However, whether the effect of celecoxib on the radiosensitivity of colorectal cancer (CRC) cells is dependent on BCCIP is largely unclear. In this study, we found that celecoxib enhanced the radiosensitivity of HeLa (a human cervical carcinoma cell line), A549 (a human lung carcinoma cell line), and HCT116 cells (a human CRC cells line). Among these cells, COX-2 expression was undetected in HCT116 cells. Treatment with celecoxib significantly increased BCCIP expression in COX-2 negative HCT116 cells. Knockdown of BCCIP obviously abrogated the enhanced radiosensitivity of HCT116 cells induced by celecoxib. A combination of celecoxib and irradiation treatment induced much more γ-H2AX foci formation, higher levels of radiation injury-related proteins phosphorylation, G2/M arrest, apoptosis, and p53 and p21 expression, and lower levels of Cyclin B1 in HCT116 cells than those in cells treated with irradiation alone. However, these changes were undetected in BCCIP-silenced HCT116 cells. Therefore, these data suggest that BCCIP gene may be a radiosensitivity-related gene in CRC. Celecoxib affects the functions of p53 and inhibits the recovery from the irradiation-induced injury by up-regulating the expression of BCCIP, and subsequently regulates the expressions of genes such as p21 and Cyclin B1 to enhance the radiosensitivity of HCT116 cells in a COX-2 independent manner. PMID:28386336

  9. Gold nanoparticles and electroporation impose both separate and synergistic radiosensitizing effects in HT-29 tumor cells: an in vitro study

    PubMed Central

    Rezaee, Zohre; Yadollahpour, Ali; Bayati, Vahid; Negad Dehbashi, Fereshteh

    2017-01-01

    Background and objective Radiation therapy (RT) is the gold standard treatment for more than half of known tumors. Despite recent improvements in RT efficiency, the side effects of ionizing radiation (IR) in normal tissues are a dose-limiting factor that restricts higher doses in tumor treatment. One approach to enhance the efficiency of RT is the application of radiosensitizers to selectively increase the dose at the tumor site. Gold nanoparticles (GNPs) and electroporation (EP) have shown good potential as radiosensitizers for RT. This study aims to investigate the sensitizing effects of EP, GNPs, and combined GNPs-EP on the dose enhancement factor (DEF) for 6 MV photon energy. Methods Radiosensitizing effects of EP, GNPs, and combinations of GNPs-EP were comparatively investigated in vitro for intestinal colon cancer (HT-29) and Chinese hamster ovary (CHO) cell lines by MTT assay and colony formation assay at 6 MV photon energy in six groups: IR (control group), GNPs+IR, GNPs (24 h)+IR, EP+IR, GNPs+EP+IR, and GNPs (24 h)+EP+IR. Results Treatment of both cell lines with EP, GNPs, and combined GNPs-EP significantly enhanced the response of cells to irradiation. However, the HT-29 showed higher DEF values for all groups. In addition, the DEF value for HT-29 cells for GNPs+IR, GNPs (24 h)+IR, EP+IR, GNPs+EP+IR, and GNPs (24 h)+EP+IR was, respectively, 1.17, 1.47, 1.36, 2.61, and 2.89, indicating synergistic radiosensitizing effect for the GNPs (24 h)+EP+IR group. Furthermore, the synergistic effect was observed just for HT-29 tumor cell lines. Conclusion Combined GNPs-EP protocols induced synergistic radiosensitizing effect in HT-29 cells, and the effect is also tumor specific. This combined therapy can be beneficially used for the treatment of intrinsically less radiosensitive tumors. PMID:28260889

  10. Enhancement of radiosensitivity by dual inhibition of the HER family with ZD1839 ('Iressa') and trastuzumab ('Herceptin')

    SciTech Connect

    Fukutome, Mika . E-mail: fukutome@rad.twmu.ac.jp; Maebayashi, Katsuya; Nasu, Sachiko; Seki, Kaori; Mitsuhashi, Norio

    2006-10-01

    Purpose: The aims of this study were twofold: (1) to examine the effects of dual inhibition of 2 members of the HER family, the epidermoid growth factor receptor (EGFR) and HER2/neu, by gefitinib (ZD1839) and trastuzumab on radiosensitivity; and (2) to explore the molecular mechanism of radiosensitization especially focusing on the survival signal transduction pathways by using A431 human vulvar squamous carcinoma cells expressing EGFR and HER2/neu. Methods and Materials: The effects of inhibitors on Radiation-induced activation of EGFR and/or HER2/neu, and the intracellular proteins that are involved in their downstream signaling, were quantified by the Western blot. Radiosensitizing effects by the blockage of EGFR and/or HER2/neu were determined by a clonogenic assay. Results: Radiation-induced activation of the EGFR and HER2/neu was inhibited with ZD1839 and/or trastuzumab. ZD1839 also inhibited Radiation-induced phosphorylation of HER2/neu. Radiation in combination with the HER family inhibitors inhibited the activation of Akt and MEK1/2, the downstream survival signaling of the HER family. ZD1839 enhanced radiosensitivity with a dose-modifying factor (DMF) (SF3) of 1.45 and trastuzumab did so with a DMF (SF3) of 1.11. Simultaneous blockade of EGFR and HER2/neu induced a synergistic radiosensitizing effect with a DMF (SF3) of 2.29. Conclusions: The present data suggest that a dual EGFR and HER2/neu targeting may have potential for radiosensitization in tumors in which both of these pathways are active.

  11. Replication-Dependent Radiosensitization of Human Glioma Cells by Inhibition of Poly(ADP-Ribose) Polymerase: Mechanisms and Therapeutic Potential

    SciTech Connect

    Dungey, Fiona A.; Loeser, Dana A.; Chalmers, Anthony J.

    2008-11-15

    Purpose: Current treatments for glioblastoma multiforme are inadequate and limited by the radiation sensitivity of normal brain. Because glioblastoma multiforme are rapidly proliferating tumors within nondividing normal tissue, the therapeutic ratio might be enhanced by combining radiotherapy with a replication-specific radiosensitizer. KU-0059436 (AZD2281) is a potent and nontoxic inhibitor of poly(ADP-ribose) polymerase-1 (PARP-1) undergoing a Phase II clinical trial as a single agent. Methods and Materials: Based on previous observations that the radiosensitizing effects of PARP inhibition are more pronounced in dividing cells, we investigated the mechanisms underlying radiosensitization of human glioma cells by KU-0059436, evaluating the replication dependence of this effect and its therapeutic potential. Results: KU-0059436 increased the radiosensitivity of four human glioma cell lines (T98G, U373-MG, UVW, and U87-MG). Radiosensitization was enhanced in populations synchronized in S phase and abrogated by concomitant exposure to aphidicolin. Sensitization was further enhanced when the inhibitor was combined with a fractionated radiation schedule. KU-0059436 delayed repair of radiation-induced DNA breaks and was associated with a replication-dependent increase in {gamma}H2AX and Rad51 foci. Conclusion: The results of our study have shown that KU-0059436 increases radiosensitivity in a replication-dependent manner that is enhanced by fractionation. A mechanism is proposed whereby PARP inhibition increases the incidence of collapsed replication forks after ionizing radiation, generating persistent DNA double-strand breaks. These observations indicate that KU-0059436 is likely to enhance the therapeutic ratio achieved by radiotherapy in the treatment of glioblastoma multiforme. A Phase I clinical trial is in development.

  12. Preclinical Investigations of a Novel Small Molecule Radiosensitizer of Prostate Cancer

    DTIC Science & Technology

    2012-07-01

    cancer cells (PC3 and DU145) with only a short exposure of 1 hr. Animal studies with daily treatment (50 mg/kg) showed no toxicity. We have...which condition(s) is most effective at killing the cancer cells based on the Dose Enhancement Ratio (DER) at Survival Fractions of 0.1 and/or 0.001...We have in vivo studies to investigating the radiosensitization of NS-123 in male adult nude (nu/nu) mice with implanted tumor cells. Based on

  13. Immunosuppression by hypoxic cell radiosensitizers: a phenomenon of potential clinical importance

    SciTech Connect

    Rockwell, S.; Kapp, D.S.

    1982-06-01

    The nitroimidazoles metronidazole, misonidazol, and desmethyl misonidazole are currently undergoing clinical trials as possible adjuncts to radiotherapy. Ongoing clinical trials are evaluating the effectiveness of these agents and also documenting the pharmacokinetics and toxicities of radiosensitizing doses of these drugs in man. A variety of toxic effects have been noted in man, including anorexia, nausea and vomiting, peripheral neuropathy, central nervous system symptoms, ototoxicity, allergy, and fear. Laboratory studies have also suggested that these agents have potential to be mutagenic, carcinogenic, and teratogenic. In the editorial presented, the author attempts to draw attention to an additional toxic effect of nitroimidazoles - the inhibition of cell-mediated immune responses. (JMT)

  14. [Comparative characteristics of the modification of radiosensitivity of mice and rats by a hypoxic mixture].

    PubMed

    Vasin, M V

    1986-01-01

    A comparative study was made of changes in radiosensitivity of mice and rats given hypoxic mixtures (GHM) containing 6 to 15% of oxygen. The radioprotective effect of the GHM was more pronounced in mice than rats. The dependence of the radioprotective effect of the GHM on the oxygen content was well approximated by the equations: (Formula: see text). In experiments on rats, the oxygen content of 13.8% was shown to be a threshold the exceeding of which removed the modifying effect of the GHM.

  15. Can Drugs Enhance Hypofractionated Radiotherapy? A Novel Method of Modeling Radiosensitization Using In Vitro Data

    SciTech Connect

    Ohri, Nitin; Dicker, Adam P.; Lawrence, Yaacov Richard

    2012-05-01

    Purpose: Hypofractionated radiotherapy (hRT) is being explored for a number of malignancies. The potential benefit of giving concurrent chemotherapy with hRT is not known. We sought to predict the effects of combined modality treatments by using mathematical models derived from laboratory data. Methods and Materials: Data from 26 published clonogenic survival assays for cancer cell lines with and without the use of radiosensitizing chemotherapy were collected. The first three data points of the RT arm of each assay were used to derive parameters for the linear quadratic (LQ) model, the multitarget (MT) model, and the generalized linear quadratic (gLQ) model. For each assay and model, the difference between the predicted and observed surviving fractions at the highest tested RT dose was calculated. The gLQ model was fitted to all the data from each RT cell survival assay, and the biologically equivalent doses in 2-Gy fractions (EQD2s) of clinically relevant hRT regimens were calculated. The increase in cell kill conferred by the addition of chemotherapy was used to estimate the EQD2 of hRT along with a radiosensitizing agent. For comparison, this was repeated using conventionally fractionated RT regimens. Results: At a mean RT dose of 8.0 Gy, the average errors for the LQ, MT, and gLQ models were 1.63, 0.83, and 0.56 log units, respectively, favoring the gLQ model (p < 0.05). Radiosensitizing chemotherapy increased the EQD2 of hRT schedules by an average of 28% to 82%, depending on disease site. This increase was similar to the gains predicted for the addition of chemotherapy to conventionally fractionated RT. Conclusions: Based on published in vitro assays, the gLQ equation is superior to the LQ and MT models in predicting cell kill at high doses of RT. Modeling exercises demonstrate that significant increases in biologically equivalent dose may be achieved with the addition of radiosensitizing agents to hRT. Clinical study of this approach is warranted.

  16. In vivo study of breast carcinoma radiosensitization by targeting eIF4E

    SciTech Connect

    Yang, Hua; Li, Li-Wen; Shi, Mei; Wang, Jian-Hua; Xiao, Feng; Zhou, Bin; Diao, Li-Qiong; Long, Xiao-Li; Liu, Xiao-Li; Xu, Lin

    2012-07-13

    Highlights: Black-Right-Pointing-Pointer eIF4E is associated with the formation and progression for breast cancer. Black-Right-Pointing-Pointer pSecX-t4EBP1 can downregulated the expression of eIF4E in direct binding. Black-Right-Pointing-Pointer We transfected pSecX-t4EBP1 into a mouse xenograft model. Black-Right-Pointing-Pointer It can significantly inhibit tumor growth and enhance the radiosensitivity. Black-Right-Pointing-Pointer The possible mechanism is downregulation of HIF-1{alpha} expression. -- Abstract: Background: Eukaryotic initiation factor eIF4E, an important regulator of translation, plays a crucial role in the malignant transformation, progression and radioresistance of many human solid tumors. The overexpression of this gene has been associated with tumor formation in a wide range of human malignancies, including breast cancer. In the present study, we attempted to explore the use of eIF4E as a therapeutic target to enhance radiosensitivity for breast carcinomas in a xenograft BALB/C mice model. Materials and methods: Ninety female BALB/C mice transfected with EMT-6 cells were randomly divided into six groups: control, irradiation (IR), pSecX-t4EBP1, pSecX-t4EBP1 + irradiation, pSecX and pSecX + irradiation. At the end of the experiments, all mice were sacrificed, the xenografts were harvested to measure the tumor volume and mass, and the tumor inhibition rates were calculated. Apoptosis was detected with a flow cytometric assay. Immunohistochemistry was used to detect the expression of HIF-1{alpha}. Results: The xenografts in pSecX-t4EBP1 mice showed a significantly delayed growth and smaller tumor volume, with a higher tumor inhibition rate compared with the control and pSecX groups. A similar result was obtained in the pSecX-t4EBP1 + IR group compared with IR alone and pSecX + irradiation. The expression of HIF-1{alpha} in the tumor cells was significantly decreased, while the apoptosis index was much higher. Conclusions: pSecX-t4EBP1 can

  17. Radiosensitization of Escherichia coli and Salmonella typhi in presence of active compounds

    NASA Astrophysics Data System (ADS)

    Lacroix, M.; Chiasson, F.; Borsa, J.; Ouattara, B.

    2004-09-01

    The radiosensitization of Escherichia coli and Salmonella typhi in ground beef was evaluated in the presence of 18 active compounds. Medium fat ground beef (23% fat) was inoculated with E. coli or S. typhi and each active compound was added separately at various concentrations. For E. coli, the most efficient compounds were trans-cinnamaldehyde, thymol and thyme. For S. typhi, the most efficient compounds was trans-cinnamaldehyde, carvacrol and thymol. The addition of tetrasodium pyrophosphate, carvacrol and ascorbic acid had no effect on the irradiation sensitivity of E. coli. For S. typhi, only ascorbic acid had no effect.

  18. CELL-SPECIFIC RADIOSENSITIZATION BY GOLD NANOPARTICLES AT MEGAVOLTAGE RADIATION ENERGIES

    PubMed Central

    Jain, Suneil; Coulter, Jonathan A.; Hounsell, Alan R.; Butterworth, Karl T.; McMahon, Stephen J.; Hyland, Wendy B.; Muir, Mark F.; Dickson, Glenn R.; Prise, Kevin M.; Currell, Fred J.; O'Sullivan, Joe M.; Hirst, David G.

    2010-01-01

    Purpose Gold nanoparticles (GNPs) have been shown to cause sensitization with kilovoltage (kV) radiation. Differences in the absorption coefficient between gold and soft tissue, as a function of photon energy, predict that maximum enhancement should occur in the kilovoltage (kV) range, with almost no enhancement at megavoltage (MV) energies. Recent studies have shown that GNPs are not biologically inert, causing oxidative stress and even cell death, suggesting a possible biological mechanism for sensitization. The purpose of this study was to assess GNP radiosensitization at clinically relevant MV X-ray energies. Methods and Materials Cellular uptake, intracellular localization, and cytotoxicity of GNPs were assessed in normal L132, prostate cancer DU145, and breast cancer MDA-MB-231 cells. Radiosensitization was measured by clonogenic survival at kV and MV photon energies and MVelectron energies. Intracellular DNA double-strand break (DSB) induction and DNA repair were determined and GNP chemosensitization was assessed using the radiomimetic agent bleomycin. Results GNP uptake occurred in all cell lines and was greatest in MDA-MB-231 cells with nanoparticles accumulating in cytoplasmic lysosomes. In MDA-MB-231 cells, radiation sensitizer enhancement ratios (SERs) of 1.41, 1.29, and 1.16 were achieved using 160 kVp, 6 MV, and 15 MV X-ray energies, respectively. No significant effect was observed in L132 or DU145 cells at kV or MV energies (SER 0.97-1.08). GNP exposure did not increase radiation-induced DSB formation or inhibit DNA repair; however, GNP chemosensitization was observed in MDA-MB-231 cells treated with bleomycin (SER 1.38). Conclusions We have demonstrated radiosensitization in MDA-MB-231 cells at MV X-ray energies. The sensitization was cell-specific with comparable effects at kV and MV energies, no increase in DSB formation, and GNP chemopotentiation with bleomycin, suggesting a possible biological mechanism of radiosensitization. PMID:21095075

  19. Relationship between DNA double-strand break rejoining and cell survival after exposure to ionizing radiation in human fibroblast strains with differing ATM/p53 status: Implications for evaluation of clinical radiosensitivity

    SciTech Connect

    Mirzayans, Razmik; Severin, Diane; Murray, David . E-mail: davem@cancerboard.ab.ca

    2006-12-01

    Purpose: To better understand the impact of defects in the DNA damage-surveillance network on the various cell-based assays used for the prediction of patient radiosensitivity. Methods and Materials: We examined noncancerous human fibroblast strains from individuals with ataxia telangiectasia (ataxia telangiectasia mutated [ATM] deficient) or Li-Fraumeni syndrome (p53 deficient) using the neutral comet, H2AX phosphorylation, and clonogenic survival assays. Results: Using the comet assay, we found that, compared with normal fibroblasts, cells lacking either ATM or p53 function exhibited a reduced rate of double-strand break (DSB) rejoining early ({<=}4 h) after exposure to 8 Gy of {gamma}-radiation and also exhibited high levels of unrejoined DSBs later after irradiation. ATM-deficient and p53-deficient fibroblasts also exhibited abnormally increased levels of phosphorylated H2AX ({gamma}-H2AX) at later intervals after irradiation. In the clonogenic assay, ATM-deficient cells exhibited marked radiosensitivity and p53-deficient cells had varying degrees of radioresistance compared with normal fibroblasts. Conclusion: Regardless of whether ataxia telangiectasia and Li-Fraumeni syndrome fibroblasts are DSB-repair deficient per se, it is apparent that p53 and ATM defects greatly influence the cellular phenotype as evidenced by the neutral comet and {gamma}-H2AX assays. Our data suggest that the {gamma}-H2AX levels observed at later intervals after irradiation may represent a reliable measure of the overall DSB rejoining capabilities of human fibroblasts. However, it appears that using this parameter as a predictor of radiosensitivity without knowledge of the cells' p53 status could lead to incorrect conclusions.

  20. Combined effect of polymorphisms in Rad51 and Xrcc3 on breast cancer risk and chromosomal radiosensitivity.

    PubMed

    Vral, A; Willems, P; Claes, K; Poppe, B; Perletti, Gianpaolo; Thierens, H

    2011-01-01

    Enhanced in vitro chromosomal radiosensitivity (CRS) has been proposed as a marker for low-penetrance gene mutations predisposing to breast cancer (BC). Since the double strand break (DSB) is the most detrimental form of DNA damage induced by ionizing radiation, it is possible that mutations in genes encoding proteins involved in DSB repair affect breast cancer risk. The purpose of the present study was to examine whether five single nucleotide polymorphisms (SNPs) in Rad51 and Xrcc3 (rs1801320, rs1801321, rs1799796, rs861539 and rs1799794) exhibited an association with breast cancer susceptibility in a Belgian population of BC patients with a known or putative genetic predisposition. We also ascertained whether a relationship exists between the occurrence of the variant alleles of these variations and in vitro CRS. Blood samples were obtained from BC patients and from the control population that included healthy female individuals. Variations in the 5' UTR of Rad51 and Xrcc3 were genotyped, and statistical analysis was performed. The results showed that low-penetrant variations in Rad51 and Xrcc3, two proteins belonging to the homologous recombination DSB repair pathway, may modify BC risk in patients already carrying a pathological mutation in the highly penetrant BC genes BRCA1 and BRCA2. Combined risk genotype analysis revealed that Rad51 SNPs enhance BC risk in BRCA2 patients, whereas Xrcc3 SNPs significantly enhance BC risk in carriers of BRCA1 mutations and in patients with hereditary BC. When four putative risk genotypes of Rad51 and Xrcc3 were combined, positive significant odds ratios were obtained in the entire patient population and in patients with a hereditary history of disease. Although obtained from a limited number of patients, our data are supportive of a polygenic model whereby combinations of weak variations are responsible for an enhanced BC risk by acting jointly with high-penetrant mutations in BRCA1 or BRCA2.

  1. DNA damage response (DDR) pathway engagement in cisplatin radiosensitization of non-small cell lung cancer.

    PubMed

    Sears, Catherine R; Cooney, Sean A; Chin-Sinex, Helen; Mendonca, Marc S; Turchi, John J

    2016-04-01

    Non-small cell lung cancers (NSCLC) are commonly treated with a platinum-based chemotherapy such as cisplatin (CDDP) in combination with ionizing radiation (IR). Although clinical trials have demonstrated that the combination of CDDP and IR appear to be synergistic in terms of therapeutic efficacy, the mechanism of synergism remains largely uncharacterized. We investigated the role of the DNA damage response (DDR) in CDDP radiosensitization using two NSCLC cell lines. Using clonogenic survival assays, we determined that the cooperative cytotoxicity of CDDP and IR treatment is sequence dependent, requiring administration of CDDP prior to IR (CDDP-IR). We identified and interrogated the unique time and agent-dependent activation of the DDR in NSCLC cells treated with cisplatin-IR combination therapy. Compared to treatment with CDDP or IR alone, CDDP-IR combination treatment led to persistence of γH2Ax foci, a marker of DNA double-strand breaks (DSB), for up to 24h after treatment. Interestingly, pharmacologic inhibition of DDR sensor kinases revealed the persistence of γ-H2Ax foci in CDDP-IR treated cells is independent of kinase activation. Taken together, our data suggest that delayed repair of DSBs in NSCLC cells treated with CDDP-IR contributes to CDDP radiosensitization and that alterations of the DDR pathways by inhibition of specific DDR kinases can augment CDDP-IR cytotoxicity by a complementary mechanism.

  2. Radiosensitivity study and radiation effects on morphology characterization of grey oyster mushroom Pleurotus sajor-caju

    NASA Astrophysics Data System (ADS)

    Rashid, Rosnani Abdul; Daud, Fauzi; Senafi, Sahidan; Awang, Mat Rasol; Mohamad, Azhar; Mutaat, Hassan Hamdani; Maskom, Mohd Meswan

    2014-09-01

    Radiosensitive dosage and morphology characterization of irradiated grey oyster mushroom Pleurotus sajor-caju by gamma rays was investigated due to effects of irradiation. In order to establish the effect, mycelium of P. sajor-caju was irradiated by gamma rays at dose 0.1 to 8.0 kGy with dose rate 0.227 Gy sec-1. The irradiation of mycelia was carried out at the radiation facility in Malaysian Nuclear Agency. The radiosensitivity study was performed by evaluating the percentage of survival irradiated mycelia. The lethal dose of the mycelium P. sajor-caju was determined at 4.0 kGy and LD50 to be equal at 2.2 kGy. The radiation effects on morphology were evaluated based on growth rate of irradiated mycelia, mycelia types, colonization period on substrate, morphology of fruit bodies and yields. The results shown growth rate of irradiated mycelium was slightly lower than the control and decreased as the dose increased. Irradiation was found can induced the primordia formation on PDA and the BE of irradiated seed is higher than to control. The irradiation is proven to be useful for generating new varieties of mushroom with commercial value to the industry.

  3. A signature motif in LIM proteins mediates binding to checkpoint proteins and increases tumour radiosensitivity

    PubMed Central

    Xu, Xiaojie; Fan, Zhongyi; Liang, Chaoyang; Li, Ling; Wang, Lili; Liang, Yingchun; Wu, Jun; Chang, Shaohong; Yan, Zhifeng; Lv, Zhaohui; Fu, Jing; Liu, Yang; Jin, Shuai; Wang, Tao; Hong, Tian; Dong, Yishan; Ding, Lihua; Cheng, Long; Liu, Rui; Fu, Shenbo; Jiao, Shunchang; Ye, Qinong

    2017-01-01

    Tumour radiotherapy resistance involves the cell cycle pathway. CDC25 phosphatases are key cell cycle regulators. However, how CDC25 activity is precisely controlled remains largely unknown. Here, we show that LIM domain-containing proteins, such as FHL1, increase inhibitory CDC25 phosphorylation by forming a complex with CHK2 and CDC25, and sequester CDC25 in the cytoplasm by forming another complex with 14-3-3 and CDC25, resulting in increased radioresistance in cancer cells. FHL1 expression, induced by ionizing irradiation in a SP1- and MLL1-dependent manner, positively correlates with radioresistance in cancer patients. We identify a cell-penetrating 11 amino-acid motif within LIM domains (eLIM) that is sufficient for binding CHK2 and CDC25, reducing the CHK2–CDC25 and CDC25–14-3-3 interaction and enhancing CDC25 activity and cancer radiosensitivity accompanied by mitotic catastrophe and apoptosis. Our results provide novel insight into molecular mechanisms underlying CDC25 activity regulation. LIM protein inhibition or use of eLIM may be new strategies for improving tumour radiosensitivity. PMID:28094252

  4. Radiosensitivity study and radiation effects on morphology characterization of grey oyster mushroom Pleurotus sajor-caju

    SciTech Connect

    Rashid, Rosnani Abdul; Awang, Mat Rasol; Mohamad, Azhar; Mutaat, Hassan Hamdani; Maskom, Mohd Meswan; Daud, Fauzi; Senafi, Sahidan

    2014-09-03

    Radiosensitive dosage and morphology characterization of irradiated grey oyster mushroom Pleurotus sajor-caju by gamma rays was investigated due to effects of irradiation. In order to establish the effect, mycelium of P. sajor-caju was irradiated by gamma rays at dose 0.1 to 8.0 kGy with dose rate 0.227 Gy sec{sup −1}. The irradiation of mycelia was carried out at the radiation facility in Malaysian Nuclear Agency. The radiosensitivity study was performed by evaluating the percentage of survival irradiated mycelia. The lethal dose of the mycelium P. sajor-caju was determined at 4.0 kGy and LD{sub 50} to be equal at 2.2 kGy. The radiation effects on morphology were evaluated based on growth rate of irradiated mycelia, mycelia types, colonization period on substrate, morphology of fruit bodies and yields. The results shown growth rate of irradiated mycelium was slightly lower than the control and decreased as the dose increased. Irradiation was found can induced the primordia formation on PDA and the BE of irradiated seed is higher than to control. The irradiation is proven to be useful for generating new varieties of mushroom with commercial value to the industry.

  5. [The influence of geomagnetic field on blood leukocyte radiosensitivity and gender determination in humans].

    PubMed

    Ivanov, S D; Iamshanov, V A; Koshelevskiĭ, V K; Ivanova, A S; Ivanova, T M; Glushkov, R K; Semenov, E V; Petrov, A N

    2003-01-01

    The gender and age features of the geomagnetic field (GMF) influence (K-indexes) on the leukocyte radiosensitivity (S) in human blood in case of normal and enhanced levels of metal-ecotoxicants (Pb, Cd, Hg, Mn, Zn, Cu) in blood was studied, as well as the impact of the GMF intensity alterations on the child gender determination. In the whole studied population (n = 244) it was observed a negative relationship between S- and K-indexes. It was shown that the most changes of blood leukocyte radiosensitivity depended on the GMF oscillations in men older than 45 years. In case of metal-ecotoxicant concentrations in blood near normal level there were observed significant relationships between S- and K-indexes, which was infringed by more than 2-fold excess of these toxicant concentrations in blood. Retrospective analysis showed that in case of the GMF intensity enhancement in the conception moment the girls were born mostly, and in case of the lowering--the boys were.

  6. Inhibition of hypoxia-induced miR-155 radiosensitizes hypoxic lung cancer cells.

    PubMed

    Babar, Imran A; Czochor, Jennifer; Steinmetz, Allison; Weidhaas, Joanne B; Glazer, Peter M; Slack, Frank J

    2011-11-15

    miR-155 is a prominent microRNA (miRNA) that regulates genes involved in immunity and cancer-related pathways. miR-155 is overexpressed in lung cancer, which correlates with poor patient prognosis. It is unclear how miR-155 becomes increased in lung cancers and how this increase contributes to reduced patient survival. Here, we show that hypoxic conditions induce miR-155 expression in lung cancer cells and trigger a corresponding decrease in a validated target, FOXO3A. Furthermore, we find that increased levels of miR-155 radioprotects lung cancer cells, while inhibition of miR-155 radiosensitizes these cells. Moreover, we reveal a therapeutically important link between miR-155 expression, hypoxia, and irradiation by demonstrating that anti-miR-155 molecules also sensitize hypoxic lung cancer cells to irradiation. Our study helps explain how miR-155 becomes elevated in lung cancers, which contain extensive hypoxic microenvironments, and demonstrates that inhibition of miR-155 may have important therapeutic potential as a means to radiosensitize hypoxic lung cancer cells.

  7. In vivo radiosensitization efficacy of KU-2285 and etanidazole at clinically relevant low radiation doses

    SciTech Connect

    Oya, Natsuo; Shibamoto, Yuta; Sasai, Keisuke; Abe, Mitsuyuki; Sugiyama, Taketoshi )

    1993-12-01

    The in vivo radiosensitization efficacy of KU-2285 (a fluorinated nitroimidazole derivative) at clinically relevant low radiation doses (2-4 Gy) was compared with that of etanidazole using four types of assays with EMT6, SCCVII, and C[sup 3]H mammary tumors. The in vivo-in vitro cytokinesis-block micronucleus assay and the chromosomal aberration assay were used to assess the sensitizing effect at single doses of 2-4 Gy. After in vivo treatment for tumors, tumor cells were cultured in the presence of cytochalasin B for the former assay or demecolcine for the latter assay, and the micronucleus frequency in binucleate cells and the chromosomal frequency in metaphase cells were evaluated after 42 hr and 3 hr of culture. In addition, an in vivo-in vitro colony assay and a growth delay assay were performed using fractionated irradiation regimens (4 Gy [times] 5). The sensitizer enhancement ratio for 100-400 mg/kg of KU-2285 was between 1.12 and 1.42. KU-2285 was a more efficient sensitizer than etanidazole in 3 of 9 experiments and as efficient as etanidazole in the remaining six experiments. Both the micronucleus assay and the chromosomal aberration assay appeared to be very useful in evaluating the in vivo sensitizing effect at low radiation doses. KU-2285 had a definite radiosensitizing effect even at low radiation doses, and clinical trials of KU-2285 may be warranted. 23 refs., 5 figs., 1 tab.

  8. Investigation of gold nanoparticle radiosensitization mechanisms using a free radical scavenger and protons of different energies.

    PubMed

    Jeynes, J C G; Merchant, M J; Spindler, A; Wera, A-C; Kirkby, K J

    2014-11-07

    Gold nanoparticles (GNPs) have been shown to sensitize cancer cells to x-ray radiation, particularly at kV energies where photoelectric interactions dominate and the high atomic number of gold makes a large difference to x-ray absorption. Protons have a high cross-section for gold at a large range of relevant clinical energies, and so potentially could be used with GNPs for increased therapeutic effect.Here, we investigate the contribution of secondary electron emission to cancer cell radiosensitization and investigate how this parameter is affected by proton energy and a free radical scavenger. We simulate the emission from a realistic cell phantom containing GNPs after traversal by protons and x-rays with different energies. We find that with a range of proton energies (1-250 MeV) there is a small increase in secondaries compared to a much larger increase with x-rays. Secondary electrons are known to produce toxic free radicals. Using a cancer cell line in vitro we find that a free radical scavenger has no protective effect on cells containing GNPs irradiated with 3 MeV protons, while it does protect against cells irradiated with x-rays. We conclude that GNP generated free radicals are a major cause of radiosensitization and that there is likely to be much less dose enhancement effect with clinical proton beams compared to x-rays.

  9. LET-dependent radiosensitization effects of gold nanoparticles for proton irradiation

    NASA Astrophysics Data System (ADS)

    Li, Sha; Penninckx, Sébastien; Karmani, Linda; Heuskin, Anne-Catherine; Watillon, Kassandra; Marega, Riccardo; Zola, Jerome; Corvaglia, Valentina; Genard, Geraldine; Gallez, Bernard; Feron, Olivier; Martinive, Philippe; Bonifazi, Davide; Michiels, Carine; Lucas, Stéphane

    2016-11-01

    The development of new modalities and protocols is of major interest to improve the outcome of cancer treatment. Given the appealing physical properties of protons and the emerging evidence of biological relevance of the use of gold nanoparticles (GNPs), the radiosensitization effects of GNPs (5 or 10 nm) have been investigated in vitro in combination with a proton beam of different linear energy transfer (LET). After the incubation with GNPs for 24 h, nanoparticles were observed in the cytoplasm of A431 cells exposed to 10 nm GNPs, and in the cytoplasm as well as the nucleus of cells exposed to 5 nm GNPs. Cell uptake of 0.05 mg ml-1 of GNPs led to 0.78 pg Au/cell and 0.30 pg Au/cell after 24 h incubation for 10 and 5 nm GNPs respectively. A marked radiosensitization effect of GNPs was observed with 25 keV μm-1 protons, but not with 10 keV μm-1 protons. This effect was more pronounced for 10 nm GNPs than for 5 nm GNPs. By using a radical scavenger, a major role of reactive oxygen species in the amplification of the death of irradiated cell was identified. All together, these results open up novel perspectives for using high-Z metallic NPs in protontherapy.

  10. Molecularly Targeted Agents as Radiosensitizers in Cancer Therapy—Focus on Prostate Cancer

    PubMed Central

    Alcorn, Sara; Walker, Amanda J.; Gandhi, Nishant; Narang, Amol; Wild, Aaron T.; Hales, Russell K.; Herman, Joseph M.; Song, Danny Y.; DeWeese, Theodore L.; Antonarakis, Emmanuel S.; Tran, Phuoc T.

    2013-01-01

    As our understanding of the molecular pathways driving tumorigenesis improves and more druggable targets are identified, we have witnessed a concomitant increase in the development and production of novel molecularly targeted agents. Radiotherapy is commonly used in the treatment of various malignancies with a prominent role in the care of prostate cancer patients, and efforts to improve the therapeutic ratio of radiation by technologic and pharmacologic means have led to important advances in cancer care. One promising approach is to combine molecularly targeted systemic agents with radiotherapy to improve tumor response rates and likelihood of durable control. This review first explores the limitations of preclinical studies as well as barriers to successful implementation of clinical trials with radiosensitizers. Special considerations related to and recommendations for the design of preclinical studies and clinical trials involving molecularly targeted agents combined with radiotherapy are provided. We then apply these concepts by reviewing a representative set of targeted therapies that show promise as radiosensitizers in the treatment of prostate cancer. PMID:23863691

  11. Radiosensitizers in Pancreatic Cancer – Preclinical and Clinical Exploits with Molecularly Targeted Agents

    PubMed Central

    Walker, Amanda J.; Alcorn, Sara; Narang, Amol; Nugent, Katriana; Wild, Aaron T.; Herman, Joseph M.; Tran, Phuoc T.

    2013-01-01

    There has been an explosion in the number of molecularly targeted agents engineered to inhibit specific molecular pathways driving the tumorigenic phenotype in cancer cells. Some of these molecularly targeted agents have demonstrated robust clinical effects, but few result in meaningful durable responses. Therapeutic radiation is used to treat a majority of cancer patients with recent technologic and pharmacologic enhancements, leading to improvements in the therapeutic ratio for cancer care. Radiotherapy has a very specific role in select cases of postoperative and locally advanced pancreatic cancer patients, but control of metastatic disease still appears to be the major limiting factor behind improvements in cure. Recent rapid autopsy pathologic findings suggest a sub-group of advanced pancreatic cancer patients where death is caused from local disease progression and who would thus benefit from improved local control. One promising approach is to combine molecularly targeted agents with radiotherapy to improve tumor response rates and likelihood of durable local control. We review suggested recommendations on the investigation of molecularly targeted agents as radiosensitizers from preclinical studies to implementation in phase I–II clinical trials. We then discuss a select set of molecularly targeted therapies that we believe show promise as radiosensitizers in the treatment of pancreatic cancer. PMID:24331186

  12. Cell cycle-dependent radiosensitivity in two-cell mouse embryos in culture

    SciTech Connect

    Domon, M.

    1980-02-01

    The radiosensitivity in embryo systems varies depending on factors such as genetic background, oxygen environment, developmental stage, and age of the embryo in cell cycle. This paper is concerned with the involvement of cell cycle age in radiosensitivity of two-cell mouse embryos. Thus the doses needed for 50% killing of blastocyst formation in vitro (LD/sub 50/) of X rays for the two-cell mouse embryos in culture were measured during their cell cycle. The cell cycle in the two-cell embryos was quite peculiar; the cell cycle time of 18 h was divided into a long DNA post synthesis phase (G/sub 2/) plus mitosis (M) of 14 h and a short DNA synthesis phase (S) of 4 h. Results indicate that the LD/sub 50/ varies roughly from 100 to 600 rad within the cell cycle. Thus a major factor in determining the sensitivity to ionizing radiation of two-cell mouse embryos in vitro and perhaps in vivo is their position in the cell division cycle at the time of irradiation.

  13. Slug inhibition increases radiosensitivity of oral squamous cell carcinoma cells by upregulating PUMA.

    PubMed

    Jiang, Fangfang; Zhou, Lijie; Wei, Changbo; Zhao, Wei; Yu, Dongsheng

    2016-08-01

    As a new strategy, radio-gene therapy was widely used for the treatment of cancer patients in recent few years. Slug was involved in the radioresistance of various cancers and has been found to have an anti-apoptotic effect. This study aims to investigate whether the modulation of Slug expression by siRNA affects oral squamous cell carcinoma sensitivity to X-ray irradiation through upregulating PUMA. Two oral squamous cell carcinoma cell lines (HSC3 and HSC6) were transfected with small interfering RNA (siRNA) targeting Slug and subjected to radiotherapy in vitro. After transfection with Slug siRNA, both HSC3 and HSC6 cells showed relatively lower expression of Slug and higher expression of PUMA. The Slug siRNA transfected cells showed decreased survival and proliferation rates, an increased apoptosis rate and enhanced radiosensitivity to X-ray irradiation. Our results revealed that Slug siRNA transfection in combination with radiation increased the expression of PUMA, which contributed to radiosensitivity of oral squamous cell carcinoma cells. Thus, controlling the expression of Slug might contribute to enhance sensitivity of HSC3 and HSC6 cells toward X-ray irradiation in vitro by upregulating PUMA.

  14. Internalization pathways into cancer cells of gadolinium-based radiosensitizing nanoparticles.

    PubMed

    Rima, Wael; Sancey, Lucie; Aloy, Marie-Thérèse; Armandy, Emma; Alcantara, Gustavo B; Epicier, Thierry; Malchère, Annie; Joly-Pottuz, Lucile; Mowat, Pierre; Lux, François; Tillement, Olivier; Burdin, Béatrice; Rivoire, Annie; Boulé, Christelle; Anselme-Bertrand, Isabelle; Pourchez, Jérémie; Cottier, Michèle; Roux, Stéphane; Rodriguez-Lafrasse, Claire; Perriat, Pascal

    2013-01-01

    Over the last few decades, nanoparticles have been studied in theranostic field with the objective of exhibiting a long circulation time through the body coupled to major accumulation in tumor tissues, rapid elimination, therapeutic potential and contrast properties. In this context, we developed sub-5 nm gadolinium-based nanoparticles that possess in vitro efficient radiosensitizing effects at moderate concentration when incubated with head and neck squamous cell carcinoma cells (SQ20B). Two main cellular internalization mechanisms were evidenced and quantified: passive diffusion and macropinocytosis. Whereas the amount of particles internalized by passive diffusion is not sufficient to induce in vitro a significant radiosensitizing effect, the cellular uptake by macropinocytosis leads to a successful radiotherapy in a limited range of particles incubation concentration. Macropinocytosis processes in two steps: formation of agglomerates at vicinity of the cell followed by their collect via the lamellipodia (i.e. the "arms") of the cell. The first step is strongly dependent on the physicochemical characteristics of the particles, especially their zeta potential that determines the size of the agglomerates and their distance from the cell. These results should permit to control the quantity of particles internalized in the cell cytoplasm, promising ambitious opportunities towards a particle-assisted radiotherapy using lower radiation doses.

  15. Proton and photon beams interaction with radiosensitizing agents in human glioblastoma cells

    NASA Astrophysics Data System (ADS)

    Lafiandra, M.

    2016-03-01

    In oncological field, chemoradiotherapy treatments that combine radiations to radiosensitizing chemical agents are spreading out. The aim of this kind of treatment is to obtain a better tumor local control and at the same time to reduce the distant failure. The combination of radiation with microtubule-stabilizing agents is very promising in cancer therapy. In the present study, the combination of clinical proton beams and the microtubule-stabilizing agent Epothilone B has been investigated in human glioblastoma cells cultured in vitro. Photon beams have been used for comparison. Cell survival has been evaluated by colony forming assay and the interaction mechanism between radiation and Epothilone B has been investigated: survival curves relative to the combined treatment (protons or photons with Epothilone B) showed a linear trend, different from the linear quadratic behavior found with radiation alone. The analysis performed showed a synergism in the radiation-drug interaction. Thus, Epothilone B in conjunction with radiation acts as a radiosensitizer. Finally proton Relative Biological Effectiveness has been determined and results are reported in this paper.

  16. Inhibition of HAS2 induction enhances the radiosensitivity of cancer cells via persistent DNA damage

    SciTech Connect

    Shen, Yan Nan; Shin, Hyun-Jin; Joo, Hyun-Yoo; Park, Eun-Ran; Kim, Su-Hyeon; Hwang, Sang-Gu; Park, Sang Jun; Kim, Chun-Ho; Lee, Kee-Ho

    2014-01-17

    Highlights: •HAS2 may be a promising target for the radiosensitization of human cancer. •HAS2 is elevated (up to ∼10-fold) in irradiated radioresistant and -sensitive cancer cells. •HAS2 knockdown sensitizes cancer cells to radiation. •HAS2 knockdown potentiates irradiation-induced DNA damage and apoptotic death. •Thus, the irradiation-induced up-regulation of HAS2 contributes to the radioresistance of cancer cells. -- Abstract: Hyaluronan synthase 2 (HAS2), a synthetic enzyme for hyaluronan, regulates various aspects of cancer progression, including migration, invasion and angiogenesis. However, the possible association of HAS2 with the response of cancer cells to anticancer radiotherapy, has not yet been elucidated. Here, we show that HAS2 knockdown potentiates irradiation-induced DNA damage and apoptosis in cancer cells. Upon exposure to radiation, all of the tested human cancer cell lines exhibited marked (up to 10-fold) up-regulation of HAS2 within 24 h. Inhibition of HAS2 induction significantly reduced the survival of irradiated radioresistant and -sensitive cells. Interestingly, HAS2 depletion rendered the cells to sustain irradiation-induced DNA damage, thereby leading to an increase of apoptotic death. These findings indicate that HAS2 knockdown sensitizes cancer cells to radiation via persistent DNA damage, further suggesting that the irradiation-induced up-regulation of HAS2 contributes to the radioresistance of cancer cells. Thus, HAS2 could potentially be targeted for therapeutic interventions aimed at radiosensitizing cancer cells.

  17. Interaction of nitroimidazole sensitizers and oxygen in the radiosensitization of mammalian cells at ultrahigh dose rates

    SciTech Connect

    Michaels, H.B.; Ling, C.C.; Epp, E.R.; Peterson, E.C.

    1981-03-01

    When CHO cells, equilibrated with 0.44% oxygen, are irradiated with single 3-nsec pulses of electrons from a 600-kV-field emission source, a breaking survival curve is observed. The breaking behavior, believed to be the result of radiolytic oxygen depletion, can be prevented by the presence of a relatively low concentration of the hypoxic cell sensitizer misonidazole; similar results are obtained with metronidazole and Ro-05-9963. The resulting survival curves exhibit a sensitized response similar to that obtained with conventional dose rate radiation for CHO cells under this oxygen concentration. This degree of sensitization is greater than that observed for CHO cells irradiated at ultrahigh dose rates under the same concentration of sensitizer in nitrogen. The data suggest that the nitroimidazole compounds interfere with the radiation chemical oxygen depletion process and that the radiosensitization observed in the nonbreaking survival curve is the consequence of sensitization by both the nitroimidazole and, primarily, the oxygen rather than a direct subsitution for oxygen by the sensitizer. This conclusion is also supported by data obtained in double-pulse experiments. The results are discussed with regard to the mechanisms of the oxygen depletion process and radiosensitization.

  18. Mitochondrial stress controls the radiosensitivity of the oxygen effect: Implications for radiotherapy

    PubMed Central

    Richardson, Richard B.; Harper, Mary-Ellen

    2016-01-01

    It has been more than 60 years since the discovery of the oxygen effect that empirically demonstrates the direct association between cell radiosensitivity and oxygen tension, important parameters in radiotherapy. Yet the mechanisms underlying this principal tenet of radiobiology are poorly understood. Better understanding of the oxygen effect may explain difficulty in eliminating hypoxic tumor cells, a major cause of regrowth after therapy. Our analysis utilizes the Howard-Flanders and Alper formula, which describes the relationship of radiosensitivity with oxygen tension. Here, we assign and qualitatively assess the relative contributions of two important mechanisms. The first mechanism involves the emission of reactive oxygen species from the mitochondrial electron transport chain, which increases with oxygen tension. The second mechanism is related to an energy and repair deficit, which increases with hypoxia. Following a radiation exposure, the uncoupling of the oxidative phosphorylation system (proton leak) in mitochondria lowers the emission of reactive oxygen species which has implications for fractionated radiotherapy, particularly of hypoxic tumors. Our analysis shows that, in oxygenated tumor and normal cells, mitochondria, rather than the nucleus, are the primary loci of radiotherapy effects, especially for low linear energy transfer radiation. Therefore, the oxygen effect can be explained by radiation-induced effects in mitochondria that generate reactive oxygen species, which in turn indirectly target nuclear DNA. PMID:26894978

  19. Nicotinamide increases thyroid radiosensitivity by stimulating nitric oxide synthase expression and the generation of organic peroxides.

    PubMed

    Agote Robertson, M; Finochietto, P; Gamba, C A; Dagrosa, M A; Viaggi, M E; Franco, M C; Poderoso, J J; Juvenal, G J; Pisarev, M A

    2006-01-01

    Differentiated thyroid cancer and hyperthyroidism are treated with radioiodine. However, when the radioisotope dose exceeds certain limits, the patient must be hospitalized to avoid contact with people that would otherwise be exposed to radiation. It would be desirable to obtain a similar therapeutic effect using lower radioiodine doses. Radiosensitizers can be utilized for this purpose. Nicotinamide (NA) increases thyroid radiosensitivity to 131I in both normal and goitrous glands. NA causes a significant increase in thyroid blood flow, which would increase tissue oxygenation and tissue damage via free radicals. Wistar rats were treated with either nicotinamide (NA), 131I or both. The expression of the three isoforms of nitric oxide synthase (NOS) in the thyroid (Western blot) and the activities of SOD, GPx, catalase and organic peroxides were determined. Treatment with NA or 131I increased the expression of eNOS and the generation of organic peroxides. When administered jointly, they showed a synergistic effect. No changes were observed in the other NOS isoforms or in the activities of catalase, glutathione peroxidase and superoxide dismutase. NA potentiates the effect of 131I by increasing eNOS, which would in turn stimulate NO production, increasing thyroid blood flow and tissue damage via organic peroxides.

  20. Radiosensitizing effect of PSMC5, a 19S proteasome ATPase, in H460 lung cancer cells.

    PubMed

    Yim, Ji-Hye; Yun, Hong Shik; Lee, Su-Jae; Baek, Jeong-Hwa; Lee, Chang-Woo; Song, Ji-Young; Um, Hong-Duck; Park, Jong Kuk; Kim, Jae-Sung; Park, In-Chul; Hwang, Sang-Gu

    2016-01-01

    The function of PSMC5 (proteasome 26S subunit, ATPase 5) in tumors, particularly with respect to cancer radioresistance, is not known. Here, we identified PSMC5 as a novel radiosensitivity biomarker, demonstrating that radiosensitive H460 cells were converted to a radioresistance phenotype by PSMC5 depletion. Exposure of H460 cells to radiation induced a marked accumulation of cell death-promoting reactive oxygen species, but this effect was blocked in radiation-treated H460 PSMC5-knockdown cells through downregulation of the p53-p21 pathway. Interestingly, PSMC5 depletion in H460 cells enhanced both AKT activation and MDM2 transcription, thereby promoting the degradation of p53 and p21 proteins. Furthermore, specific inhibition of AKT with triciribine or knockdown of MDM2 with small interfering RNA largely restored p21 expression in PSMC5-knockdown H460 cells. Our data suggest that PSMC5 facilitates the damaging effects of radiation in radiation-responsive H460 cancer cells and therefore may serve as a prognostic indicator for radiotherapy and molecular targeted therapy in lung cancer patients.

  1. Enhancing radiosensitization in EphB4 receptor-expressing Head and Neck Squamous Cell Carcinomas

    PubMed Central

    Bhatia, Shilpa; Hirsch, Kellen; Sharma, Jaspreet; Oweida, Ayman; Griego, Anastacia; Keysar, Stephen; Jimeno, Antonio; Raben, David; Krasnoperov, Valery; Gill, Parkash S.; Pasquale, Elena B.; Wang, Xiao-Jing; Karam, Sana D.

    2016-01-01

    Members of the Eph family of receptor tyrosine kinases have been implicated in a wide array of human cancers. The EphB4 receptor is ubiquitously expressed in head and neck squamous cell carcinoma (HNSCC) and has been shown to impart tumorigenic and invasive characteristics to these cancers. In this study, we investigated whether EphB4 receptor targeting can enhance the radiosensitization of HNSCC. Our data show that EphB4 is expressed at high to moderate levels in HNSCC cell lines and patient-derived xenograft (PDX) tumors. We observed decreased survival fractions in HNSCC cells following EphB4 knockdown in clonogenic assays. An enhanced G2 cell cycle arrest with activation of DNA damage response pathway and increased apoptosis was evident in HNSCC cells following combined EphB4 downregulation and radiation compared to EphB4 knockdown and radiation alone. Data using HNSCC PDX models showed significant reduction in tumor volume and enhanced delay in tumor regrowth following sEphB4-HSA administration with radiation compared to single agent treatment. sEphB4-HSA is a protein known to block the interaction between the EphB4 receptor and its ephrin-B2 ligand. Overall, our findings emphasize the therapeutic relevance of EphB4 targeting as a radiosensitizer that can be exploited for the treatment of human head and neck carcinomas. PMID:27941840

  2. Accounting Fundamentals for Non-Accountants

    EPA Pesticide Factsheets

    The purpose of this module is to provide an introduction and overview of accounting fundamentals for non-accountants. The module also covers important topics such as communication, internal controls, documentation and recordkeeping.

  3. 32 CFR 701.111 - Disclosure accounting.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 32 National Defense 5 2012-07-01 2012-07-01 false Disclosure accounting. 701.111 Section 701.111... THE NAVY DOCUMENTS AFFECTING THE PUBLIC DON Privacy Program § 701.111 Disclosure accounting. Disclosure accounting allows the individual to determine what agencies or persons have been...

  4. 32 CFR 701.111 - Disclosure accounting.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 32 National Defense 5 2014-07-01 2014-07-01 false Disclosure accounting. 701.111 Section 701.111... THE NAVY DOCUMENTS AFFECTING THE PUBLIC DON Privacy Program § 701.111 Disclosure accounting. Disclosure accounting allows the individual to determine what agencies or persons have been...

  5. 32 CFR 701.111 - Disclosure accounting.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 5 2013-07-01 2013-07-01 false Disclosure accounting. 701.111 Section 701.111... THE NAVY DOCUMENTS AFFECTING THE PUBLIC DON Privacy Program § 701.111 Disclosure accounting. Disclosure accounting allows the individual to determine what agencies or persons have been...

  6. 32 CFR 701.111 - Disclosure accounting.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 5 2011-07-01 2011-07-01 false Disclosure accounting. 701.111 Section 701.111... THE NAVY DOCUMENTS AFFECTING THE PUBLIC DON Privacy Program § 701.111 Disclosure accounting. Disclosure accounting allows the individual to determine what agencies or persons have been...

  7. 32 CFR 701.111 - Disclosure accounting.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 5 2010-07-01 2010-07-01 false Disclosure accounting. 701.111 Section 701.111... THE NAVY DOCUMENTS AFFECTING THE PUBLIC DON Privacy Program § 701.111 Disclosure accounting. Disclosure accounting allows the individual to determine what agencies or persons have been...

  8. Employers' Perceptions of Online Accounting Education

    ERIC Educational Resources Information Center

    Tabatabaei, Manouchehr; Solomon, Alison; Strickland, Emily; Metrejean, Eddie

    2014-01-01

    The main focus of this research is on perceptions of accounting employers of those individuals obtaining their accounting education online. An online survey of accounting professionals was conducted, and the findings suggest that a candidate with a traditional education is more suitable for employment than a candidate with an online education.…

  9. An overview of accounting and budgeting.

    PubMed

    Cawein, C

    2001-01-01

    Accounting is inextricably linked with daily professional practice and commerce. No individual, organization, or business can survive without some understanding of the basic concepts of accounting. Having knowledge of fundamental concepts of accounting will relieve some of the pressures imposed by governmental regulatory agencies and legislative requirements, and assist healthcare workers in operating more effectively and competing more successfully.

  10. MiR-26a enhances the radiosensitivity of glioblastoma multiforme cells through targeting of ataxia–telangiectasia mutated

    SciTech Connect

    Guo, Pin; Lan, Jin; Ge, Jianwei; Nie, Quanmin; Guo, Liemei; Qiu, Yongming; Mao, Qing

    2014-01-15

    Glioblastoma multiforme (GBM) is notoriously resistant to radiation, and consequently, new radiosensitizers are urgently needed. MicroRNAs are a class of endogenous gene modulators with emerging roles in DNA repair. We found that overexpression of miR-26a can enhance radiosensitivity and reduce the DNA repair ability of U87 cells. However, knockdown miR-26a in U87 cells could act the converse manner. Mechanistically, this effect is mediated by direct targeting of miR-26a to the 3′UTR of ATM, which leads to reduced ATM levels and consequent inhibition of the homologous recombination repair pathway. These results suggest that miR-26a may act as a new radiosensitizer of GBM. - Highlights: ●miR-26a directly target ATM in GBM cells. ●miR-26a enhances the radiosensitivity of GBM cells. ●miR-26a could reduce the DNA repair capacity of GBM cells.

  11. Radiosensitization of Aspergillus niger and Penicillium chrysogenum using basil essential oil and ionizing radiation for food decontamination.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The Minimum Inhibitory Concentration (MIC) of basil oil, was determined for two pathogenic fungi of rice, Aspergillus niger and Penicillium chrysogenum. The antifungal activity of the basil oil in combination with ionising radiation was then investigated to determine if basil oil caused radiosensit...

  12. Niraparib (MK-4827), a novel poly(ADP-Ribose) polymerase inhibitor, radiosensitizes human lung and breast cancer cells

    PubMed Central

    Bridges, Kathleen A.; Toniatti, Carlo; Buser, Carolyn A.; Liu, Huifeng; Buchholz, Thomas A.; Meyn, Raymond E.

    2014-01-01

    The aim of this study was to assess niraparib (MK-4827), a novel poly(ADP-Ribose) polymerase (PARP) inhibitor, for its ability to radiosensitize human tumor cells. Human tumor cells derived from lung, breast and prostate cancers were tested for radiosensitization by niraparib using clonogenic survival assays. Both p53 wild-type and p53-defective lines were included. The ability of niraparib to alter the repair of radiation-induced DNA double strand breaks (DSBs) was determined using detection of γ-H2AX foci and RAD51 foci. Clonogenic survival analyses indicated that micromolar concentrations of niraparib radiosensitized tumor cell lines derived from lung, breast, and prostate cancers independently of their p53 status but not cell lines derived from normal tissues. Niraparib also sensitized tumor cells to H2O2 and converted H2O2-induced single strand breaks (SSBs) into DSBs during DNA replication. These results indicate that human tumor cells are significantly radiosensitized by the potent and selective PARP-1 inhibitor, niraparib, in the in vitro setting. The mechanism of this effect appears to involve a conversion of sublethal SSBs into lethal DSBs during DNA replication due to the inhibition of base excision repair by the drug. Taken together, our findings strongly support the clinical evaluation of niraparib in combination with radiation. PMID:24970803

  13. Silver nanoparticles outperform gold nanoparticles in radiosensitizing U251 cells in vitro and in an intracranial mouse model of glioma

    PubMed Central

    Liu, Peidang; Jin, Haizhen; Guo, Zhirui; Ma, Jun; Zhao, Jing; Li, Dongdong; Wu, Hao; Gu, Ning

    2016-01-01

    Radiotherapy performs an important function in the treatment of cancer, but resistance of tumor cells to radiation still remains a serious concern. More research on more effective radiosensitizers is urgently needed to overcome such resistance and thereby improve the treatment outcome. The goal of this study was to evaluate and compare the radiosensitizing efficacies of gold nanoparticles (AuNPs) and silver nanoparticles (AgNPs) on glioma at clinically relevant megavoltage energies. Both AuNPs and AgNPs potentiated the in vitro and in vivo antiglioma effects of radiation. AgNPs showed more powerful radiosensitizing ability than AuNPs at the same mass and molar concentrations, leading to a higher rate of apoptotic cell death. Furthermore, the combination of AgNPs with radiation significantly increased the levels of autophagy as compared with AuNPs plus radiation. These findings suggest the potential application of AgNPs as a highly effective nano-radiosensitizer for the treatment of glioma. PMID:27757033

  14. Identification and Characterization of a Small Inhibitory Peptide That Can Target DNA-PKcs Autophosphorylation and Increase Tumor Radiosensitivity

    SciTech Connect

    Sun Xiaonan; Yang Chunying; Liu Hai; Wang Qi; Wu Shixiu; Li Xia; Xie Tian; Brinkman, Kathryn L.; Teh, Bin S.; Butler, E. Brian; Xu Bo; Zheng, Shu

    2012-12-01

    Purpose: The DNA protein kinase catalytic subunit (DNA-PKcs) is one of the critical elements involved in the DNA damage repair process. Inhibition of DNA-PKcs results in hypersensitivity to ionizing radiation (IR); therefore, this approach has been explored to develop molecular targeted radiosensitizers. Here, we aimed to develop small inhibitory peptides that could specifically target DNA-PKcs autophosphorylation, a critical step for the enzymatic activation of the kinase in response to IR. Methods and Materials: We generated several small fusion peptides consisting of 2 functional domains, 1 an internalization domain and the other a DNA-PKcs autophosphorylation inhibitory domain. We characterized the internalization, toxicity, and radiosensitization activities of the fusion peptides. Furthermore, we studied the mechanisms of the inhibitory peptides on DNA-PKcs autophosphorylation and DNA repair. Results: We found that among several peptides, the biotin-labeled peptide 3 (BTW3) peptide, which targets DNA-PKcs threonine 2647 autophosphorylation, can abrogate IR-induced DNA-PKcs activation and cause prolonged {gamma}-H2AX focus formation. We demonstrated that BTW3 exposure led to hypersensitivity to IR in DNA-PKcs-proficient cells but not in DNA-PKcs-deficient cells. Conclusions: The small inhibitory peptide BTW3 can specifically target DNA-PKcs autophosphorylation and enhance radiosensitivity; therefore, it can be further developed as a novel class of radiosensitizer.

  15. Library Labor Cost Accounting System.

    ERIC Educational Resources Information Center

    Du Bois, Dan

    The Library Labor Cost Accounting System will provide visibility on current costs of manually processing library materials, at each campus as well as system-wide. The scope of the study includes the following: (1) 100 individual activities, grouped into 14 functional areas, e.g., Ordering, Receiving; and into 3 major operations: Acquisitions,…

  16. Identification of novel radiosensitizers in a high-throughput, cell-based screen for DSB repair inhibitors.

    PubMed

    Goglia, Alexander G; Delsite, Robert; Luz, Antonio N; Shahbazian, David; Salem, Ahmed F; Sundaram, Ranjini K; Chiaravalli, Jeanne; Hendrikx, Petrus J; Wilshire, Jennifer A; Jasin, Maria; Kluger, Harriet M; Glickman, J Fraser; Powell, Simon N; Bindra, Ranjit S

    2015-02-01

    Most cancer therapies involve a component of treatment that inflicts DNA damage in tumor cells, such as double-strand breaks (DSBs), which are considered the most serious threat to genomic integrity. Complex systems have evolved to repair these lesions, and successful DSB repair is essential for tumor cell survival after exposure to ionizing radiation (IR) and other DNA-damaging agents. As such, inhibition of DNA repair is a potentially efficacious strategy for chemo- and radiosensitization. Homologous recombination (HR) and nonhomologous end-joining (NHEJ) represent the two major pathways by which DSBs are repaired in mammalian cells. Here, we report the design and execution of a high-throughput, cell-based small molecule screen for novel DSB repair inhibitors. We miniaturized our recently developed dual NHEJ and HR reporter system into a 384-well plate-based format and interrogated a diverse library of 20,000 compounds for molecules that selectively modulate NHEJ and HR repair in tumor cells. We identified a collection of novel hits that potently inhibit DSB repair, and we have validated their functional activity in a comprehensive panel of orthogonal secondary assays. A selection of these inhibitors was found to radiosensitize cancer cell lines in vitro, which suggests that they may be useful as novel chemo- and radio sensitizers. Surprisingly, we identified several FDA-approved drugs, including the calcium channel blocker mibefradil dihydrochloride, that demonstrated activity as DSB repair inhibitors and radiosensitizers. These findings suggest the possibility for repurposing them as tumor cell radiosensitizers in the future. Accordingly, we recently initiated a phase I clinical trial testing mibefradil as a glioma radiosensitizer.

  17. N-acetylglucosaminyltransferase V modulates radiosensitivity and migration of small cell lung cancer through epithelial-mesenchymal transition.

    PubMed

    Huang, Chunyue; Huang, Miaojuan; Chen, Wenxia; Zhu, Weiliang; Meng, Hui; Guo, Linlang; Wei, Ting; Zhang, Jian

    2015-11-01

    N-acetylglucosaminyltransferase V (Gnt-V) has been linked to the migration of various human cancers. Recently we have found that inhibition of Gnt-V increases the radiosensitivity of cancer cells. However, the mechanisms by which Gnt-V mediates radiosensitivity and migration, especially in small cell lung cancer (SCLC) remain unknown. In our study, two SCLC cell lines (H1688 and H146) were used to investigate whether Gnt-V modulated the radiosensitivity and migration of SCLC cells through the epithelial-mesenchymal transition (EMT). The results showed that the expression of Gnt-V correlated with the N stage in patients with SCLC. Overexpression of Gnt-V led to a further increase in the relative viable cell number and survival fraction with a decrease in apoptosis rate and Bax/Bcl-2 ratio, when the cells were treated with irradiation. By contrast, knockdown of Gnt-V with irradiation resulted in a further decrease in the relative viable cell number and survival fraction but an increase in apoptosis rate and Bax/Bcl-2 ratio. Cells expressing high levels of Gnt-V increased migration whereas low levels of Gnt-V suppressed cell migration. Besides, the transient knockdown of ZEB2 led to an increase in radiosensitivity and an inhibition in the migration of SCLC cells. Furthermore, Gnt-V was negatively correlated with E-cadherin expression but positively correlated with N-cadherin, vimentin and ZEB2 expression. Finally, an in vivo study revealed that upregulation of Gnt-V caused tumour growth more quickly, as well as the expression of EMT-related markers (N-cadherin, vimentin and ZEB2). Taken together, the study suggested that an elevation of Gnt-V could lead to the radiosensitivity and migration of SCLC cells by inducing EMT, thereby highlighting Gnt-V as a potential therapeutic target for the prevention of EMT-associated tumour radioresistance and migration.

  18. Radiosensitization of Salmonella spp. and Listeria spp. in ready-to-eat baby spinach leaves.

    PubMed

    Gomes, Carmen; Moreira, Rosana G; Castell-Perez, Elena

    2011-01-01

    The FDA recently approved irradiation treatment of leafy greens such as spinach up to 1 kGy; however, it is important to reduce the dose required to decontaminate the produce while maintaining its quality. Thus, the objectives of this study were: (1) to assess the radiation sensitivities of Salmonella spp. and Listeria spp. inoculated in ready-to-eat baby spinach leaves under modified atmosphere packaging (MAP) and irradiated using a 1.35-MeV Van de Graff accelerator (the leaves were irradiated both at room temperature and at -5 °C); and (2) to understand and optimize the synergistic effect of MAP and irradiation by studying the radiolysis of ozone formation under different temperatures, the effect of dose rate on its formation, and its decomposition. Results showed that increased concentrations of oxygen in the packaging significantly increased the radiation sensitivity of the test organisms, ranging from 7% up to 25% reduction in D(10)-values. In particular, radiosensitization could be effected (P < 0.05) by production of ozone, which increases with increasing dose-rate and oxygen concentration, and reducing temperatures. Radiosensitization was demonstrated for both microorganisms with irradiation of either fresh or frozen (-5 °C) baby spinach. These results suggest that low-dose (below 1 kGy) e-beam radiation under modified atmosphere packaging (100% O(2) and N(2):O(2)[1:1]) may be a viable tool for reducing microbial populations or eliminating Salmonella spp. and Listeria spp. from baby spinach. A suggested treatment to achieve a 5-log reduction of the test organisms would be irradiation at room temperature under 100% O(2) atmosphere at a dose level of 0.7 kGy. Practical Application: Decontamination of minimally processed fruits and vegetables from food-borne pathogens presents technical and economical challenges to the produce industry. Internalized microorganisms cannot be eliminated by the current procedure (water-washed or treated with 200-ppm chlorine

  19. Inhibition on Numb/Notch signal pathway enhances radiosensitivity of lung cancer cell line H358.

    PubMed

    Song, Shi-Gang; Yu, Hong-Yang; Ma, Yan-Wei; Zhang, Feng; Xu, Xiang-Ying

    2016-10-01

    The objective of the study is to investigate the effects of the Numb/Notch signal pathway on the radiosensitivity of lung cancer cell line H358. MTT assay and colony forming assay were used to detect the effects of different doses of X-rays and MW167 on the in vitro proliferation of the lung cancer cell line H358. Flow cytometry was applied to evaluate the effects of X rays on the apoptosis of H358. Scratch assay and Transwell invasion assay were used to examine the effects of X-rays on the migration and invasion abilities of H358. The mRNA and protein expressions in the signal pathway were detected by real-time PCR and western blot. Assays in vitro confirmed the effects of the Numb/Notch pathway inhibitor on the radiosensitivity to lung cancer. MW167 enhanced the inhibiting effects of X-ray on the proliferation of H358 cell line. After the addition of MW167, the apoptosis rates significantly increased, but the invasion and migration abilities decreased significantly. Meanwhile, MW167 could dose-dependently promote the increase of expression of Numb, which is the upstream gene of the Numb/Notch signaling pathway, but inhibit the expression of and HES1. In vivo experiments revealed that cell proliferation was suppressed in the radiation, pathway inhibitor, and pathway inhibitor + radiation groups, and the pathway inhibitor + radiation group exhibited more active anti-tumor ability when compared with the blank group (all P < 0.05); Numb expression was up-regulated, but Notch1 and HES1 expressions were down-regulated in those three groups, and also, the pathway inhibitor + radiation group exhibited more significant alternation when compared with the blank group (all P < 0.05); cell apoptosis was promoted in those three groups, and the pathway inhibitor + radiation group showed more active apoptosis when compared with the blank group (all P < 0.05). Repression of the Numb/Notch pathway enhances the effects of radiotherapy on the radiosensitivity of the lung

  20. Bromodeoxyuridine-mediated radiosensitization in hum glioma: The effect of concentration, duration, and fluoropyrimidine modulation

    SciTech Connect

    McLaughlin, P.W.; Lawrence, T.S.; Seabury, H.

    1994-10-15

    To define the relative influence of duration of exposure, concentration, and modulation by fluorodeoxyuridines (FdUrd) on the incorporation of 5-bromo-2-deoxyuridine (BrdUrd) into DNA of human malignant glioma line (D-54) in vitro and in vivo. In vitro studies: an established human malignant glioma line (D-54)was exposed to a clinically achievable concentration of BrdUrd to model intravenous (1 {mu}M BrdUrd) and intraarterial (4 {mu}MBrdUrd) conditions. The influence of modulation was assessed using 1 nM FdUrd. Incorporation of BrdUrd, radiosensitization, and cytotoxicity were determined after 24, 72, and 120 h drug exposures. In Vivo studies: nude mice bearing D-54 xenografts were infused with BrdUrd at 100 mg/kg/day for 7 and 14 days or BrdUrd at 400 mg/kg/day for 5 days. The influence of modulation was assessed by combining 100 mg/kg/day of BrdUrd with 0.1, 0.3 and 1 mg/kg/day FdUrd for 7 days. Incorporation of BrddUrd into the DNA of tumor, gut, and marrow were determined. In Vitro: thymidine replacement and radiosensitization were a function of concentration, and incorporation began to plateau after 2 to 3 population doublings. Modulation with 1 nM FdUrd significantly increased incorporation. Radiosensitization was a linear function of thymidine replacement under all conditions tested. In Vivo: infusion with 400 mg/kg/day for 5 days resulted in greater tumor incorporation (10.3 {plus_minus} 0.4% thymidine replaced) than treatment with 100 mg/kg/day for 14 days (6.0 {plus_minus} 0.6% of thymidine replaced) than treatment with 100 mg/kg/day for 14 days for 14 days (6.0 {plus_minus} 0.6% of thymidine replaced). Infusion of FdUrd with BrdUrd increased normal tissue incorporation of BrdUrd, but failed to increase BrdUrd incorporation in tumor cells. These results suggest that relatively short, high dose rate infusions may be preferable to long, low dose rate infusions. 33 refs., 5 figs., 2 tabs.

  1. Transglutaminase 2 Inhibitor KCC009 Induces p53-Independent Radiosensitization in Lung Adenocarcinoma Cells

    PubMed Central

    Huayin, Sheng; Dong, Yao; Chihong, Zhu; Xiaoqian, Qian; Danying, Wan; Jianguo, Feng

    2016-01-01

    Background The expression of transglutaminase 2 (TG2) is correlated to DNA damage repair and apoptosis through the p53 pathway. The present study aimed to investigate the potential radiosensitization effect and possible mechanisms of the TG2 inhibitor KCC009 in lung cancer in vitro. Material/Methods A single hit multi-target model was used to plot survival curves and to calculate the sensitizing enhancement ratios in lung cancer wild-type or mutant p53 of H1299 cells. We performed analyses for changes of cell cycling and apoptotic responses of cells; Western blot analysis and real-time SYBR Green PCR assay were used to determine the changes of mRNA/protein expressions; ELISA assay was used for examination of cytochrome c release in cytoplasm. Results Our results showed that KCC009 induced radiosensitization in both H1299/WT-p53 and H1299/M175H-p53 cells. KCC009+IR induced G0/G1 arrest in H1299/WT cells and G2/M arrest in H1299/M175H-p53 cells. KCC009+IR also induced apoptosis in both cell lines. In addition, KCC009+IR decreased the TG2 expression, and increased the p53 expression in H1299/WT cells but not in H1299/M175H-p53 cells. KCC009+IR also increased the expression of p21, Bax, p-caspase-3, and decreased Bcl-2 and CyclinD expression in H1299/WT cells. While KCC009+IR induced phosphorylation of caspase-3 and increase Cyt-C level in the cytoplasm of, and decreased CyclinB, Bcl-2 expression in H1299/M175H-p53 cells, we noticed that Cyt-C level in the nucleus decreased in the H1299/WT cells. Conclusions KCC009, a TG2 inhibitor, exhibits potent radiosensitization effects in human lung cancer cells expressing wild-type or mutant p53 with different mechanisms. PMID:28002389

  2. Transglutaminase 2 Inhibitor KCC009 Induces p53-Independent Radiosensitization in Lung Adenocarcinoma Cells.

    PubMed

    Huaying, Sheng; Dong, Yao; Chihong, Zhu; Xiaoqian, Qian; Danying, Wan; Jianguo, Feng

    2016-12-21

    BACKGROUND The expression of transglutaminase 2 (TG2) is correlated to DNA damage repair and apoptosis through the p53 pathway. The present study aimed to investigate the potential radiosensitization effect and possible mechanisms of the TG2 inhibitor KCC009 in lung cancer in vitro. MATERIAL AND METHODS A single hit multi-target model was used to plot survival curves and to calculate the sensitizing enhancement ratios in lung cancer wild-type or mutant p53 of H1299 cells. We performed analyses for changes of cell cycling and apoptotic responses of cells; Western blot analysis and real-time SYBR Green PCR assay were used to determine the changes of mRNA/protein expressions; ELISA assay was used for examination of cytochrome c release in cytoplasm. RESULTS Our results showed that KCC009 induced radiosensitization in both H1299/WT-p53 and H1299/M175H-p53 cells. KCC009+IR induced G0/G1 arrest in H1299/WT cells and G2/M arrest in H1299/M175H-p53 cells. KCC009+IR also induced apoptosis in both cell lines. In addition, KCC009+IR decreased the TG2 expression, and increased the p53 expression in H1299/WT cells but not in H1299/M175H-p53 cells. KCC009+IR also increased the expression of p21, Bax, p-caspase-3, and decreased Bcl-2 and CyclinD expression in H1299/WT cells. While KCC009+IR induced phosphorylation of caspase-3 and increase Cyt-C level in the cytoplasm of, and decreased CyclinB, Bcl-2 expression in H1299/M175H-p53 cells, we noticed that Cyt-C level in the nucleus decreased in the H1299/WT cells. CONCLUSIONS KCC009, a TG2 inhibitor, exhibits potent radiosensitization effects in human lung cancer cells expressing wild-type or mutant p53 with different mechanisms.

  3. Cell progression and radiosensitivity of T1-prospermatogonia in Wistar rats.

    PubMed

    Hilscher, W M; Trott, K R; Hilscher, W

    1982-05-01

    T1-prospermatogonia pass through a quiescent stage which lasts from before birth until day 4 after birth (p.n.). They progress into DNA synthesis and mitosis in two synchronous waves which are separated by 24 hours in the evenings of day 4 and 5. The first wave contains about 25 per cent of the total population, the second 75 per cent. The mean duration of S-phase is 10 hours, the mean duration of G2-phase is 4 hours. After irradiation, the capacity of T1-prospermatogonia to produce the normal number of proliferating and differentiating cells in the testes is reduced. During maturation, between day 21 post-conception (p.c.) and day 5 p.n. the radiosensitivity of T1-prospermatogonia decreases by a factor of over 5.

  4. Contribution of hydroxyl radical to radiosensitization: a study of DNA damage

    SciTech Connect

    Skov, K.A.

    1984-09-01

    Using the radioprotector dimethylsulfoxide, DMSO, as a scavenger of hydroxyl radicals, the proportions of DNA damage caused by OH were determined in mammalian cells irradiated in hypoxia with or without the radiosensitizers misonidazole and TAN or in air. Yields of both single-strand breaks (SSB) and base/sugar damage (MLS for Micrococcus luteus sensitive sites) were measured for each situation. Most of the damage enhanced by the sensitizers was found to be OH dependent, for both MLS and SSB classes of damage. The sensitizer enhancement ratios in the presence of scavenger and the degree of protection afforded by the scavenger determined for total (MSL + SSB) damage agree well with those derived from corresponding survival experiments.

  5. International Accounting and the Accounting Educator.

    ERIC Educational Resources Information Center

    Laribee, Stephen F.

    The American Assembly of Collegiate Schools of Business (AACSB) has been instrumental in internationalizing the accounting curriculum by means of accreditation requirements and standards. Colleges and universities have met the AACSB requirements either by providing separate international accounting courses or by integrating international topics…

  6. Health savings accounts and health reimbursement arrangements: assets, account balances, and rollovers, 2006-2011.

    PubMed

    Fronstin, Paul

    2012-01-01

    ASSET LEVELS GROWING: In 2011, there was $12.4 billion in health savings accounts (HSAs) and health reimbursement arrangements (HRAs), spread across 8.4 million accounts, according to data from the 2011 EBRI/MGA Consumer Engagement in Health Care Survey, sponsored by EBRI and Matthew Greenwald & Associates. This is up from 2006, when there were 1.3 million accounts with $873.4 million in assets, and 2010, when 5.4 million accounts held $7.3 billion in assets. AFTER LEVELING OFF, AVERAGE ACCOUNT BALANCES INCREASED: After average account balances leveled off in 2008 and 2009, and fell slightly in 2010, they increased in 2011. In 2006, account balances averaged $696. They increased to $1,320 in 2007, a 90 percent increase. Account balances averaged $1,356 in 2008 and $1,419 in 2009, 3 percent and 5 percent increases, respectively. In 2010, average account balances fell to $1,355, down 4.5 percent from the previous year. In 2011, average account balances increased to $1,470, a 9 percent increase from 2010. TOTAL AND AVERAGE ROLLOVERS INCREASE: After declining to $1,029 in 2010, average rollover amounts increased to $1,208 in 2011. Total assets being rolled over increased as well: $6.7 billion was rolled over in 2011, up from $3.7 billion in 2010. The percentage of individuals without a rollover remained at 13 percent in 2011. HEALTHY BEHAVIOR DOES NOT MEAN HIGHER ACCOUNT BALANCES AND HIGHER ROLLOVERS: Individuals who smoke have more money in their accounts than those who do not smoke. In contrast, obese individuals have less money in their account than the nonobese. There is very little difference in account balances by level of exercise. Very small differences were found in account balances and rollover amounts between individuals who used cost or quality information, compared with those who did not use such information. However, next to no relationship was found between either account balance or rollover amounts and various cost-conscious behaviors. When a difference

  7. Targeted radiosensitization of ETS fusion-positive prostate cancer through PARP1 inhibition.

    PubMed

    Han, Sumin; Brenner, J Chad; Sabolch, Aaron; Jackson, Will; Speers, Corey; Wilder-Romans, Kari; Knudsen, Karen E; Lawrence, Theodore S; Chinnaiyan, Arul M; Feng, Felix Y

    2013-10-01

    ETS gene fusions, which result in overexpression of an ETS transcription factor, are considered driving mutations in approximately half of all prostate cancers. Dysregulation of ETS transcription factors is also known to exist in Ewing's sarcoma, breast cancer, and acute lymphoblastic leukemia. We previously discovered that ERG, the predominant ETS family member in prostate cancer, interacts with the DNA damage response protein poly (ADP-ribose) polymerase 1 (PARP1) in human prostate cancer specimens. Therefore, we hypothesized that the ERG-PARP1 interaction may confer radiation resistance by increasing DNA repair efficiency and that this radio-resistance could be reversed through PARP1 inhibition. Using lentiviral approaches, we established isogenic models of ERG overexpression in PC3 and DU145 prostate cancer cell lines. In both cell lines, ERG overexpression increased clonogenic survival following radiation by 1.25 (±0.07) fold (mean ± SEM) and also resulted in increased PARP1 activity. PARP1 inhibition with olaparib preferentially radiosensitized ERG-positive cells by a factor of 1.52 (±0.03) relative to ERG-negative cells (P < .05). Neutral and alkaline COMET assays and immunofluorescence microscopy assessing γ-H2AX foci showed increased short- and long-term efficiencies of DNA repair, respectively, following radiation that was preferentially reversed by PARP1 inhibition. These findings were verified in an in vivo xenograft model. Our findings demonstrate that ERG overexpression confers radiation resistance through increased efficiency of DNA repair following radiation that can be reversed through inhibition of PARP1. These results motivate the use of PARP1 inhibitors as radiosensitizers in patients with localized ETS fusion-positive cancers.

  8. Mutations in Succinate Dehydrogenase Subunit C Increase Radiosensitivity and Bystander Responses

    NASA Astrophysics Data System (ADS)

    Zhou, Hongning; Hei, Tom K.

    Although radiation-induced bystander effect is well studied in the past decade, the precise mech-anisms are still unclear. It is likely that a combination of pathways involving both primary and secondary signaling processes is involved in producing a bystander effect. There is recent evidence that mitochondria play a critical role in bystander responses. Recently studies found that a mutation in succinate dehydrogenese subunit C (SDHC), an integral membrane protein in complex II of the electron transport chain, resulted in increased superoxide, oxidative stress, apoptosis, tumorigenesis, and genomic instability, indicating that SDHC play a critical role in maintaining mitochondrial function. In the present study, using Chinese hamster fibroblasts (B1 cells) and the mutants (B9 cells) containing a single base substitution that produced a premature stop codon resulting in a 33-amino acid COOH-terminal truncation of the SDHC protein, we found that B9 cells had an increase in intracellular superoxide content, nitric oxide species, and mitochondrial membrane potential when compared with wild type cells. After irradiated with a grade of doses of gamma rays, B9 cells show an increased radiosensitivity, especially at high doses. The HPRT- mutant yield after gamma-ray irradiation in B9 cells was significantly higher than that of B1 cells. A single, 3Gy dose of gamma-rays increased the background mutant level by more than 4 fold. In contrast, the mutant induction was less than 2 fold in B1 cells. In addition, B9 cells produced a higher bystander mutagenesis after alpha particle irradiation than the B1 cells. Furthermore, pretreated with carboxy-2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (c-PTIO), a nitric oxide scavenger, significantly decreased the bystander effect. Our findings demonstrate that a mutation in SDHC increases radiosensitivity in both directly irradiated cells and in neighboring bystander cells, and mito-chondrial function play an essential role in

  9. Radiosensitizing effect of lapatinib in human epidermal growth factor receptor 2-positive breast cancer cells

    PubMed Central

    Park, Ji Min; Kim, Dan Hyo; Kim, In Ah

    2016-01-01

    Trastuzumab has been widely used for the treatment of human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer, however, it cannot easily cross the blood-brain barrier (BBB) and is known to increase the incidence of brain metastases. In contrast, lapatinib has a low molecular weight and can cross the BBB and it could be useful to treat brain metastases in patients with HER2-positive breast cancer. To explore the impact of lapatinib on radiation response, we conducted an in vitro experiment using SKBR3 and BT474 breast carcinoma cells exhibiting HER2/neu amplification. Lapatinib down-regulated phosphorylated (p)-HER2, p-epidermal growth factor receptor, p-AKT, and p-extracellular signal-regulated kinase. Pretreatment of lapatinib increased the radiosensitivity of SKBR3 (sensitizer enhancement ratio [SER]: 1.21 at a surviving fraction of 0.5) and BT474 (SER: 1.26 at a surviving fraction of 0.5) cells and hindered the repair of DNA damage, as suggested by the prolongation of radiation-induced γH2AX foci and the down-regulation of phosphorylated DNA-dependent protein kinase, catalytic subunit (p-DNAPKcs). Increases in radiation-induced apoptosis and senescence were suggested to be the major modes of cell death induced by the combination of lapatinib and radiation. Furthermore, lapatinib did not radiosensitize a HER2- negative breast cancer cell line or normal human astrocytes. These findings suggest that lapatinib can potentiate radiation-induced cell death in HER2-overexpressing breast cancer cells and may increase the efficacy of radiotherapy. A phase II clinical trial using lapatinib concurrently with whole-brain radiation therapy (WBRT) is currently being conducted. PMID:27738326

  10. Bacterial radiosensitization by using radiation processing in combination with essential oil: Mechanism of action

    NASA Astrophysics Data System (ADS)

    Lacroix, Monique; Caillet, Stéphane; Shareck, Francois

    2009-07-01

    Spice extracts under the form of essential oils were tested for their efficiency to increase the relative radiosensitivity of Listeria monocytogenes and Escherichia coli O157H7 in culture media. The two pathogens were treated by gamma-irradiation alone or in combination with oregano essential oil to evaluate their mechanism of action. The membrane murein composition, and the intracellular and extracellular concentration of ATP was determined. The bacterial strains were treated with two irradiation doses: 1.2 kGy to induce cell damage and 3.5 kGy to cause cell death for L. monocytogenes. A dose of 0.4 kGy to induce cell damages, 1.1 kGy to obtain viable but nonculturable (VBNC) state and 1.3 kGy to obtain a lethal dose was also applied on E. coli O157H7. Oregano essential oil was used at 0.020% and 0.025% (w/v), which is the minimum inhibitory concentration (MIC) for L. monocytogenes. For E. coli O157H7, a concentration of 0.006% and 0.025% (w/v) which is the minimum inhibitory concentration was applied. The use of essential oils in combination with irradiation has permitted an increase of the bacterial radiosensitization by more than 3.1 times. All treatments had also a significant effect ( p⩽0.05) on the murein composition, although some muropeptides did not seem to be affected by the treatment. Each treatment influenced differently the relative percentage and number of muropeptides. There was a significant ( p⩽0.05) correlation between the reduction of intracellular ATP and increase in extracellular ATP following treatment of the cells with oregano oil. The reduction of intracellular ATP was even more important when essential oil was combined with irradiation, but irradiation of L. monocytogenes alone induced a significant decrease ( p⩽0.05) of the internal ATP without affecting the external ATP.

  11. Radioprotection and Cell Cycle Arrest of Intestinal Epithelial Cells by Darinaparsin, a Tumor Radiosensitizer

    SciTech Connect

    Tian, Junqiang; Doi, Hiroshi; Saar, Matthias; Santos, Jennifer; Li, Xuejun; Peehl, Donna M.; Knox, Susan J.

    2013-12-01

    Purpose: It was recently reported that the organic arsenic compound darinaparsin (DPS) is a cytotoxin and radiosensitizer of tumor cells in vitro and in subcutaneous xenograft tumors. Surprisingly, it was also found that DPS protects normal intestinal crypt epithelial cells (CECs) from clonogenic death after ionizing radiation (IR). Here we tested the DPS radiosensitizing effect in a clinically relevant model of prostate cancer and explored the radioprotective effect and mechanism of DPS on CECs. Methods and Materials: The radiation modification effect of DPS was tested in a mouse model of orthotopic xenograft prostate cancer and of IR-induced acute gastrointestinal syndrome. The effect of DPS on CEC DNA damage and DNA damage responses was determined by immunohistochemistry. Results: In the mouse model of IR-induced gastrointestinal syndrome, DPS treatment before IR accelerated recovery from body weight loss and increased animal survival. DPS decreased post-IR DNA damage and cell death, suggesting that the radioprotective effect was mediated by enhanced DNA damage repair. Shortly after DPS injection, significant cell cycle arrest was observed in CECs at both G1/S and G2/M checkpoints, which was accompanied by the activation of cell cycle inhibitors p21 and growth arrest and DNA-damage-inducible protein 45 alpha (GADD45A). Further investigation revealed that DPS activated ataxia telangiectasia mutated (ATM), an important inducer of DNA damage repair and cell cycle arrest. Conclusions: DPS selectively radioprotected normal intestinal CECs and sensitized prostate cancer cells in a clinically relevant model. This effect may be, at least in part, mediated by DNA damage response activation and has the potential to significantly increase the therapeutic index of radiation therapy.

  12. Cytosolic phospholipaseA2 inhibition with PLA-695 radiosensitizes tumors in lung cancer animal models.

    PubMed

    Thotala, Dinesh; Craft, Jeffrey M; Ferraro, Daniel J; Kotipatruni, Rama P; Bhave, Sandeep R; Jaboin, Jerry J; Hallahan, Dennis E

    2013-01-01

    Lung cancer remains the leading cause of cancer deaths in the United States and the rest of the world. The advent of molecularly directed therapies holds promise for improvement in therapeutic efficacy. Cytosolic phospholipase A2 (cPLA2) is associated with tumor progression and radioresistance in mouse tumor models. Utilizing the cPLA2 specific inhibitor PLA-695, we determined if cPLA2 inhibition radiosensitizes non small cell lung cancer (NSCLC) cells and tumors. Treatment with PLA-695 attenuated radiation induced increases of phospho-ERK and phospho-Akt in endothelial cells. NSCLC cells (LLC and A549) co-cultured with endothelial cells (bEND3 and HUVEC) and pre-treated with PLA-695 showed radiosensitization. PLA-695 in combination with irradiation (IR) significantly reduced migration and proliferation in endothelial cells (HUVEC & bEND3) and induced cell death and attenuated invasion by tumor cells (LLC &A549). In a heterotopic tumor model, the combination of PLA-695 and radiation delayed growth in both LLC and A549 tumors. LLC and A549 tumors treated with a combination of PLA-695 and radiation displayed reduced tumor vasculature. In a dorsal skin fold model of LLC tumors, inhibition of cPLA2 in combination with radiation led to enhanced destruction of tumor blood vessels. The anti-angiogenic effects of PLA-695 and its enhancement of the efficacy of radiotherapy in mouse models of NSCLC suggest that clinical trials for its capacity to improve radiotherapy outcomes are warranted.

  13. Volume effects and region-dependent radiosensitivity of the parotid gland

    SciTech Connect

    Konings, Antonius W.T. . E-mail: a.w.t.konings@med.rug.nl; Cotteleer, Femmy; Faber, Hette; Luijk, Peter van; Meertens, Harm; Coppes, Rob P.

    2005-07-15

    Purpose: To detect volume effects and possible regional differences in radiosensitivity of the rat parotid gland. Methods and Materials: Parotid glands of male albino Wistar rats were locally X-irradiated, with collimators with conformal radiation portals used to supply 100% volume and 50% cranial/caudal partial volumes. High-resolution magnetic resonance imaging was used to provide the outlines of the parotid glands. Single doses of up to 40 Gy were applied, and the effects on saliva secretion, measured with the aid of miniaturized Lashley cups, were followed up to 365 days after the irradiation. Results: Under conditions of equal mean absorbed doses and small variations in dose distribution, a pertinent volume effect was observed for late but not for early radiation damage. The late effects were different for the cranial part as compared with the caudal part of the parotid gland. The reduction in flow rate was much more severe after irradiation in the cranial part. After a single dose of 30 Gy, the reductions in flow rates were approximately 65% and 25% for the cranial and caudal parts, respectively. At that dose, no saliva flow was observed after irradiation of 100% of the gland. Conclusion: From the rat model studies presented, it is concluded that late radiation damage after partial irradiation of parotid glands shows region-dependent volume effects. This finding is expected to be relevant to the radiosensitivity of human salivary glands, and it implies that the predictive power of the mean dose concept in radiotherapeutic practice is limited. The finding of region-dependent late radiation damage also challenges the basic assumptions of most current normal tissue complication probability models for parotid gland function.

  14. Radiation dose to radiosensitive organs in PET/CT myocardial perfusion examination using versatile optical fibre

    NASA Astrophysics Data System (ADS)

    Salasiah, M.; Nordin, A. J.; Fathinul Fikri, A. S.; Hishar, H.; Tamchek, N.; Taiman, K.; Ahmad Bazli, A. K.; Abdul-Rashid, H. A.; Mahdiraji, G. A.; Mizanur, R.; Noor, Noramaliza M.

    2013-05-01

    Cardiac positron emission tomography (PET) provides a precise method in order to diagnose obstructive coronary artery disease (CAD), compared to single photon emission tomography (SPECT). PET is suitable for obese and patients who underwent pharmacologic stress procedures. It has the ability to evaluate multivessel coronary artery disease by recording changes in left ventricular function from rest to peak stress and quantifying myocardial perfusion (in mL/min/g of tissue). However, the radiation dose to the radiosensitive organs has become crucial issues in the Positron Emission Tomography/Computed Tomography(PET/CT) scanning procedure. The objective of this study was to estimate radiation dose to radiosensitive organs of patients who underwent PET/CT myocardial perfusion examination at Centre for Diagnostic Nuclear Imaging, Universiti Putra Malaysia in one month period using versatile optical fibres (Ge-B-doped Flat Fibre) and LiF (TLD-100 chips). All stress and rest paired myocardial perfusion PET/CT scans will be performed with the use of Rubidium-82 (82Rb). The optic fibres were loaded into plastic capsules and attached to patient's eyes, thyroid and breasts prior to the infusion of 82Rb, to accommodate the ten cases for the rest and stress PET scans. The results were compared with established thermoluminescence material, TLD-100 chips. The result shows that radiation dose given by TLD-100 and Germanium-Boron-doped Flat Fiber (Ge-B-doped Flat Fiber) for these five organs were comparable to each other where the p>0.05. For CT scans,thyroid received the highest dose compared to other organs. Meanwhile, for PET scans, breasts received the highest dose.

  15. miR-195 enhances the radiosensitivity of colorectal cancer cells by suppressing CARM1

    PubMed Central

    Zheng, Li; Chen, Jiangtao; Zhou, Zhongyong; He, Zhikuan

    2017-01-01

    Background microRNAs (miRNAs) can regulate the sensitivity of cancer cells to chemotherapy and radiotherapy. Aberrant expression of miR-195 has been found to be involved in colorectal cancer (CRC); however, its function and underlying mechanism in the radioresistance of CRC remains unclear. Methods The levels of miR-195 and CARM1 were detected by quantitative reverse transcription-polymerase chain reaction and Western blot analysis in HCT-116 and HT-29 cells, respectively. Colony survival and apoptosis were determined by clonogenic assay and flow cytometry analysis, respectively. The apoptosis-related proteins Bax, Bcl-2, and γ-H2AX were detected using Western blot. The targets of miR-195 were identified by bioinformatic prediction and luciferase reporter assays. CRC cells in vitro and in vivo were exposed to different doses of X-ray radiations. Results miR-195 was downregulated, and CARM1 was upregulated in HCT-116 and HT-29 cells. miR-195 overexpression or CARM1 knockdown suppressed colony survival, induced apoptosis, promoted expression of Bax and γ-H2AX, and inhibited Bcl-2 expression in CRC cells. CARM1 was identified and validated to be a functional target of miR-195. Moreover, restored expression of CARM1 reversed the enhanced radiosensitivity of CRC cells induced by miR-195. Furthermore, miR-195 increased the sensitivity of CRC cells to radiation in vivo. Conclusion miR-195 enhances radiosensitivity of CRC cells through suppressing CARM1. Therefore, miR-195 acts as a potential regulator of radioresistance for CRC cells and as a promising therapeutic target for CRC patients. PMID:28255246

  16. ZnFe2O4 nanoparticles as radiosensitizers in radiotherapy of human prostate cancer cells.

    PubMed

    Meidanchi, Alireza; Akhavan, Omid; Khoei, Samideh; Shokri, Ali A; Hajikarimi, Zahra; Khansari, Nakisa

    2015-01-01

    Nanoparticles of high-Z elements exhibit stronger photoelectric effects than soft tissues under gamma irradiation. Hence, they can be used as effective radiosensitizers for increasing the efficiency of current radiotherapy. In this work, superparamagnetic zinc ferrite spinel (ZnFe2O4) nanoparticles were synthesized by a hydrothermal reaction method and used as radiosensitizers in cancer therapy. The magnetic nanoparticles showed fast separation from solutions (e.g., ~1 min for 2 mg mL(-1) of the nanoparticles in ethanol) by applying an external magnetic field (~1T). The ZnFe2O4 nanoparticles were applied in an in vitro radiotherapy of lymph node carcinoma of prostate cells (as high radioresistant cells) under gamma irradiation of (60)Co source. The nanoparticles exhibited no significant effects on the cancer cells up to the high concentration of 100 μg mL(-1), in the absence of gamma irradiation. The gamma irradiation alone (2Gy dose) also showed no significant effects on the cells. However, gamma irradiation in the presence of 100 μg mL(-1) ZnFe2O4 nanoparticles resulted in ~53% inactivation of the cells (~17 times higher than the inactivation that occurred under gamma irradiation alone) after 24h. The higher cell inactivation was assigned to interaction of gamma radiation with nanoparticles (photoelectric effect), resulting in a high level electron release in the media of the radioresistant cells. Our results indicated that ZnFe2O4 nanoparticles not only can be applied in increasing the efficiency of radiotherapy, but also can be easily separated from the cell environment by using an external magnetic field after the radiotherapy.

  17. Radiosensitization of Oropharyngeal Squamous Cell Carcinoma Cells by Human Papillomavirus 16 Oncoprotein E6*I

    SciTech Connect

    Pang, Ervinna; Delic, Naomi C.; Hong, Angela; Zhang Mei; Rose, Barbara R.; Lyons, J. Guy

    2011-03-01

    Purpose: Patients with oropharyngeal squamous cell carcinoma (OSCC) whose disease is associated with high-risk human papillomavirus (HPV) infection have a significantly better outcome than those with HPV-negative disease, but the reasons for the better outcome are not known. We postulated that they might relate to an ability of HPV proteins to confer a better response to radiotherapy, a commonly used treatment for OSCC. Methods and Materials: We stably expressed the specific splicing-derived isoforms, E6*I and E6*II, or the entire E6 open reading frame (E6total), which gives rise to both full length and E6*I isoforms, in OSCC cell lines. Radiation resistance was measured in clonogenicity assays, p53 activity was measured using transfected reporter genes, and flow cytometry was used to analyze cell cycle and apoptosis. Results: E6*I and E6total sensitized the OSCC cells to irradiation, E6*I giving the greatest degree of radiosensitization (approximately eightfold lower surviving cell fraction at 10 Gy), whereas E6*II had no effect. In contrast to radiosensitivity, E6*I was a weaker inhibitor than E6total of tumor suppressor p53 transactivator activity in the same cells. Flow cytometric analyses showed that irradiated E6*I expressing cells had a much higher G2M:G1 ratio than control cells, indicating that, after G2, cells were diverted from the cell cycle to programmed cell death. Conclusion: This study supports a role for E6*I in the enhanced responsiveness of HPV-positive oropharyngeal carcinomas to p53-independent radiation-induced death.

  18. The Myb-p300-CREB axis modulates intestine homeostasis, radiosensitivity and tumorigenesis

    PubMed Central

    Sampurno, S; Bijenhof, A; Cheasley, D; Xu, H; Robine, S; Hilton, D; Alexander, W S; Pereira, L; Mantamadiotis, T; Malaterre, J; Ramsay, R G

    2013-01-01

    The gastrointestinal (GI) epithelium is constantly renewing, depending upon the intestinal stem cells (ISC) regulated by a spectrum of transcription factors (TFs), including Myb. We noted previously in mice with a p300 mutation (plt6) within the Myb-interaction-domain phenocopied Myb hypomorphic mutant mice with regard to thrombopoiesis, and here, changes in GI homeostasis. p300 is a transcriptional coactivator for many TFs, most prominently cyclic-AMP response element-binding protein (CREB), and also Myb. Studies have highlighted the importance of CREB in proliferation and radiosensitivity, but not in the GI. This prompted us to directly investigate the p300–Myb–CREB axis in the GI. Here, the role of CREB has been defined by generating GI-specific inducible creb knockout (KO) mice. KO mice show efficient and specific deletion of CREB, with no evident compensation by CREM and ATF1. Despite complete KO, only modest effects on proliferation, radiosensitivity and differentiation in the GI under homeostatic or stress conditions were evident, even though CREB target gene pcna (proliferating cell nuclear antigen) was downregulated. creb and p300 mutant lines show increased goblet cells, whereas a reduction in enteroendocrine cells was apparent only in the p300 line, further resembling the Myb hypomorphs. When propagated in vitro, crebKO ISC were defective in organoid formation, suggesting that the GI stroma compensates for CREB loss in vivo, unlike in MybKO studies. Thus, it appears that p300 regulates GI differentiation primarily through Myb, rather than CREB. Finally, active pCREB is elevated in colorectal cancer (CRC) cells and adenomas, and is required for the expression of drug transporter, MRP2, associated with resistance to Oxaliplatin as well as several chromatin cohesion protein that are relevant to CRC therapy. These data raise the prospect that CREB may have a role in GI malignancy as it does in other cancer types, but unlike Myb, is not critical for GI

  19. Panitumumab as a radiosensitizing agent in KRAS wild-type locally advanced rectal cancer.

    PubMed

    Mardjuadi, Feby Ingriani; Carrasco, Javier; Coche, Jean-Charles; Sempoux, Christine; Jouret-Mourin, Anne; Scalliet, Pierre; Goeminne, Jean-Charles; Daisne, Jean-François; Delaunoit, Thierry; Vuylsteke, Peter; Humblet, Yves; Meert, Nicolas; van den Eynde, Marc; Moxhon, Anne; Haustermans, Karin; Canon, Jean-Luc; Machiels, Jean-Pascal

    2015-09-01

    Our goal was to optimize the radiosensitizing potential of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies, when given concomitantly with preoperative radiotherapy in KRAS wild-type locally advanced rectal cancer (LARC). Based on pre-clinical studies conducted by our group, we designed a phase II trial in which panitumumab (6 mg/kg/q2 weeks) was combined with preoperative radiotherapy (45 Gy in 25 fractions) to treat cT3-4/N + KRAS wild-type LARC. The primary endpoint was complete pathologic response (pCR) (H0 = 5%, H1 = 17%, α = 0.05, β = 0.2). From 19 enrolled patients, 17 (89%) were evaluable for pathology assessment. Although no pCR was observed, seven patients (41%) had grade 3 Dworak pathological tumor regression. The regimen was safe and was associated with 95% of sphincter-preservation rate. No NRAS, BRAF, or PI3KCA mutation was found in this study, but one patient (5%) showed loss of PTEN expression. The quantification of plasma EGFR ligands during treatment showed significant upregulation of plasma TGF-α and EGF following panitumumab administration (p < 0.05). At surgery, patients with important pathological regression (grade 3 Dworak) had higher plasma TGF-α (p = 0.03) but lower plasma EGF (p = 0.003) compared to those with grade 0-2 Dworak. Our study suggests that concomitant panitumumab and preoperative radiotherapy in KRAS wild-type LARC is feasible and results in some tumor regression. However, pCR rate remained modest. Given that the primary endpoint of our study was not reached, we remain unable to recommend the use of panitumumab as a radiosensitizer in KRAS wild-type LARC outside a research setting.

  20. Stereotactic Ablative Radiotherapy Should Be Combined With a Hypoxic Cell Radiosensitizer

    SciTech Connect

    Brown, J. Martin; Diehn, Maximilian; Loo, Billy W.

    2010-10-01

    Purpose: To evaluate the effect of tumor hypoxia on the expected level of cell killing by regimens of stereotactic ablative radiotherapy (SABR) and to determine the extent to which the negative effect of hypoxia could be prevented using a clinically available hypoxic cell radiosensitizer. Results and Discussion: We have calculated the expected level of tumor cell killing from regimens of SABR, both with and without the assumption that 20% of the tumor cells are hypoxic, using the standard linear quadratic model and the universal survival curve modification. We compare the results obtained with our own clinical data for lung tumors of different sizes and with published data from other studies. We also have calculated the expected effect on cell survival of adding the hypoxic cell sensitizer etanidazole at clinically achievable drug concentrations. Modeling tumor cell killing with any of the currently used regimens of SABR produces results that are inconsistent with the majority of clinical findings if tumor hypoxia is not considered. However, with the assumption of tumor hypoxia, the expected level of cell killing is consistent with clinical data. For only some of the smallest tumors are the clinical data consistent with no tumor hypoxia, but there could be other reasons for the sensitivity of these tumors. The addition of etanidazole at clinically achievable tumor concentrations produces a large increase in the expected level of tumor cell killing from the large radiation doses used in SABR. Conclusions: The presence of tumor hypoxia is a major negative factor in limiting the curability of tumors by SABR at radiation doses that are tolerable to surrounding normal tissues. However, this negative effect of hypoxia could be overcome by the addition of clinically tolerable doses of the hypoxic cell radiosensitizer etanidazole.

  1. A Harmonious Accounting Duo?

    ERIC Educational Resources Information Center

    Schapperle, Robert F.; Hardiman, Patrick F.

    1992-01-01

    Accountants have urged "harmonization" of standards between the Governmental Accounting Standards Board and the Financial Accounting Standards Board, recommending similar reporting of like transactions. However, varying display of similar accounting events does not necessarily indicate disharmony. The potential for problems because of…

  2. The radiosensitizing effect of immunoadjuvant OM-174 requires cooperation between immune and tumor cells through interferon-gamma and inducible nitric oxide synthase

    SciTech Connect

    Ridder, Mark de . E-mail: Mark.De.Ridder@vub.ac.be; Verovski, Valeri N.; Chiavaroli, Carlo; Berge, Dirk L. van den; Monsaert, Christinne; Law, Kalun; Storme, Guy A.

    2006-12-01

    Purpose: To explore whether antitumor immunoadjuvant OM-174 can stimulate immune cells to produce interferon-{gamma} (IFN-{gamma}) and thereby radiosensitize tumor cells. Methods and Materials: Splenocytes from BALB/c mice were stimulated by OM-174 at plasma-achievable concentrations (0.03-3 {mu}g/mL), and afterward analyzed for the expression and secretion of IFN-{gamma} by reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. Stimulated splenocytes were used as a source of IFN-{gamma} to radiosensitize hypoxic EMT-6 tumor cells through the cytokine-inducible isoform of nitric oxide synthase (iNOS). Results: OM-174 activated the production of IFN-{gamma} at high levels that reached 70 ng/mL in normoxia (21% oxygen) and 27 ng/mL in tumor-relevant hypoxia (1% oxygen). This caused up to 2.1-fold radiosensitization of EMT-6 tumor cells, which was associated with the iNOS-mediated production of the radiosensitizing molecule nitric oxide, as confirmed by accumulation of its oxidative metabolite nitrite, Western blot analysis, and reverse transcriptase-polymerase chain reaction. Both iNOS activation and radiosensitization were counteracted by neutralizing antibodies against IFN-{gamma}. The same mechanism of radiosensitization through the IFN-{gamma} secretion pathway was identified for IL-12 + IL-18, which are known to mediate IFN-{gamma} responses. Hypoxia displayed a dual effect on the immune-tumor cell interaction, by downregulating the expression of the IFN-{gamma} gene while upregulating iNOS at transcriptional level. Conclusion: Immunoadjuvant OM-174 is an efficient radiosensitizer of tumor cells through activation of the IFN-{gamma} secretion pathway in immune cells. This finding indicates a rationale for combining immunostimulatory and radiosensitizing strategies and extends the potential therapeutic applications of OM-174.

  3. Radiosensitization of TPGS-emulsified docetaxel-loaded poly(lactic-co-glycolic acid) nanoparticles in CNE-1 and A549 cells.

    PubMed

    Shi, Wei; Yuan, Yin; Chu, Min; Zhao, Shuang; Song, Qingle; Mu, Xiaoqian; Xu, Shuangbing; Zhang, Zhiping; Yang, Kunyu

    2016-03-01

    Docetaxel is among the most effective radiosensitizers. It is widely used as radiosensitizer in many tumors, including head and neck carcinoma. Nevertheless, poor solubility and severe hypersensitivity limit its clinical use and its therapeutic effect remains to be improved. In this study, docetaxel-loaded polymeric nanoparticles were prepared by nanoprecipitation method to be new radiosensitizer with lower side effects and higher efficacy. The physiochemical characteristics of the nanoparticles were studied. Two human tumor cell lines which are resistant to radiotherapy were used in this research. We have compared the radioenhancement efficacy of docetaxel-loaded nanoparticles with docetaxel in A549 and CNE-1 cells. Compared with docetaxel, radiosensitization of docetaxel-loaded nanoparticles was improved significantly (sensitization enhancement ratio in A549 increased 1.24-fold to 1.68-fold when the radiation was applied 2 h after the drug, p < 0.01, sensitization enhancement ratio in CNE-1 increased 1.32-fold to 1.61-fold, p < 0.05). We explored the mechanisms for the radiosensitization efficiency and the difference between docetaxel and docetaxel-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles. The improved radiosensitization efficacy was associated with enhanced G2/M arrest, promoted apoptosis and the role of D-alpha-tocopheryl polyethylene glycol 1000 succinate which will enhance the cell uptake and inhibit the multiple drug resistance. Moreover, the radiosensitization efficacy of docetaxel-loaded nanoparticles was more prominent than docetaxel. In conclusion, tocopheryl polyethylene glycol 1000 succinate-emulsified docetaxel-loaded PLGA nanoparticles were more efficacious and fewer adverse effects were observed than with the commercial docetaxel formulation. Thus, PLGA nanoparticles hold promise as a radiosensitizing agent.

  4. Rigosertib is a more effective radiosensitizer than cisplatin in concurrent chemo-radiation treatment of cervical carcinoma, in vitro and in vivo

    PubMed Central

    Agoni, Lorenzo; Basu, Indranil; Gupta, Seema; Alfieri, Alan; Gambino, Angela; Goldberg, Gary L.; Reddy, E. Premkumar; Guha, Chandan

    2014-01-01

    Summary Rigosertib is a novel anti-mitotic agent that induces selective G2/M arrest in cancer cells. Our study shows that rigosertib, when administered concurrently with radiotherapy, acts as a radiosensitizer with greater efficacy than cisplatin, the standard drug in concurrent chemo-radiotherapy for cervical malignancies. Rigosertib, combined with radiotherapy, appears to be a potential therapeutic agent for the clinical management of cervical carcinoma. Rigosertib as a radiosensitizer for cervical carcinoma PMID:24529717

  5. Modulation of Sonic hedgehog signaling and WW domain containing oxidoreductase WOX1 expression enhances radiosensitivity of human glioblastoma cells.

    PubMed

    Chiang, Ming-Fu; Chen, Hsin-Hong; Chi, Chih-Wen; Sze, Chun-I; Hsu, Ming-Ling; Shieh, Hui-Ru; Lin, Chin-Ping; Tsai, Jo-Ting; Chen, Yu-Jen

    2015-03-01

    WW domain containing oxidoreductase, designated WWOX, FOR or WOX1, is a known pro-apoptotic factor when ectopically expressed in various types of cancer cells, including glioblastoma multiforme (GBM). The activation of sonic hedgehog (Shh) signaling, especially paracrine Shh secretion in response to radiation, is associated with impairing the effective irradiation of cancer cells. Here, we examined the role of Shh signaling and WOX1 overexpression in the radiosensitivity of human GBM cells. Our results showed that ionizing irradiation (IR) increased the cytoplasmic Shh and nuclear Gli-1 content in GBM U373MG and U87MG cells. GBM cells with exogenous Shh treatment exhibited similar results. Pretreatment with Shh peptides protected U373MG and U87MG cells against IR in a dose-dependent manner. Cyclopamine, a Hedgehog/Smoothened (SMO) inhibitor, reversed the protective effect of Shh in U87MG cells. Cyclopamine increased Shh plus IR-induced H2AX, a marker of DNA double-strand breaks, in these cells. To verify the role of Shh signaling in the radiosensitivity of GBM cells, we tested the effect of the Gli family zinc finger 1 (Gli-1) inhibitor zerumbone and found that it could sensitize GBM cells to IR. We next examined the role of WOX1 in radiosensitivity. Overexpression of WOX1 enhanced the radiosensitivity of U87MG (possessing wild type p53 or WTp53) but not U373MG (harboring mutant p53 or MTp53) cells. Pretreatment with Shh peptides protected both WOX1-overexpressed U373MG and U87MG cells against IR and increased the cytoplasmic Shh and nuclear Gli-1 content. Zerumbone enhanced the radiosensitivity of WOX1-overexpressed U373MG and U87MG cells. In conclusion, overexpression of WOX1 preferentially sensitized human GBM cells possessing wild type p53 to radiation therapy. Blocking of Shh signaling may enhance radiosensitivity independently of the expression of p53 and WOX1. The crosstalk between Shh signaling and WOX1 expression in human glioblastoma warrants further

  6. Custom accounts receivable modeling.

    PubMed

    Veazie, J

    1994-04-01

    In hospital and clinic management, accounts are valued as units and handled equally--a $20 account receives the same minimum number of statements as a $20,000 account. Quite often, the sheer number of accounts a hospital or clinic has to handle forces executives to manage accounts by default and failure--accounts mature on an aging track and, if left unpaid by patients, eventually are sent to collections personnel. Of the bad-debt accounts placed with collections agencies, many are misclassified as charity or hardship cases, while others could be collected by hospital or clinic staff with a limited amount of additional effort.

  7. Identification of vitamin B1 metabolism as a tumor-specific radiosensitizing pathway using a high-throughput colony formation screen

    PubMed Central

    Buffa, Francesca M.; Yu, Sheng; Ebner, Daniel V.; Howarth, Alison; Folkes, Lisa K.; Budwal, Balam; Chu, Kwun-Ye; Durrant, Lisa; Muschel, Ruth J.; McKenna, W. Gillies; Higgins, Geoff S.

    2015-01-01

    Colony formation is the gold standard assay for determining reproductive cell death after radiation treatment, since effects on proliferation often do not reflect survival. We have developed a high-throughput radiosensitivity screening method based on clonogenicity and screened a siRNA library against kinases. Thiamine pyrophosphokinase-1 (TPK1), a key component of Vitamin B1/thiamine metabolism, was identified as a target for radiosensitization. TPK1 knockdown caused significant radiosensitization in cancer but not normal tissue cell lines. Other means of blocking this pathway, knockdown of thiamine transporter-1 (THTR1) or treatment with the thiamine analogue pyrithiamine hydrobromide (PyrH) caused significant tumor specific radiosensitization. There was persistent DNA damage in cells irradiated after TPK1 and THTR1 knockdown or PyrH treatment. Thus this screen allowed the identification of thiamine metabolism as a novel radiosensitization target that affects DNA repair. Short-term modulation of thiamine metabolism could be a clinically exploitable strategy to achieve tumor specific radiosensitization. PMID:25788274

  8. Ranking Accounting Authors and Departments in Accounting Education: Different Methodologies--Significantly Different Results

    ERIC Educational Resources Information Center

    Bernardi, Richard A.; Zamojcin, Kimberly A.; Delande, Taylor L.

    2016-01-01

    This research tests whether Holderness Jr., D. K., Myers, N., Summers, S. L., & Wood, D. A. [(2014). "Accounting education research: Ranking institutions and individual scholars." "Issues in Accounting Education," 29(1), 87-115] accounting-education rankings are sensitive to a change in the set of journals used. It provides…

  9. A deficiency in DNA repair and DNA-PKcs expression in the radiosensitive BALB/c mouse

    NASA Technical Reports Server (NTRS)

    Okayasu, R.; Suetomi, K.; Yu, Y.; Silver, A.; Bedford, J. S.; Cox, R.; Ullrich, R. L.

    2000-01-01

    We have studied the efficiency of DNA double strand break (DSB) rejoining in primary cells from mouse strains that show large differences in in vivo radiosensitivity and tumor susceptibility. Cells from radiosensitive, cancer-prone BALB/c mice showed inefficient end joining of gamma ray-induced DSBs as compared with cells from all of the other commonly used strains and F1 hybrids of C57BL/6 and BALB/c mice. The BALB/c repair phenotype was accompanied by a significantly reduced expression level of DNA-PKcs protein as well as a lowered DNA-PK activity level as compared with the other strains. In conjunction with published reports, these data suggest that natural genetic variation in nonhomologous end joining processes may have a significant impact on the in vivo radiation response of mice.

  10. Use of Mitochondria-Specific Dye MKT-077 as a Radiosensitizer to Preoperatively Treat Locally Advanced Breast Cancer

    DTIC Science & Technology

    2007-04-01

    AD_________________ Award Number: W81XWH-05-1-0264 TITLE: Use of Mitochondria-Specific Dye MKT ...From - To) 18 Mar 2006 – 17 Mar 2007 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Use of Mitochondria-Specific Dye MKT -077 as a Radiosensitizer to...is to determine if the rhodacyanine analog dye, MKT -077, can be used to inhibit breast cancer cell oxygen metabolism and raise tumor oxygen levels

  11. Use of Mitochondria-Specific Dye MKT-077 as a Radiosensitizer to Preoperatively Treat Locally Advanced Breast Cancer

    DTIC Science & Technology

    2008-04-01

    AD_________________ Award Number: W81XWH-05-1-0264 TITLE: Use of Mitochondria-Specific Dye MKT ...18 MAR 2005 - 17 MAR 2008 4. TITLE AND SUBTITLE Use of Mitochondria-Specific Dye MKT -077 as a Radiosensitizer to Preoperatively 5a. CONTRACT NUMBER...SUPPLEMENTARY NOTES 14. ABSTRACT The major goal of this project is to determine if the rhodacyanine analog dye, MKT -077, can be used to

  12. SU-E-T-668: Radiosensitizing Effect of Bosutinib On Prostate and Colon Cancers: A Pilot in Vitro Study

    SciTech Connect

    Wang, B; Cvetkovic, D; Chen, L; Ma, C; Wang, C

    2015-06-15

    Purpose: Recently it has been reported that Bosutinib, a clinical kinase inhibitor, can enhance the tumor cell chemosensitivity by overriding DNA damage checkpoints. However, to the best of our knowledge, there is no report on its effect on cell radiosensitivity in the literature. The objective of the present study is to determine whether Bosutinib has the potential to be used as a radiosensitizer for various cancer cell lines. Methods: In this study, we tested 4 cell lines derived from human prostate (LNCaP, PC-3, DU-145) and colon (HT-29) cancers. The cells were seeded into 12-well plates 24 hours prior to the radiation treatments. For each cell line, we designed 4 study groups, namely, the control, Bosutinib, radiotherapy, and radiotherapy+Bosutinib groups. We used 6 MV photon beams from a Siemens Artiste accelerator to deliver 2 Gy dose in one fraction to the cells in the radiotherapy and radiotherapy+Bosutinib groups. Immediately after irradiation, the cells in the radiotherapy+Bosutinib group were treated with Bosutinib (1µM) for 3 hours. The cell survival was evaluated through clonogenic assays. Results: The cell survival rates of the LNCaP, PC-3, DU-145, and HT-29 cells were found to be 21%, 92%, 76%, and 93% for the radiotherapy group; 21%, 69%, 67%, and 81% for the radiotherapy+Bosutinib group; and 103%, 107%, 86%, and 102% for the Bosutinib group, respectively. Although synergetic cell killing was not seen for the LNCaP and DU-145 cell lines in this study, the cell survival data from the clonogenic assay indicated that Bosutinib could enhance the sensitivity of PC-3 and HT-29 cells to radiation treatment. Conclusion: Our preliminary results demonstrated the possibility of Bosutinib as a radiosensitizer for certain prostate and colon cancers, which are resistant to radiotherapy. Further studies are warranted to quantify the radiosensitizing effect of Bosutinib.

  13. The Effects of G2-Phase Enrichment and Checkpoint Abrogation on Low-Dose Hyper-Radiosensitivity

    SciTech Connect

    Krueger, Sarah A.; Wilson, George D.; Piasentin, Evano; Joiner, Michael C.; Marples, Brian

    2010-08-01

    Purpose: An association between low-dose hyper-radiosensitivity (HRS) and the 'early' G2/M checkpoint has been established. An improved molecular understanding of the temporal dynamics of this relationship is needed before clinical translation can be considered. This study was conducted to characterize the dose response of the early G2/M checkpoint and then determine whether low-dose radiation sensitivity could be increased by synchronization or chemical inhibition of the cell cycle. Methods and Materials: Two related cell lines with disparate HRS status were used (MR4 and 3.7 cells). A double-thymidine block technique was developed to enrich the G2-phase population. Clonogenic cell survival, radiation-induced G2-phase cell cycle arrest, and deoxyribonucleic acid double-strand break repair were measured in the presence and absence of inhibitors to G2-phase checkpoint proteins. Results: For MR4 cells, the dose required to overcome the HRS response (approximately 0.2 Gy) corresponded with that needed for the activation of the early G2/M checkpoint. As hypothesized, enriching the number of G2-phase cells in the population resulted in an enhanced HRS response, because a greater proportion of radiation-damaged cells evaded the early G2/M checkpoint and entered mitosis with unrepaired deoxyribonucleic acid double-strand breaks. Likewise, abrogation of the checkpoint by inhibition of Chk1 and Chk2 also increased low-dose radiosensitivity. These effects were not evident in 3.7 cells. Conclusions: The data confirm that HRS is linked to the early G2/M checkpoint through the damage response of G2-phase cells. Low-dose radiosensitivity could be increased by manipulating the transition of radiation-damaged G2-phase cells into mitosis. This provides a rationale for combining low-dose radiation therapy with chemical synchronization techniques to improve increased radiosensitivity.

  14. Silencing Fibronectin Extra Domain A Enhances Radiosensitivity in Nasopharyngeal Carcinomas Involving an FAK/Akt/JNK Pathway

    SciTech Connect

    Ou Juanjuan; Pan Feng; Geng Peiliang; Wei Xing; Xie Ganfeng; Deng Jia; Pang Xueli; Liang Houjie

    2012-03-15

    Purpose: Fibronectin extra domain A (EDA) is known to play important roles in angiogenesis, lymphangiogenesis, and metastasis in malignant tumors. The present study examined the effect of EDA on the radioresistance potential of nasopharyngeal carcinoma (NPC). Methods and Materials: EDA expression levels in blood samples and tumor tissues of NPC patients were tested by enzyme-linked immunosorbent assay and immunohistochemistry. Radiosensitivity was tested by colony survival assay. Apoptosis was determined by flow cytometry. The expressions of EDA, cleaved caspase 9, cleaved caspase 3, cleaved PARP, Bcl-2, and the levels of phosphorylated FAK, Akt, and JNK were measured by Western blot. Xenografts were used to confirm the effect of EDA on radiosensitivity in vivo. Results: EDA levels in blood samples of advanced NPC patients were much higher than those in early-stage patients. In tumor tissues, the positive expressions of EDA in NPC tumor tissues were shown to be correlated with the differentiation degrees of cancer cells and lymph node metastases. Additionally, the expression of EDA is positively correlated with the expression of antiapoptotic gene (Bcl2), but negatively correlated with the expressions of apoptotic genes (cleaved caspase-3, cleaved caspase-9, cleaved PARP). In vitro, EDA-silenced NPC cells CNE-2 shows substantially enhanced radiosensitivity with lower colony survival and more apoptosis in response to radiation. In vivo, EDA-silenced xenografts were more sensitive to radiation. At the molecular level, FAK/Akt/JNK signaling was demonstrated to be inactivated in EDA-silenced CNE-2 cells. Conclusions: EDA strongly affected the radiosensitivity of NPC cells. FAK/Akt/JNK signaling was found to be a potential signaling mediating EDA function.

  15. Enliven Your Classroom with Accounting Rotation Plan.

    ERIC Educational Resources Information Center

    Barrett, Evelyn C.

    1981-01-01

    Recommends a rotation process for teaching accounting. Discusses student goals, selected proper materials (cassette tapes, computer simulation center, journals, and business forms), work stations, how to track student progress, and individual work paces. (CT)

  16. NASA Accountability Report

    NASA Technical Reports Server (NTRS)

    1997-01-01

    NASA is piloting fiscal year (FY) 1997 Accountability Reports, which streamline and upgrade reporting to Congress and the public. The document presents statements by the NASA administrator, and the Chief Financial Officer, followed by an overview of NASA's organizational structure and the planning and budgeting process. The performance of NASA in four strategic enterprises is reviewed: (1) Space Science, (2) Mission to Planet Earth, (3) Human Exploration and Development of Space, and (4) Aeronautics and Space Transportation Technology. Those areas which support the strategic enterprises are also reviewed in a section called Crosscutting Processes. For each of the four enterprises, there is discussion about the long term goals, the short term objectives and the accomplishments during FY 1997. The Crosscutting Processes section reviews issues and accomplishments relating to human resources, procurement, information technology, physical resources, financial management, small and disadvantaged businesses, and policy and plans. Following the discussion about the individual areas is Management's Discussion and Analysis, about NASA's financial statements. This is followed by a report by an independent commercial auditor and the financial statements.

  17. Down-regulation of survivin expression by small interfering RNA induces pancreatic cancer cell apoptosis and enhances its radiosensitivity

    PubMed Central

    Guan, Hai-Tao; Xue, Xing-Huan; Dai, Zhi-Jun; Wang, Xi-Jing; Li, Ang; Qin, Zhao-Yin

    2006-01-01

    AIM: To investigate the inhibitory effect of small interfering RNA (siRNA) on the expression of survivin in pancreatic cancer cell line PC-2 and the role of siRNA in inducing PC-2 cell apoptosis and enhancing its radiosensitivity. METHODS: A siRNA plasmid expression vector against survivin was constructed and transfected into PC-2 cells with LipofectamineTM 2000. The down regulation of survivin expression was detected by semi-quantitive RT-PCR and immunohistochemical SP method and the role of siRNA in inducing PC-2 cell apoptosis and enhancing its radiosensitivity was detected by flow cytometry. RESULTS: The sequence-specific siRNA efficiently and specifically down-regulated the expression of survivin at both mRNA and protein levels. The expression inhibition ratio was 81.25% at mRNA level detected by semi-quantitive RT-PCR and 74.24% at protein level detected by immunohistochemical method. Forty-eight hours after transfection,apoptosis was induced in 7.03% cells by siRNA and in 14.58% cells by siRNA combined with radiation. CONCLUSION: The siRNA plasmid expression vector against survivin can inhibit the expression of survivin in PC-2 cells efficiently and specifically. Inhibiting the expression of survivin can induce apoptosis of PC-2 cells and enhance its radiosensitivity significantly. RNAi against survivin is of potential value in gene therapy of pancreatic cancer. PMID:16718816

  18. Biomarkers of radiosensitivity in a-bomb survivors pregnant at the time of bombings in hiroshima and nagasaki.

    PubMed

    Miles, Edward F; Tatsukawa, Yoshimi; Funamoto, Sachiyo; Kamada, Naoko; Nakashima, Eiji; Kodama, Yoshiaki; Seed, Thomas; Kusonoki, Yoichiro; Nakachi, Kei; Fujiwara, Saeko; Akahoshi, Masazumi; Neriishi, Kazuo

    2011-01-01

    Purpose. There is evidence in the literature of increased maternal radiosensitivity during pregnancy. Materials and Methods. We tested this hypothesis using information from the atomic-bomb survivor cohort, that is, the Adult Health Study database at the Radiation Effects Research Foundation, which contains data from a cohort of women who were pregnant at the time of the bombings of Hiroshima and Nagasaki. Previous evaluation has demonstrated long-term radiation dose-response effects. Results/Conclusions. Data on approximately 250 women were available to assess dose-response rates for serum cholesterol, white blood cell count, erythrocyte sedimentation rate, and serum hemoglobin, and on approximately 85 women for stable chromosome aberrations, glycophorin A locus mutations, and naïve CD4 T-cell counts. Although there is no statistically significant evidence of increased radiosensitivity in pregnant women, the increased slope of the linear trend line in the third trimester with respect to stable chromosome aberrations is suggestive of an increased radiosensitivity.

  19. Lack of a correlation between micronucleus formation and radiosensitivity in established and primary cultures of human tumours.

    PubMed Central

    Villa, R.; Zaffaroni, N.; Gornati, D.; Costa, A.; Silvestrini, R.

    1994-01-01

    The radiation-induced genotoxic damage in three established cell lines and 15 primary cultures of human malignant melanoma and ovarian carcinoma showing different radiosensitivity was tested by the cytokinesis-block micronucleus assay. A dose-related increase in micronucleus frequency was observed in all the cell systems. The mean number of micronuclei per Gy of ionising radiation per binucleated cell was respectively 0.44 +/- 0.0075 and 0.43 +/- 0.04 for M14 and JR8 malignant melanoma cell lines and 0.19 +/- 0.013 for the A2780 ovarian cancer cell line. The number of micronuclei did not rank the cell lines in the same order of radiosensitivity as clonogenic cell survival, which showed a surviving fraction at 2 Gy of 0.38 +/- 0.02 for JR8, 0.34 +/- 0.05 for M14 and 0.22 +/- 0.007 for A2780. As regards primary tumour cultures, no correlation was observed between micronucleus induction and surviving fraction at 2 Gy. In conclusion, the discrepancy we observed between micronucleus formation and cell death raises doubts about the potential of the micronucleus assay as a preclinical means to predict radiosensitivity. Images Figure 1 PMID:7981062

  20. Synthesis, in vitro cytotoxicity and radiosensitizing activity of novel 3-[(2,4-dinitrophenylamino)alkyl] derivatives of 5-fluorouracil.

    PubMed

    Khalaj, Ali; Abdi, Khosrou; Ostad, Seyed Nasser; Khoshayand, Mohammad Reza; Lamei, Navid; Nedaie, Hasan Ali

    2014-02-01

    Previously, it was reported that 3[3-(2,4-dinitrophenylamino)-propyl]-5-fluorouracil 8c unlike its components 5-fluorouracil (5-FU) 6 and 2,4-dinitroaniline 2 in HT-29 cells under aerobic conditions had no cytotoxicity but showed radiosensitizing activity. In this study several analogues of 8c differing in the number of linking methylene groups were prepared and tested for in vitro cytotoxicity and radiosensitizing activity under both aerobic and hypoxic conditions. Tethered compound 8a was prepared in one pot by the reaction of 5-FU 6 with paraformaldehyde and 2,4-dinitroaniline 2 in the presence of the concentrated hydrochloric acid, and compounds 8b-f were prepared by the reaction of N-(bromoalkyl)-2,4-dinitrobenzeneamines 5b-f with 1-(t-butoxycarbonyl)-5-fluorouracil 7 followed by hydrolysis of the protecting group. The cytotoxicity of the tested compounds were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and propidium iodide (PI)-digitonin assays and values of sensitization enhancement ratio (SER) as a measure of the radiosensitizing activity were measured from radiation survival curves in the absence and presence of each sensitizer for 37% survival respectively. Results showed that tethered compounds 8a-f induced time- and concentration-dependent cytotoxicity under hypoxia but had no significant effect under aerobic conditions. These compounds also showed selective and concentration-dependent radiocytotoxicity under hypoxic conditions.

  1. Biomarkers of Radiosensitivity in A-Bomb Survivors Pregnant at the Time of Bombings in Hiroshima and Nagasaki

    DOE PAGES

    Miles, Edward F.; Tatsukawa, Yoshimi; Funamoto, Sachiyo; ...

    2011-01-01

    Purpose . There is evidence in the literature of increased maternal radiosensitivity during pregnancy. Materials and Methods . We tested this hypothesis using information from the atomic-bomb survivor cohort, that is, the Adult Health Study database at the Radiation Effects Research Foundation, which contains data from a cohort of women who were pregnant at the time of the bombings of Hiroshima and Nagasaki. Previous evaluation has demonstrated long-term radiation dose-response effects. Results/Conclusions . Data on approximately 250 women were available to assess dose-response rates for serum cholesterol, white blood cell count, erythrocyte sedimentation rate, and serum hemoglobin, and onmore » approximately 85 women for stable chromosome aberrations, glycophorin A locus mutations, and naïve CD4 T-cell counts. Although there is no statistically significant evidence of increased radiosensitivity in pregnant women, the increased slope of the linear trend line in the third trimester with respect to stable chromosome aberrations is suggestive of an increased radiosensitivity.« less

  2. The transcriptional regulator gene E2 of the Human Papillomavirus (HPV) 16 influences the radiosensitivity of cervical keratinocytes

    PubMed Central

    2012-01-01

    Background Clinical studies have demonstrated that HPV induced tumors constitute a specific subclass of cancer with a better response to radiation treatment. The purpose of this study was to investigate meaning of viral E2-gene for radiosensitivity. Methods W12 cells contain episomal HPV 16 genomes, whereas S12 cells, which derive from the W12 line, contain HPV DNA as integrated copies. Clonogenic survival was analyzed using 96-well in vitro test. Using flow cytometry cell cycle analyses were performed. Expression of pRb and p53 were analyzed using intracellular staining. Results W12 cells (intact E2 gene) showed a lower survival fraction than S12 cells. W12 cells developed a G2/M block 24 h after irradiation with 2 Gy whereas S12 showed no G2/M bloc. After irradiation S12 cells developed polyploidy and pRb-positive cells decreased. W12 cells showed no change of pRb-positive cells. Conclusions Depending on E2 gene status differences in cell cycle regulation might cause radioresistance. The E2/E7/pRb pathway seems to influence HPV-induced radiosensitivity. Our experiments demonstrated an effect of HPV on radiosensitivity of cervical keratinocytes via viral transcription regulator E2 pathway. PMID:23134732

  3. Highly efficient radiosensitization of human glioblastoma and lung cancer cells by a G-quadruplex DNA binding compound

    PubMed Central

    Merle, Patrick; Gueugneau, Marine; Teulade-Fichou, Marie-Paule; Müller-Barthélémy, Mélanie; Amiard, Simon; Chautard, Emmanuel; Guetta, Corinne; Dedieu, Véronique; Communal, Yves; Mergny, Jean-Louis; Gallego, Maria; White, Charles; Verrelle, Pierre; Tchirkov, Andreï

    2015-01-01

    Telomeres are nucleoprotein structures at the end of chromosomes which stabilize and protect them from nucleotidic degradation and end-to-end fusions. The G-rich telomeric single-stranded DNA overhang can adopt a four-stranded G-quadruplex DNA structure (G4). Stabilization of the G4 structure by binding of small molecule ligands enhances radiosensitivity of tumor cells, and this combined treatment represents a novel anticancer approach. We studied the effect of the platinum-derived G4-ligand, Pt-ctpy, in association with radiation on human glioblastoma (SF763 and SF767) and non-small cell lung cancer (A549 and H1299) cells in vitro and in vivo. Treatments with submicromolar concentrations of Pt-ctpy inhibited tumor proliferation in vitro with cell cycle alterations and induction of apoptosis. Non-toxic concentrations of the ligand were then combined with ionizing radiation. Pt-ctpy radiosensitized all cell lines with dose-enhancement factors between 1.32 and 1.77. The combined treatment led to increased DNA breaks. Furthermore, a significant radiosensitizing effect of Pt-ctpy in mice xenografted with glioblastoma SF763 cells was shown by delayed tumor growth and improved survival. Pt-ctpy can act in synergy with radiation for efficient killing of cancer cells at concentrations at which it has no obvious toxicity per se, opening perspectives for future therapeutic applications. PMID:26542881

  4. LMAL Accounting Office 1936

    NASA Technical Reports Server (NTRS)

    1936-01-01

    Accounting Office: The Langley Memorial Aeronautical Laboratory's accounting office, 1936, with photographs of the Wright brothers on the wall. Although the Lab was named after Samuel P. Langley, most of the NACA staff held the Wrights as their heroes.

  5. Changing Lives through Lifelong Learning Accounts

    ERIC Educational Resources Information Center

    Council for Adult and Experiential Learning (NJ1), 2007

    2007-01-01

    As conceived by the Council for Adult and Experiential Learning (CAEL), Lifelong Learning Accounts (LiLAs[SM]) are employer-matched, portable individual accounts used to finance employee education and training. They provide employees with an affordable means of upgrading their skills and knowledge, while helping to meet the needs of employers and…

  6. Intelligent Accountability in Education

    ERIC Educational Resources Information Center

    O'Neill, Onora

    2013-01-01

    Systems of accountability are "second order" ways of using evidence of the standard to which "first order" tasks are carried out for a great variety of purposes. However, more accountability is not always better, and processes of holding to account can impose high costs without securing substantial benefits. At their worst,…

  7. Accounting Education in Crisis

    ERIC Educational Resources Information Center

    Turner, Karen F.; Reed, Ronald O.; Greiman, Janel

    2011-01-01

    Almost on a daily basis new accounting rules and laws are put into use, creating information that must be known and learned by the accounting faculty and then introduced to and understood by the accounting student. Even with the 150 hours of education now required for CPA licensure, it is impossible to teach and learn all there is to learn. Over…

  8. Automated Accounting. Instructor Guide.

    ERIC Educational Resources Information Center

    Moses, Duane R.

    This curriculum guide was developed to assist business instructors using Dac Easy Accounting College Edition Version 2.0 software in their accounting programs. The module consists of four units containing assignment sheets and job sheets designed to enable students to master competencies identified in the area of automated accounting. The first…

  9. Accounting & Computing Curriculum Guide.

    ERIC Educational Resources Information Center

    Avani, Nathan T.; And Others

    This curriculum guide consists of materials for use in teaching a competency-based accounting and computing course that is designed to prepare students for employability in the following occupational areas: inventory control clerk, invoice clerk, payroll clerk, traffic clerk, general ledger bookkeeper, accounting clerk, account information clerk,…

  10. The Accounting Capstone Problem

    ERIC Educational Resources Information Center

    Elrod, Henry; Norris, J. T.

    2012-01-01

    Capstone courses in accounting programs bring students experiences integrating across the curriculum (University of Washington, 2005) and offer unique (Sanyal, 2003) and transformative experiences (Sill, Harward, & Cooper, 2009). Students take many accounting courses without preparing complete sets of financial statements. Accountants not only…

  11. Electrotransfer of plasmid DNA radiosensitizes B16F10 tumors through activation of immune response

    PubMed Central

    Savarin, Monika; Kamensek, Urska; Cemazar, Maja; Heller, Richard

    2017-01-01

    Abstract Background Tumor irradiation combined with adjuvant treatments, either vascular targeted or immunomodulatory, is under intense investigation. Gene electrotransfer of therapeutic genes is one of these approaches. The aim of this study was to determine, whether gene electrotransfer of plasmid encoding shRNA for silencing endoglin, with vascular targeted effectiveness, can radiosensitize melanoma B16F10 tumors. Materials and methods The murine melanoma B16F10 tumors, growing on the back of C57Bl/6 mice, were treated by triple gene electrotransfer and irradiation. The antitumor effect was evaluated by determination of tumor growth delay and proportion of tumor free mice. Furthermore, histological analysis of tumors (necrosis, apoptosis, proliferation, vascularization, presence of hypoxia and infiltration of immune cells,) was used to evaluate the therapeutic mechanisms. Results Gene electrotransfer of plasmid silencing endoglin predominantly indicated vascular targeted effects of the therapy, since significant tumor growth delay and 44% of tumor free mice were obtained. In addition, irradiation had minor effects on radioresistant melanoma, with 11% of mice tumor free. The combined treatment resulted in excellent effectiveness with 88% of mice tumor free, with more than half resistant to secondary tumor challenge, which was observed also with the plasmid devoid of the therapeutic gene. Histological analysis of tumors in the combined treatment group, demonstrated similar mode of action of the gene electrotransfer of plasmid encoding shRNA for silencing endoglin and devoid of it, both through the induction of an immune response. Conclusions The results of this study indicate that irradiation can in radioresistant melanoma tumors, by release of tumor associated antigens, serve as activator of the immune response, besides directly affecting tumor cells and vasculature. The primed antitumor immune response can be further boosted by gene electrotransfer of plasmid

  12. Preclinical Evaluation of Genexol-PM, a Nanoparticle Formulation of Paclitaxel, as a Novel Radiosensitizer for the Treatment of Non-Small Cell Lung Cancer

    SciTech Connect

    Werner, Michael E.; Cummings, Natalie D.; Sethi, Manish; Wang, Edina C.; Sukumar, Rohit; Moore, Dominic T.; Wang, Andrew Z.

    2013-07-01

    Purpose: A key research objective in radiation oncology is to identify agents that can improve chemoradiation therapy. Nanoparticle (NP) chemotherapeutics possess several properties, such as preferential accumulation in tumors, that are uniquely suited for chemoradiation therapy. To facilitate the clinical translation of NP chemotherapeutics in chemoradiation therapy, we conducted preclinical evaluation of Genexol-PM, the only clinically approved NP chemotherapeutic with a controlled drug release profile, as a radiosensitizer using non-small cell lung cancer (NSCLC) as a model disease. Methods and Materials: The physical characteristics and drug release profile of Genexol-PM were characterized. Genexol-PM's efficacy as a radiosensitizer was evaluated in vitro using NSCLC cell lines and in vivo using mouse xenograft models of NSCLC. Paclitaxel dose to normal lung and liver after Genexol-PM administration were quantified and compared with that after Taxol administration. Results: Genexol-PM has a size of 23.91 ± 0.41 nm and surface charge of −8.1 ± 3.1 mV. It releases paclitaxel in a controlled release profile. In vitro evaluation of Genexol-PM as a radiosensitizer showed it is an effective radiosensitizer and is more effective than Taxol, its small molecule counterpart, at the half maximal inhibitory concentration. In vivo study of Genexol-PM as a radiosensitizer demonstrated that it is more effective as a radiosensitizer than Taxol. We also found that Genexol-PM leads to lower paclitaxel exposure to normal lung tissue than Taxol at 6 hours postadministration. Conclusions: We have demonstrated that Genexol-PM is more effective than Taxol as a radiosensitizer in the preclinical setting and holds high potential for clinical translation. Our data support the clinical evaluation of Genexol-PM in chemoradiation therapy for NSCLC.

  13. Celecoxib Induced Tumor Cell Radiosensitization by Inhibiting Radiation Induced Nuclear EGFR Transport and DNA-Repair: A COX-2 Independent Mechanism

    SciTech Connect

    Dittmann, Klaus H. Mayer, Claus; Ohneseit, Petra A.; Raju, Uma; Andratschke, Nickolaus H.; Milas, Luka; Rodemann, H. Peter

    2008-01-01

    Purpose: The purpose of the study was to elucidate the molecular mechanisms mediating radiosensitization of human tumor cells by the selective cyclooxygenase (COX)-2 inhibitor celecoxib. Methods and Materials: Experiments were performed using bronchial carcinoma cells A549, transformed fibroblasts HH4dd, the FaDu head-and-neck tumor cells, the colon carcinoma cells HCT116, and normal fibroblasts HSF7. Effects of celecoxib treatment were assessed by clonogenic cell survival, Western analysis, and quantification of residual DNA damage by {gamma}H{sub 2}AX foci assay. Results: Celecoxib treatment resulted in a pronounced radiosensitization of A549, HCT116, and HSF7 cells, whereas FaDu and HH4dd cells were not radiosensitized. The observed radiosensitization could neither be correlated with basal COX-2 expression pattern nor with basal production of prostaglandin E2, but was depended on the ability of celecoxib to inhibit basal and radiation-induced nuclear transport of epidermal growth factor receptor (EGFR). The nuclear EGFR transport was strongly inhibited in A549-, HSF7-, and COX-2-deficient HCT116 cells, which were radiosensitized, but not in FaDu and HH4dd cells, which resisted celecoxib-induced radiosensitization. Celecoxib inhibited radiation-induced DNA-PK activation in A549, HSF7, and HCT116 cells, but not in FaDu and HH4dd cells. Consequentially, celecoxib increased residual {gamma}H2AX foci after irradiation, demonstrating that inhibition of DNA repair has occurred in responsive A549, HCT116, and HSF7 cells only. Conclusions: Celecoxib enhanced radiosensitivity by inhibition of EGFR-mediated mechanisms of radioresistance, a signaling that was independent of COX-2 activity. This novel observation may have therapeutic implications such that COX-2 inhibitors may improve therapeutic efficacy of radiation even in patients whose tumor radioresistance is not dependent on COX-2.

  14. The potential value of the neutral comet assay and the expression of genes associated with DNA damage in assessing the radiosensitivity of tumor cells.

    PubMed

    Jayakumar, Sundarraj; Bhilwade, Hari N; Pandey, Badri N; Sandur, Santosh K; Chaubey, Ramesh C

    2012-10-09

    The assessment of tumor radiosensitivity would be particularly useful in optimizing the radiation dose during radiotherapy. Therefore, the degree of correlation between radiation-induced DNA damage, as measured by the alkaline and the neutral comet assays, and the clonogenic survival of different human tumor cells was studied. Further, tumor radiosensitivity was compared with the expression of genes associated with the cellular response to radiation damage. Five different human tumor cell lines were chosen and the radiosensitivity of these cells was established by clonogenic assay. Alkaline and neutral comet assays were performed in γ-irradiated cells (2-8Gy; either acute or fractionated). Quantitative PCR was performed to evaluate the expression of DNA damage response genes in control and irradiated cells. The relative radiosensitivity of the cell lines assessed by the extent of DNA damage (neutral comet assay) immediately after irradiation (4Gy or 6Gy) was in agreement with radiosensitivity pattern obtained by the clonogenic assay. The survival fraction of irradiated cells showed a better correlation with the magnitude of DNA damage measured by the neutral comet assay (r=-0.9; P<0.05; 6Gy) than evaluated by alkaline comet assay (r=-0.73; P<0.05; 6Gy). Further, a significant correlation between the clonogenic survival and DNA damage was observed in cells exposed to fractionated doses of radiation. Of 15 genes investigated in the gene expression study, HSP70, KU80 and RAD51 all showed significant positive correlations (r=0.9; P<0.05) with tumor radiosensitivity. Our study clearly demonstrated that the neutral comet assay was better than alkaline comet assay for assessment of radiosensitivities of tumor cells after acute or fractionated doses of irradiation.

  15. Unit days in accounts receivable: a management tool.

    PubMed

    Davis, J L

    1984-10-01

    The importance and usefulness of the statistic "Days in accounts receivable" are well known among patient accounts managers. The same principles that apply to that well-known statistic may also be effectively applied to a single unit within any patient accounting department. With the calculation of a unit days in accounts receivable, the same evaluation and measurements of efficiency may be applied to individual files and patient accounts representatives. The results allow individual employees participation in the same measurable goals and objectives as are applied to the overall operation of the department, as well as supplying the patient accounts manager an additional valuable tool in analyzing total accounts receivable.

  16. Ethical accountability in the cyberspace

    SciTech Connect

    Nance, K.L.; Strohmaier, M.

    1994-12-31

    Conformance with ethical behavior consists of adherence to the standards of conduct for any given group. When standards are not formalized, there can exist ethical disparity from which many diverse problems can result. These problems are especially evident in the cyberspace. Within the cyberspace, the {open_quote}given group{close_quote} is culturally and ethnically diverse. As such, it $8 difficult to hold the individuals to a nonformalized set of standards. Several important issues need to be addressed in order to balance each individual`s dual needs for freedom of expression and protection in the cyberspace. These issues include development of formalized standards, a general protocol for cross- cultural interaction, and ethical accountability.

  17. Health savings accounts and health reimbursement arrangements: assets, account balances, and rollovers, 2006-2010.

    PubMed

    Fronstin, Paul

    2011-01-01

    ASSET LEVELS GROWING: In 2010, there was $7.7 billion in health savings accounts (HSAs) and health reimbursement arrangements (HRAs), spread across 5.7 million accounts. This is up from 2006, when there were 1.2 million accounts with $835.4 million in assets, and 2009, when 5 million accounts held $7.1 billion in assets. AFTER LEVELING OFF, AVERAGE ACCOUNT BALANCE DROPS SLIGHTLY: Increases in average account balances leveled off in 2008 and 2009, and fell slightly in 2010. In 2006, account balances averaged $696. They increased to $1,320 in 2007, a 90 percent increase. Account balances averaged $1,356 in 2008 and $1,419 in 2009, 3 percent and 5 percent increases, respectively. In 2010, average account balances fell to $1,355, down 4.5 percent from the previous year. AVERAGE ROLLOVER DECLINES, WHILE TOTAL ROLLOVERS INCREASE: Despite a decline in the average rollover amount in 2010, total assets being rolled over have been increasing. $4.2 billion was rolled over in 2010, up from $4 billion in 2009. The average rollover increased from $592 in 2006 to $1,295 in 2009, and fell to $1,029 in 2010. The percentage of individuals without a rollover decreased from 23 percent in 2006 to 10 percent in 2009 and increased slightly to 13 percent in 2010. HEALTHY BEHAVIOR MEANS HIGHER ACCOUNT BALANCES AND HIGHER ROLLOVERS: Individuals who exercised, those who did not smoke, and those who were not obese had higher account balances and higher rollovers than those with less healthy behaviors. It was also found that individuals who used cost or quality information had higher account balances and higher rollovers compared with those who did not use such information. However, no relationship was found between either account balance or rollover amounts and various cost-conscious behaviors such as checking pricing before getting services or asking for generic drugs instead of brand names, among other things. DIFFERENCES IN ACCOUNT BALANCES: Men have higher account balances than women

  18. Individual Education.

    ERIC Educational Resources Information Center

    Corsini, Raymond

    1981-01-01

    Paper presented at the 66th Convention of the International Association of Pupil Personnel Workers, October 20, 1980, Baltimore, Maryland, describes individual education based on the principles of Alfred Adler. Defines six advantages of individual education, emphasizing student responsibility, mutual respect, and allowing students to progress at…

  19. Evaluation of Severe Combined Immunodeficiency and Combined Immunodeficiency Pediatric Patients on the Basis of Cellular Radiosensitivity

    PubMed Central

    Lobachevsky, Pavel; Woodbine, Lisa; Hsiao, Kuang-Chih; Choo, Sharon; Fraser, Chris; Gray, Paul; Smith, Jai; Best, Nickala; Munforte, Laura; Korneeva, Elena; Martin, Roger F.; Jeggo, Penny A.; Martin, Olga A.

    2016-01-01

    Pediatric patients with severe or nonsevere combined immunodeficiency have increased susceptibility to severe, life-threatening infections and, without hematopoietic stem cell transplantation, may fail to thrive. A subset of these patients have the radiosensitive (RS) phenotype, which may necessitate conditioning before hematopoietic stem cell transplantation, and this conditioning includes radiomimetic drugs, which may significantly affect treatment response. To provide statistical criteria for classifying cellular response to ionizing radiation as the measure of functional RS screening, we analyzed the repair capacity and survival of ex vivo irradiated primary skin fibroblasts from five dysmorphic and/or developmentally delayed pediatric patients with severe combined immunodeficiency and combined immunodeficiency. We developed a mathematical framework for the analysis of γ histone 2A isoform X foci kinetics to quantitate DNA-repair capacity, thus establishing crucial criteria for identifying RS. The results, presented in a diagram showing each patient as a point in a 2D RS map, were in agreement with findings from the assessment of cellular RS by clonogenic survival and from the genetic analysis of factors involved in the nonhomologous end-joining repair pathway. We provide recommendations for incorporating into clinical practice the functional assays and genetic analysis used for establishing RS status before conditioning. This knowledge would enable the selection of the most appropriate treatment regimen, reducing the risk for severe therapy-related adverse effects. PMID:26151233

  20. Radiosensitization of human breast cancer cells to ultraviolet light by 5-fluorouracil

    PubMed Central

    SASAKI, KAZUHITO; TSUNO, NELSON H.; SUNAMI, EIJI; KAWAI, KAZUSHIGE; SHUNO, YASUTAKA; HONGO, KUMIKO; HIYOSHI, MASAYA; KANEKO, MANABU; MURONO, KOJI; TADA, NORIKO; NIREI, TAKAKO; KITAYAMA, JOJI; TAKAHASHI, KOKI; NAGAWA, HIROKAZU

    2011-01-01

    Ultraviolet light B (UVB) phototherapy is widely used to treat dermatological diseases and therefore may be a potential optional strategy in the treatment of a skin lesion infiltrated by a malignant tumor. Currently, little is known regarding the effect of UVB phototherapy on human breast cancer cells. The present study aimed to investigate the effect of UVB phototherapy, as well as the potential effect of 5-fluorouracil (5-FU), the first-line anticancer drug for breast cancer, on radiosensitizing MCF-7 human breast cancer cells, in an attempt to develop new therapeutic strategies for the treatment of locoregional recurrence of breast cancer. MCF-7 cells were incubated in the presence of 5-FU for 48 h, and UVB irradiation at 750 mJ/cm2 was administered in the midterm of 5-FU treatment. The viability of MCF-7 cells was analyzed by the trypan blue staining method. Apoptosis was quantified by flow cytometry and Hoechst 33258 staining. The cell cycle was evaluated by flow cytometry after the staining of cells with propidium iodide. The combination treatment of 5-FU and UVB resulted in a strong potentiation of the inhibitory effect of MCF-7 cell growth, dependent on the intra-S phase cell cycle arrest and induction of apoptosis, when compared to treatment with 5-FU or UVB alone. In conclusion, 5-FU sensitized human breast cancer cells to UVB phototherapy, and this combination therapy is an effective and promising strategy for the treatment of breast cancer, particularly for locoregional recurrence. PMID:22866105

  1. Abnormal clinical pharmacokinetics of the developmental radiosensitizers pimonidazole (Ro 03-8799) and etanidazole (SR 2508)

    SciTech Connect

    Maughan, T.S.; Newman, H.F.; Bleehen, N.M.; Ward, R.; Workman, P. )

    1990-05-01

    The hypoxic cell radiosensitizers Ro 03-8799 (pimonidazole) and SR 2508 (etanidazole) are under evaluation as single agents (Phase III) and in combination (Phase I). Ro 03-8799 produces an acute, transient central nervous system syndrome, whereas SR 2508 causes cumulative, peripheral neurotoxicity; both effects are dose-limiting. Pharmacokinetic studies have shown the importance of area under the plasma drug concentration versus time curve (AUC) in predicting the risk of peripheral neuropathy. Most patients have very similar pharmacokinetic parameters. This study reports 2/25 patients receiving 0.75 g/m2 Ro 03-8799 plus 2.0 g/m2 SR 2508 who showed significant discrepancies in drug handling. One patient exhibited a markedly elevated AUC and prolonged t1/2 beta for SR 2508 and this was associated with an unusually rapid onset of peripheral neuropathy. A second patient showed normal handling of SR 2508 but prolonged values for both t1/2 alpha and t1/2 beta for Ro 03-8799 and unusually low levels of its N-oxide metabolite. In addition a low peak Ro 03-8799 concentration combined with a very high volume of distribution was found in this patient, leading to a normal AUC value and toxicity profile. Both patients exhibited a relatively low creatinine clearance. The mechanisms which may underlie these findings are discussed, and the importance of pharmacokinetic monitoring in the use of these agents is emphasized.

  2. Differential in radiosensitizing potency of enantiomers of the fatty acid synthase inhibitor C75.

    PubMed

    Rae, Colin; Babich, John W; Mairs, Robert J

    2017-01-01

    The elevated activity of fatty acid synthase has been reported in a number of cancer types. Inhibition of this enzyme has been demonstrated to induce cancer cell death and reduce tumor growth. In addition, the fatty acid synthase inhibitor drug C75 has been reported to synergistically enhance the cancer-killing ability of ionizing radiation. However, clinical use of C75 has been limited due to its producing weight loss, believed to be caused by alterations in the activity of carnitine palmitoyltransferase-1. C75 is administered in the form of a racemic mixture of (-) and (+) enantiomers that may differ in their regulation of fatty acid synthase and carnitine palmitoyltransferase-1. Therefore, we assessed the relative cancer-killing potency of different enantiomeric forms of C75 in prostate cancer cells. These results suggest that (-)-C75 is the more cytotoxic enantiomer and has greater radiosensitizing capacity than (+)-C75. These observations will stimulate the development of fatty acid synthase inhibitors that are selective for cancer cells and enhance the tumor-killing activity of ionizing radiation, while minimizing weight loss in cancer patients.

  3. Activating Akt1 mutations alter DNA double strand break repair and radiosensitivity.

    PubMed

    Oeck, S; Al-Refae, K; Riffkin, H; Wiel, G; Handrick, R; Klein, D; Iliakis, G; Jendrossek, V

    2017-02-17

    The survival kinase Akt has clinical relevance to radioresistance. However, its contributions to the DNA damage response, DNA double strand break (DSB) repair and apoptosis remain poorly defined and often contradictory. We used a genetic approach to explore the consequences of genetic alterations of Akt1 for the cellular radiation response. While two activation-associated mutants with prominent nuclear access, the phospho-mimicking Akt1-TDSD and the clinically relevant PH-domain mutation Akt1-E17K, accelerated DSB repair and improved survival of irradiated Tramp-C1 murine prostate cancer cells and Akt1-knockout murine embryonic fibroblasts in vitro, the classical constitutively active membrane-targeted myrAkt1 mutant had the opposite effects. Interestingly, DNA-PKcs directly phosphorylated Akt1 at S473 in an in vitro kinase assay but not vice-versa. Pharmacological inhibition of DNA-PKcs or Akt restored radiosensitivity in tumour cells expressing Akt1-E17K or Akt1-TDSD. In conclusion, Akt1-mediated radioresistance depends on its activation state and nuclear localization and is accessible to pharmacologic inhibition.

  4. Mannose Phosphate Isomerase Regulates Fibroblast Growth Factor Receptor Family Signaling and Glioma Radiosensitivity

    PubMed Central

    Cazet, Aurélie; Charest, Jonathan; Bennett, Daniel C.; Sambrooks, Cecilia Lopez; Contessa, Joseph N.

    2014-01-01

    Asparagine-linked glycosylation is an endoplasmic reticulum co- and post- translational modification that enables the transit and function of receptor tyrosine kinase (RTK) glycoproteins. To gain insight into the regulatory role of glycosylation enzymes on RTK function, we investigated shRNA and siRNA knockdown of mannose phosphate isomerase (MPI), an enzyme required for mature glycan precursor biosynthesis. Loss of MPI activity reduced phosphorylation of FGFR family receptors in U-251 and SKMG-3 malignant glioma cell lines and also resulted in significant decreases in FRS2, Akt, and MAPK signaling. However, MPI knockdown did not affect ligand-induced activation or signaling of EGFR or MET RTKs, suggesting that FGFRs are more susceptible to MPI inhibition. The reductions in FGFR signaling were not caused by loss of FGF ligands or receptors, but instead were caused by interference with receptor dimerization. Investigations into the cellular consequences of MPI knockdown showed that cellular programs driven by FGFR signaling, and integral to the clinical progression of malignant glioma, were impaired. In addition to a blockade of cellular migration, MPI knockdown also significantly reduced glioma cell clonogenic survival following ionizing radiation. Therefore our results suggest that targeted inhibition of enzymes required for cell surface receptor glycosylation can be manipulated to produce discrete and limited consequences for critical client glycoproteins expressed by tumor cells. Furthermore, this work identifies MPI as a potential enzymatic target for disrupting cell surface receptor-dependent survival signaling and as a novel approach for therapeutic radiosensitization. PMID:25314669

  5. miR-25 modulates NSCLC cell radio-sensitivity through directly inhibiting BTG2 expression

    SciTech Connect

    He, Zhiwei Liu, Yi Xiao, Bing Qian, Xiaosen

    2015-02-13

    A large proportion of the NSCLC patients were insensitive to radiotherapy, but the exact mechanism is still unclear. This study explored the role of miR-25 in regulating sensitivity of NSCLC cells to ionizing radiation (IR) and its downstream targets. Based on measurement in tumor samples from NSCLC patients, this study found that miR-25 expression is upregulated in both NSCLC and radio-resistant NSCLC patients compared the healthy and radio-sensitive controls. In addition, BTG expression was found negatively correlated with miR-25a expression in the both tissues and cells. By applying luciferase reporter assay, we verified two putative binding sites between miR-25 and BTG2. Therefore, BTG2 is a directly target of miR-25 in NSCLC cancer. By applying loss-and-gain function analysis in NSCLC cell lines, we demonstrated that miR-25-BTG2 axis could directly regulated BTG2 expression and affect radiotherapy sensitivity of NSCLC cells. - Highlights: • miR-25 is upregulated, while BTG2 is downregulated in radioresistant NSCLC patients. • miR-25 modulates sensitivity to radiation induced apoptosis. • miR-25 directly targets BTG2 and suppresses its expression. • miR-25 modulates sensitivity to radiotherapy through inhibiting BTG2 expression.

  6. Radiosensitivity of human natural killer cells: Binding and cytotoxic activities of natural killer cell subsets

    SciTech Connect

    Rana, R.; Vitale, M.; Mazzotti, G.; Manzoli, L.; Papa, S. )

    1990-10-01

    The sensitivity of human natural killer (NK) cell activities (both binding and killing) after exposure of peripheral blood mononuclear cells to different doses of gamma radiation was studied. A panel of monoclonal antibodies was used to identify the NK and T-lymphocyte subsets and to evaluate their radiosensitivity. Peripheral blood mononuclear cells were irradiated with low (2-6 Gy) and high (10-30 Gy) doses and NK cell binding and cytotoxic activity against K562 target cells were studied after 3 h and 48 h in culture. The primary damage to NK cell activity was identified at the postbinding level and affected mainly the lytic machinery. After 48 h culture postirradiation, an overall depression of cytotoxic activity was observed, but ionizing radiation produced either a selection of the more cytotoxic NK cell subsets, which therefore might be considered more resistant to radiation damage than the less cytotoxic NK cells, or a long-term stimulation of cytotoxic activity in surviving cells.

  7. Cytogenetic characterization of low-dose hyper-radiosensitivity in Cobalt-60 irradiated human lymphoblastoid cells.

    PubMed

    Joshi, Gnanada S; Joiner, Michael C; Tucker, James D

    2014-12-01

    The dose-effect relationships of cells exposed to ionizing radiation are frequently described by linear quadratic (LQ) models over an extended dose range. However, many mammalian cell lines, when acutely irradiated in G2 at doses ≤0.3Gy, show hyper-radiosensitivity (HRS) as measured by reduced clonogenic cell survival, thereby indicating greater cell lethality than is predicted by extrapolation from high-dose responses. We therefore hypothesized that the cytogenetic response in G2 cells to low doses would also be steeper than predicted by LQ extrapolation from high doses. We tested our hypothesis by exposing four normal human lymphoblastoid cell lines to 0-400cGy of Cobalt-60 gamma radiation. The cytokinesis block micronucleus assay was used to determine the frequencies of micronuclei and nucleoplasmic bridges. To characterize the dependence of the cytogenetic damage on dose, univariate and multivariate regression analyses were used to compare the responses in the low- (HRS) and high-dose response regions. Our data indicate that the slope of the response for all four cell lines at ≤20cGy during G2 is greater than predicted by an LQ extrapolation from the high-dose responses for both micronuclei and bridges. These results suggest that the biological consequences of low-dose exposures could be underestimated and may not provide accurate risk assessments following such exposures.

  8. Betulinyl Sulfamates as Anticancer Agents and Radiosensitizers in Human Breast Cancer Cells

    PubMed Central

    Bache, Matthias; Münch, Christin; Güttler, Antje; Wichmann, Henri; Theuerkorn, Katharina; Emmerich, Daniel; Paschke, Reinhard; Vordermark, Dirk

    2015-01-01

    Betulinic acid (BA), a natural compound of birch bark, is cytotoxic for many tumors. Recently, a betulinyl sulfamate was described that inhibits carbonic anhydrases (CA), such as CAIX, an attractive target for tumor-selective therapy strategies in hypoxic cancer cells. Data on combined CAIX inhibition with radiotherapy are rare. In the human breast cancer cell lines MDA-MB231 and MCF7, the effects of BA and betulinyl sulfamates on cellular and radiobiological behavior under normoxia and hypoxia were evaluated. The two most effective betulinyl sulfamates CAI 1 and CAI 3 demonstrated a 1.8–2.8-fold higher cytotoxicity than BA under normoxia in breast cancer cells, with IC50 values between 11.1 and 18.1 µM. BA exhibits its strongest cytotoxicity with IC50 values of 8.2 and 16.4 µM under hypoxia. All three substances show a dose-dependent increase in apoptosis, inhibition of migration, and inhibition of hypoxia-induced gene expression. In combination with irradiation, betulinyl sulfamates act as radiosensitizers, with DMF10 values of 1.47 (CAI 1) and 1.75 (CAI 3) under hypoxia in MDA-MB231 cells. BA showed additive effects in combination with irradiation. Taken together; our results suggest that BA and betulinyl sulfamates seem to be attractive substances to combine with radiotherapy; particularly for hypoxic breast cancer. PMID:26540049

  9. Activating Akt1 mutations alter DNA double strand break repair and radiosensitivity

    PubMed Central

    Oeck, S.; Al-Refae, K.; Riffkin, H.; Wiel, G.; Handrick, R.; Klein, D.; Iliakis, G.; Jendrossek, V.

    2017-01-01

    The survival kinase Akt has clinical relevance to radioresistance. However, its contributions to the DNA damage response, DNA double strand break (DSB) repair and apoptosis remain poorly defined and often contradictory. We used a genetic approach to explore the consequences of genetic alterations of Akt1 for the cellular radiation response. While two activation-associated mutants with prominent nuclear access, the phospho-mimicking Akt1-TDSD and the clinically relevant PH-domain mutation Akt1-E17K, accelerated DSB repair and improved survival of irradiated Tramp-C1 murine prostate cancer cells and Akt1-knockout murine embryonic fibroblasts in vitro, the classical constitutively active membrane-targeted myrAkt1 mutant had the opposite effects. Interestingly, DNA-PKcs directly phosphorylated Akt1 at S473 in an in vitro kinase assay but not vice-versa. Pharmacological inhibition of DNA-PKcs or Akt restored radiosensitivity in tumour cells expressing Akt1-E17K or Akt1-TDSD. In conclusion, Akt1-mediated radioresistance depends on its activation state and nuclear localization and is accessible to pharmacologic inhibition. PMID:28209968

  10. Radiosensitizing effect of gold nanoparticles in carbon ion irradiation of human cervical cancer cells

    SciTech Connect

    Kaur, Harminder; Avasthi, D. K.; Pujari, Geetanjali; Sarma, Asitikantha

    2013-07-18

    Noble metal nanoparticles have received considerable attention in biotechnology for their role in bio sensing due to surface plasmon resonance, medical diagnostics due to better imaging contrast and therapy. The radiosensitization effect of gold nanoparticles (AuNP) has been gaining popularity in radiation therapy of cancer cells. The better depth dose profile of energetic ion beam proves its superiority over gamma radiation for fighting against cancer. In the present work, the glucose capped gold nanoparticles (Glu-AuNP) were synthesised and internalized in the HeLa cells. Transmission electron microscopic analysis of ultrathin sections of Glu-AuNP treated HeLa cells confirmed the internalization of Glu-AuNPs. Control HeLa cells and Glu-AuNp treated HeLa cells were irradiated at different doses of 62 MeV 12C ion beam (LET - 290keV/{mu}m) at BIO beam line of using 15UD Pelletron accelerator at Inter University Accelerator Centre, New Delhi, India. The survival fraction was assessed by colony forming assay which revealed that the dose of carbon ion for 90% cell killing in Glu-AuNP treated HeLa cells and control HeLa cells are 2.3 and 3.2 Gy respectively. This observation shows {approx} 28% reduction of {sup 12}C{sup 6+} ion dose for Glu-AuNP treated HeLa cells as compared to control HeLa cells.

  11. Differential in radiosensitizing potency of enantiomers of the fatty acid synthase inhibitor C75

    PubMed Central

    Babich, John W.; Mairs, Robert J.

    2016-01-01

    Abstract The elevated activity of fatty acid synthase has been reported in a number of cancer types. Inhibition of this enzyme has been demonstrated to induce cancer cell death and reduce tumor growth. In addition, the fatty acid synthase inhibitor drug C75 has been reported to synergistically enhance the cancer‐killing ability of ionizing radiation. However, clinical use of C75 has been limited due to its producing weight loss, believed to be caused by alterations in the activity of carnitine palmitoyltransferase‐1. C75 is administered in the form of a racemic mixture of (−) and (+) enantiomers that may differ in their regulation of fatty acid synthase and carnitine palmitoyltransferase‐1. Therefore, we assessed the relative cancer‐killing potency of different enantiomeric forms of C75 in prostate cancer cells. These results suggest that (−)‐C75 is the more cytotoxic enantiomer and has greater radiosensitizing capacity than (+)‐C75. These observations will stimulate the development of fatty acid synthase inhibitors that are selective for cancer cells and enhance the tumor‐killing activity of ionizing radiation, while minimizing weight loss in cancer patients. PMID:27901292

  12. Towards novel radiosensitizing agents: the role of cytosolic PLA2α in combined modality cancer therapy

    PubMed Central

    Craft, Jeffrey M; Hallahan, Dennis

    2012-01-01

    The radioresistant nature of some tumors serves as an obstacle to curative therapy for several poor-prognosis malignancies. The radiosensitivity of a cancer is dependent not only on the intrinsic ability of tumor cells to recover from radiation-induced damage, but also the ability of stromal elements (e.g., vasculature) in the tumor microenvironment to survive and continue proliferating in the face of ionizing radiation. In this regard, it is important to understand the initial events activating radiation-induced signal transduction pathways. Among these events is the activation of cytosolic phospholipase A2α and the subsequent production of the lipid second messengers. These events occur within minutes following exposure to ionizing radiation, and have been shown to enhance cell viability through a number of prosurvival signaling pathways. Furthermore, inhibition of cytosolic phospholipase A2α has now been shown to reduce the viability of endothelial cells in culture after exposure to ionizing radiation, as well as slowing the growth of tumors in animal models of cancer. PMID:21644828

  13. Radiosensitizing effect of gold nanoparticles in carbon ion irradiation of human cervical cancer cells

    NASA Astrophysics Data System (ADS)

    Kaur, Harminder; Avasthi, D. K.; Pujari, Geetanjali; Sarma, Asitikantha

    2013-07-01

    Noble metal nanoparticles have received considerable attention in biotechnology for their role in bio sensing due to surface plasmon resonance, medical diagnostics due to better imaging contrast and therapy. The radiosensitization effect of gold nanoparticles (AuNP) has been gaining popularity in radiation therapy of cancer cells. The better depth dose profile of energetic ion beam proves its superiority over gamma radiation for fighting against cancer. In the present work, the glucose capped gold nanoparticles (Glu-AuNP) were synthesised and internalized in the HeLa cells. Transmission electron microscopic analysis of ultrathin sections of Glu-AuNP treated HeLa cells confirmed the internalization of Glu-AuNPs. Control HeLa cells and Glu-AuNp treated HeLa cells were irradiated at different doses of 62 MeV 12C ion beam (LET - 290keV/μm) at BIO beam line of using 15UD Pelletron accelerator at Inter University Accelerator Centre, New Delhi, India. The survival fraction was assessed by colony forming assay which revealed that the dose of carbon ion for 90% cell killing in Glu-AuNP treated HeLa cells and control HeLa cells are 2.3 and 3.2 Gy respectively. This observation shows ˜ 28% reduction of 12C6+ ion dose for Glu-AuNP treated HeLa cells as compared to control HeLa cells.

  14. Enhancement of radiosensitivity in H1299 cancer cells by actin-associated protein cofilin

    SciTech Connect

    Lee, Y.-J. . E-mail: lee_yi_jang@hotmail.com; Sheu, T.-J.; Keng, Peter C.

    2005-09-23

    Cofilin is an actin-associated protein that belongs to the actin depolymerization factor/cofilin family and is important for regulation of actin dynamics. Cofilin can import actin monomers into the nucleus under certain stress conditions, however the biological effects of nuclear transport are unclear. In this study, we found that over-expression of cofilin led to increased radiation sensitivity in human non-small lung cancer H1299 cells. Cell survival as determined by colony forming assay showed that cells over-expressing cofilin were more sensitive to ionizing radiation (IR) than normal cells. To determine whether the DNA repair capacity was altered in cofilin over-expressing cells, comet assays were performed on irradiated cells. Repair of DNA damage caused by ionizing radiation was detected in cofilin over-expressing cells after 24 h of recovery. Consistent with this observation, the key components for repair of DNA double-strand breaks, including Rad51, Rad52, and Ku70/Ku80, were down-regulated in cofilin over-expressing cells after IR exposure. These findings suggest that cofilin can influence radiosensitivity by altering DNA repair capacity.

  15. Evaluation of Severe Combined Immunodeficiency and Combined Immunodeficiency Pediatric Patients on the Basis of Cellular Radiosensitivity.

    PubMed

    Lobachevsky, Pavel; Woodbine, Lisa; Hsiao, Kuang-Chih; Choo, Sharon; Fraser, Chris; Gray, Paul; Smith, Jai; Best, Nickala; Munforte, Laura; Korneeva, Elena; Martin, Roger F; Jeggo, Penny A; Martin, Olga A

    2015-09-01

    Pediatric patients with severe or nonsevere combined immunodeficiency have increased susceptibility to severe, life-threatening infections and, without hematopoietic stem cell transplantation, may fail to thrive. A subset of these patients have the radiosensitive (RS) phenotype, which may necessitate conditioning before hematopoietic stem cell transplantation, and this conditioning includes radiomimetic drugs, which may significantly affect treatment response. To provide statistical criteria for classifying cellular response to ionizing radiation as the measure of functional RS screening, we analyzed the repair capacity and survival of ex vivo irradiated primary skin fibroblasts from five dysmorphic and/or developmentally delayed pediatric patients with severe combined immunodeficiency and combined immunodeficiency. We developed a mathematical framework for the analysis of γ histone 2A isoform X foci kinetics to quantitate DNA-repair capacity, thus establishing crucial criteria for identifying RS. The results, presented in a diagram showing each patient as a point in a 2D RS map, were in agreement with findings from the assessment of cellular RS by clonogenic survival and from the genetic analysis of factors involved in the nonhomologous end-joining repair pathway. We provide recommendations for incorporating into clinical practice the functional assays and genetic analysis used for establishing RS status before conditioning. This knowledge would enable the selection of the most appropriate treatment regimen, reducing the risk for severe therapy-related adverse effects.

  16. Autophagy inhibition radiosensitizes in vitro, yet reduces radioresponses in vivo due to deficient immunogenic signalling

    PubMed Central

    Ko, A; Kanehisa, A; Martins, I; Senovilla, L; Chargari, C; Dugue, D; Mariño, G; Kepp, O; Michaud, M; Perfettini, J-L; Kroemer, G; Deutsch, E

    2014-01-01

    Clinical oncology heavily relies on the use of radiotherapy, which often leads to merely transient responses that are followed by local or distant relapse. The molecular mechanisms explaining radioresistance are largely elusive. Here, we identified a dual role of autophagy in the response of cancer cells to ionizing radiation. On one hand, we observed that the depletion of essential autophagy-relevant gene products, such as ATG5 and Beclin 1, increased the sensitivity of human or mouse cancer cell lines to irradiation, both in vitro (where autophagy inhibition increased radiation-induced cell death and decreased clonogenic survival) and in vivo, after transplantation of the cell lines into immunodeficient mice (where autophagy inhibition potentiated the tumour growth-inhibitory effect of radiotherapy). On the other hand, when tumour proficient or deficient for autophagy were implanted in immunocompetent mice, it turned out that defective autophagy reduced the efficacy of radiotherapy. Indeed, radiotherapy elicited an anti-cancer immune response that was dependent on autophagy-induced ATP release from stressed or dying tumour cells and was characterized by dense lymphocyte infiltration of the tumour bed. Intratumoural injection of an ecto-ATPase inhibitor restored the immune infiltration of autophagy-deficient tumours post radiotherapy and improved the growth-inhibitory effect of ionizing irradiation. Altogether, our results reveal that beyond its cytoprotective function, autophagy confers immunogenic properties to tumours, hence amplifying the efficacy of radiotherapy in an immunocompetent context. This has far-reaching implications for the development of pharmacological radiosensitizers. PMID:24037090

  17. Time dependent modulation of tumor radiosensitivity by a pan HDAC inhibitor: abexinostat.

    PubMed

    Rivera, Sofia; Leteur, Céline; Mégnin, Frédérique; Law, Frédéric; Martins, Isabelle; Kloos, Ioana; Depil, Stéphane; Modjtahedi, Nazanine; Perfettini, Jean Luc; Hennequin, Christophe; Deutsch, Eric

    2017-01-25

    Despite prominent role of radiotherapy in lung cancer management, there is an urgent need for strategies increasing therapeutic efficacy. Reversible epigenetic changes are promising targets for combination strategies using HDAC inhibitors (HDACi).Here we evaluated on two NSCLC cell lines, the antitumor effect of abexinostat, a novel pan HDACi combined with irradiation in vitro in normoxia and hypoxia, by clonogenic assays, demonstrating that abexinostat enhances radiosensitivity in a time dependent way with mean SER10 between 1.6 and 2.5 for A549 and H460. We found, by immunofluorescence staining, flow cytometry assays and western blotting, in abexinostat treated cells, increasing radio-induced caspase dependent apoptosis and persistent DNA double-strand breaks associated with decreased DNA damage signalling and repair. Interestingly, we demonstrated on nude mice xenografts that abexinostat potentiates tumor growth delay in combined modality treatments associating not only abexinostat and irradiation but also when adding cisplatin.Altogether, our data demonstrate in vitro and in vivo anti-tumor effect potentiation by abexinostat combined with irradiation in NSCLC. Moreover, our work suggests for the first time to our knowledge promising triple combination opportunities with HDACi, irradiation and cisplatin which deserves further investigations and could be of major interest in the treatment of NSCLC.

  18. Saving Performance in Individual Development Accounts: Does Marital Status Matter?

    ERIC Educational Resources Information Center

    Grinstein-Weiss, Michal; Zhan, Min; Sherraden, Michael

    2006-01-01

    Research indicates that marriage has a large effect on reducing the risk of poverty and is associated with a higher probability of attaining affluence over the life course when compared with nonmarriage. Using data from the American Dream Demonstration (N = 2,364), this study compares savings performances of married and unmarried low-income…

  19. Accounting for Individual Variability in Inversion Shortcut Use

    ERIC Educational Resources Information Center

    Dube, Adam K.; Robinson, Katherine M.

    2010-01-01

    This study investigated whether children's inversion shortcut use (i.e., reasoning that no calculations are required for the problem 4 x 8 divided by 8, as the answer is the first number) is related to their analogical reasoning ability, short-term memory capacity, and working memory capacity. Children from Grades 6 and 8 solved multiplication and…

  20. Holding Individuals Accountable and Deterring Money Laundering Act

    THOMAS, 113th Congress

    Rep. Waters, Maxine [D-CA-43

    2013-10-23

    01/09/2014 Referred to the Subcommittee on Crime, Terrorism, Homeland Security, and Investigations. (All Actions) Tracker: This bill has the status IntroducedHere are the steps for Status of Legislation:

  1. 26 CFR 1.408-2 - Individual retirement accounts.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... the interests of a large number of variable annuity contract holders. (4) Fitness to handle funds—(i... event of a liquidation proceeding under the Securities Investor Protection Act of 1970 in effect as of... required to submit a written application. This approval takes effect on the first day after December...

  2. 26 CFR 1.408-2 - Individual retirement accounts.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... determination of policies, the investment and disposition of property held in a fiduciary capacity, and the direction and review of the actions of all employees utilized by the applicant in the exercise of its... received after January 5, 1995, no initial application will be accepted by the Commissioner unless...

  3. Behavioral Objectives: The Paper Tiger of Accountability:

    ERIC Educational Resources Information Center

    Thompson, John; And Others

    1973-01-01

    Accountability based solely on behavioral objectives accomplished in classrooms is immoral and incomplete. Individual needs, interests and experiences are ignored in attempts to formulate behavioral objectives for the class as a whole. Humanistic aspects which determine the course of an individual's behavior are largely unmeasurable by the usual…

  4. Emerging accounting trends accounting for leases.

    PubMed

    Valletta, Robert; Huggins, Brian

    2010-12-01

    A new model for lease accounting can have a significant impact on hospitals and healthcare organizations. The new approach proposes a "right-of-use" model that involves complex estimates and significant administrative burden. Hospitals and health systems that draw heavily on lease arrangements should start preparing for the new approach now even though guidance and a final rule are not expected until mid-2011. This article highlights a number of considerations from the lessee point of view.

  5. Radiosensitivity of fibroblasts obtained from a cafe-au-lait spot and normal-appearing skin of a patient with neurofibromatosis (NF-6)

    SciTech Connect

    Hannan, M.A.; Smith, B.P.; Sigut, D.; Sackey, K. )

    1990-07-15

    Fibroblast cells derived from a cafe-au-lait spot and normal-appearing skin of a neurofibromatosis (NF-6) patient were studied for radiosensitivity in comparison with two normal cell lines used as controls. No difference in radiosensitivity was observed between the patient's cell lines and the controls using acute gamma-irradiation. However, a markedly increased radiosensitivity of the fibroblasts obtained from the patient's skin of normal appearance was demonstrated after chronic gamma-irradiation. The cells from the cafe-au-lait spot showed intermediate sensitivity to chronic irradiation as compared with the control cell lines and the fibroblasts derived from the normal skin of the patient. These results showed the usefulness of chronic irradiation in detecting increased cellular radiosensitivity which may result from a unique DNA repair defect in an NF patient. We suggest that enhanced genetic changes in radiosensitive NF patients may lead to formation of cafe-au-lait lesions and certain tumors. Such a transformation may be associated with production of radiotolerant cells.

  6. Inhibiting GLUT-1 expression and PI3K/Akt signaling using apigenin improves the radiosensitivity of laryngeal carcinoma in vivo.

    PubMed

    Bao, Yang-Yang; Zhou, Shui-Hong; Lu, Zhong-Jie; Fan, Jun; Huang, Ya-Ping

    2015-10-01

    Hypoxia is an important factor in radioresistance of laryngeal carcinoma. Glucose transporter-1 (GLUT-1) is an important hypoxic marker in malignant tumors, including laryngeal carcinoma. Apigenin is a natural phytoestrogen flavonoid that has potential anticancer effects. Various studies have reported that the effects of apigenin on lowering GLUT-1 expression were involved in downregulation of the PI3K/Akt pathway. Thus, apigenin may improve the radiosensitivity of laryngeal carcinoma by suppressing the expression of GLUT-1 via the PI3K/Akt pathway. The effect of GLUT-1 and PI3K/Akt pathway-related factor expressions by apigenin or antisense oligonucleotides (AS-ODNs) on the radiosensitivity of laryngeal carcinoma in vivo was assessed. The xenograft volume, xenograft weight and apoptosis detection were performed to determine radiosensitivity. The results showed that apigenin or apigenin plus GLUT-1 AS-ODNs improved the radiosensitivity of xenografts. Apigenin or apigenin plus GLUT-1 reduced the expression of GLUT-1, Akt, and PI3K mRNA after X-ray radiation. We found similar results at the protein level. The results suggest that the effects of apigenin on inhibiting xenograft growth and enhancing xenograft radiosensitivity may be associated with suppressing the expression of GLUT-1 via the PI3K/Akt pathway. In addition, apigenin may enhance the effects of GLUT-1 AS-ODNs via the same mechanism.

  7. Development of a Novel Enzyme-Targeting Radiosensitizer (New KORTUC) Using a Gelatin-Based Hydrogel Instead of a Sodium Hyaluronate

    PubMed Central

    Morita-Tokuhiro, Shiho; Ogawa, Yasuhiro; Yokota, Norikazu; Tsuzuki, Akira; Oda, Hideki; Ishida, Naoya; Aoyama, Nobutaka; Nishioka, Akihito

    2016-01-01

    We recently developed Kochi Oxydol-Radiation Therapy for Unresectable Carcinomas (KORTUC) as a strategy to increase intratumoral oxygen concentrations and degrade antioxidant enzymes such as peroxidase and catalase. We then developed KORTUC II, which uses sodium hyaluronate containing hydrogen peroxide as a radiosensitizer. KORTUC II requires twice-weekly administration to sustain its effects, but decreasing the frequency of radiosensitizer injections to once-weekly would reduce the burden on the patients and the physicians. The goal of this study was thus to develop a new formulation of KORTUC (New KORTUC) that only requires once-weekly administration. We performed experimental studies using a mouse tumor model and biodegradable hydrogel. C3H/He mice were allocated to control, KORTUC, or hydrogel groups. At 72 h after injection, each tumor was irradiated with a 6 MeV electron beam to a total dose of 30 Gy. During a 62-day observation period, changes in tumor volume and survival rates were assessed in each group. Tumor growth rate was slowest in the hydrogel groups. These data suggest that hydrogel could represent a useful adjunct as a long-acting radiosensitizer in place of sodium hyaluronate. New KORTUC, which contains hydrogen peroxide and hydrogel, exerted a radiosensitizing effect that persisted beyond 72 h following injection of the agent. Use of this new formulation allows radiosensitizer injections to be performed once-weekly with good effect. PMID:26751477

  8. PLATO IV Accountancy Index.

    ERIC Educational Resources Information Center

    Pondy, Dorothy, Comp.

    The catalog was compiled to assist instructors in planning community college and university curricula using the 48 computer-assisted accountancy lessons available on PLATO IV (Programmed Logic for Automatic Teaching Operation) for first semester accounting courses. It contains information on lesson access, lists of acceptable abbreviations for…

  9. Leadership for Accountability.

    ERIC Educational Resources Information Center

    Lashway, Larry

    2001-01-01

    This document explores issues of leadership for accountability and reviews five resources on the subject. These include: (1) "Accountability by Carrots and Sticks: Will Incentives and Sanctions Motivate Students, Teachers, and Administrators for Peak Performance?" (Larry Lashway); (2) "Organizing Schools for Teacher Learning"…

  10. The Choreography of Accountability

    ERIC Educational Resources Information Center

    Webb, P. Taylor

    2006-01-01

    The prevailing performance discourse in education claims school improvements can be achieved through transparent accountability procedures. The article identifies how teachers generate performances of their work in order to satisfy accountability demands. By identifying sources of teachers' knowledge that produce choreographed performances, I…

  11. Cluster Guide. Accounting Occupations.

    ERIC Educational Resources Information Center

    Beaverton School District 48, OR.

    Based on a recent task inventory of key occupations in the accounting cluster taken in the Portland, Oregon, area, this curriculum guide is intended to assist administrators and teachers in the design and implementation of high school accounting cluster programs. The guide is divided into four major sections: program organization and…

  12. The Accountability Illusion: Ohio

    ERIC Educational Resources Information Center

    Thomas B. Fordham Institute, 2009

    2009-01-01

    The intent of the No Child Left Behind (NCLB) Act of 2001 is to hold schools accountable for ensuring that all their students achieve mastery in reading and math, with a particular focus on groups that have traditionally been left behind. Under NCLB, states submit accountability plans to the U.S. Department of Education detailing the rules and…

  13. The Accountability Illusion: Florida

    ERIC Educational Resources Information Center

    Thomas B. Fordham Institute, 2009

    2009-01-01

    The intent of the No Child Left Behind (NCLB) Act of 2001 is to hold schools accountable for ensuring that all their students achieve mastery in reading and math, with a particular focus on groups that have traditionally been left behind. Under NCLB, states submit accountability plans to the U.S. Department of Education detailing the rules and…

  14. The Accountability Illusion: Minnesota

    ERIC Educational Resources Information Center

    Thomas B. Fordham Institute, 2009

    2009-01-01

    The intent of the No Child Left Behind (NCLB) Act of 2001 is to hold schools accountable for ensuring that all their students achieve mastery in reading and math, with a particular focus on groups that have traditionally been left behind. Under NCLB, states submit accountability plans to the U.S. Department of Education detailing the rules and…

  15. The Accountability Illusion: Wisconsin

    ERIC Educational Resources Information Center

    Thomas B. Fordham Institute, 2009

    2009-01-01

    The intent of the No Child Left Behind (NCLB) Act of 2001 is to hold schools accountable for ensuring that all their students achieve mastery in reading and math, with a particular focus on groups that have traditionally been left behind. Under NCLB, states submit accountability plans to the U.S. Department of Education detailing the rules and…

  16. The Accountability Illusion: Vermont

    ERIC Educational Resources Information Center

    Thomas B. Fordham Institute, 2009

    2009-01-01

    The intent of the No Child Left Behind (NCLB) Act of 2001 is to hold schools accountable for ensuring that all their students achieve mastery in reading and math, with a particular focus on groups that have traditionally been left behind. Under NCLB, states submit accountability plans to the U.S. Department of Education detailing the rules and…

  17. The Evolution of Accountability

    ERIC Educational Resources Information Center

    Webb, P. Taylor

    2011-01-01

    Campus 2020: Thinking ahead is a policy in British Columbia (BC), Canada, that attempted to hold universities accountable to performance. Within, I demonstrate how this Canadian articulation of educational accountability intended to develop "governmentality constellations" to control the university and regulate its knowledge output. This…

  18. The Coming Accounting Crisis

    ERIC Educational Resources Information Center

    Eaton, Tim V.

    2007-01-01

    The accounting profession is facing a potential crisis not only from the overall shortage of accounting faculty driven by smaller numbers of new faculty entering the profession as many existing faculty retire but also from changes that have been less well documented. This includes: (1) changes in attitude towards the roles of teaching, service and…

  19. Accountability in Education.

    ERIC Educational Resources Information Center

    Chippendale, P. R., Ed.; Wilkes, Paula V., Ed.

    This collection of papers delivered at a conference on accountability held at Darling Downs Institute of Advanced Education in Australia examines the meaning of accountability in education for teachers, lecturers, government, parents, administrators, education authorities, and the society at large. In Part 1, W. G. Walker attempts to answer the…

  20. The Accountability Illusion: Nevada

    ERIC Educational Resources Information Center

    Thomas B. Fordham Institute, 2009

    2009-01-01

    The intent of the No Child Left Behind (NCLB) Act of 2001 is to hold schools accountable for ensuring that all their students achieve mastery in reading and math, with a particular focus on groups that have traditionally been left behind. Under NCLB, states submit accountability plans to the U.S. Department of Education detailing the rules and…

  1. 77 FR 43542 - Cost Accounting Standards: Cost Accounting Standards 412 and 413-Cost Accounting Standards...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-07-25

    ... BUDGET Office of Federal Procurement Policy 48 CFR Part 9904 Cost Accounting Standards: Cost Accounting Standards 412 and 413--Cost Accounting Standards Pension Harmonization Rule AGENCY: Cost Accounting... correcting amendments. SUMMARY: The Office of Federal Procurement Policy (OFPP), Cost Accounting...

  2. Individualizing Medicare.

    PubMed

    Chollet, D J

    1999-05-01

    Despite the enactment of significant changes to the Medicare program in 1997, Medicare's Hospital Insurance trust fund is projected to be exhausted just as the baby boom enters retirement. To address Medicare's financial difficulties, a number of reform proposals have been offered, including several to individualize Medicare financing and benefits. These proposals would attempt to increase Medicare revenues and reduce Medicare expenditures by having individuals bear risk--investment market risk before retirement and insurance market risk after retirement. Many fundamental aspects of these proposals have yet to be worked out, including how to guarantee a baseline level of saving for health insurance after retirement, how retirees might finance unanticipated health insurance price increases after retirement, the potential implications for Medicaid of inadequate individual saving, and whether the administrative cost of making the system fair and adequate ultimately would eliminate any rate-of-return advantages from allowing workers to invest their Medicare contributions in corporate stocks and bonds.

  3. Health savings accounts and health reimbursement arrangements: assets, account balances, and rollovers, 2006-2009.

    PubMed

    Fronstin, Paul

    2010-06-01

    ASSET LEVELS GROWING: In 2009, there was $7.1 billion in consumer-driven health plans (CDHPs), which include health savings accounts (or HSAs) and health reimbursement arrangements (or HRAs), spread across 5 million accounts. This is up from 2006, when there were 1.2 million accounts with $835.4 million in assets, and 2008, when 4.2 million accounts held $5.7 billion in assets. AVERAGE ACCOUNT BALANCE LEVELING OFF: Increases in average account balances appear to have leveled off. In 2006, account balances averaged $696. They increased to $1320 in 2007, a 90 percent increase. Account balances averaged $1356 in 2008 and $1419 in 2009, 3 percent and 5 percent increases, respectively. TYPICAL ENROLLEE: The typical CDHP enrollee was more likely than traditional plan enrollees to be young, unmarried, higher-income, educated, and exhibit healthy behavior. No differences were found between CDHPs enrollees and traditional plan enrollees with respect to gender, race, and presence of children. MORE ROLLOVERS: Overall, the number of people with a rollover, as well as the total level of assets being rolled over, have been increasing. The average rollover increased from $592 in 2006 to $1295 in 2009. DIFFERENCES IN ACCOUNT BALANCES: Men tend to have higher account balances than women, account balances increase with household income, education has a significant impact on account balances independent of income and other variables, and no statistically significant differences in account balances were found by smoking, obesity, or the presence of chronic health conditions. Individuals who developed a budget to manage their health care expenses had a higher account balance ($1726) than those who did not ($1428), but otherwise, no statistically significant differences in average account balances were found between individuals who exhibited various aspects of cost-conscious decision-making behaviors and those who did not. DIFFERENCES IN ROLLOVER AMOUNTS: Men rolled over more money than

  4. Cooperative effect of BI-69A11 and celecoxib enhances radiosensitization by modulating DNA damage repair in colon carcinoma.

    PubMed

    Pal, Ipsita; Dey, Kaushik Kumar; Chaurasia, Madhuri; Parida, Sheetal; Das, Subhayan; Rajesh, Y; Sharma, Kulbhushan; Chowdhury, Tamohan; Mandal, Mahitosh

    2016-05-01

    Amplification of PI3K-Akt pathway promotes radioresistance in various cancers including colorectal carcinoma. Local recurrence in colon cancer causes poor prognosis affecting overall survival of cancer-affected patient population. To avoid local recurrence, pre-operative or post-operative additional radiotherapy is given. However, main concern regarding radiotherapy is to increase the radiosensitivity of malignant cell without hampering the activities of normal cells. In this context, addition of two or more than two chemotherapeutic drugs as a radiosensitizer is a common practice in radiation biology. BI-69A11 earlier showed potential apoptosis-inducing effect in melanoma and colon carcinoma. Celecoxib showed anti-cancer effects in both COX-2 dependent and independent pathways and used to act as a radiosensitizing enhancer. Here, we suggest that the combination of BI-69A11 and celecoxib inhibits the phosphorylation of ataxia telangiectasia mutated (ATM) kinase and DNA-PK responsible for ionizing radiation (IR)-induced double-strand break (DSB) repair. Moreover, the combinatorial effect of BI-69A11 and celecoxib attenuates the IR-induced G2/M cell cycle arrest. Furthermore, this combination also impairs IR-induced activation of Akt and downstream targets of ATM. This might lead to induced activation of apoptotic pathway after triple therapy treatment modulating pro-apoptotic and anti-apoptotic proteins. This activation of apoptotic pathway also showed the interdependence of PUMA and BAD in triple combination-treated colon cancer cells in a p53 independent manner. This study reveals the therapeutic potential of the triple combination therapy in prevention of radioresistance. Besides, it also demonstrates the cytotoxic effects of triple combination therapy in colon cancer. This study shows utility and potential implication on safety of the patients undergoing radiation therapy.

  5. Hepatocytes Determine the Hypoxic Microenvironment and Radiosensitivity of Colorectal Cancer Cells Through Production of Nitric Oxide That Targets Mitochondrial Respiration

    SciTech Connect

    Jiang, Heng; Verovski, Valeri N.; Leonard, Wim; Law, Ka Lun; Vermeersch, Marieke; Storme, Guy; Van den Berge, Dirk; Gevaert, Thierry; Sermeus, Alexandra; De Ridder, Mark

    2013-03-01

    Purpose: To determine whether host hepatocytes may reverse hypoxic radioresistance through nitric oxide (NO)-induced oxygen sparing, in a model relevant to colorectal cancer (CRC) liver metastases. Methods and Materials: Hepatocytes and a panel of CRC cells were incubated in a tissue-mimetic coculture system with diffusion-limited oxygenation, and oxygen levels were monitored by an oxygen-sensing fluorescence probe. To activate endogenous NO production, cocultures were exposed to a cytokine mixture, and the expression of inducible nitric oxide synthase was analyzed by reverse transcription–polymerase chain reaction, Western blotting, and NO/nitrite production. The mitochondrial targets of NO were examined by enzymatic activity. To assess hypoxic radioresponse, cocultures were irradiated and reseeded for colonies. Results: Resting hepatocytes consumed 10-40 times more oxygen than mouse CT26 and human DLD-1, HT29, HCT116, and SW480 CRC cells, and thus seemed to be the major effectors of hypoxic conditioning. As a result, hepatocytes caused uniform radioprotection of tumor cells at a 1:1 ratio. Conversely, NO-producing hepatocytes radiosensitized all CRC cell lines more than 1.5-fold, similar to the effect of selective mitochondrial inhibitors. The radiosensitizing effect was associated with a respiratory self-arrest of hepatocytes at the level of aconitase and complex II, which resulted in profound reoxygenation of tumor cells through oxygen sparing. Nitric oxide–producing hepatocytes were at least 10 times more active than NO-producing macrophages to reverse hypoxia-induced radioresistance. Conclusions: Hepatocytes were the major determinants of the hypoxic microenvironment and radioresponse of CRC cells in our model of metabolic hypoxia. We provide evidence that reoxygenation and radiosensitization of hypoxic CRC cells can be achieved through oxygen sparing induced by endogenous NO production in host hepatocytes.

  6. Intranuclear Delivery of a Novel Antibody-Derived Radiosensitizer Targeting the DNA-Dependent Protein Kinase Catalytic Subunit

    SciTech Connect

    Xiong Hairong; Lee, Robert J.; Haura, Eric B.; Edwards, John G.; Dynan, William S.; Li Shuyi

    2012-07-01

    Purpose: To inhibit DNA double-strand break repair in tumor cells by delivery of a single-chain antibody variable region fragment (ScFv 18-2) to the cell nucleus. ScFv 18-2 binds to a regulatory region of the DNA-dependent protein kinase (DNA-PK), an essential enzyme in the nonhomologous end-joining pathway, and inhibits DNA end-joining in a cell-free system and when microinjected into single cells. Development as a radiosensitizer has been limited by the lack of a method for intranuclear delivery to target cells. We investigated a delivery method based on folate receptor-mediated endocytosis. Methods and Materials: A recombinant ScFv 18-2 derivative was conjugated to folate via a scissile disulfide linker. Folate-ScFv 18-2 was characterized for its ability to be internalized by tumor cells and to influence the behavior of ionizing radiation-induced repair foci. Radiosensitization was measured in a clonogenic survival assay. Survival curves were fitted to a linear-quadratic model, and between-group differences were evaluated by an F test. Sensitization ratios were determined based on mean inhibitory dose. Results: Human KB and NCI-H292 lung cancer cells treated with folate-conjugated ScFv 18-2 showed significant radiosensitization (p < 0.001). Sensitization enhancement ratios were 1.92 {+-} 0.42 for KB cells and 1.63 {+-} 0.13 for NCI-H292 cells. Studies suggest that treatment inhibits repair of radiation-induced DSBs, as evidenced by the persistence of {gamma}-H2AX-stained foci and by inhibition of staining with anti-DNA-PKcs phosphoserine 2056. Conclusions: Folate-mediated endocytosis is an effective method for intranuclear delivery of an antibody-derived DNA repair inhibitor.

  7. Poor Prognosis Associated With Human Papillomavirus α7 Genotypes in Cervical Carcinoma Cannot Be Explained by Intrinsic Radiosensitivity

    SciTech Connect

    Hall, John S.; Iype, Rohan; Armenoult, Lucile S.C.; Taylor, Janet; Miller, Crispin J.; Davidson, Susan; Sanjose, Silvia de; Bosch, Xavier; Stern, Peter L.; West, Catharine M.L.

    2013-04-01

    Purpose: To investigate the relationship between human papillomavirus (HPV) genotype and outcome after radiation therapy and intrinsic radiosensitivity. Methods and Materials: HPV genotyping was performed on cervix biopsies by polymerase chain reaction using SPF-10 broad-spectrum primers, followed by deoxyribonucleic acid enzyme immunoassay and genotyping by reverse hybridization line probe assay (LiPA{sub 25}) (version 1) (n=202). PapilloCheck and quantitative reverse transcription-polymerase chain reaction were used to genotype cervix cancer cell lines (n=16). Local progression-free survival after radiation therapy alone was assessed using log-rank and Cox proportionate hazard analyses. Intrinsic radiosensitivity was measured as surviving fraction at 2 Gy (SF2) using clonogenic assays. Results: Of the 202 tumors, 107 (53.0%) were positive for HPV16, 29 (14.4%) for HPV18, 9 (4.5%) for HPV45, 23 (11.4%) for other HPV genotypes, and 22 (10.9%) were negative; 11 (5.5%) contained multiple genotypes, and 1 tumor was HPV X (0.5%). In 148 patients with outcome data, those with HPVα9-positive tumors had better local progression-free survival compared with α7 patients in univariate (P<.004) and multivariate (hazard ratio 1.54, 95% confidence interval 1.11-1.76, P=.021) analyses. There was no difference in the median SF2 of α9 and α7 cervical tumors (n=63). In the cell lines, 9 were α7 and 4 α9 positive and 3 negative. There was no difference in SF2 between α9 and α7 cell lines (n=14). Conclusion: The reduced radioresponsiveness of α7 cervical tumors is not related to intrinsic radiosensitivity.

  8. Sodium Selenite Radiosensitizes Hormone-Refractory Prostate Cancer Xenograft Tumors but Not Intestinal Crypt Cells In Vivo

    SciTech Connect

    Tian Junqiang; Ning Shouchen; Knox, Susan J.

    2010-09-01

    Purpose: We have previously shown that sodium selenite (SSE) increases radiation-induced cell killing of human prostate carcinoma cells in vitro. In this study we further evaluated the in vivo radiosensitizing effect of SSE in prostate cancer xenograft tumors and normal radiosensitive intestinal crypt cells. Methods and Materials: Immunodeficient (SCID) mice with hormone-independent LAPC-4 (HI-LAPC-4) and PC-3 xenograft tumors (approximately 200 mm{sup 3}) were divided into four groups: control (untreated), radiation therapy (XRT, local irradiation), SSE (2 mg/kg, intraperitoneally, 3 times/week), and XRT plus SSE. The XRT was given at the beginning of the regimen as a single dose of 5 Gy for HI-LAPC-4 tumors and a single dose of 7 Gy followed by a fractional dose of 3 Gy/d for 5 days for PC-3 tumors. The tumor volume was measured 3 times per week. The radiosensitizing effect of SSE on normal intestinal epithelial cells was assessed by use of a crypt cell microcolony assay. Results: In the efficacy study, SSE alone significantly inhibited the tumor growth in HI-LAPC-4 tumors but not PC-3 tumors. Sodium selenite significantly enhanced the XRT-induced tumor growth inhibition in both HI-LAPC-4 and PC-3 tumors. In the toxicity study, SSE did not affect the intestinal crypt cell survival either alone or in combination with XRT. Conclusions: Sodium selenite significantly enhances the effect of radiation on well-established hormone-independent prostate tumors and does not sensitize the intestinal epithelial cells to radiation. These results suggest that SSE may increase the therapeutic index of XRT for the treatment of prostate cancer.

  9. Multiple dose study of the combined radiosensitizers Ro 03-8799 (pimonidazole) and SR 2508 (etanidazole)

    SciTech Connect

    Bleehen, N.M.; Newman, H.F.; Maughan, T.S.; Workman, P.

    1989-04-01

    The hypoxic cell radiosensitizers Ro 03-8799 and SR 2508 have different clinical toxicities. The former produces an acute but transient central nervous system syndrome, whereas the latter produces cumulative peripheral neuropathy. Following single dose studies, an escalating multiple dose schedule using both drugs in combination showed no unexpected adverse reactions at lower doses. This study identifies the clinical tolerance and pharmacokinetics when doses in the region of the maximal tolerated dose are given to 26 patients receiving infusions of 0.75 g/m2 Ro 03-8799 and 2 g/m2 SR 2508 three times per week. At 15 doses, 3/4 patients experienced WHO grade 2 peripheral neuropathy, whereas at 12 doses 1/9 developed grade 2 and 6/9 developed grade 1 neuropathies. This represents a lower dose of SR 2508 than can be given alone suggesting that some interaction between the two drugs does exist in terms of chronic peripheral neurotoxicity. Pharmacokinetic studies show no adverse interactions between the two drugs and minimal inter-patient variation. From bivariate analysis, cumulative AUC for Ro 03-8799 has the most significant correlation with the development of peripheral neuropathy. Tumor drug concentrations normalized to the administered dose show mean values of 34 micrograms/g Ro 03-8799 and 76 micrograms/g SR 2508 30 minutes after infusion. These could be expected to produce a single dose sensitizer enhancement ratio of 1.5. The combination of the two sensitizers at the maximum tolerable dose may be expected to give an increased therapeutic efficacy over either drug alone.

  10. Ionizing Radiation Activates AMP-Activated Kinase (AMPK): A Target for Radiosensitization of Human Cancer Cells

    SciTech Connect

    Sanli, Toran; Rashid, Ayesha; Liu Caiqiong

    2010-09-01

    Purpose: Adenosine monophosphate (AMP)-activated kinase (AMPK) is a molecular energy sensor regulated by the tumor suppressor LKB1. Starvation and growth factors activate AMPK through the DNA damage sensor ataxia-telangiectasia mutated (ATM). We explored the regulation of AMPK by ionizing radiation (IR) and its role as a target for radiosensitization of human cancer cells. Methods and Materials: Lung, prostate, and breast cancer cells were treated with IR (2-8 Gy) after incubation with either ATM or AMPK inhibitors or the AMPK activator metformin. Then, cells were subjected to either lysis and immunoblotting, immunofluorescence microscopy, clonogenic survival assays, or cell cycle analysis. Results: IR induced a robust phosphorylation and activation of AMPK in all tumor cells, independent of LKB1. IR activated AMPK first in the nucleus, and this extended later into cytoplasm. The ATM inhibitor KU-55933 blocked IR activation of AMPK. AMPK inhibition with Compound C or anti-AMPK {alpha} subunit small interfering RNA (siRNA) blocked IR induction of the cell cycle regulators p53 and p21{sup waf/cip} as well as the IR-induced G2/M arrest. Compound C caused resistance to IR, increasing the surviving fraction after 2 Gy, but the anti-diabetic drug metformin enhanced IR activation of AMPK and lowered the surviving fraction after 2 Gy further. Conclusions: We provide evidence that IR activates AMPK in human cancer cells in an LKB1-independent manner, leading to induction of p21{sup waf/cip} and regulation of the cell cycle and survival. AMPK appears to (1) participate in an ATM-AMPK-p21{sup waf/cip} pathway, (2) be involved in regulation of the IR-induced G2/M checkpoint, and (3) may be targeted by metformin to enhance IR responses.

  11. ATM-Dependent Hyper-Radiosensitivity in Mammalian Cells Irradiated by Heavy Ions

    SciTech Connect

    Xue Lian; Yu Dong Furusawa, Yoshiya; Cao Jianping; Okayasu, Ryuichi; Fan Saijun

    2009-09-01

    Purpose: Low-dose hyper-radiosensitivity (HRS) and the later appearing radioresistance (termed induced radioresistance [IRR]) was mainly studied in low linear energy transfer (LET) radiation with survival observation. The aim of this study was to find out whether equivalent hypersensitivity occurred in high LET radiation, and the roles of ataxia telangiectasia mutated (ATM) kinase. Methods and Materials: Survival and mutation were measured by clonogenic assay and HPRT mutation assay. ATM Ser1981 activation was detected by Western blotting and immunofluorescent staining. Pretreatment of specific ATM inhibitor (10 {mu}M KU55933) and activator (20 {mu}g/mL chloroquine) before carbon radiation were adopted to explore the involvement of ATM. The roles of ATM were also investigated in its G2/M checkpoint function with histone H3 phosphorylation analysis and flow cytometric assay, and DNA double strand break (DSB) repair function measured using {gamma}-H2AX foci assay. Results: HRS/IRR was observed with survival and mutation in normal human skin fibroblast cells by carbon ions, while impaired in cells with intrinsic ATM deficiency or normal cells modified with specific ATM activator or inhibitor before irradiation. The dose-response pattern of ATM kinase activation was concordant with the transition from HRS to IRR. The ATM-dependent 'early' G2 checkpoint arrest and DNA DSB repair efficiency could explain the difference between HRS and IRR. Conclusions: These data demonstrate that the HRS/IRR by carbon ion radiation is an ATM-dependent phenomenon in the cellular response to DNA damage.

  12. WE-G-BRE-02: Biological Modeling of Gold Nanoparticle Radiosensitization for Proton Therapy

    SciTech Connect

    Lin, Y; Paganetti, H; Schuemann, J

    2014-06-15

    Purpose: The aim of this work is to investigate the radiosensitization effect of gold nanoparticles (GNP) in a proton beam. A computational model was built using the Local Effect Model (LEM) to predict the biological outcome of gold nanoparticle (GNP) sensitization. We present the results using a clinical proton beam, 6MV photon beam and two kilovoltage photon beams. Methods: First, Monte Carlo simulations were carried out using TOPAS (TOol for PArticle Simulation) to obtain the spatial dose distribution in the vicinity of GNPs. The dose distribution was then used as an input for LEM, which predicts dose-response curves for high linear energy transfer radiation using the track structure. The cell survival curves were evaluated for three particle sources (proton beam, MV photon beam and kV photon beam), various treatment depths for each particle source, various GNP uptakes and two different GNP sizes. Results: For proton therapy, the GNP sensitization effect is highly dependent on the treatment depth due to the energy-dependent interaction probability. We predict that if GNPs can be taken up by the cell nucleus, proton therapy can be significantly enhanced. If GNPs are only internalized into the cytoplasm, proton therapy can still be enhanced by GNPs and if GNPs are not internalized into cells, there will be no direct damage to the nucleus. For the same GNP uptake and concentration, the cell survival at 2Gy is reduced by 80% using kilovoltage photons, 50% using protons and only 2% using clinical MV photons. Finally, for the same weight of GNPs taken up by the cells, 10 nm GNPs causes 3 times more damage than 50 nm GNPs. Conclusion: We showed that GNPs have potential to be used to enhance radiation therapy for clinical proton beams.

  13. Evaluation of a tetrazolium-based semiautomated colorimetric assay: assessment of radiosensitivity

    SciTech Connect

    Carmichael, J.; DeGraff, W.G.; Gazdar, A.F.; Minna, J.D.; Mitchell, J.B.

    1987-02-15

    Radiation survival curves were generated for V79 Chinese hamster and two human lung cancer cell lines (NCI-H460 and NCI-H249) with doubling times of 10, 20, and 85 h, respectively, using a standard clonogenic assay, a dye exclusion assay, and a semiautomated colorimetric assay utilizing a tetrazolium salt, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenylformazan bromide. Comparable results for D0 and extrapolation number (n) were observed for all assays in the lines with doubling times of 10 and 20 h. In these instances the tumor cell lines had undergone seven or more doublings after radiation. For the tumor line (H249) with an 80-h doubling time the D0S were comparable between the assays while the extrapolation number was increased in the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenylformazan bromide assay, a result probably related to the lower number of doublings (less than 4) after radiation. We then tested the ability of the assays to detect radiation protection and sensitization using known agents. We found that cysteamine treatment resulted in radioprotection (by a factor of 8 at 8 Gy) while 5-bromo-2-deoxyuridine incorporation caused enhancement of radiation sensitivity in all three assays. We conclude that, while optimal conditions for each cell line (cell number plated and doubling time) must be established, using characterized tumor cell lines, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenylformazan bromide assay could be automated and thus be of great value in screening large numbers of potential radiosensitizers or protectors.

  14. Radiosensitizing Effect of a Phenylbutyrate-Derived Histone Deacetylase Inhibitor in Hepatocellular Carcinoma

    SciTech Connect

    Lu, Yen-Shen; Chou, Chia-Hung; Tzen, Kai-Yuan; Gao, Ming; Cheng, Ann-Lii; Kulp, Samuel K.; Cheng, Jason Chia-Hsien

    2012-06-01

    Purpose: Radiotherapy is integrated into the multimodal treatment of localized hepatocellular carcinoma (HCC) refractory to conventional treatment. Tumor control remains unsatisfactory and the sublethal effect associates with secondary spread. The use of an effective molecularly targeted agent in combination with radiotherapy is a potential therapeutic approach. Our aim was to assess the effect of combining a phenylbutyrate-derived histone deacetylase (HDAC) inhibitor, AR-42, with radiotherapy in in vitro and in vivo models of human HCC. Methods and Materials: Human HCC cell lines (Huh-7 and PLC-5) were used to evaluate the in vitro synergism of combining AR-42 with irradiation. Flow cytometry analyzed the cell cycle changes, whereas Western blot investigated the protein expressions after the combined treatment. Severe combined immunodeficient (SCID) mice bearing ectopic and orthotopic HCC xenografts were treated with AR-42 and/or radiotherapy for the in vivo response. Results: AR-42 significantly enhanced radiation-induced cell death by the inhibition of the DNA end-binding activity of Ku70, a highly versatile regulatory protein for DNA repair, telomere maintenance, and apoptosis. In ectopic xenografts of Huh-7 and PLC-5, pretreatment with AR-42 significantly enhanced the tumor-suppressive effect of radiotherapy by 48% and 66%, respectively. A similar combinatorial effect of AR-42 (10 and 25 mg/kg) and radiotherapy was observed in Huh-7 orthotopic model of tumor growth by 52% and 82%, respectively. This tumor suppression was associated with inhibition of intratumoral Ku70 activity as well as reductions in markers of HDAC activity and proliferation, and increased apoptosis. Conclusion: AR-42 is a potent, orally bioavailable inhibitor of HDAC with therapeutic value as a radiosensitizer of HCC.

  15. SU-E-T-518: Investigation of Gold Nanoparticle Radiosensitization for Carbon Ion Therapy

    SciTech Connect

    Lin, Y; Held, K; Paganetti, H; Schuemann, J; McMahon, S

    2015-06-15

    Purpose The aim of this work is to investigate the radiosensitization effect of gold nanoparticles (GNP) in carbon ion irradiation. Nano-scale dosimetric characteristics of GNP interaction with carbon ions as well as the secondary particles generated as a carbon beam traverses the water phantom were studied. Methods Monte Carlo simulations were carried out using TOPAS (Tool for Particle Simulation). First, a water phantom was irradiated by the carbon ion beam and the particle shower spectrum at several depths was recorded in phase spaces. We analyzed the number and energy spectrum of each particle type. Then, the phase spaces obtained from Step 1 were modified to nanometer scale to irradiate a single 50 nm GNP. The secondary electrons that escaped from the GNPs following interactions with each particle type were recorded as phase spaces. The number and energy spectrum of the secondary electrons were studied. The same simulations were repeated replacing the GNPs with water nanoparticles (WNPs) with the same size. The energy absorbed in either GNP or WNP was scored. Results There is a large amount of secondary particles generated through carbon ion beam interaction with the water phantom. Analysis of the secondary electrons generated by the primary particles which escape from the nanoparticle revealed that majority (above 80%) of these electrons were generated by the GNP interaction with Carbon beam itself, making it the biggest contributor to the enhancement. The ratio of the energy absorbed by GNP and WNP is about 8–10 for charged particles and above 3000 for gammas. Conclusion We showed in the study the GNPs may potentially be used to enhance carbon ion therapy, and the main mechanism of enhancement is the interaction with Carbon ion particles itself.

  16. Radiosensitization of Glioblastoma Cell Lines by the Dual PI3K and mTOR Inhibitor NVP-BEZ235 Depends on Drug-Irradiation Schedule12

    PubMed Central

    Kuger, Sebastian; Graus, Dorothea; Brendtke, Rico; Günther, Nadine; Katzer, Astrid; Lutyj, Paul; Polat, Bülent; Chatterjee, Manik; Sukhorukov, Vladimir L; Flentje, Michael; Djuzenova, Cholpon S

    2013-01-01

    Previous studies have shown that the dual phosphatidylinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) inhibitor NVP-BEZ235 radiosensitizes tumor cells if added shortly before ionizing radiation (IR) and kept in culture medium thereafter. The present study explores the impact of inhibitor and IR schedule on the radiosensitizing ability of NVP-BEZ235 in four human glioblastoma cell lines. Two different drug-IR treatment schedules were compared. In schedule I, cells were treated with NVP-BEZ235 for 24 hours before IR and the drug was removed before IR. In schedule II, the cells were exposed to NVP-BEZ235 1 hour before, during, and up to 48 hours after IR. The cellular response was analyzed by colony counts, expression of marker proteins of the PI3K/AKT/mTOR pathway, cell cycle, and DNA damage. We found that under schedule I, NVP-BEZ235 did not radiosensitize cells, which were mostly arrested in G1 phase during IR exposure. In addition, the drug-pretreated and irradiated cells exhibited less DNA damage but increased expressions of phospho-AKT and phospho-mTOR, compared to controls. In contrast, NVP-BEZ235 strongly enhanced the radiosensitivity of cells treated according to schedule II. Possible reasons of radiosensitization by NVP-BEZ235 under schedule II might be the protracted DNA repair, prolonged G2/M arrest, and, to some extent, apoptosis. In addition, the PI3K pathway was downregulated by the NVP-BEZ235 at the time of irradiation under schedule II, as contrasted with its activation in schedule I. We found that, depending on the drug-IR schedule, the NVP-BEZ235 can act either as a strong radiosensitizer or as a cytostatic agent in glioblastoma cells. PMID:23544169

  17. Human Resource Accounting.

    DTIC Science & Technology

    1984-12-01

    I AD-RI54 787 HUMAN RESOURCE ACCOUNTING (U) NAVAL POSTGRADUATE SCHOOL 1/2 F MONTEREY CR J C MARTINS DEC 84 1UNCLASSIFIED /G 5/9 NL -~~ .. 2. . L...Monterey, California JUN1im THESISG HUMAN RESOURCE ACCOUNTING by Joaquim C. Martins LLJ.. December 1984 Thesis Advisor: R.A. McGonigal Approved for...REPORT & PECRI00 COVERED Master’s Thesis; Human Resource Accounting Dcme 94- ’ 6. PERFORMING ORG. REPORT NUMBER 7. AUTOR(*) . CONTRACT OR GRANT NUMBER

  18. [Individualizing Education.

    ERIC Educational Resources Information Center

    Horrigan, William J.

    The individually guided education (IGE) program developed by the Kettering Foundation was implemented in September of 1973 at the John F. Kennedy Memorial Junior High School in Woburn, Massachusetts. The components of the program described in this speech include pupil and teacher scheduling, physical layout, pupil selection and adjustment,…

  19. Ideas for the Accounting Classroom.

    ERIC Educational Resources Information Center

    Kerby, Debra; Romine, Jeff

    2003-01-01

    Innovative ideas for accounting education include having students study accounting across historical periods, using businesses for student research, exploring nontraditional accounting careers, and collaborating with professional associations. (SK)

  20. Readability of Accounting Books.

    ERIC Educational Resources Information Center

    Razek, Joseph R.; And Others

    1982-01-01

    This article describes the results of a survey of the readability of most of the intermediate and advanced accounting textbooks currently in use at colleges and universities throughout the United States. (CT)