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Sample records for radiation resistant tumors

  1. Analysis of DNA methylation and gene expression in radiation-resistant head and neck tumors

    Science.gov (United States)

    Chen, Xiaofei; Liu, Liang; Mims, Jade; Punska, Elizabeth C; Williams, Kristin E; Zhao, Weiling; Arcaro, Kathleen F; Tsang, Allen W; Zhou, Xiaobo; Furdui, Cristina M

    2015-01-01

    Resistance to radiation therapy constitutes a significant challenge in the treatment of head and neck squamous cell cancer (HNSCC). Alteration in DNA methylation is thought to play a role in this resistance. Here, we analyzed DNA methylation changes in a matched model of radiation resistance for HNSCC using the Illumina HumanMethylation450 BeadChip. Our results show that compared to radiation-sensitive cells (SCC-61), radiation-resistant cells (rSCC-61) had a significant increase in DNA methylation. After combining these results with microarray gene expression data, we identified 84 differentially methylated and expressed genes between these 2 cell lines. Ingenuity Pathway Analysis revealed ILK signaling, glucocorticoid receptor signaling, fatty acid α-oxidation, and cell cycle regulation as top canonical pathways associated with radiation resistance. Validation studies focused on CCND2, a protein involved in cell cycle regulation, which was identified as hypermethylated in the promoter region and downregulated in rSCC-61 relative to SCC-61 cells. Treatment of rSCC-61 and SCC-61 with the DNA hypomethylating agent 5-aza-2'deoxycitidine increased CCND2 levels only in rSCC-61 cells, while treatment with the control reagent cytosine arabinoside did not influence the expression of this gene. Further analysis of HNSCC data from The Cancer Genome Atlas found increased methylation in radiation-resistant tumors, consistent with the cell culture data. Our findings point to global DNA methylation status as a biomarker of radiation resistance in HNSCC, and suggest a need for targeted manipulation of DNA methylation to increase radiation response in HNSCC. PMID:25961636

  2. Acquired Tumor Cell Radiation Resistance at the Treatment Site Is Mediated Through Radiation-Orchestrated Intercellular Communication

    Energy Technology Data Exchange (ETDEWEB)

    Aravindan, Natarajan, E-mail: naravind@ouhsc.edu [Department of Radiation Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (United States); Aravindan, Sheeja; Pandian, Vijayabaskar; Khan, Faizan H.; Ramraj, Satish Kumar; Natt, Praveen [Department of Radiation Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (United States); Natarajan, Mohan [Department of Pathology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas (United States)

    2014-03-01

    Purpose: Radiation resistance induced in cancer cells that survive after radiation therapy (RT) could be associated with increased radiation protection, limiting the therapeutic benefit of radiation. Herein we investigated the sequential mechanistic molecular orchestration involved in radiation-induced radiation protection in tumor cells. Results: Radiation, both in the low-dose irradiation (LDIR) range (10, 50, or 100 cGy) or at a higher, challenge dose IR (CDIR), 4 Gy, induced dose-dependent and sustained NFκB-DNA binding activity. However, a robust and consistent increase was seen in CDIR-induced NFκB activity, decreased DNA fragmentation, apoptosis, and cytotoxicity and attenuation of CDIR-inhibited clonal expansion when the cells were primed with LDIR prior to challenge dose. Furthermore, NFκB manipulation studies with small interfering RNA (siRNA) silencing or p50/p65 overexpression unveiled the influence of LDIR-activated NFκB in regulating CDIR-induced DNA fragmentation and apoptosis. LDIR significantly increased the transactivation/translation of the radiation-responsive factors tumor necrosis factor-α (TNF-α), interleukin-1α (IL-1α), cMYC, and SOD2. Coculture experiments exhibit LDIR-influenced radiation protection and increases in cellular expression, secretion, and activation of radiation-responsive molecules in bystander cells. Individual gene-silencing approach with siRNAs coupled with coculture studies showed the influence of LDIR-modulated TNF-α, IL-1α, cMYC, and SOD2 in induced radiation protection in bystander cells. NFκB inhibition/overexpression studies coupled with coculture experiments demonstrated that TNF-α, IL-1α, cMYC, and SOD2 are selectively regulated by LDIR-induced NFκB. Conclusions: Together, these data strongly suggest that scattered LDIR-induced NFκB-dependent TNF-α, IL-1α, cMYC, and SOD2 mediate radiation protection to the subsequent challenge dose in tumor cells.

  3. Molecular Imaging Biomarkers of Resistance to Radiation Therapy for Spontaneous Nasal Tumors in Canines

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    Bradshaw, Tyler J. [Department of Medical Physics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin (United States); Bowen, Stephen R. [Departments of Radiation Oncology and Radiology, University of Washington, Seattle, Washington (United States); Deveau, Michael A. [Department of Small Animal Clinical Sciences, Texas A& M University, College Station, Texas (United States); Kubicek, Lyndsay [Angell Animal Medical Center, Boston, Massachusetts (United States); White, Pamela [Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin (United States); Bentzen, Søren M. [Division of Biostatistics and Bioinformatics, University of Maryland Greenebaum Cancer Center, and Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, Maryland (United States); Chappell, Richard J. [Department of Biostatistics and Medical Informatics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin (United States); Forrest, Lisa J. [Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin (United States); Jeraj, Robert, E-mail: rjeraj@wisc.edu [Department of Medical Physics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin (United States); Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin (United States)

    2015-03-15

    Purpose: Imaging biomarkers of resistance to radiation therapy can inform and guide treatment management. Most studies have so far focused on assessing a single imaging biomarker. The goal of this study was to explore a number of different molecular imaging biomarkers as surrogates of resistance to radiation therapy. Methods and Materials: Twenty-two canine patients with spontaneous sinonasal tumors were treated with accelerated hypofractionated radiation therapy, receiving either 10 fractions of 4.2 Gy each or 10 fractions of 5.0 Gy each to the gross tumor volume. Patients underwent fluorodeoxyglucose (FDG)-, fluorothymidine (FLT)-, and Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM)-labeled positron emission tomography/computed tomography (PET/CT) imaging before therapy and FLT and Cu-ATSM PET/CT imaging during therapy. In addition to conventional maximum and mean standardized uptake values (SUV{sub max}; SUV{sub mean}) measurements, imaging metrics providing response and spatiotemporal information were extracted for each patient. Progression-free survival was assessed according to response evaluation criteria in solid tumor. The prognostic value of each imaging biomarker was evaluated using univariable Cox proportional hazards regression. Multivariable analysis was also performed but was restricted to 2 predictor variables due to the limited number of patients. The best bivariable model was selected according to pseudo-R{sup 2}. Results: The following variables were significantly associated with poor clinical outcome following radiation therapy according to univariable analysis: tumor volume (P=.011), midtreatment FLT SUV{sub mean} (P=.018), and midtreatment FLT SUV{sub max} (P=.006). Large decreases in FLT SUV{sub mean} from pretreatment to midtreatment were associated with worse clinical outcome (P=.013). In the bivariable model, the best 2-variable combination for predicting poor outcome was high midtreatment FLT SUV{sub max} (P=.022) in

  4. Sensitivity to ionizing radiation and chemotherapeutic agents in gemcitabine-resistant human tumor cell lines

    NARCIS (Netherlands)

    van Bree, Chris; Castro Kreder, Natasja; Loves, Willem J. P.; Franken, Nicolaas A. P.; Peters, Godefridus J.; Haveman, Jaap

    2002-01-01

    Purpose: To determine cross-resistance to anti-tumor treatments in 2',2'difluorodeoxycytidine (dFdC, gemcitabine)-resistant human tumor cells. Methods and Materials: Human lung carcinoma cells SW-1573 (SWp) were made resistant to dFdC (SWg). Sensitivity to cisplatin (cDDP), paclitaxel,

  5. Significance of Epidermal Growth Factor Receptor in the Radiation Resistance of Glioblastoma Tumors

    Science.gov (United States)

    Petrás, Miklós; Lajtos, Tamás; Pintye, Éva; Feuerstein, Burt G.; Szöllősi, János; Vereb, György

    2008-12-01

    In the United States, a dramatically increased incidence and mortality of brain tumors have been observed over the past decades. Of the ˜44 thousand new cases of primary malignant and benign brain tumors diagnosed per year, high grade astrocytomas or multiform glioblastomas show particularly bad prognosis in spite of therapeutic developments. Current management of multiform glioblastoma includes the most extensive surgical resection possible, followed by adjuvant radio- and chemotherapy. However, treatment is frequently hampered by decreased radiosensitivity of the tumor. Recent studies revealed that subpopulations of glioblastoma cells show amplified checkpoint activation of the cell cycle upon ionizing radiation, which induces overactivation of DNA repair processes and leads to maintained proliferation rate as well as clinically observed radioresistance and recurrence of the tumor over time. In addition, overexpression of some transmembrane receptors has also been implicated in radioresistance. However, the role of the overexpressed proteins can only be interpreted reliably if their multi-faceted molecular interactions are properly characterized. Thus, based on recent evidence for the functional crosstalk between certain cell adhesion molecules and receptor tyrosine kinases, we have examined the molecular interactions of the receptor tyrosine kinase EGFR and the cell adhesion molecule β1-integrin using flow cytometric and microscopic fluorescence resosnance energy transfer (FRET) measurements on two cellular model systems showing similar expression patterns to low and high grade astrocytomas. On the one hand, U251 glioblastoma clones established by introducing varying amounts of extra chromosome 7 into the cells, and on the other hand stable, high and low EGFR expressing transfenctant U251 NCI sublines were investigated. The results revealed that increased EGFR and β1-integrin expression levels correlate with stronger EGFR—β1-integrin heteroassociation

  6. A study of radiation sensitivity and drug-resistance by DNA methylation in human tumor cell lines

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    Jung, Il Lae; Kim, In Gyu; Kim, Kug Chan

    2009-12-15

    It has recently been known that functional loss of tumor suppressive genes may com from DNA methylation on the chromosome. This kind of tumorigenesis has became one of the major field related to the epigenetics, whose study would be an important fundamental approach in cancer therapy market. In this study, we firstly selected two radiation-resistant mutant H460 cells, which doesn't show any significant cytotoxic effect compared to their parental wild type H460. We found that the two mutants has decreased level of PTEN, whose expression has known to be related to the cell differentiation and growth. We also found that the level of PTEN was greatly different in two lung adenocarcinoma, H460 and A549, in which more radiation-resistant A549 cells showed the decreased PTEN expression. This difference in PTEN expression between two cells was resulted from their different methylation on 5 CpG islands. We expect to know more profoundly through investigating the PTEN-related downstream genes.

  7. Biological improvement of radiation resistance

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    Chun, K. J.; Lee, Y. K.; Kim, J. S.; Kim, J. K.; Lee, S. J

    2000-08-01

    To investigate the mechanisms of gene action related to the radiation resistance in microorganisms could be essentially helpful for the development of radiation protectants and hormeric effects of low dose radiation. This book described isolation of radiation-resistant microorganisms, induction of radiation-resistant and functionally improved mutants by gamma-ray radiation, cloning and analysis of the radiation resistance related genes and analysis of the expressed proteins of the radiation resistant related genes.

  8. NEW RADIATION RESISTANT GREASES

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    DasGupta, Sharda; Slobodian, J.T.

    1962-11-20

    New radiation resistant greases were prepared from commercially available greases by carrying out radioinduced reactions with styrene. The radiation tolerances of the products were 250-1000 fold more than the starting materials and any product of similar properties now available. The various properties of the new products initially and after exposure to large radiation doses were in no case inferior to the original greases and in some respects improvements were observed. Radiation tolerance of commercial greases could be enhanced by the addition of polystyrene to form a physical mixture rather than copolymers. The reaction mechanisms involved at all stages were studied using infrared spectroscopic techniques. (P.C.H.)

  9. Maximizing Tumor Immunity With Fractionated Radiation

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    Schaue, Doerthe, E-mail: dschaue@mednet.ucla.edu [Department of Radiation Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA (United States); Ratikan, Josephine A.; Iwamoto, Keisuke S.; McBride, William H. [Department of Radiation Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA (United States)

    2012-07-15

    Purpose: Technologic advances have led to increased clinical use of higher-sized fractions of radiation dose and higher total doses. How these modify the pathways involved in tumor cell death, normal tissue response, and signaling to the immune system has been inadequately explored. Here we ask how radiation dose and fraction size affect antitumor immunity, the suppression thereof, and how this might relate to tumor control. Methods and Materials: Mice bearing B16-OVA murine melanoma were treated with up to 15 Gy radiation given in various-size fractions, and tumor growth followed. The tumor-specific immune response in the spleen was assessed by interferon-{gamma} enzyme-linked immunospot (ELISPOT) assay with ovalbumin (OVA) as the surrogate tumor antigen and the contribution of regulatory T cells (Tregs) determined by the proportion of CD4{sup +}CD25{sup hi}Foxp3{sup +} T cells. Results: After single doses, tumor control increased with the size of radiation dose, as did the number of tumor-reactive T cells. This was offset at the highest dose by an increase in Treg representation. Fractionated treatment with medium-size radiation doses of 7.5 Gy/fraction gave the best tumor control and tumor immunity while maintaining low Treg numbers. Conclusions: Radiation can be an immune adjuvant, but the response varies with the size of dose per fraction. The ultimate challenge is to optimally integrate cancer immunotherapy into radiation therapy.

  10. Radiation resistance of acinetobacter spp.

    Science.gov (United States)

    Whitby, James L.

    1995-02-01

    The radiation resistance of 78 different strains of Acinetobacter sp. 42 from clinical isolates and 36 from other sources were compared with 15 clinical isolates and 12 other strains from Denmark. None of the Canadian strains was as resistant as resistant-enhanced Danish strains. Four strains had D 10 values of 3.1-3.6 kGy. Irradiated and unirradiated cells from all strains grew well, when cultured in Trypticase-Soy Broth at 30°C. Most cultures grew after overnight incubation. It was concluded that there would be no difficulty in detecting these strains, using ISO methodology for establishing the radiation sterilization dose for devices.

  11. Microbial radiation-resistance mechanisms.

    Science.gov (United States)

    Jung, Kwang-Woo; Lim, Sangyong; Bahn, Yong-Sun

    2017-07-01

    Organisms living in extreme environments have evolved a wide range of survival strategies by changing biochemical and physiological features depending on their biological niches. Interestingly, organisms exhibiting high radiation resistance have been discovered in the three domains of life (Bacteria, Archaea, and Eukarya), even though a naturally radiationintensive environment has not been found. To counteract the deleterious effects caused by radiation exposure, radiation- resistant organisms employ a series of defensive systems, such as changes in intracellular cation concentration, excellent DNA repair systems, and efficient enzymatic and non-enzymatic antioxidant systems. Here, we overview past and recent findings about radiation-resistance mechanisms in the three domains of life for potential usage of such radiationresistant microbes in the biotechnology industry.

  12. Optical imaging of radiation-induced metabolic changes in radiation-sensitive and resistant cancer cells

    Science.gov (United States)

    Alhallak, Kinan; Jenkins, Samir V.; Lee, David E.; Greene, Nicholas P.; Quinn, Kyle P.; Griffin, Robert J.; Dings, Ruud P. M.; Rajaram, Narasimhan

    2017-06-01

    Radiation resistance remains a significant problem for cancer patients, especially due to the time required to definitively determine treatment outcome. For fractionated radiation therapy, nearly 7 to 8 weeks can elapse before a tumor is deemed to be radiation-resistant. We used the optical redox ratio of FAD/(FAD+NADH) to identify early metabolic changes in radiation-resistant lung cancer cells. These radiation-resistant human A549 lung cancer cells were developed by exposing the parental A549 cells to repeated doses of radiation (2 Gy). Although there were no significant differences in the optical redox ratio between the parental and resistant cell lines prior to radiation, there was a significant decrease in the optical redox ratio of the radiation-resistant cells 24 h after a single radiation exposure (p=0.01). This change in the redox ratio was indicative of increased catabolism of glucose in the resistant cells after radiation and was associated with significantly greater protein content of hypoxia-inducible factor 1 (HIF-1α), a key promoter of glycolytic metabolism. Our results demonstrate that the optical redox ratio could provide a rapid method of determining radiation resistance status based on early metabolic changes in cancer cells.

  13. Radiation therapy for metastatic spinal tumors

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    Kida, Akio; Fukuda, Haruyuki [Osaka City Univ. (Japan). Medical School; Taniguchi, Shuji; Sakai, Kazuaki

    2000-02-01

    The results of radiation therapy for metastatic spinal tumors were evaluated in terms of pain relief, improvement of neurological impairment, and survival. Between 1986 and 1995, 52 symptomatic patients with metastatic spinal tumors treated with radiation therapy were evaluated. The patients all received irradiation of megavoltage energy. Therapeutic efficacy was evaluated in terms of pain relief and improvement of neurological impairment. Pain relief was observed in 29 (61.7%) of 47 patients with pain. Therapy was effective for 17 (70.8%) of 24 patients without neurological impairment, and efficacy was detected in 12 (52.2%) of 23 patients with neurological impairment. Improvement of neurological symptoms was obtained in seven (25.0%) of 28 patients with neurological impairment. Radiation therapy was effective for pain relief in patients with metastatic spinal tumors. In patients with neurological impairment, less pain relief was observed than in those without impairment. Improvement of neurological impairment was restricted, but radiation therapy was thought to be effective in some cases in the early stage of neurological deterioration. Radiation therapy for metastatic spinal tumors contraindicated for surgery was considered effective for improvement of patients' activities of daily living. (author)

  14. Radiation therapy-associated invasive bladder tumors

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    Sella, A.; Dexeus, F.H.; Chong, C.; Ro, J.Y.; Logothetis, C.J.

    1989-03-01

    Radiotherapy-associated bladder carcinoma was found in 3.7 percent of 244 cases of advanced urothelial carcinoma. Average age at diagnosis of the bladder tumor was 63.1 years, with a mean of 20.5 years between radiation treatment and diagnosis. All 9 patients presented with gross hematuria. Eight patients had transitional cell carcinoma, 7/8 (87.5%) also had vascular or lymphatic invasion, and 1 was adenocarcinoma. Mean survival was 15.4 months (range 1-40 mos.), with a 55.5 percent one-year disease-free survival after diagnosis. Four patients died of bladder tumor, 4 were alive with no evidence of disease, and 1 was alive with metastasis.

  15. CERN selects Fujikura's radiation resistant fiber

    CERN Multimedia

    2007-01-01

    "Fujikura Europe Ltd. (search for Fujikura Europe) today announced that its radiation resistant singlemode optical fiber has been selected by CERN to provide communicaton links within the world's largest particle accelerator..."(2/3 page)

  16. Radiation-resistant fibre for particle accelerator

    CERN Multimedia

    2007-01-01

    "Radiation-resistant optical fibre is being used by CERN, the European Laboratory for Particle Physics, in the world's largest particle accelerator, the Large Hadron Collider (LHC) near Geneva." (1 page)

  17. Research of radiation-resistant microbial organisms

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    Kim, Dongho; Lim, Sangyong; Joe, Minho; Park, Haejoon; Song, Hyunpa; Im, Seunghun; Kim, Haram; Kim, Whajung; Choi, Jinsu; Park, Jongchun

    2012-01-15

    Many extremophiles including radiation-resistant bacteria Deinococcus radiodurans have special characteristics such as novel enzymes and physiological active substances different from known biological materials and are being in the spotlight of biotechnology science. In this research, basic technologies for the production of new genetic resources and microbial strains by a series of studies in radiation-resistant microbial organisms were investigated and developed. Mechanisms required for radiation-resistant in Deinococcus radiodurans were partly defined by analyzing the function of dinB, pprI, recG, DRA{sub 0}279, pprM, and two-component signal transduction systems. To apply genetic resource and functional materials from Deinococcus species, omics analysis in response to cadmium, construction of macroscopic biosensor, and characterization of carotenoids and chaperon protein were performed. Additionally, potential use of D. geothermalis in monosaccharide production from non-biodegradable plant materials was evaluated. Novel radiation resistant yeasts and bacteria were isolated and identified from environmental samples to obtain microbial and genomic resources. An optimal radiation mutant breeding method was set up for efficient and rapid isolation of target microbial mutants. Furthermore, an efficient ethanol producing mutant strain with high production yield and productivity was constructed using the breeding method in collaboration with Korea Research Institute of Bioscience and Biotechnology. Three Deinococcal bioindicators for radiation dosage confirmation after radiation sterilization process were developed. These results provide a comprehensive information for novel functional genetic elements, enzymes, and physiological active substances production or application. Eventually, industrial microbial cell factories based on radiation resistant microbial genomes can be developed and the technologies can be diffused to bioindustry continuously by this project.

  18. Development of application technology of radiation-resistant microorganism

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    Kim, Dong Ho; Lim, Sang Yong; Joe, Min Ho; Jung, Jin Woo; Jung, Sun Wook; Song, Du Sup; Choi, Young Ji [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

    2009-02-15

    The scope of the project is divided into of three parts; (i) to define the survival strategy of radiation-resistant microbes, especially Deinococcus (ii) acquisition of gene resources encoding the novel protein and related with the production of functional materials (iii) development of control technology against radiation-resistant microbes. To this aim, first, the whole transcriptional response of the D. radiodurans strain haboring pprI mutation, which plays an important role in radiation resistance, was analyzed by cDNA microarray. The anti-oxidant activity of the major carotenoid of D. radiodurans, deinoxanthin, was analyzed and the strain was constructed, in which the gene necessary for bio- synthesis of deinoxanthin is deleted. The response to cadmium of D. radiodurans was also investigated through cDNA microarray analysis. Radiogenic therapy, one of the cancer treatments, is designed to use radiation-inducible gene for the treatment. To develop the gene-transfer vehicle for radiogenic therapy, we have investigated the virulence mechanism of Salmonella, which is tumor-targeting bacteria and studied the synergistic effect of some anti-cancer agents on radiation treatment for cancer. Finally, we confirmed that irradiation could decompose a fungus toxin, patulin, into various harmless by-products.

  19. Role of Interleukin-6 in the Radiation Response of Liver Tumors

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    Chen, Miao-Fen, E-mail: miaofen@adm.cgmh.org.tw [Department of Radiation Oncology, Chang Gung Memorial Hospital, Chiayi, Taiwan (China); College of Medicine, Chang Gung University, Taiwan (China); Hsieh, Ching-Chuan [College of Medicine, Chang Gung University, Taiwan (China); Department of General Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan (China); Chen, Wen-Cheng [Department of Radiation Oncology, Chang Gung Memorial Hospital, Chiayi, Taiwan (China); College of Medicine, Chang Gung University, Taiwan (China); Lai, Chia-Hsuan [Department of Radiation Oncology, Chang Gung Memorial Hospital, Chiayi, Taiwan (China)

    2012-12-01

    Purpose: To investigate the role of interleukin (IL)-6 in biological sequelae and tumor regrowth after irradiation for hepatic malignancy, which are critical for the clinical radiation response of liver tumors. Methods and Materials: The Hepa 1-6 murine hepatocellular cancer cell line was used to examine the radiation response by clonogenic assays and tumor growth delay in vivo. After irradiation in a single dose of 6 Gy in vitro or 15 Gy in vivo, biological changes including cell death and tumor regrowth were examined by experimental manipulation of IL-6 signaling. The effects of blocking IL-6 were assessed by cells preincubated in the presence of IL-6-neutralizing antibody for 24 hours or stably transfected with IL-6-silencing vectors. The correlations among tumor responses, IL-6 levels, and myeloid-derived suppressor cells (MDSC) recruitment were examined using animal experiments. Results: Interleukin-6 expression was positively linked to irradiation and radiation resistance, as demonstrated by in vitro and in vivo experiments. Interleukin-6-silencing vectors induced more tumor inhibition and DNA damage after irradiation. When subjects were irradiated with a sublethal dose, the regrowth of irradiated tumors significantly correlated with IL-6 levels and MDSC recruitment in vivo. Furthermore, blocking of IL-6 could overcome irradiation-induced MDSC recruitment and tumor regrowth after treatment. Conclusion: These data demonstrate that IL-6 is important in determining the radiation response of liver tumor cells. Irradiation-induced IL-6 and the subsequent recruitment of MDSC could be responsible for tumor regrowth. Therefore, treatment with concurrent IL-6 inhibition could be a potential therapeutic strategy for increasing the radiation response of tumors.

  20. Bacterial and archaeal resistance to ionizing radiation

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    Confalonieri, F; Sommer, S, E-mail: fabrice.confalonieri@u-psud.fr, E-mail: suzanne.sommer@u-psud.fr [University Paris-Sud, CNRS UMR8621, Institut de Genetique et Microbiologie, Batiments 400-409, Universite Paris-Sud, 91405 Orsay (France)

    2011-01-01

    Organisms living in extreme environments must cope with large fluctuations of temperature, high levels of radiation and/or desiccation, conditions that can induce DNA damage ranging from base modifications to DNA double-strand breaks. The bacterium Deinococcus radiodurans is known for its resistance to extremely high doses of ionizing radiation and for its ability to reconstruct a functional genome from hundreds of radiation-induced chromosomal fragments. Recently, extreme ionizing radiation resistance was also generated by directed evolution of an apparently radiation-sensitive bacterial species, Escherichia coli. Radioresistant organisms are not only found among the Eubacteria but also among the Archaea that represent the third kingdom of life. They present a set of particular features that differentiate them from the Eubacteria and eukaryotes. Moreover, Archaea are often isolated from extreme environments where they live under severe conditions of temperature, pressure, pH, salts or toxic compounds that are lethal for the large majority of living organisms. Thus, Archaea offer the opportunity to understand how cells are able to cope with such harsh conditions. Among them, the halophilic archaeon Halobacterium sp and several Pyrococcus or Thermococcus species, such as Thermococcus gammatolerans, were also shown to display high level of radiation resistance. The dispersion, in the phylogenetic tree, of radioresistant prokaryotes suggests that they have independently acquired radioresistance. Different strategies were selected during evolution including several mechanisms of radiation byproduct detoxification and subtle cellular metabolism modifications to help cells recover from radiation-induced injuries, protection of proteins against oxidation, an efficient DNA repair tool box, an original pathway of DNA double-strand break repair, a condensed nucleoid that may prevent the dispersion of the DNA fragments and specific radiation-induced proteins involved in

  1. Unusual ovarian stromal tumor with radiation changes mimicking carcinoma.

    Science.gov (United States)

    Bohn, Olga L; Zhao, Chengquan; Jones, Mirka W

    2011-04-27

    Radiation-related changes including fibrosis, nuclear enlargement, hyperchromasia and cytoplasmic vacuolization may alter the appearance of normal ovarian tissue and ovarian tumors. We describe radiation-related changes in ovarian stromal neoplasm with mixed features of sclerosing stromal tumor and fibrothecoma. The right ovarian mass was discovered in a 38 year-old woman with past history of invasive squamous cell carcinoma of the cervix treated with cone biopsy and brachytherapy. The low power architecture of cellular pseudolobules and small sheets of tumor cells with scattered hyaline plaques was consisted with the pattern of combined sclerosing stromal tumor and fibrothecoma. However, the presence of severe cytologic atypia, as well as clear cell and signet ring differentiation and arrangements of tumor cells in single files and nests, raised a possibility of primary or metastatic carcinoma. The tumor cells were positive for calretinin, vimentin, inhibin, and WT1 and negative for AE1/3, cytokeratin 7 and 20, CD99, estrogen and progesterone receptors, mammaglobin, chromogranin, and S100 protein. Based on the results of immunostains and a subsequently provided history of radiation, a diagnosis of sex cord stromal tumor with mixed fibrothecoma and sclerosing stromal differentiation was made. Radiation-related atypia and fibrosis in sex cord stromal tumor may create a pattern mimicking carcinoma and therefore, in the presence of unusual histology, the use of immunohistochemistry is recommended.

  2. Unusual Ovarian Stromal Tumor with Radiation Changes Mimicking Carcinoma

    Directory of Open Access Journals (Sweden)

    Olga L. Bohn, Chengquan Zhao, Mirka W. Jones

    2011-01-01

    Full Text Available Radiation-related changes including fibrosis, nuclear enlargement, hyperchromasia and cytoplasmic vacuolization may alter the appearance of normal ovarian tissue and ovarian tumors. We describe radiation-related changes in ovarian stromal neoplasm with mixed features of sclerosing stromal tumor and fibrothecoma. The right ovarian mass was discovered in a 38 year-old woman with past history of invasive squamous cell carcinoma of the cervix treated with cone biopsy and brachytherapy. The low power architecture of cellular pseudolobules and small sheets of tumor cells with scattered hyaline plaques was consisted with the pattern of combined sclerosing stromal tumor and fibrothecoma. However, the presence of severe cytologic atypia, as well as clear cell and signet ring differentiation and arrangements of tumor cells in single files and nests, raised a possibility of primary or metastatic carcinoma. The tumor cells were positive for calretinin, vimentin, inhibin, and WT1 and negative for AE1/3, cytokeratin 7 and 20, CD99, estrogen and progesterone receptors, mammaglobin, chromogranin, and S100 protein. Based on the results of immunostains and a subsequently provided history of radiation, a diagnosis of sex cord stromal tumor with mixed fibrothecoma and sclerosing stromal differentiation was made. Radiation-related atypia and fibrosis in sex cord stromal tumor may create a pattern mimicking carcinoma and therefore, in the presence of unusual histology, the use of immunohistochemistry is recommended.

  3. Radiation oxygen biology with pulse electron paramagnetic resonance imaging in animal tumors.

    Science.gov (United States)

    Redler, Gage; Elas, Martyna; Epel, Boris; Barth, Eugene D; Halpern, Howard J

    2013-01-01

    The reduced oxygen in tumors (hypoxia) generates radiation resistance and limits tumor control probability (TCP) at radiation doses without significant normal tissue complication. Modern radiation therapy delivery with intensity-modulated radiation therapy (IMRT) enables complex, high-dose gradient patterns, which avoid sensitive human tissues and organs. EPR oxygen images may allow selection of more resistant parts of a tumor to which to deliver more radiation dose to enhance TCP. EPR O2 images are obtained using injected narrow-line, low relaxation rate trityl spin probes that enable pulse radiofrequency EPR O2 images of tumors in the legs of mice, rats, and rabbits, the latter exceeding 4 cm in size. Low relaxation rates of trityls have enabled novel T1-, rather than T2-, based oximetry, which provides near absolute pO2 imaging. Tomographic image formation and filtered back projection reconstruction are used to generate these images with fixed, linear stepped gradients. Images obtained both with T2 and T1 oximetric images have demonstrated the complex in vivo mechanism explaining the unexpected efficacy of TNFerade, a radiation-inducible adenoviral construct to locally produce TNF-induced vascular as well as radiation damage [1, 2]. The unexpected efficacy of large-dose radiation fractions is seen to be due to an interaction between host microvasculature and tumor cells producing a prompt (15 min) postradiation hypoxia, paralyzing tumor cell repair, and sensitizing tumors. Finally, cure of tumors treated to a single 50 % control dose shows a significant dependence on EPR O2 image hypoxic fractions, best shown with the fraction of voxels less than 10 Torr (HF10). We show that these O2 images provide a quantitative basis for measuring tumor and normal tissue response to abnormally low O2 levels. Measurements of vascular endothelial growth factor (VEGF) production in a specific syngeneic mouse fibrosarcoma, FSa versus fraction of tissue voxels with pO2 less than 10

  4. Oxygenation of spontaneous canine tumors during fractionated radiation therapy

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    Achermann, R.E.; Ohlerth, S.M.; Bley, C.R.; Inteeworn, N.; Schaerz, M.; Wergin, M.C.; Kaser-Hotz, B. [Section of Diagnostic Imaging and Radiation Oncology, Veterinary School, Univ. of Zurich (Switzerland); Gassmann, M. [Inst. for Veterinary Physiology, Univ. of Zurich (Switzerland); Roos, M. [Inst. for Social and Preventive Medicine, Univ. of Zurich (Switzerland)

    2004-05-01

    Background and purpose: tumor oxygenation predicts treatment outcome, and reoxygenation is considered important in the efficacy of fractionated radiation therapy. Therefore, the purpose of this study was to document the changes of the oxygenation status in spontaneous canine tumors during fractionated radiation therapy using polarographic needle electrodes. Material and methods: tumor oxygen partial pressure (pO{sub 2}) measurements were performed with the eppendorf-pO{sub 2}-Histograph. The measurements were done under general anesthesia, and probe tracks were guided with ultrasound. pO{sub 2} was measured before radiation therapy in all dogs. In patients treated with curative intent, measurements were done sequentially up to eight times (total dose: 45-59.5 Gy). Oxygenation status of the palliative patient group was examined before each fraction of radiation therapy up to five times (total dose: 24-30 Gy). Results: 15/26 tumors had a pretreatment median pO{sub 2} {<=} 10 mmHg. The pO{sub 2} values appeared to be quite variable in individual tumors during fractionated radiation therapy. The pO{sub 2} of initially hypoxic tumors (pretreatment median pO{sub 2} {<=} 10 mmHg) remained unchanged during fractionated radiotherapy, whereas in initially normoxic tumors the pO{sub 2} decreased. Conclusion: hypoxia is common in spontaneous canine tumors, as 57.7% of the recorded values were {>=} 10 mmHg. The data of this study showed that initially hypoxic tumors remained hypoxic, whereas normoxic tumors became more hypoxic. (orig.)

  5. CERN selects Fujikura's radiation resistant fibre

    CERN Multimedia

    2007-01-01

    "Fujikura today announced that its radiation resistant single mode optical fibre has been selected by CERN, the European Laboratory for Particle Physics, to provide communication links within the world's largest particle accelerator - the Large hadron Collider (LHC) - near Genevan, Switzerland. (1/2 page)

  6. CERN selects Fujikura's radiation resistant fiber

    CERN Multimedia

    2007-01-01

    "Fujikura recently announced that its radiation resistant single mode optical fiber has been selected by CERN, the European Laboratory for Particle Physics, to provide communication links within the world's largest particle accelerator - the Large Hadron Collider (LHC) - near Geneva, Switzerland." (1/2 page)

  7. Sustainably Sourced, Thermally Resistant, Radiation Hard Biopolymer

    Science.gov (United States)

    Pugel, Diane

    2011-01-01

    This material represents a breakthrough in the production, manufacturing, and application of thermal protection system (TPS) materials and radiation shielding, as this represents the first effort to develop a non-metallic, non-ceramic, biomaterial-based, sustainable TPS with the capability to also act as radiation shielding. Until now, the standing philosophy for radiation shielding involved carrying the shielding at liftoff or utilizing onboard water sources. This shielding material could be grown onboard and applied as needed prior to different radiation landscapes (commonly seen during missions involving gravitational assists). The material is a bioplastic material. Bioplastics are any combination of a biopolymer and a plasticizer. In this case, the biopolymer is a starch-based material and a commonly accessible plasticizer. Starch molecules are composed of two major polymers: amylase and amylopectin. The biopolymer phenolic compounds are common to the ablative thermal protection system family of materials. With similar constituents come similar chemical ablation processes, with the potential to have comparable, if not better, ablation characteristics. It can also be used as a flame-resistant barrier for commercial applications in buildings, homes, cars, and heater firewall material. The biopolymer is observed to undergo chemical transformations (oxidative and structural degradation) at radiation doses that are 1,000 times the maximum dose of an unmanned mission (10-25 Mrad), indicating that it would be a viable candidate for robust radiation shielding. As a comparison, the total integrated radiation dose for a three-year manned mission to Mars is 0.1 krad, far below the radiation limit at which starch molecules degrade. For electron radiation, the biopolymer starches show minimal deterioration when exposed to energies greater than 180 keV. This flame-resistant, thermal-insulating material is non-hazardous and may be sustainably sourced. It poses no hazardous

  8. Effects of radiation on metastasis and tumor cell migration.

    Science.gov (United States)

    Vilalta, Marta; Rafat, Marjan; Graves, Edward E

    2016-08-01

    It is well known that tumor cells migrate from the primary lesion to distant sites to form metastases and that these lesions limit patient outcome in a majority of cases. However, the extent to which radiation influences this process and to which migration in turn alters radiation response remains controversial. There are preclinical and clinical reports showing that focal radiotherapy can both increase the development of distant metastasis, as well as that it can induce the regression of established metastases through the abscopal effect. More recently, preclinical studies have suggested that radiation can attract migrating tumor cells and may, thereby, facilitate tumor recurrence. In this review, we summarize these phenomena and their potential mechanisms of action, and evaluate their significance for modern radiation therapy strategies.

  9. Radiation-induced nitric oxide mitigates tumor hypoxia and radioresistance in a murine SCCVII tumor model

    Energy Technology Data Exchange (ETDEWEB)

    Nagane, Masaki, E-mail: nagane@vetmed.hokudai.ac.jp [Laboratory of Radiation Biology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo (Japan); Yasui, Hironobu, E-mail: yassan@vetmed.hokudai.ac.jp [Laboratory of Radiation Biology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo (Japan); Yamamori, Tohru, E-mail: yamamorit@vetmed.hokudai.ac.jp [Laboratory of Radiation Biology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo (Japan); Zhao, Songji, E-mail: zsi@med.hokudai.ac.jp [Department of Tracer Kinetics and Bioanalysis, Graduate School of Medicine, Hokkaido University, Sapporo (Japan); Kuge, Yuji, E-mail: kuge@med.hokudai.ac.jp [Central Institute of Isotope Science, Hokkaido University, Sapporo (Japan); Tamaki, Nagara, E-mail: natamaki@med.hokudai.ac.jp [Department of Nuclear Medicine, Graduate School of Medicine, Hokkaido University, Sapporo (Japan); Kameya, Hiromi, E-mail: kameya@affrc.go.jp [Food Safety Division, National Food Research Institute, Tsukuba (Japan); Nakamura, Hideo, E-mail: naka@science-edu.org [Department of Chemistry, Hokkaido University of Education, Hakodate (Japan); Fujii, Hirotada, E-mail: hgfujii@sapmed.ac.jp [Center for Medical Education, Sapporo Medical University, Sapporo (Japan); Inanami, Osamu, E-mail: inanami@vetmed.hokudai.ac.jp [Laboratory of Radiation Biology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo (Japan)

    2013-08-02

    Highlights: •IR-induced NO increased tissue perfusion and pO{sub 2}. •IR increased NO production in tumors without changes in the mRNA and protein levels of NOS isoforms. •NOS activity assay showed that IR upregulated eNOS activity in tumors. •IR-induced NO decreased tumor hypoxia and altered tumor radiosensitivity. -- Abstract: Tumor hypoxia, which occurs mainly as a result of inadequate tissue perfusion in solid tumors, is a well-known challenge for successful radiotherapy. Recent evidence suggests that ionizing radiation (IR) upregulates nitric oxide (NO) production and that IR-induced NO has the potential to increase intratumoral circulation. However, the kinetics of NO production and the responsible isoforms for NO synthase in tumors exposed to IR remain unclear. In this study, we aimed to elucidate the mechanism by which IR stimulates NO production in tumors and the effect of IR-induced NO on tumor radiosensitivity. Hoechst33342 perfusion assay and electron spin resonance oxymetry showed that IR increased tissue perfusion and pO{sub 2} in tumor tissue. Immunohistochemical analysis using two different hypoxic probes showed that IR decreased hypoxic regions in tumors; treatment with a nitric oxide synthase (NOS) inhibitor, L-NAME, abrogated the effects of IR. Moreover, IR increased endothelial NOS (eNOS) activity without affecting its mRNA or protein expression levels in SCCVII-transplanted tumors. Tumor growth delay assay showed that L-NAME decreased the anti-tumor effect of fractionated radiation (10 Gy × 2). These results suggested that IR increased eNOS activity and subsequent tissue perfusion in tumors. Increases in intratumoral circulation simultaneously decreased tumor hypoxia. As a result, IR-induced NO increased tumor radiosensitivity. Our study provides a new insight into the NO-dependent mechanism for efficient fractionated radiotherapy.

  10. Radiation immunomodulatory gene tumor therapy of rats with intracerebral glioma tumors

    DEFF Research Database (Denmark)

    Persson, Bertil R R; Koch, Catrin Bauréus; Grafström, Gustav

    2010-01-01

    Single-fraction radiation therapy with 5 or 15 Gy (60)Co gamma radiation was combined with intraperitoneal injections of syngeneic interferon gamma (IFN-gamma)-transfected cells in rats with intracerebral N29 or N32 glioma tumors at days 7, 21 and 35 after inoculation. For intracerebral N29 tumors......, single-fraction radiation therapy with 5 or 15 Gy had no significant effect on the survival time. Immunization with IFN-gamma-transfected N29 cells significantly increased the survival time by 61%. Single-fraction radiation therapy with 5 Gy combined with immunization increased the survival time...... significantly by 87% and complete remissions by 75% while with 15 Gy the survival time increased 45% with 38% complete remissions. For intracerebral N32 tumors, single-fraction radiation therapy with 15 Gy increased the survival time significantly by 20%. Immunization by itself had no significant effect...

  11. Technological progress in radiation therapy for brain tumors

    LENUS (Irish Health Repository)

    Vernimmen, Frederik Jozef

    2014-01-01

    To achieve a good therapeutic ratio the radiation dose to the tumor should be as high as possible with the lowest possible dose to the surrounding normal tissue. This is especially the case for brain tumors. Technological ad- vancements in diagnostic imaging, dose calculations, and radiation delivery systems, combined with a better un- derstanding of the pathophysiology of brain tumors have led to improvements in the therapeutic results. The widely used technology of delivering 3-D conformal therapy with photon beams (gamma rays) produced by Li-near Accelerators has progressed into the use of Intensity modulated radiation therapy (IMRT). Particle beams have been used for several decades for radiotherapy because of their favorable depth dose characteristics. The introduction of clinically dedicated proton beam therapy facilities has improved the access for cancer patients to this treatment. Proton therapy is of particular interest for pediatric malignancies. These technical improvements are further enhanced by the evolution in tumor physiology imaging which allows for improved delineation of the tumor. This in turn opens the potential to adjust the radiation dose to maximize the radiobiological effects. The advances in both imaging and radiation therapy delivery will be discussed.

  12. Therapeutic Implications for Overcoming Radiation Resistance in Cancer Therapy

    Science.gov (United States)

    Kim, Byeong Mo; Hong, Yunkyung; Lee, Seunghoon; Liu, Pengda; Lim, Ji Hong; Lee, Yong Heon; Lee, Tae Ho; Chang, Kyu Tae; Hong, Yonggeun

    2015-01-01

    Ionizing radiation (IR), such as X-rays and gamma (γ)-rays, mediates various forms of cancer cell death such as apoptosis, necrosis, autophagy, mitotic catastrophe, and senescence. Among them, apoptosis and mitotic catastrophe are the main mechanisms of IR action. DNA damage and genomic instability contribute to IR-induced cancer cell death. Although IR therapy may be curative in a number of cancer types, the resistance of cancer cells to radiation remains a major therapeutic problem. In this review, we describe the morphological and molecular aspects of various IR-induced types of cell death. We also discuss cytogenetic variations representative of IR-induced DNA damage and genomic instability. Most importantly, we focus on several pathways and their associated marker proteins responsible for cancer resistance and its therapeutic implications in terms of cancer cell death of various types and characteristics. Finally, we propose radiation-sensitization strategies, such as the modification of fractionation, inflammation, and hypoxia and the combined treatment, that can counteract the resistance of tumors to IR. PMID:26569225

  13. Therapeutic Implications for Overcoming Radiation Resistance in Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Byeong Mo Kim

    2015-11-01

    Full Text Available Ionizing radiation (IR, such as X-rays and gamma (γ-rays, mediates various forms of cancer cell death such as apoptosis, necrosis, autophagy, mitotic catastrophe, and senescence. Among them, apoptosis and mitotic catastrophe are the main mechanisms of IR action. DNA damage and genomic instability contribute to IR-induced cancer cell death. Although IR therapy may be curative in a number of cancer types, the resistance of cancer cells to radiation remains a major therapeutic problem. In this review, we describe the morphological and molecular aspects of various IR-induced types of cell death. We also discuss cytogenetic variations representative of IR-induced DNA damage and genomic instability. Most importantly, we focus on several pathways and their associated marker proteins responsible for cancer resistance and its therapeutic implications in terms of cancer cell death of various types and characteristics. Finally, we propose radiation-sensitization strategies, such as the modification of fractionation, inflammation, and hypoxia and the combined treatment, that can counteract the resistance of tumors to IR.

  14. Myeloid-derived cells in tumors: effects of radiation.

    Science.gov (United States)

    Vatner, Ralph E; Formenti, Silvia C

    2015-01-01

    The discrepancy between the in vitro and in vivo response to radiation is readily explained by the fact that tumors do not exist independently of the host organism; cancer cells grow in the context of a complex microenvironment composed of stromal cells, vasculature, and elements of the immune system. As the antitumor effect of radiotherapy depends in part on the immune system, and myeloid-derived cells in the tumor microenvironment modulate the immune response to tumors, it follows that understanding the effect of radiation on myeloid cells in the tumor is likely to be essential for comprehending the antitumor effects of radiotherapy. In this review, we describe the phenotype and function of these myeloid-derived cells, and stress the complexity of studying this important cell compartment owing to its intrinsic plasticity. With regard to the response to radiation of myeloid cells in the tumor, evidence has emerged demonstrating that it is both model and dose dependent. Deciphering the effects of myeloid-derived cells in tumors, particularly in irradiated tumors, is key for attempting to pharmacologically modulate their actions in the clinic as part of cancer therapy. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  15. High Radiation Resistance IMM Solar Cell

    Science.gov (United States)

    Pan, Noren

    2015-01-01

    Due to high launch costs, weight reduction is a key driver for the development of new solar cell technologies suitable for space applications. This project is developing a unique triple-junction inverted metamorphic multijunction (IMM) technology that enables the manufacture of very lightweight, low-cost InGaAsP-based multijunction solar cells. This IMM technology consists of indium (In) and phosphorous (P) solar cell active materials, which are designed to improve the radiation-resistant properties of the triple-junction solar cell while maintaining high efficiency. The intrinsic radiation hardness of InP materials makes them of great interest for building solar cells suitable for deployment in harsh radiation environments, such as medium Earth orbit and missions to the outer planets. NASA Glenn's recently developed epitaxial lift-off (ELO) process also will be applied to this new structure, which will enable the fabrication of the IMM structure without the substrate.

  16. Sub-lethal radiation enhances anti-tumor immunotherapy in a transgenic mouse model of pancreatic cancer

    Directory of Open Access Journals (Sweden)

    Hanahan Douglas

    2002-05-01

    Full Text Available Abstract Background It is not uncommon to observe circulating tumor antigen-specific T lymphocytes in cancer patients despite a lack of significant infiltration and destruction of their tumors. Thus, an important goal for tumor immunotherapy is to identify ways to modulate in vivo anti-tumor immunity to achieve clinical efficacy. We investigate this proposition in a spontaneous mouse tumor model, Rip1-Tag2. Methods Experimental therapies were carried out in two distinctive trial designs, intended to either intervene in the explosive growth of small tumors, or regress bulky end-stage tumors. Rip1-Tag2 mice received a single transfer of splenocytes from Tag-specific, CD4+ T cell receptor transgenic mice, a single sub-lethal radiation, or a combination therapy in which the lymphocyte transfer was preceded by the sub-lethal radiation. Tumor burden, the extent of lymphocyte infiltration into solid tumors and host survival were used to assess the efficacy of these therapeutic approaches. Results In either intervention or regression, the transfer of Tag-specific T cells alone did not result in significant lymphocyte infiltration into solid tumors, not did it affect tumor growth or host survival. In contrast, the combination therapy resulted in significant reduction in tumor burden, increase in lymphocyte infiltration into solid tumors, and extension of survival. Conclusions The results indicate that certain types of solid tumors may be intrinsically resistant to infiltration and destruction by tumor-specific T lymphocytes. Our data suggest that such resistance can be disrupted by sub-lethal radiation. The combinatorial approach presented here merits consideration in the design of clinical trials aimed to achieve T cell-mediated anti-tumor immunity.

  17. Extreme Ionizing-Radiation-Resistant Bacterium

    Science.gov (United States)

    Vaishampayan, Parag A.; Venkateswaran, Kasthuri J.; Schwendner, Petra

    2013-01-01

    There is a growing concern that desiccation and extreme radiation-resistant, non-spore-forming microorganisms associated with spacecraft surfaces can withstand space environmental conditions and subsequent proliferation on another solar body. Such forward contamination would jeopardize future life detection or sample return technologies. The prime focus of NASA s planetary protection efforts is the development of strategies for inactivating resistance-bearing micro-organisms. Eradi cation techniques can be designed to target resistance-conferring microbial populations by first identifying and understanding their physiologic and biochemical capabilities that confers its elevated tolerance (as is being studied in Deinococcus phoenicis, as a result of this description). Furthermore, hospitals, food, and government agencies frequently use biological indicators to ensure the efficacy of a wide range of radiation-based sterilization processes. Due to their resistance to a variety of perturbations, the nonspore forming D. phoenicis may be a more appropriate biological indicator than those currently in use. The high flux of cosmic rays during space travel and onto the unshielded surface of Mars poses a significant hazard to the survival of microbial life. Thus, radiation-resistant microorganisms are of particular concern that can survive extreme radiation, desiccation, and low temperatures experienced during space travel. Spore-forming bacteria, a common inhabitant of spacecraft assembly facilities, are known to tolerate these extreme conditions. Since the Viking era, spores have been utilized to assess the degree and level of microbiological contamination on spacecraft and their associated spacecraft assembly facilities. Members of the non-sporeforming bacterial community such as Deinococcus radiodurans can survive acute exposures to ionizing radiation (5 kGy), ultraviolet light (1 kJ/m2), and desiccation (years). These resistive phenotypes of Deinococcus enhance the

  18. The influence of the stem cell marker ALDH and the EGFR-PI3 kinase act signaling pathway on the radiation resistance of human tumor cell lines; Der Einfluss des Stammzellmarkers ALDH und des EGFR-PI3 Kinase-Akt Signalwegs auf die Strahlenresistenz humaner Tumorzelllinien

    Energy Technology Data Exchange (ETDEWEB)

    Mihatsch, Julia

    2014-07-14

    Cancer is the second leading cause of death in industriated nations. Besides surgery and chemotherapy, radiotherapy (RT) is an important approach by which about 60% of patients are treated. The response of these patients to RT is very heterogenous. On the one hand, there are patients with tumors which are radiosensitive and can be cured, but on the other hand patients bear tumors which are quite resistant to radiotherapy. A Radioresistant phenotype of tumor cells causes treatment failure consequently leading to a limited response to radiotherapy. It is proposed, that radiotherapy outcome mainly depends on the potential of radiation on controlling growth, proliferation and survival of a specific population of tumor cells called cancer stem cells (CSCs) or tumor-initiating cells. Based on experimental studies so far reported it is assumed that the population of CSC varies in tumors from different entities and is relatively low compared to the tumor bulk cells in general. According to the CSC hypothesis, it might be concluded that the differential response of tumors to radiotherapy depends on CSC populations, since these supposedly slow replicating cells are able to initiate a tumor, to self renew indefinitely and to generate the differentiated progeny of a tumor. Besides the role of cancer stem cells in radiotherapy response, ionizing radiation (IR) activates the epidermal growth factor receptor (EGFR) and its downstream signaling pathways such as phosphoinositide 3-kinase (PI3K)/Akt, mitogen-activated protein kinase (MAPK) and Janus kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathways. Among these pathways, PI3K/Akt is one of the most important pathways involved in post-irradiation survival: Activation of Akt results in activation of DNA-dependent protein kinase, catalytic subunit (DNA-PKcs). DNA-PKcs is a core enzyme involved in repair of IR-induced DNA-double strand breaks (DNA-DSB) through non-homologous end joining (NHEJ). The aim of the

  19. Radiation therapy for metastatic choroidal tumors

    Energy Technology Data Exchange (ETDEWEB)

    Ochiai, Yuko; Sunakawa, Mitsuko (National Kyoto Hospital (Japan)); Hiraoka, Masahiro

    1992-03-01

    We treated 3 eyes in 2 cases of metastatic choroidal malignancy by applying x-ray angled 5deg from a linear accelerator. One case was a 35-year-old female with breast cancer metastasized in both choroids. The second was a 59-year-old male with choroidal metastasis in one eye from malignant lymphoma of the cerebellum. Immediate regression of the tumor followed in all the eyes with resolution of secondary retinal detachment. The treatment was free of complications including cataract or corneal erosion. (author).

  20. Tumor vascular disruption using various radiation types

    Directory of Open Access Journals (Sweden)

    JJ Bevelacqua

    2014-04-01

    Full Text Available The feasibility of disrupting a tumor’s vascular structure with various radiation types and radionuclides is investigated. Calculated absorbed dose profiles for photons and 4He ions suggest that low-energy beta-gamma and alpha emitting radionuclides can deposit sufficient absorbed dose to disrupt a tumor’s vascular structure while minimizing the dose outside the blood vessel. Candidate radionuclides uniformly distributed in microspheres are theoretically investigated with respect to their vascular disruption potential and to offer an alternative to 90Y microsphere therapy. Requisite activities of candidate low-energy beta-gamma and alpha emitting radionuclides to facilitate vascular disruption are calculated.

  1. WE-E-BRE-12: Tumor Microenvironment Dynamics Following Radiation

    Energy Technology Data Exchange (ETDEWEB)

    Campos, D; Niles, D; Adamson, E; Torres, A; Kissick, M; Eliceiri, K; Kimple, R [University of Wisconsin, Madison, WI (United States)

    2014-06-15

    Purpose: This work aims to understand the radiation-induced interplay between tumor oxygenation and metabolic activity. These dynamics can potentially serve as biomarkers in assessing treatment response allowing for patient-specific adaptive radiotherapy. Methods: Using patient-derived xenografts of head and neck cancer we assessed tumor oxygenation via fiber-optic probe monitored hemoglobin saturation and Blood Oxygen Level Dependent (BOLD) MRI. Measurements were taken before and after a 10 Gy dose of radiation. Changes in metabolic activity were measured via Fluorescence Lifetime IMaging (FLIM) with the appropriate controls following a 10 Gy dose of radiation. FLIM can non-invasively monitor changes in fluorescence in response to the microenvironment including being able to detect free and bound states of the intrinsically fluorescent metabolite NADH (Nicotinamide Adenine Dinucleotide). With this information FLIM can accurately quantify the metabolic state of cells that have been radiated. To model the observed changes, a two-compartment, source-sink simulation relating hemoglobin saturation and metabolic activity was performed using MATLAB. Results: Hemoglobin saturation as measured by interstitial probe and BOLD-MRI decreased by 30% within 15 minutes following radiation. FLIM demonstrated a decrease in the mean fluorescence lifetime of NADH by 100 ps following 10 Gy indicating a shift towards glycolytic pathways. Simulation of radiation-induced alterations in tumor oxygenation demonstrated that these changes can be the result of changes in either vasculature or metabolic activity. Conclusion: Radiation induces significant changes in hemoglobin saturation and metabolic activity. These alterations occur on time scales approximately the duration of common radiation treatments. Further understanding these dynamics has important implications with regard to improvement of therapy and biomarkers of treatment response.

  2. Ultraviolet radiation-induced murine tumors produced in the absence of ultraviolet radiation-induced systemic tumor immunosuppression.

    Science.gov (United States)

    Menzies, S W; Greenoak, G E; Reeve, V E; Gallagher, C H

    1991-06-01

    Using micro-UV-irradiation versus whole-dorsal irradiation for inducing cutaneous carcinomas in Skh:HRI mice and an assay for UV radiation (UVR)-induced systemic tumor immunosuppression, the dependence upon systemic immunosuppression for the growth of UVR-induced carcinomas was examined. Squamous cell carcinomas were produced by repeated microirradiation of 0.8-cm2 middorsal skin with xenon are solar-simulated UVR. These tumors were excised from tumor-bearing animals who 7 days later were inoculated ventrally with a cloned UVR-induced squamous cell carcinoma cell line, the T51/6. This cell line only grows in UVR-induced immunosuppressed Skh:HRI mice. In two separate experiments T51/6 inocula failed to grow significantly in the previously tumor-bearing animals (1 of 13) and in unirradiated mice (0 of 19), whereas it grew in 100% (15 of 15) of animals given a whole-dorsal subcarcinogenic UVR dose from a filtered fluorescent tube solar simulator. No sinecomitant immune response to the T51/6 was found in previously UVR-induced tumor-bearing animals. In contrast to whole-dorsal UVR-induced tumors, microirradiation-induced squamous cell carcinomas, whose original growth environment lacked UVR-induced systemic tumor immunosuppression, did not grow preferentially in mice given an immunosuppressive dose of UVR. However both the whole-dorsal and microirradiation-induced tumors were shown to be poorly antigenic, since they lacked preferential growth in athymic nude mice. These observations provide evidence that UVR-induced systemic tumor immunosuppression is not necessary for the production of UVR-induced tumors. However, it does cause a positive selection pressure during tumor formation, independent of the carcinogenic effect of UVR, which affects the transplantation biology of a tumor.

  3. Radiation resistant austenitic stainless steel alloys

    Science.gov (United States)

    Maziasz, P.J.; Braski, D.N.; Rowcliffe, A.F.

    1987-02-11

    An austenitic stainless steel alloy, with improved resistance to radiation-induced swelling and helium embrittlement, and improved resistance to thermal creep at high temperatures, consisting essentially of, by weight percent: from 16 to 18% nickel; from 13 to 17% chromium; from 2 to 3% molybdenum; from 1.5 to 2.5% manganese; from 0.01 to 0.5% silicon; from 0.2 to 0.4% titanium; from 0.1 to 0.2% niobium; from 0.1 to 0.6% vanadium; from 0.06 to 0.12% carbon; from 0.01 to 0.03% nitrogen; from 0.03 to 0.08% phosphorus; from 0.005 to 0.01% boron; and the balance iron, and wherein the alloy may be thermomechanically treated to enhance physical and mechanical properties. 4 figs.

  4. A study for radiation-related tumor microenvironment

    Energy Technology Data Exchange (ETDEWEB)

    Son, Young Sook; Hong, Seok Il; Kim, Young Soon; Jin Yong Jae; Lee, Tae Hee; Chung, Eun Kyung; Yi, Jae Yeun; Park, Myung Jin; Kim, Yun Young; Kang, Sin Keun

    1999-04-01

    In this study, we attempted to elucidate the mechanism involved in radiation-induced modification and changes of biological factors and physicochemical factors of tumor microenvironment and develop techniques and agents for the modification of tumor microenvironment which is favorable for efficient radio-cancer therapy based on our basic study. We established in vitro tumor invasion and angiogenesis model, elucidated the importance of MMPs activation and the MMPs/TIMPs complex in the invasive transition of tumor. Furthermore we showed the signaling pathway for MMPs induction through EGF receptor and TGF beta 1 stimulated E-M transition. We also established primary culture of human endothelial cells and tubule forming condition which is utilized for the detection of novel angiogenic factors. We also identified hypoxia induced signaling pathway and showed that GBE improved blood perfusion which may increase the effectiveness of radio-cancer therapy.

  5. Clusterin mediates TRAIL resistance in prostate tumor cells.

    Science.gov (United States)

    Sallman, David A; Chen, Xianghong; Zhong, Bin; Gilvary, Danielle L; Zhou, Junmin; Wei, Sheng; Djeu, Julie Y

    2007-11-01

    One of the major obstacles in curing prostate cancer is the development of drug resistance to docetaxel, which is the gold standard for the treatment of this disease. It is not only imperative to discover the molecular basis of resistance but also to find therapeutic agents that can disrupt the resistant pathways. Based on initial findings that docetaxel-resistant PC3-DR and DU145-DR prostate tumor cell lines express tumor necrosis factor-related apoptosis inducing ligand (TRAIL) receptors, we examined whether TRAIL could be used as an alternative method to kill PC3-DR and DU145-DR cells. However, these tumor cells were found to be TRAIL resistant. Because PC3-DR and DU-145-DR cells were previously shown by us to be clusterin positive, we examined if clusterin could play a role in TRAIL resistance. We found that resveratrol could sensitize docetaxel-resistant tumor cells to TRAIL, and it worked by blocking clusterin expression. In particular, small interfering RNA clusterin expression in the cell lines was sufficient to produce apoptosis by TRAIL. Further analysis indicated that resveratrol functions as an effective tyrosine kinase inhibitor, similar to its analogue, piceatannol, and could inhibit Src and Jak kinases, thus resulting in loss of Stat1 activation. We have shown earlier that Stat1 is essential for gene transcription of clusterin. These results, taken together, show that resveratrol could be a useful new therapeutic agent to combat docetaxel resistance.

  6. Performance of new polymeric materials with high radiation resistance

    Energy Technology Data Exchange (ETDEWEB)

    Hill, D.J.T.; O`Donnell, J.H.; Pomery, P.J. [Univ. of Queensland, Brisbane (Australia)

    1994-12-31

    The resistance to radiation of polymeric materials with high modulus and strength, high service temperatures, high resistance to thermal oxidation, and high chemical resistance is evaluated. Different methods of assessment are considered, which require radiation doses from 0.01 to 10 MGy.

  7. Radiation therapy for intracranial germ cell tumors. Predictive value of tumor response as evaluated by computed tomography

    Energy Technology Data Exchange (ETDEWEB)

    Ogawa, Kazuhiko; Toita, Takafumi; Kakinohana, Yasumasa; Yamaguchi, Keiichiro; Miyagi, Koichi; Kinjo, Toshihiko; Yamashiro, Katsumi; Sawada, Satoshi [Ryukyu Univ., Nishihara, Okinawa (Japan). School of Medicine

    1997-07-01

    This retrospective study analyzed the outcome in patients with intracranial germ-cell tumors to determine whether tumor response during radiation therapy can predict achievement of primary local with radiation therapy alone. Between 1983 and 1993, 22 patients with untreated primary intracranial germ cell tumors received a total whole brain radiation dose of between 18 Gy and 45 Gy (mean 31.3 Gy) with or without a localized field of 10 to 36.4 Gy (mean, 22.4 Gy), or local irradiation only (1 patient). In 10 patients with pineal tumor only, who were treated first with radiation therapy, tumor response to radiation therapy was evaluated using computed tomography (CT) (at baseline, and approximately 20 Gy and 50 Gy). Areas of calcification in the tumor were subtracted from total tumor volume. Follow-up time ranged from 2 to 12 years. Five-year actuarial survival rates for patients with germinoma were 71%, 100% for patients with a teratoma component, and 100% for patients without histologic verification. Patients with germinomas or tumors suspected of being germinomas who were given more than 50 Gy had no local relapse. There was no correlation between primary local control by radiation therapy alone and initial tumor volume. The rate of tumor volume response to irradiation assessed by CT was significantly different in those patients who relapsed compared to those who did not relapse. Tumor response during radiation therapy using CT was considered to be predictive of primary local control with radiation therapy alone. (author)

  8. Radiation resistant modified polypropylene; Polipropylen modyfikowany odporny radiacyjnie

    Energy Technology Data Exchange (ETDEWEB)

    Bojarski, J.; Zimek, Z. [Institute of Nuclear Chemistry and Technology, Warsaw (Poland)

    1997-10-01

    Radiation technology for production of radiation resistant polypropylene for medical use has been presented. The method consists in radiation induced copolymerization of polypropylene with ethylene and addition of small amount of copolymer of polyethylene and vinyl acetate. The material of proposed composition has a very good mechanical properties and elevated radiation resistivity decided on possibility of radiosterilization of products made of this material and designed for medical use. 3 figs, 3 tabs.

  9. Radiation resistance of microorganisms on unsterilized infusion sets

    DEFF Research Database (Denmark)

    Christensen, E. Ahrensburg; Kristensen, H.; Hoborn, J.

    1991-01-01

    Three different methods were used for detecting and isolating microorganisms with high radiation resistance from the microbial contamination on infusion sets prior to sterilization. By all three methods, microorganisms with a radiation resistance high enough to be a critical factor in a steriliza......Three different methods were used for detecting and isolating microorganisms with high radiation resistance from the microbial contamination on infusion sets prior to sterilization. By all three methods, microorganisms with a radiation resistance high enough to be a critical factor...

  10. Lack of ultraviolet mutagenesis in radiation-resistant bacteria

    Energy Technology Data Exchange (ETDEWEB)

    Tempest, P.R.; Moseley, B.E.B. (Edinburgh Univ. (UK). Dept. of Microbiology)

    1982-01-01

    Ultraviolet (UV) radiation did not induce rifampicin-resistant mutants in populations of the taxonomically-related radiation-resistant bacteria Deinococcus radiodurans, D. radiopugnans, D. radiophilus and D. proteolyticus, although such mutants arose spontaneously at a low frequency and at a high frequency after treatment of cultures with N-nitroso compounds. The radiation-resistant bacteria Arthrobacter radiotolerans and P-30-A were also UV-mutable. We conclude that the radiation-resistant bacteria repair UV-induced DNA damage accurately and lack an error-prone pathway for the repair of such damage.

  11. Tumor Heterogeneity, Single-Cell Sequencing, and Drug Resistance

    Directory of Open Access Journals (Sweden)

    Felix Schmidt

    2016-06-01

    Full Text Available Tumor heterogeneity has been compared with Darwinian evolution and survival of the fittest. The evolutionary ecosystem of tumors consisting of heterogeneous tumor cell populations represents a considerable challenge to tumor therapy, since all genetically and phenotypically different subpopulations have to be efficiently killed by therapy. Otherwise, even small surviving subpopulations may cause repopulation and refractory tumors. Single-cell sequencing allows for a better understanding of the genomic principles of tumor heterogeneity and represents the basis for more successful tumor treatments. The isolation and sequencing of single tumor cells still represents a considerable technical challenge and consists of three major steps: (1 single cell isolation (e.g., by laser-capture microdissection, fluorescence-activated cell sorting, micromanipulation, whole genome amplification (e.g., with the help of Phi29 DNA polymerase, and transcriptome-wide next generation sequencing technologies (e.g., 454 pyrosequencing, Illumina sequencing, and other systems. Data demonstrating the feasibility of single-cell sequencing for monitoring the emergence of drug-resistant cell clones in patient samples are discussed herein. It is envisioned that single-cell sequencing will be a valuable asset to assist the design of regimens for personalized tumor therapies based on tumor subpopulation-specific genetic alterations in individual patients.

  12. Severe hypoxia induces chemo-resistance in clinical cervical tumors through MVP over-expression

    Directory of Open Access Journals (Sweden)

    Apolinario Rosa M

    2009-08-01

    Full Text Available Abstract Oxygen molecule modulates tumour response to radiotherapy. Higher radiation doses are required under hypoxic conditions to induce cell death. Hypoxia may inhibit the non-homologous end-joining DNA repair through down regulating Ku70/80 expression. Hypoxia induces drug resistance in clinical tumours, although the mechanism is not clearly elucidated. Vaults are ribonucleoprotein particles with a hollow barrel-like structure composed of three proteins: major vault protein (MVP, vault poly(ADP-ribose polymerase, and telomerase associated protein-1 and small untranslated RNA. Over-expression of MVP has been associated with chemotherapy resistance. Also, it has been related to poor outcome in patients treated with radiotherapy alone. The aim of the present study was to assess the relation of Major Vault Protein expression and tumor hypoxia in clinical cervical tumors. MVP, p53 and angiogenesis, together with tumor oxygenation, were determined in forty-three consecutive patients suffering from localized cervix carcinoma. High MVP expression was related to severe hypoxia compared to low MVP expressing tumors (p = 0.022. Tumors over-expressing MVP also showed increased angiogenesis (p = 0.003. Besides it, in this study we show for the first time that severe tumor hypoxia is associated with high MVP expression in clinical cervical tumors. Up-regulation of MVP by hypoxia is of critical relevance as chemotherapy is currently a standard treatment for those patients. From our results it could be suggested that hypoxia not only induces increased genetic instability, oncogenic properties and metastatization, but through the correlation observed with MVP expression, another pathway of chemo and radiation resistance could be developed.

  13. Mitochondrial mutagenesis induced by tumor-specific radiation bystander effects.

    LENUS (Irish Health Repository)

    Gorman, Sheeona

    2012-02-01

    The radiation bystander effect is a cellular process whereby cells not directly exposed to radiation display cellular alterations similar to directly irradiated cells. Cellular targets including mitochondria have been postulated to play a significant role in this process. In this study, we utilized the Random Mutation Capture assay to quantify the levels of random mutations and deletions in the mitochondrial genome of bystander cells. A significant increase in the frequency of random mitochondrial mutations was found at 24 h in bystander cells exposed to conditioned media from irradiated tumor explants (p = 0.018). CG:TA mutations were the most abundant lesion induced. A transient increase in the frequency of random mitochondrial deletions was also detected in bystander cells exposed to conditioned media from tumor but not normal tissue at 24 h (p = 0.028). The increase in both point mutations and deletions was transient and not detected at 72 h. To further investigate mitochondrial dysfunction, mitochondrial membrane potential and reactive oxygen species were assessed in these bystander cells. There was a significant reduction in mitochondrial membrane potential and this was positively associated with the frequency of random point mutation and deletions in bystander cells treated with conditioned media from tumor tissue (r = 0.71, p = 0.02). This study has shown that mitochondrial genome alterations are an acute consequence of the radiation bystander effect secondary to mitochondrial dysfunction and suggests that this cannot be solely attributable to changes in ROS levels alone.

  14. Elevated Rate of Genome Rearrangements in Radiation-Resistant Bacteria.

    Science.gov (United States)

    Repar, Jelena; Supek, Fran; Klanjscek, Tin; Warnecke, Tobias; Zahradka, Ksenija; Zahradka, Davor

    2017-04-01

    A number of bacterial, archaeal, and eukaryotic species are known for their resistance to ionizing radiation. One of the challenges these species face is a potent environmental source of DNA double-strand breaks, potential drivers of genome structure evolution. Efficient and accurate DNA double-strand break repair systems have been demonstrated in several unrelated radiation-resistant species and are putative adaptations to the DNA damaging environment. Such adaptations are expected to compensate for the genome-destabilizing effect of environmental DNA damage and may be expected to result in a more conserved gene order in radiation-resistant species. However, here we show that rates of genome rearrangements, measured as loss of gene order conservation with time, are higher in radiation-resistant species in multiple, phylogenetically independent groups of bacteria. Comparison of indicators of selection for genome organization between radiation-resistant and phylogenetically matched, nonresistant species argues against tolerance to disruption of genome structure as a strategy for radiation resistance. Interestingly, an important mechanism affecting genome rearrangements in prokaryotes, the symmetrical inversions around the origin of DNA replication, shapes genome structure of both radiation-resistant and nonresistant species. In conclusion, the opposing effects of environmental DNA damage and DNA repair result in elevated rates of genome rearrangements in radiation-resistant bacteria. Copyright © 2017 Repar et al.

  15. Effects of radiation on tumor hemodynamics and NF-kappaB in breast tumors

    Science.gov (United States)

    Stantz, Keith M.; Cao, Ning; Liu, Bo; Cao, Minsong; Chin-Sinex, Helen; Mendonca, Marc; Li, Jian Jian

    2010-02-01

    Purpose: The purpose of this study is to monitor in vivo the IR dose dependent response of NF-κB and tumor hemodynamics as a function of time. Material and Methods: An MDA-231 breast cancer cell line was stably transfected with a firefly luciferase gene within the NF-kappaB promoter. Tumors on the right flank irradiated with a single fractionated dose of 5Gy or 10Gy. Over two weeks, photoacoustic spectroscopy (PCT-S), bioluminescence imaging (BLI), and dynamic contrast enhanced CT (DCE-CT) was used to monitor hemoglobin status, NF-kappaB expression, and physiology, respectively. Results: From the BLI, an increase in NF-kappaB expression was observed in both the right (irradiation) and left (nonirradiated) tumors, which peaked at 8-12 hours, returned to basal levels after 24 hours, and increased a second time from 3 to 7 days. This data identifies both a radiation-induced bystander effect and a bimodal longitudinal response associated with NF-κB-controlled luciferase promoter. The physiological results from DCE-CT measured an increase in perfusion (26%) two days after radiation and both a decrease in perfusion and an increase in fp by week 1 (10Gy cohort). PCT-S measured increased levels of oxygen saturation two days post IR, which did not change after 1 week. Initially, NF-κB would modify hemodynamics to increase oxygen delivery after IR insult. The secondary response appears to modulate tumor angiogenesis. Conclusions: A bimodal response to radiation was detected with NF-kappaB-controlled luciferase reporter with a concomitant hemodynamic response associated with tumor hypoxia. Experiments are being performed to increase statistics.

  16. Platelet-Activating Factor Receptor Ligands Protect Tumor Cells from Radiation-Induced Cell Death

    Directory of Open Access Journals (Sweden)

    Ildefonso Alves da Silva-Junior

    2018-02-01

    Full Text Available Irradiation generates oxidized phospholipids that activate platelet-activating factor receptor (PAFR associated with pro-tumorigenic effects. Here, we investigated the involvement of PAFR in tumor cell survival after irradiation. Cervical cancer samples presented higher levels of PAF-receptor gene (PTAFR when compared with normal cervical tissue. In cervical cancer patients submitted to radiotherapy (RT, the expression of PTAFR was significantly increased. Cervical cancer-derived cell lines (C33, SiHa, and HeLa and squamous carcinoma cell lines (SCC90 and SCC78 express higher levels of PAFR mRNA and protein than immortalized keratinocytes. Gamma radiation increased PAFR expression and induced PAFR ligands and prostaglandin E2 (PGE2 in these tumor cells. The blocking of PAFR with the antagonist CV3938 before irradiation inhibited PGE2 and increased tumor cells death. Similarly, human carcinoma cells transfected with PAFR (KBP were more resistant to radiation compared to those lacking the receptor (KBM. PGE2 production by irradiated KBP cells was also inhibited by CV3988. These results show that irradiation of carcinoma cells generates PAFR ligands that protect tumor cells from death and suggests that the combination of RT with a PAFR antagonist could be a promising strategy for cancer treatment.

  17. Induction of tumor necrosis factor expression and resistance in a human breast tumor cell line.

    OpenAIRE

    Spriggs, D; Imamura, K; Rodriguez, C; Horiguchi, J; Kufe, D W

    1987-01-01

    Tumor necrosis factor (TNF) is a polypeptide cytokine that is cytotoxic to some but not all tumor cells. The basis for resistance to the cytotoxic effects of this agent remains unclear. We have studied the development of TNF resistance in human ZR-75-1 breast carcinoma cells. ZR-75-1 cells have undetectable levels of TNF RNA and protein. However, TNF transcripts are transiently induced in these cells by exposure to recombinant human TNF. This induction of TNF RNA is associated with production...

  18. Synthesis and radiation resistance of fullerenes and fullerene derivatives

    Energy Technology Data Exchange (ETDEWEB)

    Shilin, V. A., E-mail: shilin@pnpi.spb.ru; Lebedev, V. T.; Sedov, V. P.; Szhogina, A. A. [St. Petersburg Nuclear Physics Institute, National Research Centre “Kurchatov Institute” (Russian Federation)

    2016-07-15

    The parameters of an electric-arc facility for the synthesis of fullerenes and endohedral metallofullerenes are optimized. The resistance of C{sub 60} and C{sub 70} fullerenes and C{sub 60}(OH){sub 30} and C{sub 70}(OH){sub 30} fullerenols against neutron irradiation is studied. It is established that the radiation resistance of the fullerenes is higher than that of the fullerenols, but the radiation resistance of the Gd@C{sub 2n} endometallofullerenes is lower than that of the corresponding Gd@C{sub 2n}(OH){sub 38} fullerenols. The radiation resistance of mixtures of Me@C{sub 2n}(OH){sub 38} (Me = Gd, Tb, Sc, Fe, and Pr) endometallofullerenes with C{sub 60}(OH){sub 30} is determined. The factors affecting the radiation resistance of the fullerenes and fullerenols are discussed.

  19. Synthesis and radiation resistance of fullerenes and fullerene derivatives

    Science.gov (United States)

    Shilin, V. A.; Lebedev, V. T.; Sedov, V. P.; Szhogina, A. A.

    2016-07-01

    The parameters of an electric-arc facility for the synthesis of fullerenes and endohedral metallofullerenes are optimized. The resistance of C60 and C70 fullerenes and C60(OH)30 and C70(OH)30 fullerenols against neutron irradiation is studied. It is established that the radiation resistance of the fullerenes is higher than that of the fullerenols, but the radiation resistance of the Gd@C2 n endometallofullerenes is lower than that of the corresponding Gd@C2 n (OH)38 fullerenols. The radiation resistance of mixtures of Me@C2 n (OH)38 ( Me = Gd, Tb, Sc, Fe, and Pr) endometallofullerenes with C60(OH)30 is determined. The factors affecting the radiation resistance of the fullerenes and fullerenols are discussed.

  20. Microbiology: this one that resists to radiations; Microbiologie: celle qui resiste aux radiations

    Energy Technology Data Exchange (ETDEWEB)

    Dupin, L

    2003-02-01

    This bacterium called Deinococcus radiodurans has a surprising resistant to radiations. It can endure 1.5 millions of rads, that is to say two hundred times more than Escherichia coli and three hundred more than man. The radiations break the DNA. the system of cell repair can correct a part of the breaks but rarely the totality. Then it often lead to genetic abnormality appearance. This bacterium is able to correct an important number of errors. Some of researchers explain that the cell is divided in four compartments, where are stored copies of genetic information. When DNA is broken, the fragments are dispersed but stay in the genetic structure. The repair system has only to catch the fragment to the bearer strands and the DNA copies can travel from a compartment to another. Some researcher think they have to look for structure genes of DNA but they are not accepted unanimously. (N.C.)

  1. Macrophage biology plays a central role during ionizing radiation-elicited tumor response

    Directory of Open Access Journals (Sweden)

    Qiuji Wu

    2017-08-01

    Full Text Available Radiation therapy is one of the major therapeutic modalities for most solid tumors. The anti-tumor effect of radiation therapy consists of the direct tumor cell killing, as well as the modulation of tumor microenvironment and the activation of immune response against tumors. Radiation therapy has been shown to promote immunogenic cells death, activate dendritic cells and enhance tumor antigen presentation and anti-tumor T cell activation. Radiation therapy also programs innate immune cells such as macrophages that leads to either radiosensitization or radioresistance, according to different tumors and different radiation regimen studied. The mechanisms underlying radiation-induced macrophage activation remain largely elusive. Various molecular players such as NF-κB, MAPKs, p53, reactive oxygen species, inflammasomes have been involved in these processes. The skewing to a pro-inflammatory phenotype thus results in the activation of anti-tumor immune response and enhanced radiotherapy effect. Therefore, a comprehensive understanding of the mechanism of radiation-induced macrophage activation and its role in tumor response to radiation therapy is crucial for the development of new therapeutic strategies to enhance radiation therapy efficacy.

  2. Tumourigenicity and radiation resistance of mesenchymal stem cells

    DEFF Research Database (Denmark)

    D'Andrea, Filippo Peder; Horsman, Michael Robert; Kassem, Moustapha

    2012-01-01

    Background. Cancer stem cells are believed to be more radiation resistant than differentiated tumour cells of the same origin. It is not known, however, whether normal nontransformed adult stem cells share the same radioresistance as their cancerous counterpart. Material and methods....... Nontumourigenic (TERT4) and tumourigenic (TRET20) cell lines, from an immortalised mesenchymal stem cell line, were grown in culture prior to irradiation and gene expression analysis. Radiation resistance was measured using a clonogenic assay. Differences in gene expression between the two cell lines, both under...... the intercellular matrix. These results also indicate that cancer stem cells are more radiation resistant than stem cells of the same origin....

  3. Biology of Extreme Radiation Resistance: The Way of Deinococcus radiodurans

    Science.gov (United States)

    Krisko, Anita; Radman, Miroslav

    2013-01-01

    The bacterium Deinococcus radiodurans is a champion of extreme radiation resistance that is accounted for by a highly efficient protection against proteome, but not genome, damage. A well-protected functional proteome ensures cell recovery from extensive radiation damage to other cellular constituents by molecular repair and turnover processes, including an efficient repair of disintegrated DNA. Therefore, cell death correlates with radiation-induced protein damage, rather than DNA damage, in both robust and standard species. From the reviewed biology of resistance to radiation and other sources of oxidative damage, we conclude that the impact of protein damage on the maintenance of life has been largely underestimated in biology and medicine. PMID:23818498

  4. Subacute brain atrophy after radiation therapy for malignant brain tumor

    Energy Technology Data Exchange (ETDEWEB)

    Asai, A.; Matsutani, M.; Kohno, T.; Nakamura, O.; Tanaka, H.; Fujimaki, T.; Funada, N.; Matsuda, T.; Nagata, K.; Takakura, K.

    1989-05-15

    Brain atrophy with mental and neurologic deterioration developing a few months after radiation therapy in patients without residual or recurrent brain tumors has been recognized. Two illustrative case reports of this pathologic entity are presented. Six autopsy cases with this entity including the two cases were reviewed neurologically, radiographically, and histopathologically. All patients presented progressive disturbances of mental status and consciousness, akinesia, and tremor-like involuntary movement. Computerized tomography (CT) demonstrated marked enlargement of the ventricles, moderate widening of the cortical sulci, and a moderately attenuated CT number for the white matter in all six patients. Four of the six patients had CSF drainage (ventriculoperitoneal shunt or continuous lumbar drainage), however, none of them improved. Histologic examination demonstrated swelling and loss of the myelin sheath in the white matter in all patients, and reactive astrocytosis in three of the six patients. Neither prominent neuronal loss in the cerebral cortex or basal ganglia, nor axonal loss in the white matter was generally identified. The blood vessels of the cerebral cortex and white matter were normal. Ependymal layer and the surrounding brain tissue were normal in all patients. These findings suggested that this pathologic condition results from demyelination secondary to direct neurotoxic effect of irradiation. The authors' previous report was reviewed and the differential diagnoses, the risk factors for this pathologic entity, and the indication for radiation therapy in aged patients with a malignant brain tumor are discussed.

  5. Translational research in ovarian carcinoma : cell biological aspects of drug resistance and tumor aggressiveness

    NARCIS (Netherlands)

    Zee, Ate Gerard Jan van der

    1994-01-01

    In this thesis diverse cell biological features that in cultured (ovarian) tumor cells have been linked to drug resistance and/or tumor aggressiveness are studied in tumor specimens of epithelial ovarian carcinomas.

  6. Utilization of SRNL-developed radiation-resistant polymer in high radiation environments

    Energy Technology Data Exchange (ETDEWEB)

    Skibo, A. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL)

    2017-09-27

    The radiation-resistant polymer developed by the Savannah River National Laboratory is adaptable for multiple applications to enhance polymer endurance and effectiveness in radiation environments. SRNL offers to collaborate with TEPCO in evaluation, testing, and utilization of SRNL’s radiation-resistant polymer in the D&D of the Fukushima Daiichi NPS. Refinement of the scope and associated costs will be conducted in consultation with TECPO.

  7. Radiation resistance and injury of Yersinia enterocolitica

    Energy Technology Data Exchange (ETDEWEB)

    El-Zawahry, Y.A.; Rowley, D.B.

    1979-01-01

    The D values of Yersinia enterocolitica strains IP134, IP107, and WA, irradiated at 25/sup 0/C in Trypticase soy broth, ranged from 9.7 to 11.8 krad. When irradiated in ground beef at 25 and -30/sup 0/C, the D value of strain IP107 and 19.5 and 38.8 krad, respectively. Cells suspended in Trypticase soy broth were more sensitive to storage at -20/sup 0/C than those mixed in ground beef. The percentages of inactivation and of injury (inability to form colonies in the presence of 3.0% NaCl) of cells stored in ground beef for 10 days at -20/sup 0/C were 70 and 23%, respectively. Prior irradiation did not alter the cell's sensitivity to storage at -20/sup 0/C, nor did storage at -20/sup 0/C alter the cell's resistance to irradiation at 25/sup 0/C. Added NaCl concentrations of up to 4.0% in Trypticase soy agar (TSA) (which contains 0.5% NaCl) had little effect on colony formation at 36/sup 0/C of unirradiated Y. enterocolitica. With added 4.0% NaCl, 79% of the cells formed colonies at 36/sup 0/C; with 5.0% NaCl added, no colonies were formed. Although 2.5% NaCl added to ground beef did not sensitize Y. enterocolitica cells to irradiation, when added to TSA it reduced the number of apparent radiation survivors. Cells uninjured by irradiation formed colonies on TSA when incubated at either 36 or 5/sup 0/C. More survivors of an exposure to 60 krad were capable of recovery and forming colonies on TSA when incubated at 36/sup 0/C for 1 day than at 5/sup 0/C for 14 days. This difference in count was considered a manifestation of injury to certain survivors of irradiation.

  8. Overcoming tumor resistance by heterologous adeno-poxvirus combination therapy

    Directory of Open Access Journals (Sweden)

    Markus Vähä-Koskela

    2014-01-01

    Full Text Available Successful cancer control relies on overcoming resistance to cell death and on activation of host antitumor immunity. Oncolytic viruses are particularly attractive in this regard, as they lyse infected tumor cells and trigger robust immune responses during the infection. However, repeated injections of the same virus promote antiviral rather than antitumor immunity and tumors may mount innate antiviral defenses to restrict oncolytic virus replication. In this article, we have explored if alternating the therapy virus could circumvent these problems. We demonstrate in two virus-resistant animal models a substantial delay in antiviral immune- and innate cellular response induction by alternating injections of two immunologically distinct oncolytic viruses, adenovirus, and vaccinia virus. Our results are in support of clinical development of heterologous adeno-/vaccinia virus therapy of cancer.

  9. Radiation resistance of endohedral metallofullerenols under neutron irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Szhogina, A. A.; Shilin, V. A., E-mail: allin-ok2@mail.ru; Sedov, V. P.; Lebedev, V. T. [St. Petersburg Nuclear Physics Institute, National Research Centre “Kurchatov Institute” (Russian Federation)

    2016-07-15

    The endohedral metallofullerenols Me@C{sub 2n}(OH){sub 38–40} + C{sub 2n}(OH){sub 38–40} (Me = Tb, Sc, Gd, Fe, Pr, Mo) have been obtained and their radiation resistance under irradiation by a neutron flux of 8 × 10{sup 13} cm{sup –2} s{sup –1} has been studied. The factors affecting the radiation resistance of endohedral metallofullerenols are discussed.

  10. WE-E-BRE-06: High-Dose Microbeam Radiation Induces Different Responses in Tumor Microenvironment Compared to Conventional Seamless Radiation in Window Chamber Tumor Models

    Energy Technology Data Exchange (ETDEWEB)

    Chang, S; Zhang, J; Hadsell, M [UNC School of Medicine, Chapel Hill, NC (United States); Fontanella, A; Schroeder, T; Palmer, G; Dewhirst, M [Duke University, Durham, NC (United States); Boss, M [North Carolina State University, Raleigh, NC (United States); Berman, K [School of Veterinary Medicine, University of Glasgow, Glasgow, Scotland (United Kingdom)

    2014-06-15

    Purpose: Microbeam radiation therapy and GRID therapy are different forms of Spatially-Fractioned Radiation Therapy (SFRT) that is fundamentally different from the conventional seamless and temporally fractionated radiation therapy. SFRT is characterized by a ultra-high dose (10s –100s Gy) dose single treatment with drastic inhomogeneity pattern of given spatial frequencies. Preclinical and limited clinical studies have shown that the SFRT treatments may offer significant improvements in reducing treatment toxicity, especially for those patients who have not benefited from the state-of-the-art radiation therapy approaches. This preliminary study aims to elucidate the underlying working mechanisms of SFRT, which currently remains poorly understood. Methods: A genetically engineered 4T1 murine mammary carcinoma cell line and nude mice skin fold window chamber were used. A nanotechnology-based 160kV x-ray irradiator delivered 50Gy (entrance dose) single treatments of microbeam or seamless radiation. Animals were in 3 groups: mock, seamless radiation, and 300μm microbeam radiation. The windows were imaged using a hyperspectral system to capture total hemoglobin/saturation, GFP fluorescence emission, RFP fluorescence emission, and vessel density at 9 time points up to 7 days post radiation. Results: We found unique physiologic changes in different tumor/normal tissue regions and differential effects between seamless and microbeam treatments. They include 1) compared to microbeam and mock radiation seamless radiation damaged more microvasculature in tumor-surrounding normal tissue, 2) a pronounced angiogenic effect was observed with vascular proliferation in the microbeam irradiated portion of the tumor days post treatment (no such effect observed in seamless and mock groups), and 3) a notable change in tumor vascular orientation was observed where vessels initially oriented parallel to the beam length were replaced by vessels running perpendicular to the irradiation

  11. Tumor Radiation Therapy Creates Therapeutic Vaccine Responses to the Colorectal Cancer Antigen GUCY2C

    Energy Technology Data Exchange (ETDEWEB)

    Witek, Matthew [Department of Radiation Oncology, Kimmel Cancer Center, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania (United States); Blomain, Erik S.; Magee, Michael S.; Xiang, Bo; Waldman, Scott A. [Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania (United States); Snook, Adam E., E-mail: adam.snook@jefferson.edu [Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania (United States)

    2014-04-01

    Purpose: Radiation therapy (RT) is thought to produce clinical responses in cancer patients, not only through direct toxicity to cancer cells and supporting tumor stroma cells, but also through activation of immunologic effectors. More recently, RT has potentiated the local and systemic effects of cancer immunotherapy (IT). However, combination regimens that maximize immunologic and clinical efficacy remain undefined. Methods and Materials: We evaluated the impact of local RT on adenoviral-mediated vaccination against the colorectal cancer antigen GUCY2C (Ad5-GUCY2C) in a murine subcutaneous tumor model using mouse CT26 colon cancer cells (CT26-GUCY2C). Immune responses were assessed by ELISpot, and clinical responses were assessed by tumor size and incidence. Results: The specific sequence of tumor-directed RT preceding Ad5-GUCY2C IT transformed inactive therapeutic Ad5-GUCY2C vaccination into a curative vaccine. GUCY2C-specific T cell responses were amplified (P<.05), tumor eradication was maximized (P<.01), and tumor volumes were minimized (P<.001) in mice whose tumors were irradiated before, compared with after, Ad5-GUCY2C vaccination. The immunologic and antitumor efficacy of Ad5-GUCY2C was amplified comparably by unfractionated (8 Gy × 1), or biologically equivalent doses of fractionated (3.5 Gy × 3), RT. The antitumor effects of sequential RT and IT (RT-IT) depended on expression of GUCY2C by tumor cells and the adenoviral vaccine vector, and tumor volumes were inversely related to the magnitude of GUCY2C-specific T cell responses. Moreover, mice cured of CT26-GUCY2C tumors by RT-IT showed long-lasting antigen-dependent protection, resisting tumors formed by GUCY2C-expressing 4T1 breast cancer cells inoculated 50 days after CT26 cells. Conclusions: Optimal sequencing of RT and IT amplifies antigen-specific local and systemic immune responses, revealing novel acute and long-term therapeutic antitumor protection. These observations underscore the importance

  12. Tumor

    Science.gov (United States)

    ... peanut plants (aflatoxins) Excessive sunlight exposure Genetic problems Obesity Radiation exposure Viruses Types of tumors known to be caused by or linked with viruses are: Cervical cancer (human papillomavirus) Most anal cancers (human papillomavirus) Some ...

  13. Radiation Resistance and Gain of Homogeneous Ring Quasi-Array

    DEFF Research Database (Denmark)

    Knudsen, H. L.

    1954-01-01

    that increases uniformly along the circle. Such quasi-arrays are azimuthally omnidirectional, and the radiated field will be mainly horizontally polarized and concentrated around the plane of the circle. In this paper expressions are obtained for the radiation resistance and the gain of homogeneous ring quasi...

  14. Tumor Cells Surviving Exposure to Proton or Photon Radiation Share a Common Immunogenic Modulation Signature, Rendering Them More Sensitive to T Cell–Mediated Killing

    Energy Technology Data Exchange (ETDEWEB)

    Gameiro, Sofia R.; Malamas, Anthony S. [Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (United States); Bernstein, Michael B. [Division of Radiation Oncology, M. D. Anderson Cancer Center, Houston, Texas (United States); Tsang, Kwong Y. [Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (United States); Vassantachart, April; Sahoo, Narayan; Tailor, Ramesh; Pidikiti, Rajesh [Division of Radiation Oncology, M. D. Anderson Cancer Center, Houston, Texas (United States); Guha, Chandan P. [Department of Radiation Oncology, Montefiore Medical Center, Bronx, New York (United States); Hahn, Stephen M.; Krishnan, Sunil [Division of Radiation Oncology, M. D. Anderson Cancer Center, Houston, Texas (United States); Hodge, James W., E-mail: jh241d@nih.gov [Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (United States)

    2016-05-01

    Purpose: To provide the foundation for combining immunotherapy to induce tumor antigen–specific T cells with proton radiation therapy to exploit the activity of those T cells. Methods and Materials: Using cell lines of tumors frequently treated with proton radiation, such as prostate, breast, lung, and chordoma, we examined the effect of proton radiation on the viability and induction of immunogenic modulation in tumor cells by flow cytometric and immunofluorescent analysis of surface phenotype and the functional immune consequences. Results: These studies show for the first time that (1) proton and photon radiation induced comparable up-regulation of surface molecules involved in immune recognition (histocompatibility leukocyte antigen, intercellular adhesion molecule 1, and the tumor-associated antigens carcinoembryonic antigen and mucin 1); (2) proton radiation mediated calreticulin cell-surface expression, increasing sensitivity to cytotoxic T-lymphocyte killing of tumor cells; and (3) cancer stem cells, which are resistant to the direct cytolytic activity of proton radiation, nonetheless up-regulated calreticulin after radiation in a manner similar to non-cancer stem cells. Conclusions: These findings offer a rationale for the use of proton radiation in combination with immunotherapy, including for patients who have failed radiation therapy alone or have limited treatment options.

  15. A Novel Radiation-Resistant Yeast, Filobasidium elegans RRY1

    Energy Technology Data Exchange (ETDEWEB)

    Singh, Harinder; Kim, Ha Ram; Song, Hyun Pa; Lim, Sang Yong; Kim, Dong Ho [Korea Atomic Energy Research Institute, Jeongeup (Korea, Republic of)

    2012-05-15

    The tolerance to ionizing radiation stress is present among different classes and species of organisms. As listed by Rainey et al., ionizing radiation resistant organisms were isolated from a variety of different sources like processed/canned food items, paper industry, soil and water samples. Apart from extensively reported bacteria and Archea group, many fungal species like Aspergillus, Curvularia, Alternaria, Cryptococcus, and Ustilago maydis have been found to be resistant to ionizing radiation. However, different environmental sources are constantly been explored for novel radioresistant organisms, which can help in understanding the molecular mechanism behind these extreme stress responses. On the basis of this, present study was initiated to find novel radiation resistant yeast from sea water source

  16. Radiation Resistant Magnets for the RIA Fragment Separator

    CERN Document Server

    Zeller, Al; Gupta, Ramesh C; Ronningen, Reginald; Sherrill, Bradley

    2005-01-01

    The high radiation fields around the production target and the beam dump in the fragment separator at the Rare Isotope Accelerator requires that radiation resistant magnets be used. Because large apertures and high gradients are required for the quadrupoles and similar demanding requirements for the dipole and sextupoles, resistive coils are difficult to justify. The radiation heating of any materials at liquid helium temperatures also requires that superconducting versions of the magnets have low cold-masses. The final optical design has taken the practical magnets limits into account and sizes and fields adjusted to what is believed to be achievable with technology that is possible with sufficient R&D. Designs with higher obtainable current densities and having good radiation tolerances that use superconducting coils are presented, as well as the radiation transport calculations that drive the material parameters.

  17. Computational Modeling of Medical Images of Brain Tumor Patients for Optimized Radiation Therapy Planning

    DEFF Research Database (Denmark)

    Agn, Mikael

    In brain tumor radiation therapy, the aim is to maximize the delivered radiation dose to the targeted tumor and at the same time minimize the dose to sensitive healthy structures – so-called organs-at-risk (OARs). When planning a radiation therapy session, the tumor and the OARs therefore need...... to be delineated on medical images of the patient’s head, to be able to optimize a radiation dose plan. In clinical practice, the delineation is performed manually with limited assistance from automatic procedures, which is both time-consuming and typically suffers from poor reproducibility. There is, therefore...

  18. Residual late radiation damage in mouse stromal tissue assessed by the tumor bed effect

    NARCIS (Netherlands)

    Haveman, Jaap; Rodermond, Hans; van Bree, Chris; Wondergem, Jan; Franken, Nicolaas A. P.

    2007-01-01

    Irradiation of murine subcutaneous stroma before implantation of tumor cells leads to retarded tumor growth. This effect is called Tumor Bed Effect (TBE) and can be used to assess the sensitivity of stromal tissue to radiation. We tested the ability of stromal tissue to recover from X-ray-induced

  19. Gamma radiation induced resistivity changes in Iron

    Science.gov (United States)

    Tundwal, Ambika; Kumar, V.; Datta, A.

    2017-03-01

    Monte Carlo Code JA-IPU is used for estimation of Frenkel pairs and their effect on change of resistivity of Iron on irradiation by gamma spectrum of Co60. The Code includes three cascade processes of incident gamma, produced electrons and recoiled atoms and simulation of the lattice structure of the target material. Change in experimentally measured resistivity of Iron is found to vary with number of Frenkel pairs as (x - 1) ln N d .

  20. RADIATION RESISTANT HTS QUADRUPOLES FOR RIA.

    Energy Technology Data Exchange (ETDEWEB)

    GUPTA,R.; ANERELLA,M.; HARRISON,M.; ET AL.

    2004-10-03

    Extremely high radiation, levels with accumulated doses comparable to those in nuclear reactors than in accelerators, and very high heat loads ({approx}15 kw) make the quadrupole magnets in the fragment separator one of the most challenging elements of the proposed Rare Isotope Accelerator (RIA). Removing large heat loads, protecting the superconducting coils against quenching, the long term survivability of magnet components, and in particular, insulation that can retain its functionality in such a harsh environment, are the major challenges associated with such magnets. A magnet design based on commercially available high temperature superconductor (HTS) and stainless steel tape insulation has been developed. HTS will efficiently remove these large heat loads and stainless steel can tolerate these large radiation doses. Construction of a model magnet has been started with several coils already built and tested. This paper presents the basic magnet design, results of the coil tests, the status and the future plans. In addition, preliminary results of radiation calculations are also presented.

  1. Recombinant human endostatin normalizes tumor vasculature and enhances radiation response in xenografted human nasopharyngeal carcinoma models.

    Directory of Open Access Journals (Sweden)

    Fang Peng

    Full Text Available BACKGROUND: Hypoxic tumor cells can reduce the efficacy of radiation. Antiangiogenic therapy may transiently "normalize" the tumor vasculature to make it more efficient for oxygen delivery. The aim of this study is to investigate whether the recombinant human endostatin (endostar can create a "vascular normalization window" to alleviate hypoxia and enhance the inhibitory effects of radiation therapy in human nasopharyngeal carcinoma (NPC in mice. METHODOLOGY/PRINCIPAL FINDINGS: Transient changes in morphology of tumor vasculature and hypoxic tumor cell fraction in response to endostar were detected in mice bearing CNE-2 and 5-8F human NPC xenografts. Various treatment schedules were tested to assess the influence of endostar on the effect of radiation therapy. Several important factors relevant to the angiogenesis were identified through immunohistochemical staining. During endostar treatment, tumor vascularity decreased, while the basement membrane and pericyte coverage associated with endothelial cells increased, which supported the idea of vessel normalization. Hypoxic tumor cell fraction also decreased after the treatment. The transient modulation of tumor physiology caused by endostar improved the effect of radiation treatment compared with other treatment schedules. The expressions of vascular endothelial growth factor (VEGF, matrix metalloproteinase-2 (MMP-2, MMP-9, and MMP-14 decreased, while the level of pigment epithelium-derived factor (PEDF increased. CONCLUSIONS: Endostar normalized tumor vasculature, which alleviated hypoxia and significantly sensitized the function of radiation in anti-tumor in human NPC. The results provide an important experimental basis for combining endostar with radiation therapy in human NPC.

  2. Radiation Therapy for Hepatocellular Carcinoma with Portal Vein Tumor Thrombosis

    Energy Technology Data Exchange (ETDEWEB)

    Park, Seung Gyu; Kim, Jin Hee; Byun, Sang Jun; Kim, Ok Bae; Hwang, Jae Seok; Oh, Young Kee; Choi, Tae Jin [Dongsan Medical Center, Keimyung University School of Medicine, Daegu (Korea, Republic of)

    2011-03-15

    To evaluate the effectiveness of radiation therapy (RT) for hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) and to analyze the prognostic factors. From December 2004 to April 2009, 70 patients who had HCC with PVTT were treated with RT at Keimyung University Dongsan Medical Center. Nineteen patients whose total dose was below 30 Gy and one patient who underwent liver transplantation were excluded. The remaining 50 patients (45 males, 5 females; median age 55 years) were analyzed. According to the LCSGJ TNM stage, there were 27 patients (54.0%) with stage III and 23 (46.0%) with stage IV. Total dose of 30-54 Gy was administered (median 45). Thirty patients (60.0%) were treated with concurrent chemoradiation therapy (CCRT). The median follow-up duration was from 13.5 months (range, 3 to 70 months). The median survival time from the start of RT was 9 months. One-year and 2-year overall survival rates were 24.9% and 11.2%, respectively. At the follow-up time, three patients (6.0%) displayed no evidence of disease. Seven patients (14.0%) were alive with disease, and 40 (80.0%) patients had expired due to disease progression. CCRT was associated with worse survival than RT alone (p=0.034). Response to RT (p=0.037), CLIP stage (p=0.017), and TNM stage (p=0.041) were statistically significant prognostic factors. There was no radiation-induced liver disease. RT is an effective and safe modality for HCC with PVTT. Further studies such as prospective randomized trials are needed to confirm the role of RT for HCC with PVTT.

  3. Metal-nanotube composites as radiation resistant materials

    Energy Technology Data Exchange (ETDEWEB)

    González, Rafael I.; Valencia, Felipe; Mella, José; Kiwi, Miguel, E-mail: m.kiwi.t@gmail.com [Departamento de Física, Facultad de Ciencias, CEDENNA, Universidad de Chile, Casilla 653, Santiago 7800024 (Chile); Duin, Adri C. T. van [Department of Mechanical and Nuclear Engineering, The Pennsylvania State University, University Park, Pennsylvania 16802 (United States); So, Kang Pyo; Li, Ju [Department of Nuclear Science and Engineering and Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 (United States); Bringa, Eduardo M. [CONICET and Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Cuyo, Mendoza 5500 (Argentina)

    2016-07-18

    The improvement of radiation resistance in nanocomposite materials is investigated by means of classical reactive molecular dynamics simulations. In particular, we study the influence of carbon nanotubes (CNTs) in an Ni matrix on the trapping and possible outgassing of He. When CNTs are defect-free, He atoms diffuse alongside CNT walls and, although there is He accumulation at the metal-CNT interface, no He trespassing of the CNT wall is observed, which is consistent with the lack of permeability of a perfect graphene sheet. However, when vacancies are introduced to mimic radiation-induced defects, He atoms penetrate CNTs, which play the role of nano-chimneys, allowing He atoms to escape the damaged zone and reduce bubble formation in the matrix. Consequently, composites made of CNTs inside metals are likely to display improved radiation resistance, particularly when radiation damage is related to swelling and He-induced embrittlement.

  4. Porous biodegradable EW62 medical implants resist tumor cell growth.

    Science.gov (United States)

    Hakimi, O; Ventura, Y; Goldman, J; Vago, R; Aghion, E

    2016-04-01

    Magnesium alloys have been widely investigated for biodegradable medical applications. However, the shielding of harmful cells (eg. bacteria or tumorous cells) from immune surveillance may be compounded by the increased porosity of biodegradable materials. We previously demonstrated the improved corrosion resistance and mechanical properties of a novel EW62 (Mg-6%Nd-2%Y-0.5%Zr)) magnesium alloy by rapid solidification followed by extrusion (RS) compared to its conventional counterpart (CC). The present in vitro study evaluated the influence of rapid solidification on cytotoxicity to murine osteosarcoma cells. We found that CC and RS corrosion extracts significantly reduced cell viability over a 24-h exposure period. Cell density was reduced over 48 h following direct contact on both CC and RS surfaces, but was further reduced on the CC surface. The direct presence of cells accelerated corrosion for both materials. The corroded RS material exhibited superior mechanical properties relative to the CC material. The data show that the improved corrosion resistance of the rapidly solidified EW62 alloy (RS) resulted in a relatively reduced cytotoxic effect on tumorous cells. Hence, the tested alloy in the form of a rapidly solidified substance may introduce a good balance between its biodegradation characteristics and cytotoxic effect towards cancerous and normal cells. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. Genetic variation in resistance to ionizing radiation

    Energy Technology Data Exchange (ETDEWEB)

    Ayala, F.J.

    1989-01-01

    The very reactive superoxide anion O[sub 2] is generated during cell respiration as well as during exposure to ionizing radiation. Organisms have evolved different mechanisms to protect against the deleterious effects of reduced oxygen species. The copper-zinc superoxide dismutase is a eukaryotic cytoplasmic enzyme that protects the cell by scavenging superoxide radicals and dismutating them to hydrogen peroxide and molecular oxygen: 20[sub 2][sup [minus

  6. Ways of providing radiation resistance of magnetic field semiconductor sensors

    CERN Document Server

    Bolshakova, I A; Holyaka, R; Matkovskii, A; Moroz, A

    2001-01-01

    Hall magnetic field sensors resistant to hard ionizing irradiation are being developed for operation under the radiation conditions of space and in charged particle accelerators. Radiation resistance of the sensors is first determined by the properties of semiconductor materials of sensitive elements; we have used microcrystals and thin layers of III-V semiconductors. Applying complex doping by rare-earth elements and isovalent impurities in certain proportions, we have obtained magnetic field sensors resistant to irradiation by fast neutrons and gamma-quanta. Tests of their radiation resistance were carried out at IBR-2 at the Joint Institute for Nuclear Research (Dubna). When exposed to neutrons with E=0.1-13 MeV and intensity of 10 sup 1 sup 0 n cm sup - sup 2 s sup - sup 1 , the main parameter of the sensors - their sensitivity to magnetic fields - changes by no more than 0.1% up to fluences of 10 sup 1 sup 4 n cm sup - sup 2. Further improvement of radiation resistance of sensor materials is expected by ...

  7. Radiation-associated breast tumors display a distinct gene expression profile

    DEFF Research Database (Denmark)

    Broeks, Annegien; Braaf, Linde M; Wessels, Lodewyk F A

    2010-01-01

    PURPOSE: Women who received irradiation for Hodgkin's lymphoma have a strong increased risk for developing breast cancer. Approximately 90% of the breast cancers in these patients can be attributed to their radiation treatment, rendering such series extremely useful to determine whether a common...... at the same age. RNA was obtained from fresh frozen tissue samples from 22 patients who developed breast cancer after Hodgkin's lymphoma (BfHL) and from 20 control breast tumors. RESULTS: Unsupervised hierarchical clustering of the profile data resulted in a clustering of the radiation-associated tumors...... radiation-associated cause underlies the carcinogenic process. METHODS AND MATERIALS: In this study we used gene expression profiling technology to assess gene expression changes in radiation-associated breast tumors compared with a set of control breast tumors of women unexposed to radiation, diagnosed...

  8. The Effects of Radiation and Dose-Fractionation on Cancer and Non-Tumor Disease Development

    Directory of Open Access Journals (Sweden)

    Gayle E. Woloschak

    2012-12-01

    Full Text Available The Janus series of radiation experiments, conducted from 1970 to 1992, explored the effects of gamma and neutron radiation on animal lifespan and disease development. Data from these experiments presents an opportunity to conduct a large scale analysis of both tumor and non-tumor disease development. This work was focused on a subset of animals from the Janus series of experiments, comparing acute or fractionated exposures of gamma or neutron radiation on the hazards associated with the development of tumor and non-tumor diseases of the liver, lung, kidney or vascular system. This study also examines how the co-occurrence of non-tumor diseases may affect tumor-associated hazards. While exposure to radiation increases the hazard of dying with tumor and non-tumor diseases, dose fractionation modulates these hazards, which varies across different organ systems. Finally, the effect that concurrent non-cancer diseases have on the hazard of dying with a tumor also differs by organ system. These results highlight the complexity in the effects of radiation on the liver, lung, kidney and vascular system.

  9. Radiation Resistance Test of Wireless Sensor Node and the Radiation Shielding Calculation

    Energy Technology Data Exchange (ETDEWEB)

    Li, Liqan; Sur, Bhaskar [Atomic Energy of Canada Limited, Ontario (Canada); Wang, Quan [University of Western Ontario, Ontario (Canada); Deng, Changjian [The University of Electronic Science and Technology, Chengdu (China); Chen, Dongyi; Jiang, Jin [Applied Physics Branch, Ontario (Korea, Republic of)

    2014-08-15

    A wireless sensor network (WSN) is being developed for nuclear power plants. Amongst others, ionizing radiation resistance is one essential requirement for WSN to be successful. This paper documents the work done in Chalk River Laboratories of Atomic Energy of Canada Limited (AECL) to test the resistance to neutron and gamma radiation of some WSN nodes. The recorded dose limit that the nodes can withstand before being damaged by the radiation is compared with the radiation environment inside a typical CANDU (CANada Deuterium Uranium) power plant reactor building. Shielding effects of polyethylene, cadmium and lead to neutron and gamma radiations are also analyzed using MCNP simulation. The shielding calculation can be a reference for the node case design when high dose rate or accidental condition (like Fukushima) is to be considered.

  10. Determination of radiation resistant of electronic components in robot system

    Energy Technology Data Exchange (ETDEWEB)

    Kang, Hee Dong [Kyungpook National University, Taegu (Korea); Kim, Do Sung [Taegu University, Taegu (Korea); Woo, Hong [Kyungsan University, Kyungsan (Korea)

    1998-04-01

    We investigated the characteristic change for the electronic components of the systems which were used in radiation area, when those were exposured by gamma rays. Bipolar transistor, FET, TTL, CMOS, operational amplifier, some capacitors, and several electronic components were selected for experiment. We applied irradiated gamma ray to the electronic components in the range of 10{sup 6} rad, by {sup 6}0Co(KAERI). We made up appropriate assessment circuit for each electronic component during the performance test, and assessed the reliability and radiation-resistance of them for the each radiation irradiation. (author). 59 refs., 35 figs., 8 tabs.

  11. Induction of Apoptosis and expression of Apoptosis-related gene products in response to radiation in murine tumors

    Energy Technology Data Exchange (ETDEWEB)

    Seong, J. S. [Yonsei Univ., Seoul (Korea, Republic of). Coll. of Medicine; Hunter, N. R.; Milas, L. [Texas Univ., Houston, TX (United States)

    1997-09-01

    To analyze the involvement of apoptosis regulatory genes p53, p21{sup waf1/cip1}, bax and bcl-2 in induction of apoptosis by radiation in murine tumors. The radiation-sensitive ovarian carcinoma OCa-I and the radiation-resistant hepatocarcinoma HCa-I were used. Tumors, 8mm in diameter, were irradiated with 25Gy and at various times after irradiation, ranging from 1 to 48 h, were analyzed histologically for apoptosis and by western blot for alterations in the expression of these genes. The p53 status of the tumors were determined by the polymerase chain reaction-single strand conformation polymorphism assay. Both tumors were positive for wild-type p53. Radiation induced apoptosis in OCa-I but not in HCa-I. Apoptosis developed rapidly, peaked at 2 h after irradiation and returned to almost the background level at 48 h. In OCa-I radiation upregulated the expression of p53, p21{sup waf1/cip1}, and the bcl-2/bax ratio was decreased. In HCa-I radiation increased the expression of both p53 and p21{sup waf1/cip1}, although the increase of the latter was small. The bcl-2/bax ratio was greatly increased. In general the observed changes occurred within a few hours after irradiation, and either preceded or coincided with development of apoptosis. The development of apoptosis required upregulation of both p53 and p21{sup waf1/cip1} as well as a decrease in bcl-2/bax ratio. In contrast, an increase in bcl-2/bax ratio prevented apoptosis in the presence of upregulated p53 and p21{sup waf1/cip1}. These findings identified the involvement of multiple oncogenes in apoptosis regulation in vivo and demonstrate the complexity that may be associated with the use of a single oncogene assessment for predicting the outcome of cancer therapy with cytotoxic agents. (author).

  12. Radiation resistance of clinical Acinetobacter spp. : A need for concern

    Energy Technology Data Exchange (ETDEWEB)

    Christensen, E.A.; Gerner-Smidt, P.; Kristensen, H. (Control Department, Statens Seruminstitut, Copenhagen (Denmark))

    1991-06-01

    As part of an epidemiological investigation of hospital infections caused by Acinetobacter spp. the radiation resistance of 15 clinical isolates and four reference strains was assessed. The radiation resistance (in D-6 values, viz. the dose necessary for reducing the initial number of colony forming units by a factor of 10(6)) was, in general, higher in the isolates of A. radioresistens than in the isolates of the A. calcoaceticus-A. baumannii complex and of A. lwoffi. However, the least resistant isolates of A. radioresistens had a D-6 value equal to or lower than the most resistant isolates of the other groups. The lowest D-6 values found were for two of the reference strains. The highest D-6 value was 35 kGy. Three isolates of A. johnsonii could not survive long enough in a dried preparation to make an assessment of the D-6 values possible. The radiation resistance of the 15 clinical isolates in the present study was higher than the resistance found in a study of similar isolates in 1970.

  13. Assessment of tumor response to radiation and vascular targeting therapy in mice using quantitative ultrasound spectroscopy

    Energy Technology Data Exchange (ETDEWEB)

    El Kaffas, Ahmed; Sadeghi-Naini, Ali; Falou, Omar; Tran, William Tyler; Czarnota, Gregory J., E-mail: gregory.czarnota@sunnybrook.ca [Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5 (Canada); Imaging Research and Physical Sciences, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5 (Canada); Departments of Medical Biophysics and Radiation Oncology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5G 1L7 (Canada); Zhou, Stephanie; Fernandes, Jason; Giles, Anoja [Imaging Research and Physical Sciences, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5 (Canada); Hashim, Amr [Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5, Canada and Imaging Research and Physical Sciences, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5 (Canada)

    2015-08-15

    Purpose: It is now recognized that the tumor vasculature is in part responsible for regulating tumor responses to radiation therapy. However, the extent to which radiation-based vascular damage contributes to tumor cell death remains unknown. In this work, quantitative ultrasound spectroscopy (QUS) methods were used to investigate the acute responses of tumors to radiation-based vascular treatments. Methods: Tumor xenografts (MDA-MB-231) were treated with single radiation doses of 2 or 8 Gy alone, or in combination with pharmacological agents that modulate vascular radiosensitivity. The midband fit, the slope, and the 0-MHz intercept QUS parameters were obtained from a linear-regression fit to the averaged power spectrum of frequency-dependent ultrasound backscatter and were used to quantify acute tumor responses following treatment administration. Power spectrums were extracted from raw volumetric radio-frequency ultrasound data obtained before and 24 h following treatment administration. These parameters have previously been correlated to tumor cell death. Staining using in situ end labeling, carbonic anhydrase 9 and cluster of differentiation 31 of tumor sections were used to assess cell death, oxygenation, and vasculature distributions, respectively. Results: Results indicate a significant midband fit QUS parameter increases of 3.2 ± 0.3 dBr and 5.4 ± 0.5 dBr for tumors treated with 2 and 8 Gy radiation combined with the antiangiogenic agent Sunitinib, respectively. In contrast, tumors treated with radiation alone demonstrated a significant midband fit increase of 4.4 ± 0.3 dBr at 8 Gy only. Preadministration of basic fibroblast growth factor, an endothelial radioprotector, acted to minimize tumor response following single large doses of radiation. Immunohistochemical analysis was in general agreement with QUS findings; an R{sup 2} of 0.9 was observed when quantified cell death was correlated with changes in midband fit. Conclusions: Results from QUS

  14. Genetic variation in resistance to ionizing radiation

    Energy Technology Data Exchange (ETDEWEB)

    Ayala, F.J.

    1992-01-01

    Results of an investigation of the gene coding for Cu, Zn superoxide dismutase (Sod) in Drosophila melanogaster seeking to understand the enzyme's role in cell protection against ionizing radiation are reported. Components of the investigation include molecular characterization of the gene; measuring the response of different genotypes to increasing levels of radiation; and investigation of the processes that maintain the Sod polymorphism in populations. While two alleles, S and F, are commonly found at the Sod locus in natural populations of D. melanogaster we have isolated from a natural population a null (CA1) mutant that yields only 3.5% of normal SOD activity. The S, F, and CA1 alleles provide a model system to investigate SOD-dependent radioresistance, because each allele yields different levels of SOD, so that S > F >> CAl. The radioprotective effects of SOD can be established by showing protective effects for the various genotypes that correspond to those inequalities. Because the allele variants studied are derived from natural populations, the proposed investigation avoids problems that arise when mutants obtained my mutagenesis are used. Moreover, each allele is studied in multiple genetic backgrounds, so that we correct for effects attributable to other loci by randomizing these effects.

  15. Influence of pretreatment polarographically measured oxygenation levels in spontaneous canine tumors treated with radiation therapy

    Energy Technology Data Exchange (ETDEWEB)

    Bley, C.R.; Ohlerth, S.; Wergin, M.; Achermann, R.; Kaser-Hotz, B. [Section of Diagnostic Imaging and Radiation Oncology, Vetsuisse Faculty, Univ. of Zurich (Switzerland); Roos, M. [Biostatistics, ISPM, Univ. of Zurich (Switzerland)

    2006-09-15

    Background and purpose: the level of hypoxia in primary tumors has been described to influence response to treatment. The aim of the present study was to investigate the impact of pretreatment oxygen level measurements in spontaneous canine tumors on treatment outcome. Material and methods: data of pretreatment tumor oxygenation status and local tumor response after primary radiation therapy in a group of spontaneously occurring tumors in dogs (n = 52) was collected. Radiation therapy was given with curative (14-17 x 3-3.5 Gy) or palliative intent (3 x 8 Gy or 4-5 x 6 Gy). Progression-free interval and overall survival were correlated to polarographically measured tumor oxygenation status. Results: in the curatively irradiated group, tumors with median p0{sub 2} values {<=} 10 mmHg tended to have shorter median progression-free interval compared to better oxygenated tumors (246 vs. 739 days). The same trend could be shown for overall survival (330 vs. 745 days), indicating a cutoff value in this region. In the group treated with lower doses of radiation, the level of oxygen was no longer found to be of prognostic value; however, in this group hemoglobin had a significant impact on outcome. Conclusion: in curatively irradiated spontaneous canine tumors, tumor hypoxia was found to be a prognostic indicator, independent of tumor histologies and volume. (orig.)

  16. Modulation of DNA methylation levels sensitizes doxorubicin-resistant breast adenocarcinoma cells to radiation-induced apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Luzhna, Lidia [Department of Biological Sciences, University of Lethbridge, AB, Canada T1K 3M4 (Canada); Kovalchuk, Olga, E-mail: olga.kovalchuk@uleth.ca [Department of Biological Sciences, University of Lethbridge, AB, Canada T1K 3M4 (Canada)

    2010-02-05

    Chemoresistant tumors often fail to respond to other cytotoxic treatments such as radiation therapy. The mechanisms of chemo- and radiotherapy cross resistance are not fully understood and are believed to be epigenetic in nature. We hypothesize that MCF-7 cells and their doxorubicin-resistant variant MCF-7/DOX cells may exhibit different responses to ionizing radiation due to their dissimilar epigenetic status. Similar to previous studies, we found that MCF-7/DOX cells harbor much lower levels of global DNA methylation than MCF-7 cells. Furthermore, we found that MCF-7/DOX cells had lower background apoptosis levels and were less responsive to radiation than MCF-7 cells. Decreased radiation responsiveness correlated to significant global DNA hypomethylation in MCF-7/DOX cells. Here, for the first time, we show that the radiation resistance of MCF-7/DOX cells can be reversed by an epigenetic treatment - the application of methyl-donor SAM. SAM-mediated reversal of DNA methylation led to elevated radiation sensitivity in MCF-7/DOX cells. Contrarily, application of SAM on the radiation sensitive and higher methylated MCF-7 cells resulted in a decrease in their radiation responsiveness. This data suggests that a fine balance of DNA methylation is needed to insure proper radiation and drug responsiveness.

  17. Intercellular Communication of Tumor Cells and Immune Cells after Exposure to Different Ionizing Radiation Qualities

    Directory of Open Access Journals (Sweden)

    Sebastian Diegeler

    2017-06-01

    Full Text Available Ionizing radiation can affect the immune system in many ways. Depending on the situation, the whole body or parts of the body can be acutely or chronically exposed to different radiation qualities. In tumor radiotherapy, a fractionated exposure of the tumor (and surrounding tissues is applied to kill the tumor cells. Currently, mostly photons, and also electrons, neutrons, protons, and heavier particles such as carbon ions, are used in radiotherapy. Tumor elimination can be supported by an effective immune response. In recent years, much progress has been achieved in the understanding of basic interactions between the irradiated tumor and the immune system. Here, direct and indirect effects of radiation on immune cells have to be considered. Lymphocytes for example are known to be highly radiosensitive. One important factor in indirect interactions is the radiation-induced bystander effect which can be initiated in unexposed cells by expression of cytokines of the irradiated cells and by direct exchange of molecules via gap junctions. In this review, we summarize the current knowledge about the indirect effects observed after exposure to different radiation qualities. The different immune cell populations important for the tumor immune response are natural killer cells, dendritic cells, and CD8+ cytotoxic T-cells. In vitro and in vivo studies have revealed the modulation of their functions due to ionizing radiation exposure of tumor cells. After radiation exposure, cytokines are produced by exposed tumor and immune cells and a modulated expression profile has also been observed in bystander immune cells. Release of damage-associated molecular patterns by irradiated tumor cells is another factor in immune activation. In conclusion, both immune-activating and -suppressing effects can occur. Enhancing or inhibiting these effects, respectively, could contribute to modified tumor cell killing after radiotherapy.

  18. Clipboard: The link between bacterial radiation resistance and cold ...

    Indian Academy of Sciences (India)

    Home; Journals; Journal of Biosciences; Volume 27; Issue 2. Clipboard: The link between bacterial radiation resistance and cold adaptation. M K Chattopadhyay. Volume 27 Issue 2 March 2002 pp 71-73 ... Author Affiliations. M K Chattopadhyay1. Centre for Cellular and Molecular Biology, Hyderabad 500 007, India ...

  19. Combined cytotoxic effects of tumor necrosis factor-alpha with various cytotoxic agents in tumor cell lines that are drug resistant due to mutated p53

    NARCIS (Netherlands)

    Sleijfer, S; Le, T. K. P.; de Jong, S.; Timmer-Bosscha, H; Withoff, S; Mulder, NH

    Several studies suggest that tumor necrosis factor-alpha (TNF) is able to overcome drug resistance in tumors. Whether TNF is able to do so in tumor cell lines that are drug resistant due to a mutation in the tumor suppressor gene p53 is unclear. Therefore, we studied the in vitro cytotoxic effects

  20. Ionizing radiation induces tumor cell lysyl oxidase secretion

    DEFF Research Database (Denmark)

    Shen, Colette J; Sharma, Ashish; Vuong, Dinh-Van

    2014-01-01

    metalloproteinases, among others, to promote tumor progression. Lysyl oxidase is known to play an important role in hypoxia-dependent cancer cell dissemination and metastasis. Here, we investigated the effects of IR on the expression and secretion of lysyl oxidase (LOX) from tumor cells. METHODS: LOX-secretion along...... with enzymatic activity was investigated in multiple tumor cell lines in response to irradiation. Transwell migration assays were performed to evaluate invasive capacity of naive tumor cells in response to IR-induced LOX. In vivo studies for confirming IR-enhanced LOX were performed employing...... immunohistochemistry of tumor tissues and ex vivo analysis of murine blood serum derived from locally irradiated A549-derived tumor xenografts. RESULTS: LOX was secreted in a dose dependent way from several tumor cell lines in response to irradiation. IR did not increase LOX-transcription but induced LOX...

  1. Deinococcus geothermalis: The Pool of Extreme Radiation Resistance Genes Shrinks

    Energy Technology Data Exchange (ETDEWEB)

    Makarova, Kira S. [National Center for Biotechnology Information; Omelchenko, Marina [National Center for Biotechnology Information; Gaidamakova, Elena [Uniformed Services University of the Health Sciences (USUHS); Matrosova, Vera [Uniformed Services University of the Health Sciences (USUHS); Vasilenko, Alexander [Uniformed Services University of the Health Sciences (USUHS); Zhai, Min [Uniformed Services University of the Health Sciences (USUHS); Lapidus, Alla L. [U.S. Department of Energy, Joint Genome Institute; Copeland, A [U.S. Department of Energy, Joint Genome Institute; Kim, Edwin [U.S. Department of Energy, Joint Genome Institute; Land, Miriam L [ORNL; Mavromatis, K [U.S. Department of Energy, Joint Genome Institute; Pitluck, Samual [U.S. Department of Energy, Joint Genome Institute; Richardson, P M [U.S. Department of Energy, Joint Genome Institute; Detter, J. Chris [U.S. Department of Energy, Joint Genome Institute; Brettin, Tom [Los Alamos National Laboratory (LANL); Saunders, Elizabeth H [Los Alamos National Laboratory (LANL); Lai, Barry [Argonne National Laboratory (ANL); Ravel, Bruce [Argonne National Laboratory (ANL); Kemner, Kenneth M [Argonne National Laboratory (ANL); Wolf, Yuri [National Center for Biotechnology Information; Sorokin, Alexei [Genetique Microbienne; Gerasimova, Anna [Research Institute of Genetics and Selection of Industrial Microorganisms, Mosco; Gelfand, Mikhail [Moscow State University; Fredrickson, James K [Pacific Northwest National Laboratory (PNNL); Koonin, Eugene [National Center for Biotechnology Information; Daly, Michael [Uniformed Services University of the Health Sciences (USUHS)

    2007-01-01

    Bacteria of the genus Deinococcus are extremely resistant to ionizing radiation (IR), ultraviolet light (UV) and desiccation. The mesophile Deinococcus radiodurans was the first member of this group whose genome was completely sequenced. Analysis of the genome sequence of D. radiodurans, however, failed to identify unique DNA repair systems. To further delineate the genes underlying the resistance phenotypes, we report the whole-genome sequence of a second Deinococcus species, the thermophile Deinococcus geothermalis, which at its optimal growth temperature is as resistant to IR, UV and desiccation as D. radiodurans, and a comparative analysis of the two Deinococcus genomes. Many D. radiodurans genes previously implicated in resistance, but for which no sensitive phenotype was observed upon disruption, are absent in D. geothermalis. In contrast, most D. radiodurans genes whose mutants displayed a radiation-sensitive phenotype in D. radiodurans are conserved in D. geothermalis. Supporting the existence of a Deinococcus radiation response regulon, a common palindromic DNA motif was identified in a conserved set of genes associated with resistance, and a dedicated transcriptional regulator was predicted. We present the case that these two species evolved essentially the same diverse set of gene families, and that the extreme stress-resistance phenotypes of the Deinococcus lineage emerged progressively by amassing cell-cleaning systems from different sources, but not by acquisition of novel DNA repair systems. Our reconstruction of the genomic evolution of the Deinococcus-Thermus phylum indicates that the corresponding set of enzymes proliferated mainly in the common ancestor of Deinococcus. Results of the comparative analysis weaken the arguments for a role of higher-order chromosome alignment structures in resistance; more clearly define and substantially revise downward the number of uncharacterized genes that might participate in DNA repair and contribute to

  2. Deinococcus geothermalis: The Pool of Extreme Radiation Resistance Genes Shrinks

    Energy Technology Data Exchange (ETDEWEB)

    Makarova, Kira S.; Omelchenko, Marina V.; Gaidamakova, Elena K.; Matrosova, Vera Y.; Vasilenko, Alexander; Zhai, Min; Lapidus, Alla; Copeland, Alex; Kim, Edwin; Land, Miriam; Mavrommatis, Konstantinos; Pitluck, Samuel; Richardson, Paul M.; Detter, Chris; Brettin, Thomas; Saunders, Elizabeth; Lai, Barry; Ravel, Bruce; Kemner, Kenneth M.; Wolf, Yuri I.; Sorokin, Alexander; Gerasimova, Anna V.; Gelfand, Mikhail S.; Fredrickson, James K.; Koonin, Eugene V.; Daly, Michael J.

    2007-07-24

    Bacteria of the genus Deinococcus are extremely resistant to ionizing radiation (IR), ultraviolet light (UV) and desiccation. The mesophile Deinococcus radiodurans was the first member of this group whose genome was completely sequenced. Analysis of the genome sequence of D. radiodurans, however, failed to identify unique DNA repair systems. To further delineate the genes underlying the resistance phenotypes, we report the whole-genome sequence of a second Deinococcus species, the thermophile Deinococcus geothermalis, which at itsoptimal growth temperature is as resistant to IR, UV and desiccation as D. radiodurans, and a comparative analysis of the two Deinococcus genomes. Many D. radiodurans genes previously implicated in resistance, but for which no sensitive phenotype was observed upon disruption, are absent in D. geothermalis. In contrast, most D. radiodurans genes whose mutants displayed a radiation-sensitive phenotype in D. radiodurans are conserved in D. geothermalis. Supporting the existence of a Deinococcus radiation response regulon, a common palindromic DNA motif was identified in a conserved set of genes associated with resistance, and a dedicated transcriptional regulator was predicted. We present the case that these two species evolved essentially the same diverse set of gene families, and that the extreme stress-resistance phenotypes of the Deinococcus lineage emerged progressively by amassing cell-cleaning systems from different sources, but not by acquisition of novel DNA repair systems. Our reconstruction of the genomic evolution of the Deinococcus-Thermus phylum indicates that the corresponding set of enzymes proliferated mainly in the common ancestor of Deinococcus. Results of the comparative analysis weaken the arguments for a role of higher-order chromosome alignment structures in resistance; more clearly define and substantially revise downward the number of uncharacterized genes that might participate in DNA repair and contribute to

  3. Deinococcus geothermalis: the pool of extreme radiation resistance genes shrinks.

    Directory of Open Access Journals (Sweden)

    Kira S Makarova

    2007-09-01

    Full Text Available Bacteria of the genus Deinococcus are extremely resistant to ionizing radiation (IR, ultraviolet light (UV and desiccation. The mesophile Deinococcus radiodurans was the first member of this group whose genome was completely sequenced. Analysis of the genome sequence of D. radiodurans, however, failed to identify unique DNA repair systems. To further delineate the genes underlying the resistance phenotypes, we report the whole-genome sequence of a second Deinococcus species, the thermophile Deinococcus geothermalis, which at its optimal growth temperature is as resistant to IR, UV and desiccation as D. radiodurans, and a comparative analysis of the two Deinococcus genomes. Many D. radiodurans genes previously implicated in resistance, but for which no sensitive phenotype was observed upon disruption, are absent in D. geothermalis. In contrast, most D. radiodurans genes whose mutants displayed a radiation-sensitive phenotype in D. radiodurans are conserved in D. geothermalis. Supporting the existence of a Deinococcus radiation response regulon, a common palindromic DNA motif was identified in a conserved set of genes associated with resistance, and a dedicated transcriptional regulator was predicted. We present the case that these two species evolved essentially the same diverse set of gene families, and that the extreme stress-resistance phenotypes of the Deinococcus lineage emerged progressively by amassing cell-cleaning systems from different sources, but not by acquisition of novel DNA repair systems. Our reconstruction of the genomic evolution of the Deinococcus-Thermus phylum indicates that the corresponding set of enzymes proliferated mainly in the common ancestor of Deinococcus. Results of the comparative analysis weaken the arguments for a role of higher-order chromosome alignment structures in resistance; more clearly define and substantially revise downward the number of uncharacterized genes that might participate in DNA repair and

  4. Radiation Therapy Induces Macrophages to Suppress T-Cell Responses Against Pancreatic Tumors in Mice.

    Science.gov (United States)

    Seifert, Lena; Werba, Gregor; Tiwari, Shaun; Giao Ly, Nancy Ngoc; Nguy, Susanna; Alothman, Sara; Alqunaibit, Dalia; Avanzi, Antonina; Daley, Donnele; Barilla, Rocky; Tippens, Daniel; Torres-Hernandez, Alejandro; Hundeyin, Mautin; Mani, Vishnu R; Hajdu, Cristina; Pellicciotta, Ilenia; Oh, Philmo; Du, Kevin; Miller, George

    2016-06-01

    The role of radiation therapy in the treatment of patients with pancreatic ductal adenocarcinoma (PDA) is controversial. Randomized controlled trials investigating the efficacy of radiation therapy in patients with locally advanced unresectable PDA have reported mixed results, with effects ranging from modest benefit to worse outcomes compared with control therapies. We investigated whether radiation causes inflammatory cells to acquire an immune-suppressive phenotype that limits the therapeutic effects of radiation on invasive PDAs and accelerates progression of preinvasive foci. We investigated the effects of radiation therapy in p48(Cre);LSL-Kras(G12D) (KC) and p48(Cre);LSLKras(G12D);LSL-Trp53(R172H) (KPC) mice, as well as in C57BL/6 mice with orthotopic tumors grown from FC1242 cells derived from KPC mice. Some mice were given neutralizing antibodies against macrophage colony-stimulating factor 1 (CSF1 or MCSF) or F4/80. Pancreata were exposed to doses of radiation ranging from 2 to 12 Gy and analyzed by flow cytometry. Pancreata of KC mice exposed to radiation had a higher frequency of advanced pancreatic intraepithelial lesions and more foci of invasive cancer than pancreata of unexposed mice (controls); radiation reduced survival time by more than 6 months. A greater proportion of macrophages from radiation treated invasive and preinvasive pancreatic tumors had an immune-suppressive, M2-like phenotype compared with control mice. Pancreata from mice exposed to radiation had fewer CD8(+) T cells than controls, and greater numbers of CD4(+) T cells of T-helper 2 and T-regulatory cell phenotypes. Adoptive transfer of T cells from irradiated PDA to tumors of control mice accelerated tumor growth. Radiation induced production of MCSF by PDA cells. A neutralizing antibody against MCSF prevented radiation from altering the phenotype of macrophages in tumors, increasing the anti-tumor T-cell response and slowing tumor growth. Radiation treatment causes macrophages

  5. Epidermal growth factor receptor expression in radiation-induced dog lung tumors by immunocytochemical localization

    Energy Technology Data Exchange (ETDEWEB)

    Leung, F.L.; Park, J.F.; Dagle, G.E.

    1993-06-01

    In studies to determine the role of growth factors in radiation-induced lung cancer, epidermal growth factor (EGFR) expression was examined by immunocytochemistry in 51 lung tumors from beagle dogs exposed to inhaled plutonium; 21 of 51 (41%) tumors were positive for EGFR. The traction of tumors positive for EGFR and the histological type of EGFR-positive tumors in the plutonium-exposed dogs were not different from spontaneous dog lung tumors, In which 36% were positive for EGFR. EGFR involvement in Pu-induced lung tumors appeared to be similar to that in spontaneous lung tumors. However, EGFR-positive staining was observed in only 1 of 16 tumors at the three lowest Pu exposure levels, compared to 20 of 35 tumors staining positive at the two highest Pu exposure levels. The results in dogs were in good agreement with the expression of EGFR reported in human non-small cell carcinoma of the lung, suggesting that Pu-induced lung tumors in the dog may be a suitable animal model to investigate the role of EGFR expression in lung carcinogenesis. In humans, EGFR expression in lung tumors has been primarily related to histological tumor types. In individual dogs with multiple primary lung tumors, the tumors were either all EGFR positive or EGFR negative, suggesting that EGFR expression may be related to the response of the individual dog as well as to the histological type of tumor.

  6. Genetic variation in resistance to ionizing radiation. [Annual report, 1989

    Energy Technology Data Exchange (ETDEWEB)

    Ayala, F.J.

    1989-12-31

    The very reactive superoxide anion O{sub 2} is generated during cell respiration as well as during exposure to ionizing radiation. Organisms have evolved different mechanisms to protect against the deleterious effects of reduced oxygen species. The copper-zinc superoxide dismutase is a eukaryotic cytoplasmic enzyme that protects the cell by scavenging superoxide radicals and dismutating them to hydrogen peroxide and molecular oxygen: 20{sub 2}{sup {minus}} + 2H {yields} H{sub 2}O{sub 2} + O{sub 2}. SOD had been shown to protect against ionizing radiation damage to DNA, viruses, bacteria, mammalian cells, whole mice, and Drosophila. Evidence that genetic differences may affect sensitivity to ionizing radiation has been shown in Drosophila since differences have been shown to exist between strains and resistance to radiation can evolve under natural selection.

  7. Radiation Therapy Induces Macrophages to Suppress Immune Responses Against Pancreatic Tumors in Mice

    Science.gov (United States)

    Seifert, Lena; Werba, Gregor; Tiwari, Shaun; Ly, Nancy Ngoc Giao; Nguy, Susanna; Alothman, Sara; Alqunaibit, Dalia; Avanzi, Antonina; Daley, Donnele; Barilla, Rocky; Tippens, Daniel; Torres-Hernandez, Alejandro; Hundeyin, Mautin; Mani, Vishnu R.; Hajdu, Cristina; Pellicciotta, Ilenia; Oh, Philmo; Du, Kevin; Miller, George

    2016-01-01

    Background & Aims The role of radiation therapy in the treatment of patients with pancreatic ductal adenocarcinoma (PDA) is controversial. Randomized controlled trials investigating the efficacy of radiation therapy in patients with locally advanced unresectable PDA have reported mixed results, with effects ranging from modest benefit to worse outcome, compared with control therapies. We investigated whether radiation causes inflammatory cells to acquire an immune-suppressive phenotype that limits the therapeutic effects of radiation on invasive PDAs and accelerates progression of pre-invasive foci. Methods We investigated the effects of radiation in p48Cre;LSL-KrasG12D (KC) and p48Cre;LSLKrasG12D;LSL-Trp53R172H (KPC) mice, as well as in C57BL/6 mice with orthotopic tumors grown from FC1242 cells derived from KPC mice. Some mice were given neutralizing antibodies against macrophage colony stimulating factor 1 (CSF1 or MCSF) or F4/80. Pancreata were exposed to doses of radiation ranging from 2–12 Gy and analyzed by flow cytometry. Results Pancreata of KC mice exposed to radiation had a higher frequency of advanced pancreatic intraepithelial lesions and more foci of invasive cancer than pancreata of unexposed mice (controls); radiation reduced survival time by more than 6 months. A greater proportion of macrophages from invasive and pre-invasive pancreatic tumors had an immune-suppressive, M2-like phenotype, compared with control mice. Pancreata from mice exposed to radiation had fewer CD8+ T cells than controls and greater numbers of CD4+ T cells of T-helper 2 and T-regulatory cell phenotypes. Adoptive transfer of T cells from irradiated PDA to tumors of control mice accelerated tumor growth. Radiation induced production of MCSF by PDA cells. An antibody against MCSF prevented radiation from altering the phenotype of macrophages in tumors, increasing the anti-tumor T-cell response and slowing tumor growth. Conclusions Radiation exposure causes macrophages in PDAs

  8. Isolation of Radiation-Resistant Bacteria from Mars Analog Antarctic Dry Valleys by Preselection, and the Correlation between Radiation and Desiccation Resistance.

    Science.gov (United States)

    Musilova, Michaela; Wright, Gary; Ward, John M; Dartnell, Lewis R

    2015-12-01

    Extreme radiation-resistant microorganisms can survive doses of ionizing radiation far greater than are present in the natural environment. Radiation resistance is believed to be an incidental adaptation to desiccation resistance, as both hazards cause similar cellular damage. Desert soils are, therefore, promising targets to prospect for new radiation-resistant strains. This is the first study to isolate radiation-resistant microbes by using gamma-ray exposure preselection from the extreme cold desert of the Antarctic Dry Valleys (a martian surface analogue). Halomonads, identified by 16S rRNA gene sequencing, were the most numerous survivors of the highest irradiation exposures. They were studied here for the first time for both their desiccation and irradiation survival characteristics. In addition, the association between desiccation and radiation resistance has not been investigated quantitatively before for a broad diversity of microorganisms. Thus, a meta-analysis of scientific literature was conducted to gather a larger data set. A strong correlation was found between desiccation and radiation resistance, indicating that an increase in the desiccation resistance of 5 days corresponds to an increase in the room-temperature irradiation survival of 1 kGy. Irradiation at -79°C (representative of average martian surface temperatures) increases the microbial radiation resistance 9-fold. Consequently, the survival of the cold-, desiccation-, and radiation-resistant organisms isolated here has implications for the potential habitability of dormant or cryopreserved life on Mars. Extremophiles-Halomonas sp.-Antarctica-Mars-Ionizing radiation-Cosmic rays.

  9. Inhibition of multidrug resistance-associated protein (MRP) activity by rifampicin in human multidrug-resistant lung tumor cells

    NARCIS (Netherlands)

    Courtois, A; Payen, L; Vernhet, L; de Vries, EGE; Guillouzo, A; Fardel, O

    1999-01-01

    The multidrug resistance-associated protein (MRP) is a drug efflux membrane pump conferring multidrug resistance on tumor cells. In order to look for compounds that can lead to reversal of such a resistance, the antituberculosis compound rifampicin, belonging to the chemical class of rifamycins, was

  10. Extreme resistance of bdelloid rotifers to ionizing radiation.

    Science.gov (United States)

    Gladyshev, Eugene; Meselson, Matthew

    2008-04-01

    Rotifers of class Bdelloidea are common invertebrate animals with highly unusual characteristics, including apparently obligate asexuality, the ability to resume reproduction after desiccation at any life stage, and a paucity of transposable genetic elements of types not prone to horizontal transmission. We find that bdelloids are also extraordinarily resistant to ionizing radiation (IR). Reproduction of the bdelloids Adineta vaga and Philodina roseola is much more resistant to IR than that of Euchlanis dilatata, a rotifer belonging to the desiccation-intolerant and facultatively sexual class Monogononta, and all other animals for which we have found relevant data. By analogy with the desiccation- and radiation-resistant bacterium Deinococcus radiodurans, we suggest that the extraordinary radiation resistance of bdelloid rotifers is a consequence of their evolutionary adaptation to survive episodes of desiccation encountered in their characteristic habitats and that the damage incurred in such episodes includes DNA breakage that is repaired upon rehydration. Such breakage and repair may have maintained bdelloid chromosomes as colinear pairs and kept the load of transposable genetic elements low and may also have contributed to the success of bdelloid rotifers in avoiding the early extinction suffered by most asexuals.

  11. Radiation resistance of wide-bandgap semiconductor power transistors

    Energy Technology Data Exchange (ETDEWEB)

    Hazdra, Pavel; Popelka, Stanislav [Department of Microelectronics, Czech Technical University in Prague (Czech Republic)

    2017-04-15

    Radiation resistance of state-of-the-art commercial wide-bandgap power transistors, 1700 V 4H-SiC power MOSFETs and 200 V GaN HEMTs, to the total ionization dose was investigated. Transistors were irradiated with 4.5 MeV electrons with doses up to 2000 kGy. Electrical characteristics and introduced defects were characterized by current-voltage (I-V), capacitance-voltage (C-V), and deep level transient spectroscopy (DLTS) measurements. Results show that already low doses of 4.5 MeV electrons (>1 kGy) cause a significant decrease in threshold voltage of SiC MOSFETs due to embedding of the positive charge into the gate oxide. On the other hand, other parameters like the ON-state resistance are nearly unchanged up to the dose of 20 kGy. At 200 kGy, the threshold voltage returns back close to its original value, however, the ON-state resistance increases and transconductance is lowered. This effect is caused by radiation defects introduced into the low-doped drift region which decrease electron concentration and mobility. GaN HEMTs exhibit significantly higher radiation resistance. They keep within the datasheet specification up to doses of 2000 kGy. Absence of dielectric layer beneath the gate and high concentration of carriers in the two dimensional electron gas channel are the reasons of higher radiation resistance of GaN HEMTs. Their degradation then occurs at much higher doses due to electron mobility degradation. (copyright 2016 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim)

  12. Human Genetic Marker for Resistance to Radiation and Chemicals

    Energy Technology Data Exchange (ETDEWEB)

    DR. Howard B. Lieberman

    2001-05-11

    TO characterize the human HRDAD9 gene and evaluate its potential as a biomarker to predict susceptibility to the deleterious health effects potentially caused by exposure to radiations or chemicals present at DOE hazardous waste cleanup sites. HRAD9 is a human gene that is highly conserved throughout evolution. Related genes have been isolated from yeasts and mice, underscoring its biological significance. Most of our previous work involved characterization of the yeast gene cognate, wherein it was determined that the corresponding protein plays a significant role in promoting resistance of cells to radiations and chemicals, and in particular, controlling cell growth in response to DNA damage.

  13. Visual outcome after fractionated stereotactic radiation therapy of benign anterior skull base tumors

    DEFF Research Database (Denmark)

    Astradsson, Arnar; Wiencke, Anne Katrine; Munck af Rosenschold, Per

    2014-01-01

    To determine visual outcome including the occurrence of radiation induced optic neuropathy (RION) as well as tumor control after fractionated stereotactic radiation therapy (FSRT) of benign anterior skull base meningiomas or pituitary adenomas. Thirty-nine patients treated with FSRT for anterior...

  14. Adding chemo after radiation treatment improves survival for adults with a type of brain tumor

    Science.gov (United States)

    Adults with low-grade gliomas, a form of brain tumor, who received chemotherapy following completion of radiation therapy lived longer than patients who received radiation therapy alone, according to long-term follow-up results from a NIH-supported random

  15. SU-E-J-267: Change in Mean CT Intensity of Lung Tumors During Radiation Treatment

    Energy Technology Data Exchange (ETDEWEB)

    Mahon, R; Tennyson, N; Weiss, E; Hugo, G [Virginia Commonwealth University, Richmond, VA (United States)

    2015-06-15

    Purpose: To evaluate CT intensity change of lung tumors during radiation therapy. Methods: Repeated 4D CT images were acquired on a CT simulator during the course of therapy for 27 lung cancer patients on IRB approved protocols. All subjects received definitive radiation treatment ± chemotherapy. CT scans were completed prior to treatment, and 2–7 times during the treatment course. Primary tumor was delineated by an experienced Radiation Oncologist. Contours were thresholded between −100 HU and 200 HU to remove airways and bone. Correlations between the change in the mean tumor intensity and initial tumor intensity, SUVmax, and tumor volume change rate were investigated. Reproducibility was assessed by evaluating the variation in mean intensity over all phases in 4DCT, for a subgroup of 19 subjects. Results: Reproducibility of tumor intensity between phases as characterized by the root mean square of standard deviation across 19 subjects was 1.8 HU. Subjects had a mean initial tumor intensity of 16.5 ± 11.6 HU and an overall reduction in HU by 10.3 ± 8.5 HU. Evaluation of the changes in tumor intensity during treatment showed a decrease of 0.3 ± 0.3 HU/day for all subjects, except three. No significant correlation was found between change in HU/day and initial HU intensity (p=0.53), initial PET SUVmax (p=0.69), or initial tumor volume (p=0.70). The rate of tumor volume change was weakly correlated (R{sup 2}=0.05) with HU change (p=0.01). Conclusion: Most lung cancer subjects showed a marked trend of decreasing mean tumor CT intensity throughout radiotherapy, including early in the treatment course. Change in HU/day is not correlated with other potential early predictors for response, such as SUV and tumor volume change. This Result supports future studies to evaluate change in tumor intensity on CT as an early predictor of response.

  16. CERTIFICATION OF THE RADIATION RESISTANCE OF COIL INSULATION MATERIAL

    CERN Document Server

    Polinski, J; Bogdan, P

    2013-01-01

    The goal of the WP 7.2.1 sub-task of the EuCARD program has been to determine the Nb3Sn based accelerator magnet coil electrical insulation resistance against irradiation, which will occur in future accelerators. The scope of the certification covers determination of mechanical, electrical and thermal properties changes due to irradiation. The report presents a selection of the insulation material candidates for future accelerator magnets as well as the definition of the radiation certification methodology with respect of radiation type, energy, doses and irradiation conditions. The test methods and results of the electrical and mechanical insulation materials properties degradation due to irradiation are presented. Thermal conductivity and Kapitza resistance at temperature range from 1.5 K to 2.0 K (superfluid helium conditions) are given.

  17. Simulating Space Radiation-Induced Breast Tumor Incidence Using Automata.

    Science.gov (United States)

    Heuskin, A C; Osseiran, A I; Tang, J; Costes, S V

    2016-07-01

    Estimating cancer risk from space radiation has been an ongoing challenge for decades primarily because most of the reported epidemiological data on radiation-induced risks are derived from studies of atomic bomb survivors who were exposed to an acute dose of gamma rays instead of chronic high-LET cosmic radiation. In this study, we introduce a formalism using cellular automata to model the long-term effects of ionizing radiation in human breast for different radiation qualities. We first validated and tuned parameters for an automata-based two-stage clonal expansion model simulating the age dependence of spontaneous breast cancer incidence in an unexposed U.S. We then tested the impact of radiation perturbation in the model by modifying parameters to reflect both targeted and nontargeted radiation effects. Targeted effects (TE) reflect the immediate impact of radiation on a cell's DNA with classic end points being gene mutations and cell death. They are well known and are directly derived from experimental data. In contrast, nontargeted effects (NTE) are persistent and affect both damaged and undamaged cells, are nonlinear with dose and are not well characterized in the literature. In this study, we introduced TE in our model and compared predictions against epidemiologic data of the atomic bomb survivor cohort. TE alone are not sufficient for inducing enough cancer. NTE independent of dose and lasting ∼100 days postirradiation need to be added to accurately predict dose dependence of breast cancer induced by gamma rays. Finally, by integrating experimental relative biological effectiveness (RBE) for TE and keeping NTE (i.e., radiation-induced genomic instability) constant with dose and LET, the model predicts that RBE for breast cancer induced by cosmic radiation would be maximum at 220 keV/μm. This approach lays the groundwork for further investigation into the impact of chronic low-dose exposure, inter-individual variation and more complex space radiation

  18. Designing Radiation Resistance in Materials for Fusion Energy

    Science.gov (United States)

    Zinkle, S. J.; Snead, L. L.

    2014-07-01

    Proposed fusion and advanced (Generation IV) fission energy systems require high-performance materials capable of satisfactory operation up to neutron damage levels approaching 200 atomic displacements per atom with large amounts of transmutant hydrogen and helium isotopes. After a brief overview of fusion reactor concepts and radiation effects phenomena in structural and functional (nonstructural) materials, three fundamental options for designing radiation resistance are outlined: Utilize matrix phases with inherent radiation tolerance, select materials in which vacancies are immobile at the design operating temperatures, or engineer materials with high sink densities for point defect recombination. Environmental and safety considerations impose several additional restrictions on potential materials systems, but reduced-activation ferritic/martensitic steels (including thermomechanically treated and oxide dispersion-strengthened options) and silicon carbide ceramic composites emerge as robust structural materials options. Materials modeling (including computational thermodynamics) and advanced manufacturing methods are poised to exert a major impact in the next ten years.

  19. Metformin: A Novel Biological Modifier of Tumor Response to Radiation Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Koritzinsky, Marianne, E-mail: mkoritzi@uhnresearch.ca

    2015-10-01

    Over the last decade, evidence has emerged to support a role for the antidiabetic drug metformin in the prevention and treatment of cancer. In particular, recent studies demonstrate that metformin enhances tumor response to radiation in experimental models, and retrospective analyses have shown that diabetic cancer patients treated with radiation therapy have improved outcomes if they take metformin to control their diabetes. Metformin may therefore be of utility for nondiabetic cancer patients treated with radiation therapy. The purpose of this review is to examine the data pertaining to an interaction between metformin and radiation, highlighting the essential steps needed to advance our current knowledge. There is also a focus on key biomarkers that should accompany prospective clinical trials in which metformin is being examined as a modifying agent with radiation therapy. Existing evidence supports that the mechanism underlying the ability of metformin to enhance radiation response is multifaceted, and includes direct radiosensitization as well as a reduction in tumor stem cell fraction, proliferation, and tumor hypoxia. Interestingly, metformin may enhance radiation response specifically in certain genetic backgrounds, such as in cells with loss of the tumor suppressors p53 and LKB1, giving rise to a therapeutic ratio and potential predictive biomarkers.

  20. The effect of hypofractionated radiation and magnetic nanoparticle hyperthermia on tumor immunogenicity and overall treatment response

    Science.gov (United States)

    Hoopes, P. Jack; Wagner, Robert J.; Song, Ailin; Osterberg, Bjorn; Gladstone, David J.; Bursey, Alicea A.; Fiering, Steven N.; Giustini, Andrew J.

    2017-02-01

    It is now known that many tumors develop molecular signals (immune checkpoint modulators) that inhibit an effective tumor immune response. New information also suggest that even well-known cancer treatment modalities such as radiation and hyperthermia generate potentially beneficial immune responses that have been blocked or mitigated by such immune checkpoints, or similar molecules. The cancer therapy challenge is to; a) identify these treatment-based immune signals (proteins, antigens, etc.); b) the treatment doses or regimens that produce them; and c) the mechanisms that block or have the potential to promote them. The goal of this preliminary study, using the B6 mouse - B16 tumor model, clinically relevant radiation doses and fractionation schemes (including those used clinically in hypofractionated radiation therapy), magnetic nanoparticle hyperthermia (mNPH) and sophisticated protein, immune and tumor growth analysis techniques and modulators, is to determine the effect of specific radiation or hyperthermia alone and combined on overall treatment efficacy and immunologic response mechanisms. Preliminary analysis suggests that radiation dose (10 Gy vs. 2 Gy) significantly alters the mechanism of cell death (apoptosis vs. mitosis vs. necrosis) and the resulting immunogenicity. Our hypothesis and data suggest this difference is protein/antigen and immune recognition-based. Similarly, our evidence suggest that radiation doses larger than the conventional 2 Gy dose and specific hyperthermia doses and techniques (including mNP hyperthermia treatment) can be immunologically different, and potentially superior to, the radiation and heat therapy regimens that are typically used in research and clinical practice.

  1. Dichloroacetate induces tumor-specific radiosensitivity in vitro but attenuates radiation-induced tumor growth delay in vivo.

    Science.gov (United States)

    Zwicker, F; Kirsner, A; Peschke, P; Roeder, F; Debus, J; Huber, P E; Weber, K J

    2013-08-01

    Inhibition of pyruvate dehydrogenase kinase (PDK) by dichloroacetate (DCA) can shift tumor cell metabolism from anaerobic glycolysis to glucose oxidation, with activation of mitochondrial activity and chemotherapy-dependent apoptosis. In radiotherapy, DCA could thus potentially enhance the frequently moderate apoptotic response of cancer cells that results from their mitochondrial dysfunction. The aim of this study was to investigate tumor-specific radiosensitization by DCA in vitro and in a human tumor xenograft mouse model in vivo. The interaction of DCA with photon beam radiation was investigated in the human tumor cell lines WIDR (colorectal) and LN18 (glioma), as well as in the human normal tissue cell lines HUVEC (endothelial), MRC5 (lung fibroblasts) and TK6 (lymphoblastoid). Apoptosis induction in vitro was assessed by DAPI staining and sub-G1 flow cytometry; cell survival was quantified by clonogenic assay. The effect of DCA in vivo was investigated in WIDR xenograft tumors growing subcutaneously on BALB/c-nu/nu mice, with and without fractionated irradiation. Histological examination included TUNEL and Ki67 staining for apoptosis and proliferation, respectively, as well as pinomidazole labeling for hypoxia. DCA treatment led to decreased clonogenic survival and increased specific apoptosis rates in tumor cell lines (LN18, WIDR) but not in normal tissue cells (HUVEC, MRC5, TK6). However, this significant tumor-specific radiosensitization by DCA in vitro was not reflected by the situation in vivo: The growth suppression of WIDR xenograft tumors after irradiation was reduced upon additional DCA treatment (reflected by Ki67 expression levels), although early tumor cell apoptosis rates were significantly increased by DCA. This apparently paradoxical effect was accompanied by a marked DCA-dependent induction of hypoxia in tumor-tissue. DCA induced tumor-specific radiosensitization in vitro but not in vivo. DCA also induced development of hypoxia in tumor tissue

  2. Flavopiridol potentiates the cytotoxic effects of radiation in radioresistant tumor cells in which p53 is mutated or Bcl-2 is overexpressed.

    Science.gov (United States)

    Hara, Takamitsu; Omura-Minamisawa, Motoko; Kang, Yun; Cheng, Chao; Inoue, Tomio

    2008-08-01

    Loss of the cell-cycle regulatory protein p53 or overexpression of the antiapoptotic protein Bcl-2 is associated with resistance to radiation in several types of cancer cells. Flavopiridol, a synthetic flavone, inhibits the growth of malignant tumors cells in vitro and in vivo through multiple mechanisms. The purpose of the present study is to clarify whether flavopiridol enhances the cytotoxic effects of radiation in tumor cells that contain dysfunction p53 or that overexpress Bcl-2. A human glioma cell line (A172/mp53) stably transfected with a plasmid containing mutated p53 and a human cervical cancer cell line (HeLa/bcl-2) transfected with a bcl-2 expression plasmid were used. Cells were incubated with flavopiridol for 24 h after radiation, and then cell viability was determined by a colony formation assay. Foci of phosphorylated histone H2AX were also evaluated as a sensitive indicator of DNA double-strand breaks. Compared with the parental wild-type cells, both transfected cell lines were more resistant to radiation. Post-treatment with flavopiridol increased the cytotoxic effects of radiation in both transfected cell lines, but not in their parental wild-type cell lines. Post-treatment with flavopiridol inhibited sublethal damage repair as well as the repair of DNA double-strand breaks in response to radiation. Flavopiridol enhanced the cytotoxic effect of radiation in radioresistant tumor cells that harbor p53 dysfunction or Bcl-2 overexpression. A combination treatment of flavopiridol with radiation has the potential to conquer the radioresistance of malignant tumors induced by the genetic alteration of p53 or bcl-2.

  3. The Impact of Chemotherapy, Radiation and Epigenetic Modifiers in Cancer Cell Expression of Immune Inhibitory and Stimulatory Molecules and Anti-Tumor Efficacy.

    Science.gov (United States)

    Chacon, Jessica Ann; Schutsky, Keith; Powell, Daniel J

    2016-11-14

    Genomic destabilizers, such as radiation and chemotherapy, and epigenetic modifiers are used for the treatment of cancer due to their apoptotic effects on the aberrant cells. However, these therapies may also induce widespread changes within the immune system and cancer cells, which may enable tumors to avoid immune surveillance and escape from host anti-tumor immunity. Genomic destabilizers can induce immunogenic death of tumor cells, but also induce upregulation of immune inhibitory ligands on drug-resistant cells, resulting in tumor progression. While administration of immunomodulatory antibodies that block the interactions between inhibitory receptors on immune cells and their ligands on tumor cells can mediate cancer regression in a subset of treated patients, it is crucial to understand how genomic destabilizers alter the immune system and malignant cells, including which inhibitory molecules, receptors and/or ligands are upregulated in response to genotoxic stress. Knowledge gained in this area will aid in the rational design of trials that combine genomic destabilizers, epigenetic modifiers and immunotherapeutic agents that may be synergized to improve clinical responses and prevent tumor escape from the immune system. Our review article describes the impact genomic destabilizers, such as radiation and chemotherapy, and epigenetic modifiers have on anti-tumor immunity and the tumor microenvironment. Although genomic destabilizers cause DNA damage on cancer cells, these therapies can also have diverse effects on the immune system, promote immunogenic cell death or survival and alter the cancer cell expression of immune inhibitor molecules.

  4. Visual outcome, endocrine function and tumor control after fractionated stereotactic radiation therapy of craniopharyngiomas in adults

    DEFF Research Database (Denmark)

    Astradsson, Arnar; Munck Af Rosenschöld, Per; Feldt-Rasmussen, Ulla

    2017-01-01

    BACKGROUND: The purpose of this study was to examine visual outcome, endocrine function and tumor control in a prospective cohort of craniopharyngioma patients, treated with fractionated stereotactic radiation therapy (FSRT). MATERIAL AND METHODS: Sixteen adult patients with craniopharyngiomas were...... eligible for analysis. They were treated with linear accelerator-based FSRT during 1999-2015. In all cases, diagnosis was confirmed by histological analysis. The prescription dose to the tumor was 54 Gy (median, range 48-54) in 1.8 or 2.0 Gy per fraction, and the maximum radiation dose to the optic nerves.......7-13.1) for visual outcome, endocrine function, and tumor control, respectively. RESULTS: Visual acuity impairment was present in 10 patients (62.5%) and visual field defects were present in 12 patients (75%) before FSRT. One patient developed radiation-induced optic neuropathy at seven years after FSRT. Thirteen...

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

    Directory of Open Access Journals (Sweden)

    Patrick Maier

    2016-01-01

    Full Text Available 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.

  6. The effect of added O(2) on the transmittance and radiation resistance of radiation resistant glasses.

    Science.gov (United States)

    Li, Weinan; Lu, Min

    2010-12-06

    One method of hardening optical glasses against radiation-induced darkening has been to add CeO(2) to the batch composition. In the present investigation we prepared a series of lanthanum crown glasses with varying degrees of CeO(2) additions and melted them at 1,400 °C with and without bubbling oxygen gas. We examined the influence of added oxygen on the optical transmissions of these glasses in the spectral range 460 to 760 nm following gamma irradiations ranging from 10 to 250 krad. The results showed that dose-for-dose the radiation-induced optical attenuations of the oxidized glasses were greater than for the glasses without added O(2).

  7. Permeability of Brain Tumor Vessels Induced by Uniform or Spatially Microfractionated Synchrotron Radiation Therapies.

    Science.gov (United States)

    Bouchet, Audrey; Potez, Marine; Coquery, Nicolas; Rome, Claire; Lemasson, Benjamin; Bräuer-Krisch, Elke; Rémy, Chantal; Laissue, Jean; Barbier, Emmanuel L; Djonov, Valentin; Serduc, Raphael

    2017-08-01

    To compare the blood-brain barrier permeability changes induced by synchrotron microbeam radiation therapy (MRT, which relies on spatial fractionation of the incident x-ray beam into parallel micron-wide beams) with changes induced by a spatially uniform synchrotron x-ray radiation therapy. Male rats bearing malignant intracranial F98 gliomas were randomized into 3 groups: untreated, exposed to MRT (peak and valley dose: 241 and 10.5 Gy, respectively), or exposed to broad beam irradiation (BB) delivered at comparable doses (ie, equivalent to MRT valley dose); both applied by 2 arrays, intersecting orthogonally the tumor region. Vessel permeability was monitored in vivo by magnetic resonance imaging 1 day before (T-1) and 1, 2, 7, and 14 days after treatment start. To determine whether physiologic parameters influence vascular permeability, we evaluated vessel integrity in the tumor area with different values for cerebral blood flow, blood volume, edema, and tissue oxygenation. Microbeam radiation therapy does not modify the vascular permeability of normal brain tissue. Microbeam radiation therapy-induced increase of tumor vascular permeability was detectable from T2 with a maximum at T7 after exposure, whereas BB enhanced vessel permeability only at T7. At this stage MRT was more efficient at increasing tumor vessel permeability (BB vs untreated: +19.1%; P=.0467; MRT vs untreated: +44.8%; Ptumor than BB. Microbeam radiation therapy-induced increased tumor vascular permeability is: (1) significantly greater; (2) earlier and more prolonged than that induced by BB irradiation, especially in highly proliferative tumor areas; and (3) targets all tumor areas discriminated by physiologic characteristics, including those not damaged by homogeneous irradiation. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. In Vivo Optical Imaging of Tumor and Microvascular Response to Ionizing Radiation

    OpenAIRE

    Azusa Maeda; Leung, Michael K. K.; Leigh Conroy; Yonghong Chen; Jiachuan Bu; Lindsay, Patricia E.; Shani Mintzberg; Carl Virtanen; Julissa Tsao; Winegarden, Neil A.; Yanchun Wang; Lily Morikawa; I. Alex Vitkin; Jaffray, David A.; Hill, Richard P.

    2012-01-01

    Radiotherapy is a widely used cancer treatment. However, understanding how ionizing radiation affects tumor cells and their vasculature, particularly at cellular, subcellular, genetic, and protein levels, has been limited by an inability to visualize the response of these interdependent components within solid tumors over time and in vivo. Here we describe a new preclinical experimental platform combining intravital multimodal optical microscopy for cellular-level longitudinal imaging, a smal...

  9. Increased tumor necrosis factor alpha mRNA after cellular exposure to ionizing radiation.

    OpenAIRE

    Hallahan, D E; Spriggs, D R; Beckett, M A; Kufe, D W; Weichselbaum, R. R.

    1989-01-01

    We report that tumor necrosis factor alpha (TNF-alpha) mRNA is increased after treatment with x-rays in certain human sarcoma cells. An increase in TNF-alpha mRNA is accompanied by the increased production of TNF-alpha protein. TNF-alpha enhances radiation lethality in both TNF-alpha-producing and -nonproducing tumor cells. These data suggest that, in addition to the direct cytotoxic effects of x-rays, production of TNF-alpha may add to radiation lethality through autocrine and paracrine mech...

  10. The tumor microenvironment underlies acquired resistance to CSF1R inhibition in gliomas

    Science.gov (United States)

    Quail, Daniela F.; Bowman, Robert L.; Akkari, Leila; Quick, Marsha L.; Schuhmacher, Alberto J.; Huse, Jason T.; Holland, Eric C.; Sutton, James C.; Joyce, Johanna A.

    2017-01-01

    Macrophages accumulate with glioblastoma multiforme (GBM) progression, and can be targeted via inhibition of colony stimulating factor-1 receptor (CSF-1R) to regress high-grade tumors in animal models of this cancer. However, whether and how resistance emerges in response to sustained CSF-1R blockade is unknown. We show that while overall survival is significantly prolonged, tumors recur in >50% of mice. Gliomas re-establish sensitivity to CSF-1R inhibition upon transplantation, indicating that resistance is tumor microenvironment-driven. Phosphatidylinositol 3-kinase (PI3K) pathway activity was elevated in recurrent GBM, driven by macrophage-derived insulin-like growth factor (IGF-1) and tumor cell IGF-1 receptor (IGF-1R). Combining IGF-1R or PI3K blockade with CSF-1R inhibition in recurrent tumors significantly prolonged overall survival. Our findings thus reveal a potential therapeutic approach for treating resistance to CSF-1R inhibitors. PMID:27199435

  11. A novel radiation-induced p53 mutation is not implicated in radiation resistance via a dominant-negative effect.

    Directory of Open Access Journals (Sweden)

    Yunguang Sun

    Full Text Available Understanding the mutations that confer radiation resistance is crucial to developing mechanisms to subvert this resistance. Here we describe the creation of a radiation resistant cell line and characterization of a novel p53 mutation. Treatment with 20 Gy radiation was used to induce mutations in the H460 lung cancer cell line; radiation resistance was confirmed by clonogenic assay. Limited sequencing was performed on the resistant cells created and compared to the parent cell line, leading to the identification of a novel mutation (del at the end of the DNA binding domain of p53. Levels of p53, phospho-p53, p21, total caspase 3 and cleaved caspase 3 in radiation resistant cells and the radiation susceptible (parent line were compared, all of which were found to be similar. These patterns held true after analysis of p53 overexpression in H460 cells; however, H1299 cells transfected with mutant p53 did not express p21, whereas those given WT p53 produced a significant amount, as expected. A luciferase assay demonstrated the inability of mutant p53 to bind its consensus elements. An MTS assay using H460 and H1299 cells transfected with WT or mutant p53 showed that the novel mutation did not improve cell survival. In summary, functional characterization of a radiation-induced p53 mutation in the H460 lung cancer cell line does not implicate it in the development of radiation resistance.

  12. Macrophage and tumor cell responses to repetitive pulsed X-ray radiation

    Science.gov (United States)

    Buldakov, M. A.; Tretyakova, M. S.; Ryabov, V. B.; Klimov, I. A.; Kutenkov, O. P.; Kzhyshkowska, J.; Bol'shakov, M. A.; Rostov, V. V.; Cherdyntseva, N. V.

    2017-05-01

    To study a response of tumor cells and macrophages to the repetitive pulsed low-dose X-ray radiation. Methods. Tumor growth and lung metastasis of mice with an injected Lewis lung carcinoma were analysed, using C57Bl6. Monocytes were isolated from a human blood, using CD14+ magnetic beads. IL6, IL1-betta, and TNF-alpha were determined by ELISA. For macrophage phenotyping, a confocal microscopy was applied. “Sinus-150” was used for the generation of pulsed X-ray radiation (the absorbed dose was below 0.1 Gy, the pulse repetition frequency was 10 pulse/sec). The irradiation of mice by 0.1 Gy pulsed X-rays significantly inhibited the growth of primary tumor and reduced the number of metastatic colonies in the lung. Furthermore, the changes in macrophage phenotype and cytokine secretion were observed after repetitive pulsed X-ray radiation. Conclusion. Macrophages and tumor cells had a different response to a low-dose pulsed X-ray radiation. An activation of the immune system through changes of a macrophage phenotype can result in a significant antitumor effect of the low-dose repetitive pulsed X-ray radiation.

  13. Spatial Positioning of RET and H4 Following Radiation Exposure Leads to Tumor Development

    Directory of Open Access Journals (Sweden)

    Yuri E. Nikiforov

    2001-01-01

    Full Text Available Exposure to ionizing radiation is a well-known risk factor for a number of human cancers, including leukemia, thyroid cancer, soft tissue sarcomas, and many others. Although it has been known for a long time that radiation exposure to the cell results in extensive DNA damage, including double strand DNA breaks, the exact mechanisms of radiation-induced carcinogenesis remain unknown. Recently, a large increase in incidence of thyroid cancer was observed in children exposed to radiation after the Chernobyl nuclear accident [1]. A high prevalence of chromosomal rearrangements involving the RET gene was found among these radiation-induced thyroid tumors [2,3]. As a result of such rearrangement, a portion of the RET gene is fused with another gene, typically with the H4 or ELE1. However, since the DNA targets of ionizing radiation are randomly distributed throughout the cell nucleus, the reason for predilection for the RET rearrangements in thyroid cells was unclear.

  14. A human colon adenocarcinoma xenograft--radiation response, cellular composition, and tumor disaggregation.

    Science.gov (United States)

    West, C M; Keng, P C; Siemann, D W; Sutherland, R M

    1987-02-01

    The human colon adenocarcinoma cell line WiDr was xenografted and the tumor characterized. When athymic mice (NCR-nu) were inoculated with 10(6) cells, tumors appeared after 7-14 days with a 93-100% take rate and grew with an initial volume-doubling time of around 6 days. For optimizing the tumor disaggregation method, a comparison was made of two dissociation procedures and of different dissociation times. An enzyme cocktail (collagenase, DNase, pronase) resulted in total viable cell yields of 1-3 X 10(7) cells/g tumor tissue. Cell yield decreased with increasing tumor weight. Disaggregation with trypsin gave lower cell yields; and so, although the plating efficiencies (PEs) were higher, the enzyme cocktail was chosen for tumor disaggregation. On the basis of morphologic identification, cell suspensions prepared from WiDr tumors, by use of the enzyme cocktail for 2 hours, contained 49% malignant cells as well as a significant fraction of nonneoplastic cells. The major nonneoplastic host cell component was macrophage (33%); lymphocytes (13%) and granulocytes (5%) also were present. Host cells could be separated from neoplastic cells by centrifugal elutriation. By mixing various proportions of host and tumor cells, it was subsequently shown that the presence of host cells did not influence the malignant cell PE unless the cell suspensions contained greater than 90% host cells. Single-cell suspensions prepared from WiDr tumors, with use of the enzyme cocktail for 2 hours, were irradiated and then plated for survival (D0 = 1.5 Gy; n = 5) (D0, the 37% dose slope). A comparison was made of the sensitivity to radiation, after the different dissociation methods. The radiation sensitivities after 1.5-hour trypsinization and 2- and 6-hour enzyme cocktail administrations were similar, but after 0.5 hour of trypsin, the cells were more sensitive to radiation.

  15. Resistance to receptor-blocking therapies primes tumors as targets for HER3-homing nanobiologics.

    Science.gov (United States)

    Sims, Jessica D; Taguiam, Jan Michael; Alonso-Valenteen, Felix; Markman, Janet; Agadjanian, Hasmik; Chu, David; Lubow, Jay; Abrol, Ravinder; Srinivas, Dustin; Jain, Anjali; Han, Bingchen; Qu, Ying; Mirzadehgan, Parisa; Hwang, Jae-Youn; Rentsendorj, Altan; Chung, Alice; Lester, Jenny; Karlan, Beth Y; Gray, Harry B; Gross, Zeev; Giuliano, Armando; Cui, Xiaojiang; Medina-Kauwe, Lali K

    2018-02-10

    Resistance to anti-tumor therapeutics is an important clinical problem. Tumor-targeted therapies currently used in the clinic are derived from antibodies or small molecules that mitigate growth factor activity. These have improved therapeutic efficacy and safety compared to traditional treatment modalities but resistance arises in the majority of clinical cases. Targeting such resistance could improve tumor abatement and patient survival. A growing number of such tumors are characterized by prominent expression of the human epidermal growth factor receptor 3 (HER3) on the cell surface. This study presents a "Trojan-Horse" approach to combating these tumors by using a receptor-targeted biocarrier that exploits the HER3 cell surface protein as a portal to sneak therapeutics into tumor cells by mimicking an essential ligand. The biocarrier used here combines several functions within a single fusion protein for mediating targeted cell penetration and non-covalent self-assembly with therapeutic cargo, forming HER3-homing nanobiologics. Importantly, we demonstrate here that these nanobiologics are therapeutically effective in several scenarios of resistance to clinically approved targeted inhibitors of the human EGF receptor family. We also show that such inhibitors heighten efficacy of our nanobiologics on naïve tumors by augmenting HER3 expression. This approach takes advantage of a current clinical problem (i.e. resistance to growth factor inhibition) and uses it to make tumors more susceptible to HER3 nanobiologic treatment. Moreover, we demonstrate a novel approach in addressing drug resistance by taking inhibitors against which resistance arises and re-introducing these as adjuvants, sensitizing tumors to the HER3 nanobiologics described here. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

  16. Choline kinase inhibitors synergize with TRAIL in the treatment of colorectal tumors and overcomes TRAIL resistance

    Directory of Open Access Journals (Sweden)

    Juan Carlos Lacal

    2016-01-01

    Conclusion: MN58b, which alone exhibits anticancer activities against a wide variety of tumor-derived cell lines, synergizes with TRAIL through a mechanism that involves DR5 upregulation. This study supports the use of MN58b in combination with TRAIL on colorectal tumors, including those that develop TRAIL resistance.

  17. Targeting c-Met receptor overcomes TRAIL-resistance in brain tumors.

    Directory of Open Access Journals (Sweden)

    Wanlu Du

    Full Text Available Tumor necrosis factor related apoptosis-inducing ligand (TRAIL induced apoptosis specifically in tumor cells. However, with approximately half of all known tumor lines being resistant to TRAIL, the identification of TRAIL sensitizers and their mechanism of action become critical to broadly use TRAIL as a therapeutic agent. In this study, we explored whether c-Met protein contributes to TRAIL sensitivity. We found a direct correlation between the c-Met expression level and TRAIL resistance. We show that the knock down c-Met protein, but not inhibition, sensitized brain tumor cells to TRAIL-mediated apoptosis by interrupting the interaction between c-Met and TRAIL cognate death receptor (DR 5. This interruption greatly induces the formation of death-inducing signaling complex (DISC and subsequent downstream apoptosis signaling. Using intracranially implanted brain tumor cells and stem cell (SC lines engineered with different combinations of fluorescent and bioluminescent proteins, we show that SC expressing a potent and secretable TRAIL (S-TRAIL have a significant anti-tumor effect in mice bearing c-Met knock down of TRAIL-resistant brain tumors. To our best knowledge, this is the first study that demonstrates c-Met contributes to TRAIL sensitivity of brain tumor cells and has implications for developing effective therapies for brain tumor patients.

  18. Tumorer

    DEFF Research Database (Denmark)

    Prause, J.U.; Heegaard, S.

    2005-01-01

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

  19. Complete adrenocorticotropin deficiency after radiation therapy for brain tumor with a normal growth hormone reserve

    Energy Technology Data Exchange (ETDEWEB)

    Sakai, Haruna; Yoshioka, Katsunobu; Yamagami, Keiko [Osaka City General Hospital (Japan)] (and others)

    2002-06-01

    A 34-year-old man with neurofibromatosis type 1, who had received radiation therapy after the excision of a brain tumor 5 years earlier, was admitted to our hospital with vomiting and weight loss. Cortisol and adrenocorticotropin (ACTH) were undetectable before and after administration of 100 {mu}g corticotropin releasing hormone. The level of growth hormone without stimulation was 24.7 ng/ml. We diagnosed him to have complete ACTH deficiency attributable to radiation therapy. This is the first known case of a patient with complete ACTH deficiency after radiation therapy and a growth hormone reserve that remained normal. (author)

  20. Differences Between Colon Cancer Primaries and Metastases Using a Molecular Assay for Tumor Radiation Sensitivity Suggest Implications for Potential Oligometastatic SBRT Patient Selection

    Energy Technology Data Exchange (ETDEWEB)

    Ahmed, Kamran A. [Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (United States); Fulp, William J.; Berglund, Anders E. [Department of Biostatistics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (United States); Hoffe, Sarah E.; Dilling, Thomas J. [Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (United States); Eschrich, Steven A. [Department of Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (United States); Shridhar, Ravi [Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (United States); Torres-Roca, Javier F., E-mail: javier.torresroca@moffitt.org [Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (United States)

    2015-07-15

    Purpose: We previously developed a multigene expression model of tumor radiation sensitivity index (RSI) with clinical validation in multiple independent cohorts (breast, rectal, esophageal, and head and neck patients). The purpose of this study was to assess differences between RSI scores in primary colon cancer and metastases. Methods and Materials: Patients were identified from our institutional review board–approved prospective observational protocol. A total of 704 metastatic and 1362 primary lesions were obtained from a de-identified metadata pool. RSI was calculated using the previously published rank-based algorithm. An independent cohort of 29 lung or liver colon metastases treated with 60 Gy in 5 fractions stereotactic body radiation therapy (SBRT) was used for validation. Results: The most common sites of metastases included liver (n=374; 53%), lung (n=116; 17%), and lymph nodes (n=40; 6%). Sixty percent of metastatic tumors, compared with 54% of primaries, were in the RSI radiation-resistant peak, suggesting metastatic tumors may be slightly more radiation resistant than primaries (P=.01). In contrast, when we analyzed metastases based on anatomical site, we uncovered large differences in RSI. The median RSIs for metastases in descending order of radiation resistance were ovary (0.48), abdomen (0.47), liver (0.43), brain (0.42), lung (0.32), and lymph nodes (0.31) (P<.0001). These findings were confirmed when the analysis was restricted to lesions from the same patient (n=139). In our independent cohort of treated lung and liver metastases, lung metastases had an improved local control rate compared to that in patients with liver metastases (2-year local control rate of 100% vs 73.0%, respectively; P=.026). Conclusions: Assessment of radiation sensitivity between primary and metastatic tissues of colon cancer histology revealed significant differences based on anatomical location of metastases. These initial results warrant validation in a larger

  1. 3D tumor tissue analogs and their orthotopic implants for understanding tumor-targeting of microenvironment-responsive nanosized chemotherapy and radiation.

    Science.gov (United States)

    Sethi, Pallavi; Jyoti, Amar; Swindell, Elden P; Chan, Ryan; Langner, Ulrich W; Feddock, Jonathan M; Nagarajan, Radhakrishnan; O'Halloran, Thomas V; Upreti, Meenakshi

    2015-11-01

    An appropriate representation of the tumor microenvironment in tumor models can have a pronounced impact on directing combinatorial treatment strategies and cancer nanotherapeutics. The present study develops a novel 3D co-culture spheroid model (3D TNBC) incorporating tumor cells, endothelial cells and fibroblasts as color-coded murine tumor tissue analogs (TTA) to better represent the tumor milieu of triple negative breast cancer in vitro. Implantation of TTA orthotopically in nude mice, resulted in enhanced growth and aggressive metastasis to ectopic sites. Subsequently, the utility of the model is demonstrated for preferential targeting of irradiated tumor endothelial cells via radiation-induced stromal enrichment of galectin-1 using anginex conjugated nanoparticles (nanobins) carrying arsenic trioxide and cisplatin. Demonstration of a multimodal nanotherapeutic system and inclusion of the biological response to radiation using an in vitro/in vivo tumor model incorporating characteristics of tumor microenvironment presents an advance in preclinical evaluation of existing and novel cancer nanotherapies. Existing in-vivo tumor models are established by implanting tumor cells into nude mice. Here, the authors described their approach 3D spheres containing tumor cells, enodothelial cells and fibroblasts. This would mimic tumor micro-environment more realistically. This interesting 3D model should reflect more accurately tumor response to various drugs and would enable the design of new treatment modalities. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  2. Quality of life after stereotactic body radiation therapy for primary and metastatic liver tumors

    NARCIS (Netherlands)

    Romero, Alejandra Mendez; Wunderink, Wouter; van Os, Rob M.; Nowak, Peter J. C. M.; Helimen, Ben J. M.; Nuyttens, Joost J.; Brandwijk, Rene P.; Verhoef, Cornelis; Ijzermans, Jan N. M.; Levendag, Peter C.

    2008-01-01

    Purpose: Stereotactic body radiation therapy (SBRT) provides a high local control rate for primary and metastatic liver tumors. The aim of this study is to assess the impact of this treatment on the patient's quality of life. This is the first report of quality of life associated with liver SBRT.

  3. In vivo optical imaging of tumor and microvascular response to ionizing radiation.

    Directory of Open Access Journals (Sweden)

    Azusa Maeda

    Full Text Available Radiotherapy is a widely used cancer treatment. However, understanding how ionizing radiation affects tumor cells and their vasculature, particularly at cellular, subcellular, genetic, and protein levels, has been limited by an inability to visualize the response of these interdependent components within solid tumors over time and in vivo. Here we describe a new preclinical experimental platform combining intravital multimodal optical microscopy for cellular-level longitudinal imaging, a small animal x-ray microirradiator for reproducible spatially-localized millimeter-scale irradiations, and laser-capture microdissection of ex vivo tissues for transcriptomic profiling. Using this platform, we have developed new methods that exploit the power of optically-enabled microscopic imaging techniques to reveal the important role of the tumor microvasculature in radiation response of tumors. Furthermore, we demonstrate the potential of this preclinical platform to study quantitatively--with cellular and sub-cellular details--the spatio-temporal dynamics of the biological response of solid tumors to ionizing radiation in vivo.

  4. In vivo optical imaging of tumor and microvascular response to ionizing radiation.

    Science.gov (United States)

    Maeda, Azusa; Leung, Michael K K; Conroy, Leigh; Chen, Yonghong; Bu, Jiachuan; Lindsay, Patricia E; Mintzberg, Shani; Virtanen, Carl; Tsao, Julissa; Winegarden, Neil A; Wang, Yanchun; Morikawa, Lily; Vitkin, I Alex; Jaffray, David A; Hill, Richard P; DaCosta, Ralph S

    2012-01-01

    Radiotherapy is a widely used cancer treatment. However, understanding how ionizing radiation affects tumor cells and their vasculature, particularly at cellular, subcellular, genetic, and protein levels, has been limited by an inability to visualize the response of these interdependent components within solid tumors over time and in vivo. Here we describe a new preclinical experimental platform combining intravital multimodal optical microscopy for cellular-level longitudinal imaging, a small animal x-ray microirradiator for reproducible spatially-localized millimeter-scale irradiations, and laser-capture microdissection of ex vivo tissues for transcriptomic profiling. Using this platform, we have developed new methods that exploit the power of optically-enabled microscopic imaging techniques to reveal the important role of the tumor microvasculature in radiation response of tumors. Furthermore, we demonstrate the potential of this preclinical platform to study quantitatively--with cellular and sub-cellular details--the spatio-temporal dynamics of the biological response of solid tumors to ionizing radiation in vivo.

  5. MRI of radiation-induced tumors of the head and neck in post-radiation nasopharyngeal carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Abrigo, Jill M.; King, Ann D.; Wong, Jeffrey K.T.; Ahuja, Anil T. [The Chinese University of Hong Kong, Prince of Wales Hospital, Department of Diagnostic Radiology and Organ Imaging, Faculty of Medicine, Hong Kong S.A.R. (China); Leung, Sing Fai [The Chinese University of Hong Kong, Prince of Wales Hospital, Department of Clinical Oncology, Faculty of Medicine, Hong Kong S.A.R. (China); Vlantis, Alexander C.; Tong, Michael C.F. [The Chinese University of Hong Kong, Prince of Wales Hospital, Department of Otolaryngology and Head and Neck Surgery, Faculty of Medicine, Hong Kong S.A.R. (China); Tse, Gary M.K. [The Chinese University of Hong Kong, Prince of Wales Hospital, Department of Anatomical and Cellular Pathology, Faculty of Medicine, Hong Kong S.A.R. (China)

    2009-05-15

    The aim of this study was to document the sites and MRI features of radiation-induced tumors (RITs) in the head and neck following treatment for nasopharyngeal carcinoma (NPC). The MRI examinations and clinical records of 20 patients with 21 RITs were reviewed retrospectively. RITs developed 3-30 years after radiotherapy and included eleven squamous cell carcinomas, six sarcomas, two neuroendocrine carcinomas, one mucoepidermoid carcinoma and one meningioma. RITs arose in the maxillary region (9), oro/hypopharynx and oral cavity (5), external auditory canal (4), nasopharynx and sphenoid sinus (2) and brain (1). Radiation-induced carcinoma and sarcoma had MRI features that were useful to distinguish them from recurrent NPC. To improve early detection of RITs, the check areas on an MRI of a patient with previous NPC treated by radiation should always include the maxillary region, tongue, and external auditory canal/temporal bone. (orig.)

  6. Treating Brain Tumor with Microbeam Radiation Generated by a Compact Carbon-Nanotube-Based Irradiator: Initial Radiation Efficacy Study.

    Science.gov (United States)

    Yuan, Hong; Zhang, Lei; Frank, Jonathan E; Inscoe, Christina R; Burk, Laurel M; Hadsell, Mike; Lee, Yueh Z; Lu, Jianping; Chang, Sha; Zhou, Otto

    2015-09-01

    Microbeam radiation treatment (MRT) using synchrotron radiation has shown great promise in the treatment of brain tumors, with a demonstrated ability to eradicate the tumor while sparing normal tissue in small animal models. With the goal of expediting the advancement of MRT research beyond the limited number of synchrotron facilities in the world, we recently developed a compact laboratory-scale microbeam irradiator using carbon nanotube (CNT) field emission-based X-ray source array technology. The focus of this study is to evaluate the effects of the microbeam radiation generated by this compact irradiator in terms of tumor control and normal tissue damage in a mouse brain tumor model. Mice with U87MG human glioblastoma were treated with sham irradiation, low-dose MRT, high-dose MRT or 10 Gy broad-beam radiation treatment (BRT). The microbeams were 280 μm wide and spaced at 900 μm center-to-center with peak dose at either 48 Gy (low-dose MRT) or 72 Gy (high-dose MRT). Survival studies showed that the mice treated with both MRT protocols had a significantly extended life span compared to the untreated control group (31.4 and 48.5% of life extension for low- and high-dose MRT, respectively) and had similar survival to the BRT group. Immunostaining on MRT mice demonstrated much higher DNA damage and apoptosis level in tumor tissue compared to the normal brain tissue. Apoptosis in normal tissue was significantly lower in the low-dose MRT group compared to that in the BRT group at 48 h postirradiation. Interestingly, there was a significantly higher level of cell proliferation in the MRT-treated normal tissue compared to that in the BRT-treated mice, indicating rapid normal tissue repairing process after MRT. Microbeam radiation exposure on normal brain tissue causes little apoptosis and no macrophage infiltration at 30 days after exposure. This study is the first biological assessment on MRT effects using the compact CNT-based irradiator. It provides an alternative

  7. A stochastic model for tumor geometry evolution during radiation therapy in cervical cancer

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Yifang; Lee, Chi-Guhn [Department of Mechanical and Industrial Engineering, University of Toronto, 5 King' s College Road, Toronto, Ontario M5S 3G8 (Canada); Chan, Timothy C. Y., E-mail: tcychan@mie.utoronto.ca [Department of Mechanical and Industrial Engineering, University of Toronto, 5 King' s College Road, Toronto, Ontario M5S 3G8, Canada and Techna Institute for the Advancement of Technology for Health, 124-100 College Street Toronto, Ontario M5G 1P5 (Canada); Cho, Young-Bin [Department of Radiation Physics, Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, 610 University of Avenue, Toronto, Ontario M5T 2M9, Canada and Department of Radiation Oncology, University of Toronto, 148-150 College Street, Toronto, Ontario M5S 3S2 (Canada); Islam, Mohammad K. [Department of Radiation Physics, Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, 610 University of Avenue, Toronto, Ontario M5T 2M9 (Canada); Department of Radiation Oncology, University of Toronto, 148-150 College Street, Toronto, Ontario M5S 3S2 (Canada); Techna Institute for the Advancement of Technology for Health, 124-100 College Street, Toronto, Ontario M5G 1P5 (Canada)

    2014-02-15

    Purpose: To develop mathematical models to predict the evolution of tumor geometry in cervical cancer undergoing radiation therapy. Methods: The authors develop two mathematical models to estimate tumor geometry change: a Markov model and an isomorphic shrinkage model. The Markov model describes tumor evolution by investigating the change in state (either tumor or nontumor) of voxels on the tumor surface. It assumes that the evolution follows a Markov process. Transition probabilities are obtained using maximum likelihood estimation and depend on the states of neighboring voxels. The isomorphic shrinkage model describes tumor shrinkage or growth in terms of layers of voxels on the tumor surface, instead of modeling individual voxels. The two proposed models were applied to data from 29 cervical cancer patients treated at Princess Margaret Cancer Centre and then compared to a constant volume approach. Model performance was measured using sensitivity and specificity. Results: The Markov model outperformed both the isomorphic shrinkage and constant volume models in terms of the trade-off between sensitivity (target coverage) and specificity (normal tissue sparing). Generally, the Markov model achieved a few percentage points in improvement in either sensitivity or specificity compared to the other models. The isomorphic shrinkage model was comparable to the Markov approach under certain parameter settings. Convex tumor shapes were easier to predict. Conclusions: By modeling tumor geometry change at the voxel level using a probabilistic model, improvements in target coverage and normal tissue sparing are possible. Our Markov model is flexible and has tunable parameters to adjust model performance to meet a range of criteria. Such a model may support the development of an adaptive paradigm for radiation therapy of cervical cancer.

  8. A stochastic model for tumor geometry evolution during radiation therapy in cervical cancer.

    Science.gov (United States)

    Liu, Yifang; Chan, Timothy C Y; Lee, Chi-Guhn; Cho, Young-Bin; Islam, Mohammad K

    2014-02-01

    To develop mathematical models to predict the evolution of tumor geometry in cervical cancer undergoing radiation therapy. The authors develop two mathematical models to estimate tumor geometry change: a Markov model and an isomorphic shrinkage model. The Markov model describes tumor evolution by investigating the change in state (either tumor or nontumor) of voxels on the tumor surface. It assumes that the evolution follows a Markov process. Transition probabilities are obtained using maximum likelihood estimation and depend on the states of neighboring voxels. The isomorphic shrinkage model describes tumor shrinkage or growth in terms of layers of voxels on the tumor surface, instead of modeling individual voxels. The two proposed models were applied to data from 29 cervical cancer patients treated at Princess Margaret Cancer Centre and then compared to a constant volume approach. Model performance was measured using sensitivity and specificity. The Markov model outperformed both the isomorphic shrinkage and constant volume models in terms of the trade-off between sensitivity (target coverage) and specificity (normal tissue sparing). Generally, the Markov model achieved a few percentage points in improvement in either sensitivity or specificity compared to the other models. The isomorphic shrinkage model was comparable to the Markov approach under certain parameter settings. Convex tumor shapes were easier to predict. By modeling tumor geometry change at the voxel level using a probabilistic model, improvements in target coverage and normal tissue sparing are possible. Our Markov model is flexible and has tunable parameters to adjust model performance to meet a range of criteria. Such a model may support the development of an adaptive paradigm for radiation therapy of cervical cancer.

  9. Radiation Resistant Hybrid Lotus Effect Photoelectrocatalytic Self-Cleaning Anti-Contamination Coatings Project

    Data.gov (United States)

    National Aeronautics and Space Administration — This project will develop radiation resistant hybrid Lotus Effect photoelectrocatalytic self-cleaning anti-contamination coatings for application to Lunar...

  10. Mobilization of Viable Tumor Cells Into the Circulation During Radiation Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Martin, Olga A. [Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, East Melbourne, VIC (Australia); Molecular Radiation Biology Laboratory, Peter MacCallum Cancer Centre, East Melbourne, VIC (Australia); The Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC (Australia); Anderson, Robin L. [The Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC (Australia); Metastasis Research Laboratory, Peter MacCallum Cancer Centre, East Melbourne, VIC (Australia); Russell, Prudence A. [Department of Anatomical Pathology, St. Vincent Hospital, Fitzroy, VIC (Australia); Ashley Cox, R. [Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, East Melbourne, VIC (Australia); Ivashkevich, Alesia [Molecular Radiation Biology Laboratory, Peter MacCallum Cancer Centre, East Melbourne, VIC (Australia); Laboratory of DNA Repair and Genomics, Centre for Innate Immunity and Infectious Disease, Monash Institute for Medical Research, Monash University, Clayton, VIC (Australia); Swierczak, Agnieszka; Doherty, Judy P. [Metastasis Research Laboratory, Peter MacCallum Cancer Centre, East Melbourne, VIC (Australia); Jacobs, Daphne H.M. [Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, East Melbourne, VIC (Australia); Smith, Jai [Molecular Radiation Biology Laboratory, Peter MacCallum Cancer Centre, East Melbourne, VIC (Australia); Siva, Shankar; Daly, Patricia E. [Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, East Melbourne, VIC (Australia); Ball, David L. [Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, East Melbourne, VIC (Australia); The Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC (Australia); and others

    2014-02-01

    Purpose: To determine whether radiation therapy (RT) could mobilize viable tumor cells into the circulation of non-small cell lung cancer (NSCLC) patients. Methods and Materials: We enumerated circulating tumor cells (CTCs) by fluorescence microscopy of blood samples immunostained with conventional CTC markers. We measured their DNA damage levels using γ-H2AX, a biomarker for radiation-induced DNA double-strand breaks, either by fluorescence-activated cell sorting or by immunofluorescence microscopy. Results: Twenty-seven RT-treated NSCLC patients had blood samples analyzed by 1 or more methods. We identified increased CTC numbers after commencement of RT in 7 of 9 patients treated with palliative RT, and in 4 of 8 patients treated with curative-intent RT. Circulating tumor cells were also identified, singly and in clumps in large numbers, during RT by cytopathologic examination (in all 5 cases studied). Elevated γ-H2AX signal in post-RT blood samples signified the presence of CTCs derived from irradiated tumors. Blood taken after the commencement of RT contained tumor cells that proliferated extensively in vitro (in all 6 cases studied). Circulating tumor cells formed γ-H2AX foci in response to ex vivo irradiation, providing further evidence of their viability. Conclusions: Our findings provide a rationale for the development of strategies to reduce the concentration of viable CTCs by modulating RT fractionation or by coadministering systemic therapies.

  11. Theranostic Nanoseeds for Efficacious Internal Radiation Therapy of Unresectable Solid Tumors

    Science.gov (United States)

    Moeendarbari, Sina; Tekade, Rakesh; Mulgaonkar, Aditi; Christensen, Preston; Ramezani, Saleh; Hassan, Gedaa; Jiang, Ruiqian; Öz, Orhan K.; Hao, Yaowu; Sun, Xiankai

    2016-02-01

    Malignant tumors are considered “unresectable” if they are adhere to vital structures or the surgery would cause irreversible damages to the patients. Though a variety of cytotoxic drugs and radiation therapies are currently available in clinical practice to treat such tumor masses, these therapeutic modalities are always associated with substantial side effects. Here, we report an injectable nanoparticle-based internal radiation source that potentially offers more efficacious treatment of unresectable solid tumors without significant adverse side effects. Using a highly efficient incorporation procedure, palladium-103, a brachytherapy radioisotope in clinical practice, was coated to monodispersed hollow gold nanoparticles with a diameter about 120 nm, to form 103Pd@Au nanoseeds. The therapeutic efficacy of 103Pd@Au nanoseeds were assessed when intratumorally injected into a prostate cancer xenograft model. Five weeks after a single-dose treatment, a significant tumor burden reduction (>80%) was observed without noticeable side effects on the liver, spleen and other organs. Impressively, >95% nanoseeds were retained inside the tumors as monitored by Single Photon Emission Computed Tomography (SPECT) with the gamma emissions of 103Pd. These findings show that this nanoseed-based brachytherapy has the potential to provide a theranostic solution to unresectable solid tumors.

  12. Risk of extrathyroid tumors following radiation treatment in infancy for thymic enlargement

    Energy Technology Data Exchange (ETDEWEB)

    Hildreth, N.G.; Shore, R.E.; Hempelmann, L.M.; Rosenstein, M.

    1985-06-01

    Two thousand eight hundred and fifty-six individuals who received X-ray treatments in infancy for an enlarged thymus gland and their 5053 nonirradiated siblings have been followed prospectively since 1953 to evaluate the risk of radiation-induced neoplastic disease. Based on the cumulative experience of five surveys of this cohort, the irradiated group has a statistically significant increased risk for both benign and malignant extrathyroid tumors, the age-adjusted relative risks being 2.0 and 2.2, respectively. Benign tumors of the bone, nervous system, salivary gland, skin, and breast (females only) and malignant tumors of the skin and breast (females only) account for the excess incidence of extrathyroid tumors among the thymic-irradiated individuals. Although a radiation-induced excess of extrathyroid tumors was suggested in an earlier survey of this cohort, small numbers restricted attribution of this excess to specific sites. The implications of these findings are discussed. Thyroid tumors are addressed in a separate paper.

  13. Low-temperature radiation-resistant material for ball-bearing retainers

    Science.gov (United States)

    Desau, P. O.; Emmons, W. F.

    1970-01-01

    Radiation resistant material, made of polyimide polymers and S-glass cloth, is used in ball bearing retainers for extreme environments. Material displays satisfactory wear resistance, lubricity, and stability. Results of comparative tests with fluorocarbon materials are given.

  14. Enhancing the radiation response of tumors but not early or late responding normal tissues using a vascular disrupting agent

    DEFF Research Database (Denmark)

    Horsman, Michael R

    2017-01-01

    % increase in ventilation rate measured by plethysmography within 9 months). A Chi-squared test was used for statistical comparisons (significance level of p radiation dose controlling 50% of irradiated tumors was 52 Gy. This significantly decreased to 45 Gy with CA4P. The radiation......INTRODUCTION: Vascular disrupting agents (VDAs) damage tumor vasculature and enhance tumor radiation response. In this pre-clinical study, we combined radiation with the leading VDA in clinical development, combretastatin A-4 phosphate (CA4P), and compared the effects seen in tumors and relevant...... normal tissues. MATERIAL AND METHODS: Radiation was applied locally to tissues in CDF1 mice to produce full radiation dose-response curves. CA4P (250 mg/kg) was intraperitoneally (i.p.) injected within 30 minutes after irradiating. Response of 200 mm3 foot implanted C3H mammary carcinomas was assessed...

  15. Sustained complete remission in a patient with platinum-resistant ovarian yolk sac tumor.

    Science.gov (United States)

    Jeyakumar, A; Chalas, E; Hindenburg, A

    2001-09-01

    Yolk sac tumors of the ovary are generally very responsive to chemotherapy; however, they are difficult to manage in the setting of platinum resistance where treatment options are limited and outcomes are poorer. We present a 39-year-old woman who had a platinum-resistant yolk sac ovarian tumor. She achieved complete remission on an innovative regimen of docetaxel, gemcitabine, and thalidomide. The combination of docetaxel, gemcitabine, and thalidomide might be an active regimen for platinum-resistant ovarian nondysgerminomas and further investigation of this combination is warranted. Copyright 2001 Academic Press.

  16. Early Cognitive Outcomes Following Proton Radiation in Pediatric Patients With Brain and Central Nervous System Tumors

    Energy Technology Data Exchange (ETDEWEB)

    Pulsifer, Margaret B., E-mail: mpulsifer@mgh.harvard.edu [Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts (United States); Sethi, Roshan V. [Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); Kuhlthau, Karen A. [Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts (United States); MacDonald, Shannon M.; Tarbell, Nancy J.; Yock, Torunn I. [Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States)

    2015-10-01

    Purpose: To report, from a longitudinal study, cognitive outcome in pediatric patients treated with proton radiation therapy (PRT) for central nervous system (CNS) tumors. Methods and Materials: Sixty patients receiving PRT for medulloblastoma (38.3%), gliomas (18.3%), craniopharyngioma (15.0%), ependymoma (11.7%), and other CNS tumors (16.7%) were administered age-appropriate measures of cognitive abilities at or near PRT initiation (baseline) and afterward (follow-up). Patients were aged ≥6 years at baseline to ensure consistency in neurocognitive measures. Results: Mean age was 12.3 years at baseline; mean follow-up interval was 2.5 years. Treatment included prior surgical resection (76.7%) and chemotherapy (61.7%). Proton radiation therapy included craniospinal irradiation (46.7%) and partial brain radiation (53.3%). At baseline, mean Wechsler Full Scale IQ was 104.6; means of all 4 Index scores were also in the average range. At follow-up, no significant change was observed in mean Wechsler Full Scale IQ, Verbal Comprehension, Perceptual Reasoning/Organization, or Working Memory. However, Processing Speed scores declined significantly (mean 5.2 points), with a significantly greater decline for subjects aged <12 years at baseline and those with the highest baseline scores. Cognitive outcome was not significantly related to gender, extent of radiation, radiation dose, tumor location, histology, socioeconomic status, chemotherapy, or history of surgical resection. Conclusions: Early cognitive outcomes after PRT for pediatric CNS tumors are encouraging, compared with published outcomes from photon radiation therapy.

  17. Endothelial Side Population Cells Contribute to Tumor Angiogenesis and Antiangiogenic Drug Resistance.

    Science.gov (United States)

    Naito, Hisamichi; Wakabayashi, Taku; Kidoya, Hiroyasu; Muramatsu, Fumitaka; Takara, Kazuhiro; Eino, Daisuke; Yamane, Keitaro; Iba, Tomohiro; Takakura, Nobuyuki

    2016-06-01

    Angiogenesis plays a crucial role in tumor growth, with an undisputed contribution of resident endothelial cells (EC) to new blood vessels in the tumor. Here, we report the definition of a small population of vascular-resident stem/progenitor-like EC that contributes predominantly to new blood vessel formation in the tumor. Although the surface markers of this population are similar to other ECs, those from the lung vasculature possess colony-forming ability in vitro and contribute to angiogenesis in vivo These specific ECs actively proliferate in lung tumors, and the percentage of this population significantly increases in the tumor vasculature relative to normal lung tissue. Using genetic recombination and bone marrow transplant models, we show that these cells are phenotypically true ECs and do not originate from hematopoietic cells. After treatment of tumors with antiangiogenic drugs, these specific ECs selectively survived and remained in the tumor. Together, our results established that ECs in the peripheral vasculature are heterogeneous and that stem/progenitor-like ECs play an indispensable role in tumor angiogenesis as EC-supplying cells. The lack of susceptibility of these ECs to antiangiogenic drugs may account for resistance of the tumor to this drug type. Thus, inhibiting these ECs might provide a promising strategy to overcome antiangiogenic drug resistance. Cancer Res; 76(11); 3200-10. ©2016 AACR. ©2016 American Association for Cancer Research.

  18. Artificial hyperglycemia as a factor potentiating selectively an anti-tumoral radiation effect

    Energy Technology Data Exchange (ETDEWEB)

    Loginov, V.M. (Akademiya Meditsinskikh Nauk SSSR, Moscow. Inst. Nejrokhirurgii)

    1983-07-01

    An important peculiarity of tumoral cells is their ability for intensive glycolysis. Potential biochemical mechanisms of this phenomenon are considered in the review. A tumoral process is closely connected with the changes in glucose metabolism in an organism. Therefore artificial hyperglycemia (AH) can be an instrument for intervention into tumoral cell energetics. Many experimental data show an increase of glucose consumption at AH. Long-term AH causes a reduction of tumor pH. Various view points on AH antitumoral effect mechanism are considered. Data on changes in a sound organism in case of long-term AH are given. It has been found that AH does not cause irreversible changes on the part of organs and systems of the organism. Experimental data on a possibility of using short-term hyperglycemia as a factor selectively potentiating antitumoral radiation effect are considered.

  19. Phenotypic characterization of drug resistance and tumor initiating cancer stem cells from human bone tumor osteosarcoma cell line OS-77

    Directory of Open Access Journals (Sweden)

    Yue Zhang

    2014-08-01

    Full Text Available The cancer stem cell theory suggest that presence of small subpopulation of cancer stem cells are the major implication in the cancer treatment and also responsible for tumor recurrence. Based on Hoechst 33342 dye exclusion technique, we have identified about 3.3% of cancer stem like side population (SP cells from human osteosarcoma OS-77 cell line whose prevalence is significantly reduced to 0.3% after treatment with verapamil. The sphere formation assay revealed that osteosarcoma SP cells are highly capable to form tumor spheres (sarcospheres. Further by immunocytochemistry and RT-PCR, we show that OS-77 SP cells have enhanced expression of stem cell surface markers such as CD44, Nanog and ATP-binding cassette (ABC transporter gene (ABCG2 which contributes to self-renewal and drug resistance, respectively. Our findings help to designing a novel therapeutic drug which could effectively target the cancer stem cells and prevent the tumor relapse.

  20. Radiation Resistance Studies of Amorphous Silicon Alloy Photovoltaic Materials

    Science.gov (United States)

    Woodyard, James R.

    1994-01-01

    The radiation resistance of commercial solar cells fabricated from hydrogenated amorphous silicon alloys was investigated. A number of different device structures were irradiated with 1.0 MeV protons. The cells were insensitive to proton fluences below 1E12 sq cm. The parameters of the irradiated cells were restored with annealing at 200 C. The annealing time was dependent on proton fluence. Annealing devices for one hour restores cell parameters for fluences below lE14 sq cm require longer annealing times. A parametric fitting model was used to characterize current mechanisms observed in dark I-V measurements. The current mechanisms were explored with irradiation fluence, and voltage and light soaking times. The thermal generation current density and quality factor increased with proton fluence. Device simulation shows the degradation in cell characteristics may be explained by the reduction of the electric field in the intrinsic layer.

  1. Cisplatin Resistant Spheroids Model Clinically Relevant Survival Mechanisms in Ovarian Tumors.

    Directory of Open Access Journals (Sweden)

    Winyoo Chowanadisai

    Full Text Available The majority of ovarian tumors eventually recur in a drug resistant form. Using cisplatin sensitive and resistant cell lines assembled into 3D spheroids we profiled gene expression and identified candidate mechanisms and biological pathways associated with cisplatin resistance. OVCAR-8 human ovarian carcinoma cells were exposed to sub-lethal concentrations of cisplatin to create a matched cisplatin-resistant cell line, OVCAR-8R. Genome-wide gene expression profiling of sensitive and resistant ovarian cancer spheroids identified 3,331 significantly differentially expressed probesets coding for 3,139 distinct protein-coding genes (Fc >2, FDR < 0.05 (S2 Table. Despite significant expression changes in some transporters including MDR1, cisplatin resistance was not associated with differences in intracellular cisplatin concentration. Cisplatin resistant cells were significantly enriched for a mesenchymal gene expression signature. OVCAR-8R resistance derived gene sets were significantly more biased to patients with shorter survival. From the most differentially expressed genes, we derived a 17-gene expression signature that identifies ovarian cancer patients with shorter overall survival in three independent datasets. We propose that the use of cisplatin resistant cell lines in 3D spheroid models is a viable approach to gain insight into resistance mechanisms relevant to ovarian tumors in patients. Our data support the emerging concept that ovarian cancers can acquire drug resistance through an epithelial-to-mesenchymal transition.

  2. In vivo studies of radiation potentiaton by iodoacetamide and observations on tumor transplantation immunity

    Energy Technology Data Exchange (ETDEWEB)

    Richards, W. Robert [Univ. of California, Berkeley, CA (United States); Kelly, Lola S. [Univ. of California, Berkeley, CA (United States)

    1970-10-01

    Iodoacetamide has been shown by others to be a radiation sensitizer for bacteria and for certain mammalian cells tested in vitro. This work describes an examination of the effectiveness of iodoacetamide used in vivo. Survival of ascites tumor cells maintained in the peritoneal cavity of mice was used as an indicator of sensitization. Survival was assessed using TD50 and total tumor cell population determination methods. A comparison of results obtained by these methods is made. The effects of oxygen tension and radiation dose rate upon results was examined. Iodoacetamide was found to be effective as a radiation sensitizer under all conditions although to a lesser degree than that reported by others for in vitro experiments with bacteria. Radioactive tracer studies indicate that iodoacetamide has rapid and total access to most if not all tissues of the body. This fact coupled with the observation of a sensitization in an in vivo system where the anoxia so prevalent in well developed tumors was present, suggests the possibility of clinical usefulness of iodoacetamide in cancer radiation therapy. Certain observations are reported on the effect of various cell and host treatment procedures upon cell population growth kinetics seen subsequent to inoculation of hosts with the cells. A hypothesis is presented which can account for the observations made by the author and also for those made by some others who report that large inocula, i.e., greater than 10 cells, are required to give rise to a lethal tumor in isologous hosts of the strain of tumor origin. The hypothesis may also account for what is known in the literature as the 'Hybrid Effect.'

  3. HER2-associated radiation resistance of breast cancer stem cells isolated from HER2-negative breast cancer cells

    Science.gov (United States)

    Duru, Nadire; Fan, Ming; Candas, Demet; Menaa, Cheikh; Liu, Hsin-Chen; Nantajit, Danupon; Wen, Yunfei; Xiao, Kai; Eldridge, Angela; Chromy, Brett A.; Li, Shiyong; Spitz, Douglas R.; Lam, Kit S.; Wicha, Max S.; Li, Jian Jian

    2012-01-01

    Purpose To understand the role of HER2-associated signaling network in breast cancer stem cells (BCSCs); using radiation-resistant breast cancer cells and clinical recurrent breast cancers to evaluate HER2-targeted therapy as a tumor eliminating strategy for recurrent HER2−/low breast cancers. Experimental Design HER2-expressing BCSCs (HER2+/CD44+/CD24−/low) were isolated from radiation-treated breast cancer MCF7 cells and in vivo irradiated MCF7 xenograft tumors. Tumor aggressiveness and radiation resistance were analyzed by gap filling, Matrigel invasion, tumor-sphere formation, and clonogenic survival assays. The HER2/CD44 feature was analyzed in 40 primary and recurrent breast cancer specimens. Protein expression profiling in HER2+/CD44+/CD24−/low versus HER2−/CD44+/CD24−/low BCSCs was conducted with 2-D DIGE and HPLC-MS/MS analysis and HER2-mediated signaling network was generated by MetaCore™ program. Results Compared to HER2-negative BCSCs, HER2+/CD44+/CD24−/low cells showed elevated aldehyde dehydrogenase (ALDH) activity and aggressiveness tested by matrigel invasion, tumor sphere formation and in vivo tumorigenesis. The enhanced aggressive phenotype and radioresistance of the HER2+/CD44+/CD24−/low cells were markedly reduced by inhibition of HER2 via siRNA or Herceptin treatments. Clinical breast cancer specimens revealed that cells co-expressing HER2 and CD44 were more frequently detected in recurrent (84.6%) than primary tumors (57.1%). In addition, 2-D DIGE and HPLC-MS/MS of HER2+/CD44+/CD24−/low versus HER2−/CD44+/CD24−/low BCSCs reported a unique HER2-associated protein profile including effectors involved in tumor metastasis, apoptosis, mitochondrial function and DNA repair. A specific feature of HER2-STAT3 network was identified. Conclusion This study provides the evidence that HER2-mediated pro-survival signaling network is responsible for the aggressive phenotype of breast cancer stem cells that could be targeted to control

  4. A kinetic model of tumor growth and its radiation response with an application to Gamma Knife stereotactic radiosurgery

    CERN Document Server

    Watanabe, Yoichi; Leder, Kevin Z; Hui, Susanta K

    2015-01-01

    We developed a mathematical model to simulate the growth of tumor volume and its response to a single fraction of high dose irradiation. We made several key assumptions of the model. Tumor volume is composed of proliferating (or dividing) cancer cells and non-dividing (or dead) cells. Tumor growth rate (or tumor volume doubling time, Td) is proportional to the ratio of the volumes of tumor vasculature and the tumor. The vascular volume grows slower than the tumor by introducing the vascular growth retardation factor, theta. Upon irradiation the proliferating cells gradually die over a fixed time period after irradiation. Dead cells are cleared away with cell clearance time, Tcl. The model was applied to simulate pre-treatment growth and post-treatment radiation response of rat rhabdomyosarcoma tumor and metastatic brain tumors of five patients who were treated by Gamma Knife stereotactic radiosurgery (GKSRS). By selecting appropriate model parameters, we showed the temporal variation of the tumors for both th...

  5. Sequential Salinomycin Treatment Results in Resistance Formation through Clonal Selection of Epithelial-Like Tumor Cells

    Directory of Open Access Journals (Sweden)

    Florian Kopp

    2014-12-01

    Full Text Available Acquiring therapy resistance is one of the major obstacles in the treatment of patients with cancer. The discovery of the cancer stem cell (CSC–specific drug salinomycin raised hope for improved treatment options by targeting therapy-refractory CSCs and mesenchymal cancer cells. However, the occurrence of an acquired salinomycin resistance in tumor cells remains elusive. To study the formation of salinomycin resistance, mesenchymal breast cancer cells were sequentially treated with salinomycin in an in vitro cell culture assay, and the resulting differences in gene expression and salinomycin susceptibility were analyzed. We demonstrated that long-term salinomycin treatment of mesenchymal cancer cells resulted in salinomycin-resistant cells with elevated levels of epithelial markers, such as E-cadherin and miR-200c, a decreased migratory capability, and a higher susceptibility to the classic chemotherapeutic drug doxorubicin. The formation of salinomycin resistance through the acquisition of epithelial traits was further validated by inducing mesenchymal-epithelial transition through an overexpression of miR-200c. The transition from a mesenchymal to a more epithelial-like phenotype of salinomycin-treated tumor cells was moreover confirmed in vivo, using syngeneic and, for the first time, transgenic mouse tumor models. These results suggest that the acquisition of salinomycin resistance through the clonal selection of epithelial-like cancer cells could become exploited for improved cancer therapies by antagonizing the tumor-progressive effects of epithelial-mesenchymal transition.

  6. Effect of Brain Tumor Presence During Radiation on Tissue Toxicity: Transcriptomic and Metabolic Changes.

    Science.gov (United States)

    Zawaski, Janice A; Sabek, Omaima M; Voicu, Horatiu; Eastwood Leung, Hon-Chiu; Gaber, M Waleed

    2017-11-15

    Radiation therapy (RT) causes functional and transcriptomic changes in the brain; however, most studies have been carried out in normal rodent brains. Here, the long-term effect of irradiation and tumor presence during radiation was investigated. Male Wistar rats ∼7 weeks old were divided into 3 groups: sham implant, RT+sham implant, and RT+tumor implant (C6 glioma). Hypofractionated irradiation (8 or 6 Gy/day for 5 days) was localized to a 1-cm strip of cranium starting 5 days after implantation, resulting in complete tumor regression and prolonged survival. Biopsy of tissue was performed in the implant area 65 days after implantation. RNA was hybridized to GeneChip Rat Exon 1.0 ST array. Data were analyzed using significant analysis of microarrays and ingenuity pathway analysis. (1)H magnetic resonance spectroscopy ((1)H-MRS) imaging was performed in the implantation site 65 to 70 days after implantation using a 9.4 T Biospec magnetic resonance imaging scanner with a quadrature rat brain array. Immunohistochemical staining for astrogliosis, HMG-CoA synthase 2, γ-aminobutyric acid (GABA) and taurine was performed at ∼65 days after implantation. Eighty-four genes had a false discovery rate tumor implant with RT+sham implant animals. The tumor presence affected networks associated with cancer/cell morphology/tissue morphology. (1)H-MRS showed significant reduction in taurine levels (Ptumor group also showed significant increase in levels of neurotransmitter GABA (P=.02). Hippocampal taurine levels were only significantly reduced in the RT+tumor group (P=.03). HMG-CoA synthase 2, GABA and taurine levels were confirmed using staining. Glial fibrillary acidic protein staining demonstrated a significant increase in inflammation that was heightened in the RT+tumor group. Our data indicate that tumor presence during radiation significantly affects long-term functional transcriptomics landscape and neurotransmitter levels at the tumor implantation site

  7. A new mixed-backbone oligonucleotide against glucosylceramide synthase sensitizes multidrug-resistant tumors to apoptosis.

    Directory of Open Access Journals (Sweden)

    Gauri A Patwardhan

    2009-09-01

    Full Text Available Enhanced ceramide glycosylation catalyzed by glucosylceramide synthase (GCS limits therapeutic efficiencies of antineoplastic agents including doxorubicin in drug-resistant cancer cells. Aimed to determine the role of GCS in tumor response to chemotherapy, a new mixed-backbone oligonucleotide (MBO-asGCS with higher stability and efficiency has been generated to silence human GCS gene. MBO-asGCS was taken up efficiently in both drug-sensitive and drug-resistant cells, but it selectively suppressed GCS overexpression, and sensitized drug-resistant cells. MBO-asGCS increased doxorubicin sensitivity by 83-fold in human NCI/ADR-RES, and 43-fold in murine EMT6/AR1 breast cancer cells, respectively. In tumor-bearing mice, MBO-asGCS treatment dramatically inhibited the growth of multidrug-resistant NCI/ADR-RE tumors, decreasing tumor volume to 37%, as compared with scrambled control. Furthermore, MBO-asGCS sensitized multidrug-resistant tumors to chemotherapy, increasing doxorubicin efficiency greater than 2-fold. The sensitization effects of MBO-asGCS relied on the decreases of gene expression and enzyme activity of GCS, and on the increases of C(18-ceramide and of caspase-executed apoptosis. MBO-asGCS was accumulation in tumor xenografts was greater in other tissues, excepting liver and kidneys; but MBO-asGCS did not exert significant toxic effects on liver and kidneys. This study, for the first time in vivo, has demonstrated that GCS is a promising therapeutic target for cancer drug resistance, and MBO-asGCS has the potential to be developed as an antineoplastic agent.

  8. Radiation resistant erbium doped fiber for ASE source and fiber gyroscope application

    Science.gov (United States)

    Pinsard, Emmanuel; Laurent, Arnaud; Robin, Thierry; Cadier, Benoît; Ferrand, Sébastien; Bonnefois, Jean-Jacques; Moluçon, Cedric; Boutillier, Mathieu

    2017-11-01

    A radiation resistant optical fiber used in a broadband source is presented. Both ASE source and Fiber Optical Gyroscope (FOG) commonly used in space missions, suffer from failures and degradation after long term exposure to radiative environment. The aim of this article is to present the results of our investigation on fiber and ASE source architecture in order to design a Radiation Resistant Erbium Doped Fiber that offers long term stability of the gyroscope performances.

  9. 15-Hydroxyprostaglandin dehydrogenase inactivation as a mechanism of resistance to celecoxib chemoprevention of colon tumors.

    LENUS (Irish Health Repository)

    Yan, Min

    2009-06-09

    Pharmacologic inhibitors of the prostaglandin-synthesizing COX-2 oncogene prevent the development of premalignant human colon adenomas. However, resistance to treatment is common. In this study, we show that the adenoma prevention activity of the COX-2 inhibitor celecoxib requires the concomitant presence of the 15-hydroxyprostaglandin dehydrogenase (15-PGDH) tumor suppressor gene, and that loss of 15-PGDH expression imparts resistance to celecoxib\\'s anti-tumor effects. We first demonstrate that the adenoma-preventive activity of celecoxib is abrogated in mice genetically lacking 15-PGDH. In FVB mice, celecoxib prevents 85% of azoxymethane-induced tumors >1 mm in size, but is essentially inactive in preventing tumor induction in 15-PGDH-null animals. Indeed, celecoxib treated 15-PGDH null animals develop more tumors than do celecoxib naive WT mice. In parallel with the loss of tumor prevention activity, celecoxib-mediated suppression of colonic PGE(2) levels is also markedly attenuated in 15-PGDH-null versus WT mice. Finally, as predicted by the murine models, humans with low colonic 15-PGDH levels also exhibit celecoxib resistance. Specifically, in a colon adenoma prevention trial, in all cases tested, individuals who developed new adenomas while receiving celecoxib treatment were also found as having low colonic 15-PGDH levels.

  10. ATP-binding cassette transporters in tumor endothelial cells and resistance to metronomic chemotherapy.

    Science.gov (United States)

    Hida, Kyoko; Kikuchi, Hiroshi; Maishi, Nako; Hida, Yasuhiro

    2017-08-01

    Drug resistance is a major problem in anticancer therapy. ATP-binding cassette (ABC) transporters have a role in the multidrug resistance. A new regimen of chemotherapy has been proposed, called "metronomic chemotherapy". Metronomic chemotherapy is the frequent, regular administration of drug doses designed to maintain low, but active, concentrations of chemotherapeutic drugs over prolonged periods of time, without causing serious toxicities. Metronomic chemotherapy regimens were developed to optimize the antitumor efficacy of agents that target the tumor vasculature instead of tumor cells, and to reduce toxicity of antineoplastic drugs [1]. Nevertheless, recent studies revealed that ABC transporters are expressed at a higher level in the endothelium in the tumor. To avoid resistance to metronomic anti-angiogenic chemotherapy, ABC transporter inhibition of tumor endothelial cells may be a promising strategy. In this mini-review, we discuss the possible mechanism of resistance to metronomic chemotherapy from the viewpoint of tumor endothelial cell biology, focusing on ABC transporters. Copyright © 2017. Published by Elsevier B.V.

  11. Simultaneous tumor and surrogate motion tracking with dynamic MRI for radiation therapy planning

    Science.gov (United States)

    Park, Seyoun; Farah, Rana; Shea, Steven M.; Tryggestad, Erik; Hales, Russell; Lee, Junghoon

    2018-01-01

    Respiration-induced tumor motion is a major obstacle for achieving high-precision radiotherapy of cancers in the thoracic and abdominal regions. Surrogate-based estimation and tracking methods are commonly used in radiotherapy, but with limited understanding of quantified correlation to tumor motion. In this study, we propose a method to simultaneously track the lung tumor and external surrogates to evaluate their spatial correlation in a quantitative way using dynamic MRI, which allows real-time acquisition without ionizing radiation exposure. To capture the lung and whole tumor, four MRI-compatible fiducials are placed on the patient’s chest and upper abdomen. Two different types of acquisitions are performed in the sagittal orientation including multi-slice 2D cine MRIs to reconstruct 4D-MRI and two-slice 2D cine MRIs to simultaneously track the tumor and fiducials. A phase-binned 4D-MRI is first reconstructed from multi-slice MR images using body area as a respiratory surrogate and groupwise registration. The 4D-MRI provides 3D template volumes for different breathing phases. 3D tumor position is calculated by 3D–2D template matching in which 3D tumor templates in the 4D-MRI reconstruction and the 2D cine MRIs from the two-slice tracking dataset are registered. 3D trajectories of the external surrogates are derived via matching a 3D geometrical model of the fiducials to their segmentations on the 2D cine MRIs. We tested our method on ten lung cancer patients. Using a correlation analysis, the 3D tumor trajectory demonstrates a noticeable phase mismatch and significant cycle-to-cycle motion variation, while the external surrogate was not sensitive enough to capture such variations. Additionally, there was significant phase mismatch between surrogate signals obtained from the fiducials at different locations.

  12. Acceptable Toxicity After Stereotactic Body Radiation Therapy for Liver Tumors Adjacent to the Central Biliary System

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    Eriguchi, Takahisa; Takeda, Atsuya; Sanuki, Naoko; Oku, Yohei; Aoki, Yousuke [Radiation Oncology Center, Ofuna Chuo Hospital, Kanagawa (Japan); Shigematsu, Naoyuki [Department of Radiology, Keio University School of Medicine, Tokyo (Japan); Kunieda, Etsuo, E-mail: kunieda-mi@umin.ac.jp [Department of Radiation Oncology, Tokai University, Kanagawa (Japan)

    2013-03-15

    Purpose: To evaluate biliary toxicity after stereotactic body radiation therapy (SBRT) for liver tumors. Methods and Materials: Among 297 consecutive patients with liver tumors treated with SBRT of 35 to 50 Gy in 5 fractions, patients who were irradiated with >20 Gy to the central biliary system (CBS), including the gallbladder, and had follow-up times >6 months were retrospectively analyzed. Toxicity profiles, such as clinical symptoms and laboratory and radiologic data especially for obstructive jaundice and biliary infection, were investigated in relation to the dose volume and length relationship for each biliary organ. Results: Fifty patients with 55 tumors were irradiated with >20 Gy to the CBS. The median follow-up period was 18.2 months (range, 6.0-80.5 months). In the dose length analysis, 39, 34, 14, and 2 patients were irradiated with >20 Gy, >30 Gy, >40 Gy, and >50 Gy, respectively, to >1 cm of the biliary tract. Seven patients were irradiated with >20 Gy to >20% of the gallbladder. Only 2 patients experienced asymptomatic bile duct stenosis. One patient, metachronously treated twice with SBRT for tumors adjacent to each other, had a transient increase in hepatic and biliary enzymes 12 months after the second treatment. The high-dose area >80 Gy corresponded to the biliary stenosis region. The other patient experienced biliary stenosis 5 months after SBRT and had no laboratory changes. The biliary tract irradiated with >20 Gy was 7 mm and did not correspond to the bile duct stenosis region. No obstructive jaundice or biliary infection was found in any patient. Conclusions: SBRT for liver tumors adjacent to the CBS was feasible with minimal biliary toxicity. Only 1 patient had exceptional radiation-induced bile duct stenosis. For liver tumors adjacent to the CBS without other effective treatment options, SBRT at a dose of 40 Gy in 5 fractions is a safe treatment with regard to biliary toxicity.

  13. Extremely high UV-C radiation resistant microorganisms from desert environments with different manganese concentrations.

    Science.gov (United States)

    Paulino-Lima, Ivan Glaucio; Fujishima, Kosuke; Navarrete, Jesica Urbina; Galante, Douglas; Rodrigues, Fabio; Azua-Bustos, Armando; Rothschild, Lynn Justine

    2016-10-01

    Desiccation resistance and a high intracellular Mn/Fe ratio contribute to ionizing radiation resistance of Deinococcus radiodurans. We hypothesized that this was a general phenomenon and thus developed a strategy to search for highly radiation-resistant organisms based on their natural environment. While desiccation is a typical feature of deserts, the correlation between radiation resistance and the intracellular Mn/Fe ratio of indigenous microorganisms or the Mn/Fe ratio of the environment, has not yet been described. UV-C radiation is highly damaging to biomolecules including DNA. It was used in this study as a selective tool because of its relevance to early life on earth, high altitude aerobiology and the search for life beyond Earth. Surface soil samples were collected from the Sonoran Desert, Arizona (USA), from the Atacama Desert in Chile and from a manganese mine in northern Argentina. Microbial isolates were selected after exposure to UV-C irradiation and growth. The isolates comprised 28 genera grouped within six phyla, which we ranked according to their resistance to UV-C irradiation. Survival curves were performed for the most resistant isolates and correlated with their intracellular Mn/Fe ratio, which was determined by ICP-MS. Five percent of the isolates were highly resistant, including one more resistant than D. radiodurans, a bacterium generally considered the most radiation-resistant organism, thus used as a model for radiation resistance studies. No correlation was observed between the occurrence of resistant microorganisms and the Mn/Fe ratio in the soil samples. However, all resistant isolates showed an intracellular Mn/Fe ratio much higher than the sensitive isolates. Our findings could represent a new front in efforts to harness mechanisms of UV-C radiation resistance from extreme environments. Copyright © 2016 Elsevier B.V. All rights reserved.

  14. Radiation related basic cancer research : research for radiation induced tumor cell killing

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    Lee, Seung Hoon; Hong, Seok Il; Cho, Kyung Ja; Kim, Byung Gi; Lee, Kee Ho; Nam, Myung Jin

    1999-04-01

    The radioresistant clones was established from human U251 glioblastoma cell line through intermittently exposed to 3 Gy gamma-radiation for six months. Treatment of SNU-16 cells with various doses of radiation, TNF alpha and PMA resulted in a decrease in cell viability. The results prove that cell death of SNU16 is a apoptosis mediated by caspase-3. We have examined the expression of bcl-2 and c-myc in cervical cancer specimens and cervical intraepithelial neoplasia (CIN) to determine the role of coexpression of bcl-3 and c-myc during progression into cervical cancer. The frequent alterations in FHIT expression in many cervical carcinomas and their cell lines suggest that FHIT gene alterations are pla a role in cervical tumorigenesis. According to these correlation between the viability and apoptosis of RD cells, the proper range of the dosage for the investigation of differentiation potency in RD cells was assessed as 1 to 3Gy.

  15. Expression of EGFR Under Tumor Hypoxia: Identification of a Subpopulation of Tumor Cells Responsible for Aggressiveness and Treatment Resistance

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    Hoogsteen, Ilse J., E-mail: i.hoogsteen@rther.umcn.nl [Department of Radiation Oncology, Radboud University Nijmegen Medical Centre, Nijmegen (Netherlands); Marres, Henri A.M.; Hoogen, Franciscus J.A. van den [Department of Otorhinolaryngology/Head-Neck Surgery, Radboud University Nijmegen Medical Centre, Nijmegen (Netherlands); Rijken, Paul F.J.W.; Lok, Jasper; Bussink, Johan; Kaanders, Johannes H.A.M. [Department of Radiation Oncology, Radboud University Nijmegen Medical Centre, Nijmegen (Netherlands)

    2012-11-01

    Purpose: Overexpression of epidermal growth factor receptor (EGFR) and tumor hypoxia have been shown to correlate with worse outcome in several types of cancer including head-and-neck squamous cell carcinoma. Little is known about the combination and possible interactions between the two phenomena. Methods and Materials: In this study, 45 cases of histologically confirmed squamous cell carcinomas of the head and neck were analyzed. All patients received intravenous infusions of the exogenous hypoxia marker pimonidazole prior to biopsy. Presence of EGFR, pimonidazole binding, and colocalization between EGFR and tumor hypoxia were examined using immunohistochemistry. Results: Of all biopsies examined, respectively, 91% and 60% demonstrated EGFR- and pimonidazole-positive areas. A weak but significant association was found between the hypoxic fractions of pimonidazole (HFpimo) and EGFR fractions (F-EGFR) and between F-EGFR and relative vascular area. Various degrees of colocalization between hypoxia and EGFR were found, increasing with distance from the vasculature. A high fraction of EGFR was correlated with better disease-free and metastasis-free survival, whereas a high degree of colocalization correlated with poor outcome. Conclusions: Colocalization of hypoxia and EGFR was demonstrated in head-and-neck squamous cell carcinomas, predominantly at longer distances from vessels. A large amount of colocalization was associated with poor outcome, which points to a survival advantage of hypoxic cells that are also able to express EGFR. This subpopulation of tumor cells might be indicative of tumor aggressiveness and be partly responsible for treatment resistance.

  16. Radiation therapy for primary carcinoma of the eyelid. Tumor control and visual function

    Energy Technology Data Exchange (ETDEWEB)

    Hata, M.; Koike, I.; Odagiri, K.; Kasuya, T.; Minagawa, Y.; Kaizu, H.; Mukai, Y.; Inoue, T. [Yokohama City Univ. Graduate School of Medicine, Kanagawa (Japan). Dept. of Radiology; Maegawa, J. [Yokohama City Univ. Graduate School of Medicine, Kanagawa (Japan). Dept. of Plastic and Reconstructive Surgery; Kaneko, A. [Yokohama City Univ. Graduate School of Medicine, Kanagawa (Japan). Dept. of Ophthalmology

    2012-12-15

    Background and purpose: Surgical excision remains the standard and most reliable curative treatment for eyelid carcinoma, but frequently causes functional and cosmetic impairment of the eyelid. We therefore investigated the efficacy and safety of radiation therapy in eyelid carcinoma. Patients and methods: Twenty-three patients with primary carcinoma of the eyelid underwent radiation therapy. Sebaceous carcinoma was histologically confirmed in 16 patients, squamous cell carcinoma in 6, and basal cell carcinoma in 1. A total dose of 50-66.6 Gy (median, 60 Gy) was delivered to tumor sites in 18-37 fractions (median, 30 fractions). Results: All but 3 of the 23 patients had survived at a median follow-up period of 49 months. The overall survival and local progression-free rates were 87% and 93% at 2 years, and 80% and 93% at 5 years, respectively. Although radiation-induced cataracts developed in 3 patients, visual acuity in the other patients was relatively well preserved. There were no other therapy-related toxicities of grade 3 or greater. Conclusion: Radiation therapy is safe and effective for patients with primary carcinoma of the eyelid. It appears to contribute to prolonged survival as a result of good tumor control, and it also facilitates functional and cosmetic preservation of the eyelid. (orig.)

  17. Leveraging Hypoxia-Activated Prodrugs to Prevent Drug Resistance in Solid Tumors.

    Directory of Open Access Journals (Sweden)

    Danika Lindsay

    2016-08-01

    Full Text Available Experimental studies have shown that one key factor in driving the emergence of drug resistance in solid tumors is tumor hypoxia, which leads to the formation of localized environmental niches where drug-resistant cell populations can evolve and survive. Hypoxia-activated prodrugs (HAPs are compounds designed to penetrate to hypoxic regions of a tumor and release cytotoxic or cytostatic agents; several of these HAPs are currently in clinical trial. However, preliminary results have not shown a survival benefit in several of these trials. We hypothesize that the efficacy of treatments involving these prodrugs depends heavily on identifying the correct treatment schedule, and that mathematical modeling can be used to help design potential therapeutic strategies combining HAPs with standard therapies to achieve long-term tumor control or eradication. We develop this framework in the specific context of EGFR-driven non-small cell lung cancer, which is commonly treated with the tyrosine kinase inhibitor erlotinib. We develop a stochastic mathematical model, parametrized using clinical and experimental data, to explore a spectrum of treatment regimens combining a HAP, evofosfamide, with erlotinib. We design combination toxicity constraint models and optimize treatment strategies over the space of tolerated schedules to identify specific combination schedules that lead to optimal tumor control. We find that (i combining these therapies delays resistance longer than any monotherapy schedule with either evofosfamide or erlotinib alone, (ii sequentially alternating single doses of each drug leads to minimal tumor burden and maximal reduction in probability of developing resistance, and (iii strategies minimizing the length of time after an evofosfamide dose and before erlotinib confer further benefits in reduction of tumor burden. These results provide insights into how hypoxia-activated prodrugs may be used to enhance therapeutic effectiveness in the

  18. Influence of Residual Tumor Volume and Radiation Dose Coverage in Outcomes for Clival Chordoma

    Energy Technology Data Exchange (ETDEWEB)

    McDonald, Mark W., E-mail: markmcdonaldmd@gmail.com [Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, Indiana (United States); Indiana University Health Proton Therapy Center, Bloomington, Indiana (United States); Linton, Okechukwu R. [Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, Indiana (United States); Moore, Michael G.; Ting, Jonathan Y. [Department of Otolaryngology, Head and Neck Surgery, Indiana University School of Medicine, Indianapolis, Indiana (United States); Cohen-Gadol, Aaron A.; Shah, Mitesh V. [Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, Indiana (United States); Goodman Campbell Brain and Spine, Indianapolis, Indiana (United States)

    2016-05-01

    Purpose: The purpose of this study was to evaluate factors associated with tumor control in clival chordomas. Methods and Materials: A retrospective review of 39 patients treated with surgery and proton therapy for clival chordomas between 2004 and 2014 was performed. The median prescribed dose was 77.4 Gy (relative biological effectiveness [RBE]); range was 70.2-79.2 Gy (RBE). Minimum and median doses to gross tumor volume (GTV), radiation dose received by 1 cm{sup 3} of GTV (D1cm{sup 3}), and the equivalent uniform dose were calculated. Receiver operating characteristics curves evaluated the predictive sensitivity and specificity for local failure of potential cutpoint values for GTV and D1cm{sup 3}. Results: After a median follow-up of 51 months, the 5-year estimate of local control (LC) was 69.6% (95% confidence interval [CI] 50.0%-89.2%), and overall survival (OS) was 81.4% (95% CI: 65.3%-97.5%). Tumor histology, GTV at the time of radiation, and prescribed radiation dose were significantly associated with local control on multivariate analysis, whereas D1cm{sup 3} was associated with overall survival. Compared to those patients whose conditions remained controlled, patients experiencing tumor failure had statistically significant larger GTVs and lower D1cm{sup 3}, and prescribed and median doses to GTV. A subset of 21 patients with GTV of ≤20 cm{sup 3} and D1cm{sup 3} of >67 Gy (RBE) had a median follow-up of 47 months. The 5-year estimate of local control in this subset was 81.1% (95% CI: 61.7%-100%; P=.004, overall comparison by GTV ≤20 cm{sup 3} stratified by D1cm{sup 3}). A D1cm{sup 3} of 74.5 Gy (RBE) had 80% sensitivity for local control and 60% specificity, whereas a GTV of 9.3 cm{sup 3} had 80% sensitivity for local control and 66.7% specificity. Conclusions: Local control of clival chordomas was associated with both smaller size of residual tumor and more complete high-dose coverage of residual tumor. Multidisciplinary care should seek

  19. Donepezil in Treating Young Patients With Primary Brain Tumors Previously Treated With Radiation Therapy to the Brain

    Science.gov (United States)

    2017-07-31

    Brain and Central Nervous System Tumors; Cognitive/Functional Effects; Long-term Effects Secondary to Cancer Therapy in Children; Neurotoxicity; Psychosocial Effects of Cancer and Its Treatment; Radiation Toxicity

  20. Design principles for radiation-resistant solid solutions

    Science.gov (United States)

    Schuler, Thomas; Trinkle, Dallas R.; Bellon, Pascal; Averback, Robert

    2017-05-01

    We develop a multiscale approach to quantify the increase in the recombined fraction of point defects under irradiation resulting from dilute solute additions to a solid solution. This methodology provides design principles for radiation-resistant materials. Using an existing database of solute diffusivities, we identify Sb as one of the most efficient solutes for this purpose in a Cu matrix. We perform density-functional-theory calculations to obtain binding and migration energies of Sb atoms, vacancies, and self-interstitial atoms in various configurations. The computed data informs the self-consistent mean-field formalism to calculate transport coefficients, allowing us to make quantitative predictions of the recombined fraction of point defects as a function of temperature and irradiation rate using homogeneous rate equations. We identify two different mechanisms according to which solutes lead to an increase in the recombined fraction of point defects; at low temperature, solutes slow down vacancies (kinetic effect), while at high temperature, solutes stabilize vacancies in the solid solution (thermodynamic effect). Extension to other metallic matrices and solutes are discussed.

  1. Decellularized matrices as in vitro models of extracellular matrix in tumor tissues at different malignant levels: Mechanism of 5-fluorouracil resistance in colorectal tumor cells.

    Science.gov (United States)

    Hoshiba, Takashi; Tanaka, Masaru

    2016-11-01

    Chemoresistance is a major barrier for tumor chemotherapy. It is well-known that chemoresistance increases with tumor progression. Chemoresistance is altered by both genetic mutations and the alteration of extracellular microenvironment. Particularly, the extracellular matrix (ECM) is remodeled during tumor progression. Therefore, ECM remodeling is expected to cause the acquisition of chemoresistance in highly malignant tumor tissue. Here, we prepared cultured cell-derived decellularized matrices that mimic native ECM in tumor tissues at different stages of malignancy, and 5-fluorouracil (5-FU) resistance was compared among these matrices. 5-FU resistance of colorectal tumor cells increased on the matrices derived from highly malignant tumor HT-29 cells, although the resistance did not increase on the matrices derived from low malignant tumor SW480 cells and normal CCD-841-CoN cells. The resistance on HT-29 cell-derived matrices increased through the activation of Akt and the upregulation of ABCB1 and ABCC1 without cell growth promotion, suggesting that ECM remodeling plays important roles in the acquisition of chemoresistance during tumor progression. It is expected that our decellularized matrices, or "staged tumorigenesis-mimicking matrices", will become preferred cell culture substrates for in vitro analysis of comprehensive ECM roles in chemoresistance and the screening and pharmacokinetic analysis of anti-cancer drugs. Copyright © 2016 Elsevier B.V. All rights reserved.

  2. Percutaneous Renal Tumor Ablation: Radiation Exposure During Cryoablation and Radiofrequency Ablation

    Energy Technology Data Exchange (ETDEWEB)

    McEachen, James C., E-mail: james.mceachen2@gmail.com [Mayo Clinic, Division of Preventive, Occupational, and Aerospace Medicine (United States); Leng, Shuai; Atwell, Thomas D. [Mayo Clinic, Department of Radiology (United States); Tollefson, Matthew K. [Mayo Clinic, Department of Urology (United States); Friese, Jeremy L. [Mayo Clinic, Department of Radiology (United States); Wang, Zhen; Murad, M. Hassan [Mayo Clinic, Division of Preventive, Occupational, and Aerospace Medicine (United States); Schmit, Grant D. [Mayo Clinic, Department of Radiology (United States)

    2016-02-15

    IntroductionOnce reserved solely for non-surgical cases, percutaneous ablation is becoming an increasingly popular treatment option for a wider array of patients with small renal masses and the radiation risk needs to be better defined as this transition continues.Materials and MethodsRetrospective review of our renal tumor ablation database revealed 425 patients who underwent percutaneous ablation for treatment of 455 renal tumors over a 5-year time period. Imparted radiation dose information was reviewed for each procedure and converted to effective patient dose and skin dose using established techniques. Statistical analysis was performed with each ablative technique.ResultsFor the 331 cryoablation procedures, the mean DLP was 6987 mGycm (SD = 2861) resulting in a mean effective dose of 104.7 mSv (SD = 43.5) and the mean CTDI{sub vol} was 558 mGy (SD = 439) resulting in a mean skin dose of 563.2 mGy (SD = 344.1). For the 124 RFA procedures, the mean DLP was 3485 mGycm (SD = 1630) resulting in a mean effective dose of 50.3 mSv (SD = 24.0) and the mean CTDI{sub vol} was 232 mGy (SD = 149) resulting in a mean skin dose of 233.2 mGy (SD = 117.4). The difference in patient radiation exposure between the two renal ablation techniques was statistically significant (p < 0.001).ConclusionBoth cryoablation and RFA imparted an average skin dose that was well below the 2 Gy deterministic threshold for appreciable sequela. Renal tumor cryoablation resulted in a mean skin and effective radiation dose more than twice that for RFA. The radiation exposure for both renal tumor ablation techniques was at the high end of the medical imaging radiation dose spectrum.

  3. Radiation therapy for malignant phyllodes tumor of the breast: An analysis of SEER data.

    Science.gov (United States)

    Kim, Yi-Jun; Kim, Kyubo

    2017-04-01

    Malignant phyllodes tumor of the breast (MPTB) accounts for less than 1% of whole breast neoplasm. Surgery is regarded as the primary treatment of choice in patients with MPTB, but the necessity of postoperative radiation therapy (RT) has been a subject of debate. Our aim was to evaluate effects of postoperative RT for MPTB using a large population database. Using the Surveillance, Epidemiology, and End Results Program (SEER) database (1983-2013), clinico-pathologic prognostic factors were evaluated. Postoperative RT, tumor extent, grade, and lymph node (LN) metastasis were included in the analysis. Univariate and multivariate Cox proportional hazards regressions were performed to evaluate prognostic power of variables on cancer specific survival (CSS). A total of 1974 patients with MPTB were reviewed. Of these, 825 (42%) and 1149 (58%) patients underwent mastectomy and breast conserving surgery (BCS), respectively. In each group, 130 (16%) and 122 (11%) patients received postoperative RT. For patients with adverse risk factors including high grade and large tumor size, postoperative RT was more likely to be performed. In multivariate analysis, age, ethnicity, tumor size, tumor extension and LN status were correlated with prognosis in mastectomy group, while postoperative RT did not affect CSS. In BCS group, age and grade were significant prognostic factors on CSS, meanwhile postoperative RT did not impact CSS in multivariate analysis. Although patients with more adverse prognostic factors underwent postoperative RT, RT groups were not inferior to non-RT group on CSS regardless of surgery (mastectomy or BCS). Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Effect of combination laser hyperthermia and radiation therapy for malignant tumor of the eyelid

    Energy Technology Data Exchange (ETDEWEB)

    Kurokawa, Tomoko [Chukyo Hospital, Nagoya, Aichi (Japan); Ando, Fumitaka; Watanabe, Michiko

    1997-10-01

    Malignant tumors of the eyelid have been treated successfully by excision of a margin of normal tissue, but cosmesis may be a problem postoperatively. To avoid the problems of surgery, we used a combination therapy of laser hyperthermia followed by radiation in 4 eyes of 4 patients (2 eyes with sebaceous gland carcinoma, 1 with squamous cell carcinoma, and 1 with basal cell carcinoma). An interstitial contact laser probe of artificial sapphire connected to a continuous wave neodymium yttrium-aluminum-garnet (Nd:YAG) laser was used to effect hyperthermia in the tumor for 15 to 20 minutes at each treatment. The laser energy was applied directly to the surface of the conjunctiva, which was anesthetized before each treatment by topical application of anesthetic drops and injection of lidocaine. The temperature around the tumor was maintained between 42 and 43 degrees C by intermittent low-power irradiation of 2 watts. Radiotherapy was administered 3 to 5 times a week using a linear accelerator set at 4 to 6 MeV to deliver 2.5 to 3.5 Gy at each session for a total of 50 to 65 Gy. None of the 4 patients experienced recurrence of eyelid tumor, and the only complications observed were madarosis (2 eyes) and cataract (1 eye). This protocol seems to be a promising method to treat malignant tumor of the eyelid. (author)

  5. The tumor microenvironment underlies acquired resistance to CSF-1R inhibition in gliomas.

    Science.gov (United States)

    Quail, Daniela F; Bowman, Robert L; Akkari, Leila; Quick, Marsha L; Schuhmacher, Alberto J; Huse, Jason T; Holland, Eric C; Sutton, James C; Joyce, Johanna A

    2016-05-20

    Macrophages accumulate with glioblastoma multiforme (GBM) progression and can be targeted via inhibition of colony-stimulating factor-1 receptor (CSF-1R) to regress high-grade tumors in animal models of this cancer. However, whether and how resistance emerges in response to sustained CSF-1R blockade is unknown. We show that although overall survival is significantly prolonged, tumors recur in >50% of mice. Gliomas reestablish sensitivity to CSF-1R inhibition upon transplantation, indicating that resistance is tumor microenvironment-driven. Phosphatidylinositol 3-kinase (PI3K) pathway activity was elevated in recurrent GBM, driven by macrophage-derived insulin-like growth factor-1 (IGF-1) and tumor cell IGF-1 receptor (IGF-1R). Combining IGF-1R or PI3K blockade with CSF-1R inhibition in recurrent tumors significantly prolonged overall survival. Our findings thus reveal a potential therapeutic approach for treating resistance to CSF-1R inhibitors. Copyright © 2016, American Association for the Advancement of Science.

  6. Effect of gold nanoparticles on radiation doses in tumor treatment: a Monte Carlo study.

    Science.gov (United States)

    Al-Musywel, H A; Laref, A

    2017-12-01

    Radiotherapy is an extensively used treatment for most tumor types. However, ionizing radiation does not discriminate between cancerous and normal cells surrounding the tumor, which can be considered as a dose-limiting factor. This can lead to the reduction of the effectiveness of tumor cell eradication with this treatment. A potential solution to this problem is loading the tumor with high-Z materials prior to radiotherapy as this can induce higher toxicity in tumor cells compared to normal ones. New advances in nanotechnology have introduced the promising use of heavy metal nanoparticles to enhance tumor treatment. The primary studies showed that gold nanoparticles (GNPs) have unique characteristics as biocompatible radiosensitizers for tumor cells. This study aimed to quantify the dose enhancement effect and its radial dose distribution by Monte Carlo simulations utilizing the EGSnrc code for the water-gold phantom loaded with seven different concentrations of Au: 0, 7, 18, 30, 50, 75, and 100 mg-Au/g-water. The phantom was irradiated with two different radionuclide sources, Ir-192 and Cs-137, which are commonly used in brachytherapy, for all concentrations. The results exhibited that gold nanoparticle-aided radiotherapy (GNRT) increases the efficacy of radiotherapy with low-energy photon sources accompanied with high Au concentration loads of up to 30 mg-Au/g-water. Our finding conducts also to the detection of dose enhancement effects in a short average range of 650 μm outside the region loaded with Au. This can indicate that the location determination is highly important in this treatment method.

  7. Quantitative ultrasound characterization of tumor cell death: ultrasound-stimulated microbubbles for radiation enhancement.

    Directory of Open Access Journals (Sweden)

    Hyunjung Christina Kim

    Full Text Available The aim of this study was to assess the efficacy of quantitative ultrasound imaging in characterizing cancer cell death caused by enhanced radiation treatments. This investigation focused on developing this ultrasound modality as an imaging-based non-invasive method that can be used to monitor therapeutic ultrasound and radiation effects. High-frequency (25 MHz ultrasound was used to image tumor responses caused by ultrasound-stimulated microbubbles in combination with radiation. Human prostate xenografts grown in severe combined immunodeficiency (SCID mice were treated using 8, 80, or 1000 µL/kg of microbubbles stimulated with ultrasound at 250, 570, or 750 kPa, and exposed to 0, 2, or 8 Gy of radiation. Tumors were imaged prior to treatment and 24 hours after treatment. Spectral analysis of images acquired from treated tumors revealed overall increases in ultrasound backscatter intensity and the spectral intercept parameter. The increase in backscatter intensity compared to the control ranged from 1.9±1.6 dB for the clinical imaging dose of microbubbles (8 µL/kg, 250 kPa, 2 Gy to 7.0±4.1 dB for the most extreme treatment condition (1000 µL/kg, 750 kPa, 8 Gy. In parallel, in situ end-labelling (ISEL staining, ceramide, and cyclophilin A staining demonstrated increases in cell death due to DNA fragmentation, ceramide-mediated apoptosis, and release of cyclophilin A as a result of cell membrane permeabilization, respectively. Quantitative ultrasound results indicated changes that paralleled increases in cell death observed from histology analyses supporting its use for non-invasive monitoring of cancer treatment outcomes.

  8. Hypoxia, lactate accumulation, and acidosis: siblings or accomplices driving tumor progression and resistance to therapy?

    Science.gov (United States)

    Mayer, Arnulf; Vaupel, Peter

    2013-01-01

    This chapter briefly summarizes the most important processes by which hypoxia, lactate accumulation, and acidosis may influence malignant progression and therapeutic resistance of solid malignant tumors. While these phenomena are often elements of an integrated reaction, they may occur independently of each other under certain circumstances. The latter information may be of interest with regard to possible "targeted" therapeutic interventions.

  9. Radiation-induced lung fibrosis in a tumor-bearing mouse model is associated with enhanced Type-2 immunity.

    Science.gov (United States)

    Chen, Jing; Wang, Yacheng; Mei, Zijie; Zhang, Shimin; Yang, Jie; Li, Xin; Yao, Ye; Xie, Conghua

    2016-03-01

    Lung fibrosis may be associated with Type-2 polarized inflammation. Herein, we aim to investigate whether radiation can initiate a Type-2 immune response and contribute to the progression of pulmonary fibrosis in tumor-bearing animals. We developed a tumor-bearing mouse model with Lewis lung cancer to receive either radiation therapy alone or radiation combined with Th1 immunomodulator unmethylated cytosine-phosphorothioate-guanine containing oligodeoxynucleotide (CpG-ODN). The Type-2 immune phenotype in tumors and the histological grade of lung fibrosis were evaluated in mice sacrificed three weeks after irradiation. Mouse lung tissues were analyzed for hydroxyproline and the expression of Type-1/Type-2 key transcription factors (T-bet/GATA-3). The concentration of Type-1/Type-2 cytokines in serum was measured by cytometric bead array. Lung fibrosis was observed to be more serious in tumor-bearing mice than in normal mice post-irradiation. The fibrosis score in irradiated tumor-bearing mice on Day 21 was 4.33 ± 0.82, which was higher than that of normal mice (2.00 ± 0.63; P Type-2 immunity in tumors appeared to affect the outcome of radiation damage and might be of interest for future studies on developing approaches in which Type-1-related immunotherapy and radiotherapy are used in combination. © The Author 2015. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

  10. Epigenetic Modifications and Head and Neck Cancer: Implications for Tumor Progression and Resistance to Therapy

    Directory of Open Access Journals (Sweden)

    Rogerio M. Castilho

    2017-07-01

    Full Text Available Head and neck squamous carcinoma (HNSCC is the sixth most prevalent cancer and one of the most aggressive malignancies worldwide. Despite continuous efforts to identify molecular markers for early detection, and to develop efficient treatments, the overall survival and prognosis of HNSCC patients remain poor. Accumulated scientific evidences suggest that epigenetic alterations, including DNA methylation, histone covalent modifications, chromatin remodeling and non-coding RNAs, are frequently involved in oral carcinogenesis, tumor progression, and resistance to therapy. Epigenetic alterations occur in an unsystematic manner or as part of the aberrant transcriptional machinery, which promotes selective advantage to the tumor cells. Epigenetic modifications also contribute to cellular plasticity during tumor progression and to the formation of cancer stem cells (CSCs, a small subset of tumor cells with self-renewal ability. CSCs are involved in the development of intrinsic or acquired therapy resistance, and tumor recurrences or relapse. Therefore, the understanding and characterization of epigenetic modifications associated with head and neck carcinogenesis, and the prospective identification of epigenetic markers associated with CSCs, hold the promise for novel therapeutic strategies to fight tumors. In this review, we focus on the current knowledge on epigenetic modifications observed in HNSCC and emerging Epi-drugs capable of sensitizing HNSCC to therapy.

  11. Understanding and Targeting Tumor Microenvironment in Prostate Cancer to Inhibit Tumor Progression and Castration Resistance

    Science.gov (United States)

    2016-10-01

    project. I was invited to give an oral presentation of the preliminary data for the proposed new works at the PCRP - Innovative Minds in Prostate...pc −/− model, which initiates tumor development at 6 to 8 weeks and progresses to early invasive carcinoma by 14 weeks of age, serial CyTOF analyses...PCa) cells (EpCAM + CD45 − ), nonimmune TME cells (EpCAM − CD45 − ), T cells (CD45 + CD3 + TCRβ + ), B cells (CD45 + B220 + CD19 + ), natural killer

  12. A role of trial radiation therapy in the pineal region tumors

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Yeon Shil; Ryu, Mi Ryung; Chung, Su Mi; Kim, Moon Chan; Yoon, Sei Chul [The Catholic University of Korea, Seoul (Korea, Republic of)

    2002-06-15

    The aim of this retrospective study was to assess the treatment results of 30 patients with pineal region tumors who were underwent radiation therapy under the diagnosis by either CT or MRI. There was no histological verification. We analyzed the prognostic factors that have a significant effect on the overall survival (OS) and disease free survival (DFS) rates. A total 30 patients with pineal region tumors were treated between March 1983 and August 1995. After a trial radiation therapy of 20 {approx} 30 Gy/2 {approx} 3 weeks, the patients were evaluated for their clinical response and radiological response by either CT or MRI and the final treatment direction was then decided. According to their response to the trial radiation therapy and the involved site, radiation treatment was given in various field i.e., local, ventricle, whole brain and craniospinal field. The radiation dose ranged from 40.8 to 59.4 Gy (Median 50.4 Gy). The median follow up was 36.5 months (4 {approx} 172 months). An improvement or stability in the clinical symptoms was observed in 28 patients (93.3%) after the trial RT. Nineteen patients (63.3%) showed a partial or complete response by CT or MRI. The two-year and five-year survival rates of the patients were 66.7% and 55.1%, respectively. No significant difference in the survival rates according to the degree of the radiological response was observed after the trial RT. The results of univariate analysis showed that age, the primary site, the performance status(KPS {>=} 70), the degree of response after completing RT and the RT field were significant prognostic factors affecting the survival and disease free survival rates ({rho} < 0.05). The clinical and histological characteristics of pineal region tumors are quite complex and diverse. Therefore, it is difficult to predict the histological diagnosis and the possibility of radiocurability only with the initial response to RT. We think that the development of less invasive histological

  13. Co-expression of CD147 and GLUT-1 indicates radiation resistance and poor prognosis in cervical squamous cell carcinoma.

    Science.gov (United States)

    Huang, Xin-Qiong; Chen, Xiang; Xie, Xiao-Xue; Zhou, Qin; Li, Kai; Li, Shan; Shen, Liang-Fang; Su, Juan

    2014-01-01

    The aim of this study was to investigate the association of CD147 and GLUT-1, which play important roles in glycolysis in response to radiotherapy and clinical outcomes in patients with locally advanced cervical squamous cell carcinoma (LACSCC). The records of 132 female patients who received primary radiation therapy to treat LACSCC at FIGO stages IB-IVA were retrospectively reviewed. Forty-seven patients with PFS (progression-free survival) of less than 36 months were regarded as radiation-resistant. Eighty-five patients with PFS longer than 36 months were regarded as radiation-sensitive. Using pretreatment paraffin-embedded tissues, we evaluated CD147 and GLUT-1 expression by immunohistochemistry. Overexpression of CD147, GLUT-1, and CD147 and GLUT-1 combined were 44.7%, 52.9% and 36.5%, respectively, in the radiation-sensitive group, and 91.5%, 89.4% and 83.0%, respectively, in the radiation-resistant group. The 5-year progress free survival (PFS) rates in the CD147-low, CD147-high, GLUT-1-low, GLUT-1-high, CD147- and/or GLUT-1-low and CD147- and GLUT-1- dual high expression groups were 66.79%, 87.10%, 52.78%, 85.82%, 55.94%, 82.90% and 50.82%, respectively. CD147 and GLUT-1 co-expression, FIGO stage and tumor diameter were independent poor prognostic factors for patients with LACSCC in multivariate Cox regression analysis. Patients with high expression of CD147 alone, GLUT-1 alone or co-expression of CD147 and GLUT-1 showed greater resistance to radiotherapy and a shorter PFS than those with low expression. In particular, co-expression of CD147 and GLUT-1 can be considered as a negative independent prognostic factor.

  14. Flow cytometric applications of tumor biology: prospects and pitfalls. [Applications in study of spontaneous dog tumors and in drug and radiation effects on cultured V79 cells

    Energy Technology Data Exchange (ETDEWEB)

    Raju, M.R.; Johnson, T.S.; Tokita, N.; Gillette, E.L.

    1979-01-01

    A brief review of cytometry instrumentation and its potential applications in tumor biology is presented using our recent data. Age-distribution measurements of cells from spontaneous dog tumors and cultured cells after exposure to x rays, alpha particles, or adriamycin are shown. The data show that DNA fluorescence measurements have application in the study of cell kinetics after either radiation or drug treatment. Extensive and careful experimentation is needed to utilize the sophisticated developments in flow cytometry instrumentation.

  15. The enhancemeny of anti-tumor effects, immuno-activity and radiation protection after injection of EF2001(Lactic bacteria)

    Energy Technology Data Exchange (ETDEWEB)

    Amano, Morkkazu; Hasegawa, Takeo; Takahashi, Tohru [Graduate School of Health Science, Suzuka (Japan)] [and others

    2002-07-01

    EF2001 was made from Enterococcus Faecalis, and it has radiation protection effects by protection of the intestinal mucosa in the absorption function of the carcinogenesis materials. We used animals were C3H mice bearing SCC-VIII tumor. The results of this study confirmed, EF2001 has effect of radiation protection and EF2001 can absorption of carcinogenesis materials selectively.

  16. Downregulation of taurine uptake in multidrug resistant Ehrlich ascites tumor cells

    DEFF Research Database (Denmark)

    Poulsen, K A; Litman, Thomas; Eriksen, J

    2002-01-01

    In daunorubicin resistant Ehrlich ascites tumor cells (DNR), the initial taurine uptake was reduced by 56% as compared to the parental, drug sensitive Ehrlich cells. Kinetic experiments indicated that taurine uptake in Ehrlich cells occurs via both high- and low-affinity transporters. The maximal...... rate constant for the initial taurine uptake was reduced by 45% (high-affinity system) and 49% (low affinity system) in the resistant subline whereas the affinity of the transporters to taurine was unchanged. By immunoblotting we identified 3 TauT protein bands in the 50-70 kDa region. A visible...... reduction in the intensity of the band with the lowest molecular weight was observed in resistant cells. Quantitative RT-PCR indicated a significant reduction in the amount of taurine transporter mRNA in the resistant cells. Drug resistance in DNR Ehrlich cells is associated with overexpression of the mdr1...

  17. Conservation and diversity of the IrrE/DdrO-controlled radiation response in radiation-resistant Deinococcus bacteria.

    Science.gov (United States)

    Blanchard, Laurence; Guérin, Philippe; Roche, David; Cruveiller, Stéphane; Pignol, David; Vallenet, David; Armengaud, Jean; de Groot, Arjan

    2017-08-01

    The extreme radiation resistance of Deinococcus bacteria requires the radiation-stimulated cleavage of protein DdrO by a specific metalloprotease called IrrE. DdrO is the repressor of a predicted radiation/desiccation response (RDR) regulon, composed of radiation-induced genes having a conserved DNA motif (RDRM) in their promoter regions. Here, we showed that addition of zinc ions to purified apo-IrrE, and short exposure of Deinococcus cells to zinc ions, resulted in cleavage of DdrO in vitro and in vivo, respectively. Binding of IrrE to RDRM-containing DNA or interaction of IrrE with DNA-bound DdrO was not observed. The data are in line with IrrE being a zinc peptidase, and indicate that increased zinc availability, caused by oxidative stress, triggers the in vivo cleavage of DdrO unbound to DNA. Transcriptomics and proteomics of Deinococcus deserti confirmed the IrrE-dependent regulation of predicted RDR regulon genes and also revealed additional members of this regulon. Comparative analysis showed that the RDR regulon is largely well conserved in Deinococcus species, but also showed diversity in the regulon composition. Notably, several RDR genes with an important role in radiation resistance in Deinococcus radiodurans, for example pprA, are not conserved in some other radiation-resistant Deinococcus species. © 2017 The Authors. MicrobiologyOpen published by John Wiley & Sons Ltd.

  18. Sunlight suppressing rejection of 280- to 320-nm UV-radiation-induced skin tumors in mice

    Energy Technology Data Exchange (ETDEWEB)

    Morison, W.L.; Kelley, S.P.

    1985-02-01

    Repeated exposure of female C3H/HeNCR- mice to sunlight prevented the normal immunologic rejection of a UV-induced tumor. This systemic immunologic alteration was transferred to syngeneic lethally X-irradiated animals with lymphoid cells from mice exposed to sunlight. The lymphoid cells also were able to suppress the capacity of lymphoid cells from normal animals to reject a UV-induced tumor. The 295- to 320-nm wave band appeared to be responsible for this immunosuppressive effect of sunlight because suppression was prevented by filtration of the radiation through Mylar and by application of a sunscreen containing para-aminobenzoic acid. These observations may have importance in understanding the pathogenesis of sunlight-induced skin cancer in humans.

  19. RADIATION RESISTANT LED POWER SUPPLY RELEASED UNDER CERN OPEN HARDWARE LICENSE

    CERN Multimedia

    2016-01-01

    As part of the design of a new emergency lighting system for the CERN accelerator complex a new design for a radiation resistant power supply has been produced. The design is available from the Open Hardware Repository.

  20. Radiation-induced intracerebral cavernous angiomas in children with malignant brain tumors. A report of two cases

    Energy Technology Data Exchange (ETDEWEB)

    Sugiyama, Tatsuya; Matsutani, Masao; Ogura, Hiroaki; Yoshizawa, Hidehiko; Nishikawa, Ryo [Saitama Medical School, Moroyama (Japan)

    2002-06-01

    Cavernous angiomas forming in the brain after radiation therapy for pediatric brain tumors have recently attracted special interest as a late complication of radiation therapy. We report here on two children with malignant brain tumors who developed intracerebral cavernous angiomas 4 to 5 years after radiation therapy. A 14-year-old girl with a primitive neuroectodermal tumor developed a cavernous angioma in the hypothalamus after being irradiated with 55 Gy 4 years ago. The second case, 13-year-old boy with a pineal mixed germ cell tumor showed a cavernous angioma at the thalamus 5 years after receiving radiation therapy with a dose of 60 Gy. Both patients did not show any abnormal symptoms and the cavernous angiomas diagnoses were made with MRI findings. A review of 20 reported cases of radiation-induced cavernous angiomas in the brain revealed some characteristic findings. Eighteen of the 20 cases were children, fourteen cases developed hemorrhage, the radiation dose administered was distributed between 18-60 Gy (median dose of 43.5 Gy), and the median latent period was 7.5 years (range: 2-21 years). As a differential diagnosis for the recurrent tumor is guite difficult in most cases, it is necessary to observe patients who developed angioma-like lesions in the irradiated area carefully. (author)

  1. Forecasting longitudinal changes in oropharyngeal tumor morphology throughout the course of head and neck radiation therapy.

    Science.gov (United States)

    Yock, Adam D; Rao, Arvind; Dong, Lei; Beadle, Beth M; Garden, Adam S; Kudchadker, Rajat J; Court, Laurence E

    2014-08-01

    To create models that forecast longitudinal trends in changing tumor morphology and to evaluate and compare their predictive potential throughout the course of radiation therapy. Two morphology feature vectors were used to describe 35 gross tumor volumes (GTVs) throughout the course of intensity-modulated radiation therapy for oropharyngeal tumors. The feature vectors comprised the coordinates of the GTV centroids and a description of GTV shape using either interlandmark distances or a spherical harmonic decomposition of these distances. The change in the morphology feature vector observed at 33 time points throughout the course of treatment was described using static, linear, and mean models. Models were adjusted at 0, 1, 2, 3, or 5 different time points (adjustment points) to improve prediction accuracy. The potential of these models to forecast GTV morphology was evaluated using leave-one-out cross-validation, and the accuracy of the models was compared using Wilcoxon signed-rank tests. Adding a single adjustment point to the static model without any adjustment points decreased the median error in forecasting the position of GTV surface landmarks by the largest amount (1.2 mm). Additional adjustment points further decreased the forecast error by about 0.4 mm each. Selection of the linear model decreased the forecast error for both the distance-based and spherical harmonic morphology descriptors (0.2 mm), while the mean model decreased the forecast error for the distance-based descriptor only (0.2 mm). The magnitude and statistical significance of these improvements decreased with each additional adjustment point, and the effect from model selection was not as large as that from adding the initial points. The authors present models that anticipate longitudinal changes in tumor morphology using various models and model adjustment schemes. The accuracy of these models depended on their form, and the utility of these models includes the characterization of patient

  2. Forecasting longitudinal changes in oropharyngeal tumor morphology throughout the course of head and neck radiation therapy

    Science.gov (United States)

    Yock, Adam D.; Rao, Arvind; Dong, Lei; Beadle, Beth M.; Garden, Adam S.; Kudchadker, Rajat J.; Court, Laurence E.

    2014-01-01

    Purpose: To create models that forecast longitudinal trends in changing tumor morphology and to evaluate and compare their predictive potential throughout the course of radiation therapy. Methods: Two morphology feature vectors were used to describe 35 gross tumor volumes (GTVs) throughout the course of intensity-modulated radiation therapy for oropharyngeal tumors. The feature vectors comprised the coordinates of the GTV centroids and a description of GTV shape using either interlandmark distances or a spherical harmonic decomposition of these distances. The change in the morphology feature vector observed at 33 time points throughout the course of treatment was described using static, linear, and mean models. Models were adjusted at 0, 1, 2, 3, or 5 different time points (adjustment points) to improve prediction accuracy. The potential of these models to forecast GTV morphology was evaluated using leave-one-out cross-validation, and the accuracy of the models was compared using Wilcoxon signed-rank tests. Results: Adding a single adjustment point to the static model without any adjustment points decreased the median error in forecasting the position of GTV surface landmarks by the largest amount (1.2 mm). Additional adjustment points further decreased the forecast error by about 0.4 mm each. Selection of the linear model decreased the forecast error for both the distance-based and spherical harmonic morphology descriptors (0.2 mm), while the mean model decreased the forecast error for the distance-based descriptor only (0.2 mm). The magnitude and statistical significance of these improvements decreased with each additional adjustment point, and the effect from model selection was not as large as that from adding the initial points. Conclusions: The authors present models that anticipate longitudinal changes in tumor morphology using various models and model adjustment schemes. The accuracy of these models depended on their form, and the utility of these models

  3. Forecasting longitudinal changes in oropharyngeal tumor morphology throughout the course of head and neck radiation therapy

    Energy Technology Data Exchange (ETDEWEB)

    Yock, Adam D.; Kudchadker, Rajat J. [Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 and The Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, Texas 77030 (United States); Rao, Arvind [Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 and The Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, Texas 77030 (United States); Dong, Lei [Scripps Proton Therapy Center, San Diego, California 92121 and The Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, Texas 77030 (United States); Beadle, Beth M.; Garden, Adam S. [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 (United States); Court, Laurence E., E-mail: LECourt@MDAnderson.org [Department of Radiation Physics and Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 and The Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, Texas 77030 (United States)

    2014-08-15

    Purpose: To create models that forecast longitudinal trends in changing tumor morphology and to evaluate and compare their predictive potential throughout the course of radiation therapy. Methods: Two morphology feature vectors were used to describe 35 gross tumor volumes (GTVs) throughout the course of intensity-modulated radiation therapy for oropharyngeal tumors. The feature vectors comprised the coordinates of the GTV centroids and a description of GTV shape using either interlandmark distances or a spherical harmonic decomposition of these distances. The change in the morphology feature vector observed at 33 time points throughout the course of treatment was described using static, linear, and mean models. Models were adjusted at 0, 1, 2, 3, or 5 different time points (adjustment points) to improve prediction accuracy. The potential of these models to forecast GTV morphology was evaluated using leave-one-out cross-validation, and the accuracy of the models was compared using Wilcoxon signed-rank tests. Results: Adding a single adjustment point to the static model without any adjustment points decreased the median error in forecasting the position of GTV surface landmarks by the largest amount (1.2 mm). Additional adjustment points further decreased the forecast error by about 0.4 mm each. Selection of the linear model decreased the forecast error for both the distance-based and spherical harmonic morphology descriptors (0.2 mm), while the mean model decreased the forecast error for the distance-based descriptor only (0.2 mm). The magnitude and statistical significance of these improvements decreased with each additional adjustment point, and the effect from model selection was not as large as that from adding the initial points. Conclusions: The authors present models that anticipate longitudinal changes in tumor morphology using various models and model adjustment schemes. The accuracy of these models depended on their form, and the utility of these models

  4. Post-Radiation Metabolic Tumor Volume Predicts Outcome in Head-and-Neck Cancer

    Science.gov (United States)

    Murphy, James D; La, Trang H.; Chu, Karen; Quon, Andrew; Fischbein, Nancy J.; Maxim, Peter G.; Graves, Edward E.; Loo, Billy W.; Le, Quynh-Thu

    2010-01-01

    Purpose To explore the prognostic value of metabolic tumor volume measured on post-radiation 18F-fluorodeoxyglucose positron emission tomography (PET) imaging in head-and-neck cancer patients. Methods and Materials Forty-seven head-and-neck cancer patients who received pre- and post-treatment PET/CT imaging along with definitive chemoradiotherapy were included in this study. PET/CT parameters evaluated include the maximum standardized uptake value, metabolic tumor volume (MTV2.0-MTV4.0; where MTV2.0 refers to the volume above an SUV threshold of 2.0), and integrated tumor volume. Kaplan-Meier and Cox-regression models were used to test for association between PET endpoints and disease-free survival (DFS) and overall survival (OS). Results Multiple post-radiation PET endpoints correlated significantly with outcome, however the most robust predictor of disease progression and death was MTV2.0. An increase in MTV2.0 of 21cm3 (difference between 75th and 25th percentile) was associated with an increased risk of disease progression (hazard ratio [HR]=2.5, p=0.0001) and death (HR=2.0, p=0.003). In patients with non-nasopharyngeal carcinoma (non-NPC) histology (n=34), MTV2.0<18cm3 and MTV2.0≥18cm3 yielded 2-year DFS rates of 100% and 63%, respectively (p=0.006) and 2-year OS rates of 100% and 81%, respectively (p=0.009). There was no correlation between MTV2.0 and DFS or OS with NPC histology (n=13). On multivariate analysis only post-radiation MTV2.0 was predictive of DFS (HR=2.47, p=0.0001) and OS (HR=1.98, p=0.003). Conclusions Post-radiation metabolic tumor volume is an adverse prognostic factor in head-and-neck cancer. Biomarkers such as MTV are important for risk stratification, and will be valuable in the future with risk-adapted therapies. PMID:20646870

  5. Sulforaphane reduces molecular response to hypoxia in ovarian tumor cells independently of their resistance to chemotherapy.

    Science.gov (United States)

    Pastorek, Michal; Simko, Veronika; Takacova, Martina; Barathova, Monika; Bartosova, Maria; Hunakova, Luba; Sedlakova, Olga; Hudecova, Sona; Krizanova, Olga; Dequiedt, Franck; Pastorekova, Silvia; Sedlak, Jan

    2015-07-01

    One of the recently emerging anticancer strategies is the use of natural dietary compounds, such as sulforaphane, a cancer-chemopreventive isothiocyanate found in broccoli. Based on the growing evidence, sulforaphane acts through molecular mechanisms that interfere with multiple oncogenic pathways in diverse tumor cell types. Herein, we investigated the anticancer effects of bioavailable concentrations of sulforaphane in ovarian carcinoma cell line A2780 and its two derivatives, adriamycin-resistant A2780/ADR and cisplatin-resistant A2780/CP cell lines. Since tumor microenvironment is characterized by reduced oxygenation that induces aggressive tumor phenotype (such as increased invasiveness and resistance to chemotherapy), we evaluated the effects of sulforaphane in ovarian cancer cells exposed to hypoxia (2% O2). Using the cell-based reporter assay, we identified several oncogenic pathways modulated by sulforaphane in hypoxia by activating anticancer responses (p53, ARE, IRF-1, Pax-6 and XRE) and suppressing responses supporting tumor progression (AP-1 and HIF-1). We further showed that sulforaphane decreases the level of HIF-1α protein without affecting its transcription and stability. It can also diminish transcription and protein level of the HIF-1 target, CA IX, which protects tumor cells from hypoxia-induced pH imbalance and facilitates their migration/invasion. Accordingly, sulforaphane treatment leads to diminished pH regulation and reduced migration of ovarian carcinoma cells. These effects occur in all three ovarian cell lines suggesting that sulforaphane can overcome the chemoresistance of cancer cells. This offers a path potentially exploitable in sensitizing resistant cancer cells to therapy, and opens a window for the combined treatments of sulforaphane either with conventional chemotherapy, natural compounds, or with other small molecules.

  6. Diversity of ionizing radiation-resistant bacteria obtained from the Taklimakan Desert.

    Science.gov (United States)

    Yu, Li Zhi-Han; Luo, Xue-Song; Liu, Ming; Huang, Qiaoyun

    2015-01-01

    So far, little is known about the diversity of the radiation-resistant microbes of the hyperarid Taklimakan Desert. In this study, ionizing radiation (IR)-resistant bacteria from two sites in Xinjiang were investigated. After exposing the arid (water content of 0.8 ± 0.3%) and non-arid (water content of 21.3 ± 0.9%) sediment samples to IR of 3000 Gy using a (60)Co source, a total of 52 γ-radiation-resistant bacteria were isolated from the desert sample. The 16S rRNA genes of all isolates were sequenced. The phylogenetic tree places these isolates into five groups: Cytophaga-Flavobacterium-Bacteroides, Proteobacteria, Deinococcus-Thermus, Firmicutes, and Actinobacteria. Interestingly, this is the first report of radiation-resistant bacteria belonging to the genera Knoellia, Lysobacter, Nocardioides, Paracoccus, Pontibacter, Rufibacter and Microvirga. The 16s rRNA genes of four isolates showed low sequence similarities to those of the published species. Phenotypic analysis showed that all bacteria in this study are able to produce catalase, suggesting that these bacteria possess reactive oxygen species (ROS)-scavenging enzymes. These radiation-resistant bacteria also displayed diverse metabolic properties. Moreover, their radiation resistances were found to differ. The diversity of the radiation-resistant bacteria in the desert provides further ecological support for the hypothesis that the ionizing-radiation resistance phenotype is a consequence of the evolution of ROS-scavenging systems that protect cells against oxidative damage caused by desiccation. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. Exposure of tumor-bearing mice to extremely high-frequency electromagnetic radiation modifies the composition of fatty acids in thymocytes and tumor tissue.

    Science.gov (United States)

    Gapeyev, Andrew B; Kulagina, Tatiana P; Aripovsky, Alexander V

    2013-08-01

    To test the participation of fatty acids (FA) in antitumor effects of extremely high-frequency electromagnetic radiation (EHF EMR), the changes in the FA composition in the thymus, liver, blood plasma, muscle tissue, and tumor tissue in mice with Ehrlich solid carcinoma exposed to EHF EMR were studied. Normal and tumor-bearing mice were exposed to EHF EMR with effective parameters (42.2 GHz, 0.1 mW/cm2, 20 min daily during five consecutive days beginning the first day after the inoculation of tumor cells). Fatty acid composition of various organs and tissues of mice were determined using a gas chromatography. It was shown that the exposure of normal mice to EHF EMR or tumor growth significantly increased the content of monounsaturated FA (MUFA) and decreased the content of polyunsaturated FA (PUFA) in all tissues examined. Exposure of tumor-bearing mice to EHF EMR led to the recovery of FA composition in thymocytes to the state that is typical for normal animals. In other tissues of tumor-bearing mice, the exposure to EHF EMR did not induce considerable changes that would be significantly distinguished between disturbances caused by EHF EMR exposure or tumor growth separately. In tumor tissue which is characterized by elevated level of MUFA, the exposure to EHF EMR significantly decreased the summary content of MUFA and increased the summary content of PUFA. The recovery of the FA composition in thymocytes and the modification of the FA composition in the tumor under the influence of EHF EMR on tumor-bearing animals may have crucial importance for elucidating the mechanisms of antitumor effects of the electromagnetic radiation.

  8. Identifyng mechanisms of resistance to chemotherapy in osteosarcoma tumor stem cells

    OpenAIRE

    Oliveira, Vitor Emanuel Bucete

    2011-01-01

    Introdução: A teoria das células estaminais tumorais propõe que os tumores estão hierarquicamente organizados, onde existe uma pequena subpopulação de células com características de células estaminas (CSCs) responsáveis pela iniciação e manutenção do crescimento tumoral e pela resistência à quimioterapia. Com este trabalho, pretendemos estudar a sensibilidade das CSCs isoladas a partir de uma linha celular humana de osteossarcoma (MNNG/HOS) à doxorrubicina (DOX) e identificar os possíveis mec...

  9. Validation of Heat Shock Protein 70 as a Tumor-Specific Biomarker for Monitoring the Outcome of Radiation Therapy in Tumor Mouse Models

    Energy Technology Data Exchange (ETDEWEB)

    Bayer, Christine; Liebhardt, Michael E.; Schmid, Thomas E. [Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München, Munich (Germany); Trajkovic-Arsic, Marija [II Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich (Germany); Hube, Kathrin; Specht, Hanno M. [Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München, Munich (Germany); Schilling, Daniela [Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München, Munich (Germany); Clinical Kooperation Group, Innate Immunity in Tumor Biology, HelmholtzZentrum München, Munich (Germany); Gehrmann, Mathias; Stangl, Stefan [Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München, Munich (Germany); Siveke, Jens T. [II Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich (Germany); Wilkens, Jan J. [Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München, Munich (Germany); Multhoff, Gabriele, E-mail: Gabriele.multhoff@lrz.tum.de [Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München, Munich (Germany); Clinical Kooperation Group, Innate Immunity in Tumor Biology, HelmholtzZentrum München, Munich (Germany)

    2014-03-01

    Purpose: Tumor cells, in contrast to normal cells, frequently overexpress heat shock protein 70 (Hsp70) in the cytosol, present it on their cell surface, and actively release it. Therefore, soluble Hsp70 (sHsp70) was investigated as a potential tumor biomarker for monitoring the outcome of radiation therapy. Methods and Materials: Plasma from mice bearing membrane Hsp70 (mHsp70)-positive FaDu human squamous cell carcinoma of the head and neck and spontaneous pancreatic ductal adenocarcinoma (PDAC) was investigated. A cohort of mice with FaDu tumors (0.32 cm{sup 3}) was irradiated with 30 Gy, and plasma was collected 24 hours after irradiation, after the tumors had shrunk to 50% of their starting volume and after complete remission. sHsp70 levels in the plasma were quantified by enzyme-linked immunosorbent assay. Results: sHsp70 levels were significantly higher in the blood of tumor-bearing mice than that of control animals. A correlation between increasing sHsp70 plasma levels and tumor volume in the range of 0.01 cm{sup 3} to 0.66 cm{sup 3} was observed. Radiation-induced regression of the tumors was associated with significantly decreased sHsp70 levels, which returned to the level of control animals after complete remission. Conclusion: We propose sHsp70 as an innovative biomarker for detecting tumors and for monitoring the clinical outcome of radiation therapy in cancer patients.

  10. Modulating Radiation Resistance: Novel Protection Paradigms Based on Defenses against Ionizing Radiation in the Extrempohile Deinococcus radiodurans

    Science.gov (United States)

    2013-07-01

    antioxidants in the survival of prokaryotes under oxidative stress parallel the trends developing for the simple eukaryote Saccharomyces cerevisiae ...Escherichia coli, and Saccharomyces cerevisiae to Ionizing Radiation. ● New approaches to controlling the resistance properties of Bacillus spores...or a combination of these factors that are integral to achieving USAF objectives 10 Dr. Michael Daly is an accomplished scientist. He has been

  11. ROS-triggered and regenerating anticancer nanosystem: an effective strategy to subdue tumor's multidrug resistance.

    Science.gov (United States)

    Su, Zhigui; Chen, Minglei; Xiao, Yanyu; Sun, Minjie; Zong, Li; Asghar, Sajid; Dong, Mei; Li, Huipeng; Ping, Qineng; Zhang, Can

    2014-12-28

    Drug delivery strategies utilizing tumor microenvironment are recognized as a critical doorway to overcome multidrug resistance (MDR). However, the variability of tumor microenvironment at different disease stages would definitely minimize stimuli generation and eventually the therapeutic effects of these stimuli sensitive systems. Herein, we report a unique reactive oxygen species (ROS) triggered nanosystem that can replenish the ROS upon disassembly to maintain its high level. This was accomplished by a new amphiphilic polymer (TBH) composed of D-α-tocopherol polyethylene glycol 1000 succinate (TPGS), hyaluronic acid (HA) and arylboronic ester. As a linker of TPGS to HA, arylboronic ester could efficiently degrade in response to ROS resulting in dismantling of nanosystem followed by rapid release of TPGS. Owing to ROS inducing activity of TPGS with mitochondrial respiratory complex II, ROS regeneration was observed for TBH nanosystem both in MCF-7/ADR cells and tumor tissues xenografted with MCF-7/ADR cells. Furthermore, doxorubicin-loaded TBH nanosystem (DOX-TBH) revealed higher drug cytotoxicity due to enhanced retention effect on account of ROS triggered DOX release and P-gp inhibitory mechanism of TPGS. Moreover, HA significantly improved tumor targeting capability of DOX-TBH, while ROS based triggering and regenerating mechanism lead to marked inhibition of the tumor growth in the xenograft MCF-7/ADR tumor-bearing nude mice. Crown Copyright © 2014. Published by Elsevier B.V. All rights reserved.

  12. [Possibility of overcoming ACNU resistance in ACNU-resistant sublines of rat brain tumors in vitro by a calmodulin inhibitor].

    Science.gov (United States)

    Yoshida, T; Shimizu, K; Mogami, H; Sakamoto, Y; Egawa, T

    1987-02-01

    A calmodulin inhibitor, trifluoperazine, was found to enhance the cytotoxicity of ACNU in vitro in rat C6 glioma, 9L gliosarcoma and their ACNU-resistant sublines (C6/ACNU and 9L/ACNU). Uptake and retention of ACNU in these cells were studied with [14C]ACNU in the absence or presence of trifluoperazine. The results indicated that intracellular uptake and retention of ACNU in C6 and 9L cells were larger than those in C6/ACNU and 9L/ACNU cells, and that trifluoperazine increased the cellular uptake and retention of ACNU in C6 and 9L, especially in C6/ACNU and 9L/ACNU cells. The amounts of ACNU in C6/ACNU and 9L/ACNU cells reached almost the same level as those detected in C6 and 9L cells. When trifluoperazine were added along with ACNU to the culture in vitro at a concentration of 10 and 20 microM, ACNU resistance was completely overcome. Furthermore, treatment of C6 and C6/ACNU cells with 20 microM trifluoperazine did not change the cellular uptake rate of [14C]AIB (alpha-aminoisobutyric acid), which might indicate that the membrane permeability of the cells was kept intact during the drug treatment. The same phenomenon was observed in 9L and 9L/ACNU cells. It might be concluded that the enhanced effect of cytotoxicity of ACNU in ACNU-resistant rat brain tumor cells presented in this study is presumably due to the increase of intracellular concentration of ACNU resulting from the inhibition of the efflux of ACNU by trifluoperazine from the resistant cells. It was also suggested that ACNU resistance in malignant brain tumors could be overcome by combination chemotherapy with ACNU and calmodulin inhibitors.

  13. TIP-1 translocation onto the cell plasma membrane is a molecular biomarker of tumor response to ionizing radiation.

    Directory of Open Access Journals (Sweden)

    Hailun Wang

    2010-08-01

    Full Text Available Tumor response to treatment has been generally assessed with anatomic and functional imaging. Recent development of in vivo molecular and cellular imaging showed promise in time-efficient assessment of the therapeutic efficacy of a prescribed regimen. Currently, the in vivo molecular imaging is limited with shortage of biomarkers and probes with sound biological relevance. We have previously shown in tumor-bearing mice that a hexapeptide (HVGGSSV demonstrated potentials as a molecular imaging probe to distinguish the tumors responding to ionizing radiation (IR and/or tyrosine kinase inhibitor treatment from those of non-responding tumors.In this study we have studied biological basis of the HVGGSSV peptide binding within the irradiated tumors by use of tumor-bearing mice and cultured cancer cells. The results indicated that Tax interacting protein 1 (TIP-1, also known as Tax1BP3 is a molecular target that enables the selective binding of the HVGGSSV peptide within irradiated xenograft tumors. Optical imaging and immunohistochemical staining indicated that a TIP-1 specific antibody demonstrated similar biodistribution as the peptide in tumor-bearing mice. The TIP-1 antibody blocked the peptide from binding within irradiated tumors. Studies on both of human and mouse lung cancer cells showed that the intracellular TIP-1 relocated to the plasma membrane surface within the first few hours after exposure to IR and before the onset of treatment associated apoptosis and cell death. TIP-1 relocation onto the cell surface is associated with the reduced proliferation and the enhanced susceptibility to the subsequent IR treatment.This study by use of tumor-bearing mice and cultured cancer cells suggested that imaging of the radiation-inducible TIP-1 translocation onto the cancer cell surface may predict the tumor responsiveness to radiation in a time-efficient manner and thus tailor radiotherapy of cancer.

  14. Factors determining sensitivity and resistance of tumor cells to arsenic trioxide.

    Directory of Open Access Journals (Sweden)

    Serkan Sertel

    Full Text Available Previously, arsenic trioxide showed impressive regression rates of acute promyelocytic leukemia. Here, we investigated molecular determinants of sensitivity and resistance of cell lines of different tumor types towards arsenic trioxide. Arsenic trioxide was the most cytotoxic compound among 8 arsenicals investigated in the NCI cell line panel. We correlated transcriptome-wide microarray-based mRNA expression to the IC(50 values for arsenic trioxide by bioinformatic approaches (COMPARE and hierarchical cluster analyses, Ingenuity signaling pathway analysis. Among the identified pathways were signaling routes for p53, integrin-linked kinase, and actin cytoskeleton. Genes from these pathways significantly predicted cellular response to arsenic trioxide. Then, we analyzed whether classical drug resistance factors may also play a role for arsenic trioxide. Cell lines transfected with cDNAs for catalase, thioredoxin, or the anti-apoptotic bcl-2 gene were more resistant to arsenic trioxide than mock vector transfected cells. Multidrug-resistant cells overexpressing the MDR1, MRP1 or BCRP genes were not cross-resistant to arsenic trioxide. Our approach revealed that response of tumor cells towards arsenic trioxide is multi-factorial.

  15. Multiplex analysis of tumor multidrug-resistance genes expression with photonic suspension array.

    Science.gov (United States)

    Yang, Zixue; Chen, Baoan; Pei, Xiaoping; Shangguan, Fengqi

    2012-07-21

    An easy-operated suspension array based on silica colloidal crystal beads is developed for multiplex analysis of tumor multidrug-resistance genes expression, such as multidrug resistance 1 (MDR1) and multidrug resistance-associated protein 1 (MRP1), and potentially single nucleotide polymorphism. In order to obtain high fluorescence intensity, controlled PCR was used to amplify targets at the samples pretreatment stage. By optimizing the conditions a hybridization procedure, which is similar to nucleic acids analysis with binary probes, was established. Small amounts of analytes 10(-19) M could be detected by the method. The K562 cell, human myeloma cell, and its multidrug-resistance string, adriamycin-selected P-glycoprotein-overexpressed K562/A02, were analyzed by using an established procedure to validate feasibility. Clinical blood samples were detected by our method and real-time PCR simultaneously to validate accuracy. Moreover, when combined with multiplex controlled PCR, the method successfully meets the requirements of multiplex analysis. Hence, the method presented is a good method for multiplex analysis of tumor multidrug-resistance genes expression.

  16. SU-G-TeP3-09: Proton Minibeam Radiation Therapy Increases Normal Tissue Resistance

    Energy Technology Data Exchange (ETDEWEB)

    Prezado, Y; Gonzalez-Infantes, W; Juchaux, M; Martinez-Rovira, I; Peucelle, C [CNRS, Orsay, Ile de France (France); Heinrich, S; Labiod, D; Nauraye, C; Patriarca, A [Institut Curie, Orsay, Ile de France (France); Sebrie, C [Universite Paris Sud, Orsay, Ile de France (France)

    2016-06-15

    Purpose: The dose tolerances of normal tissues continue being the main limitation in radiotherapy. To overcome it, we recently proposed a novel concept: proton minibeam radiation therapy (pMBRT) [1]. It allies the physical advantages of protons with the normal tissue preservation observed when irradiated with submillimetric spatially fractionated beams (minibeam radiation therapy) [2]. The dose distributions are such that the tumor receives a homogeneous dose distribution, while normal tissues benefit from the spatial fractionation of the dose. The objective of our work was to implement this promising technique at a clinical center (Proton therapy center in Orsay) in order to evaluate the potential gain in tissue sparing. Methods: Dose distributions were measured by means of gafchromic films and a PTW microdiamond detector (60019). Once the dosimetry was established, the whole brain of 7 weeks old male Fischer 344 rats was irradiated. Half of the animals received conventional seamless proton irradiation (25 Gy in one fraction). The other rats were irradiated with pMBRT (58 Gy peak dose in one fraction). The average dose deposited in the same targeted volume was in both cases 25 Gy. Results: The first complete set of dosimetric data in such small proton field sizes was obtained [3]. Rats treated with conventional proton irradiation exhibited severe moist desquamation and permanent epilation afterwards. The minibeam group, on the other hand, exhibited no skin damage and no clinical symptoms. MRI imaging and histological analysis are planned at 6 months after irradiation. Conclusion: Our preliminary results indicate that pMBRT leads to an increase in tissue resistance. This can open the door to an efficient treatment of very radioresistant tumours. [1] Prezado et al. Med. Phys. 40, 031712, 1–8 (2013).[2] Prezado et al., Rad. Research. 184, 314-21 (2015). [3] Peucelle et al., Med. Phys. 42 7108-13 (2015).

  17. Stabilizing a Tubulysin Antibody-Drug Conjugate To Enable Activity Against Multidrug-Resistant Tumors.

    Science.gov (United States)

    Staben, Leanna R; Yu, Shang-Fan; Chen, Jinhua; Yan, Gang; Xu, Zijin; Del Rosario, Geoffrey; Lau, Jeffrey T; Liu, Luna; Guo, Jun; Zheng, Bing; Cruz-Chuh, Josefa Dela; Lee, Byoung-Chul; Ohri, Rachana; Cai, Wenwen; Zhou, Hongxiang; Kozak, Katherine R; Xu, Keyang; Lewis Phillips, Gail D; Lu, Jiawei; Wai, John; Polson, Andrew G; Pillow, Thomas H

    2017-10-12

    The tubulysins are promising anticancer cytotoxic agents due to the clinical validation of their mechanism of action (microtubule inhibition) and their particular activity against multidrug-resistant tumor cells. Yet their high potency and subsequent systemic toxicity make them prime candidates for targeted therapy, particularly in the form of antibody-drug conjugates (ADCs). Here we report a strategy to prepare stable and bioreversible conjugates of tubulysins to antibodies without loss of activity. A peptide trigger along with a quaternary ammonium salt linker connection to the tertiary amine of tubulysin provided ADCs that were potent in vitro . However, we observed metabolism of a critical acetate ester of the drug in vivo , resulting in diminished conjugate activity. We were able to circumvent this metabolic liability with the judicious choice of a propyl ether replacement. This modified tubulysin ADC was stable and effective against multidrug-resistant lymphoma cell lines and tumors.

  18. Low dose radiation and plant growth

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Sung Jae; Lee, Hae Youn; Park, Hong Sook

    2001-03-01

    Ionizing radiation includes cosmic radiation, earth radiation, radionuclides for the medical purpose and nuclear industry, fallout radiation. From the experimental results of various radiation effects on seeds or seedlings, it was found that germination rate, development, respiration rate, reproduction and blooming were accelerated compared with the control. In mammal, hormesis phenomenon manifested itself in increased disease resistance, lifespan, and decreased rate of tumor incidence. In plants, it was shown that germination, sprouting, growth, development, blooming and resistance to disease were accelerated.

  19. Depression, suicide ideation, and thyroid tumors among ukrainian adolescents exposed as children to chernobyl radiation.

    Science.gov (United States)

    Contis, George; Foley, Thomas P

    2015-05-01

    The Chernobyl Childhood Illness Program (CCIP) was a humanitarian assistance effort funded by the United States Congress. Its purpose was to assist the Ukrainian Government to identify and treat adolescents who developed mental and physical problems following their exposure as young children to Chernobyl radiation. Thirteen years after the Chernobyl nuclear plant accident in 1986, the CCIP examined 116,655 Ukrainian adolescents for thyroid diseases. Of these, 115,191 were also screened for depression, suicide ideation, and psychological problems. The adolescents lived in five of Ukraine's seven most Chernobyl radiation contaminated provinces. They were up to 6 years of age or in utero when exposed to nuclear fallout, or were born up to 45 months after Chernobyl. Ukrainian endocrinologist and ultrasonographers used physical examination and ultrasonography of the neck to evaluate the adolescents for thyroid tumors. The adolescents were then screened for depression by the Children's Depression Inventory (CDI). After this, Ukrainian psychologists conducted individual psychological interviews to corroborate the adolescents' CDI responses. Papillary thyroid carcinoma was diagnosed in eight adolescents, a high prevalence rate similar to that reported by other studies from the Soviet Union. Screening identified thyroid nodules in 1,967 adolescents (1.7%). Depression was diagnosed in 15,399 adolescents (13.2%), suicide ideation in 813 (5.3%), and attempted suicide in 354 (2.3%). Underlying components of the participants' depression were negative mood, interpersonal difficulties, negative self-esteem, ineffectiveness, and anhedonia. Depression was greater in females (77%). Those with thyroid and psychological problems were referred for treatment. The adolescents screened by CCIP represent the largest Ukrainian cohort exposed to Chernobyl radiation as children who were evaluated for both thyroid tumors and depression. The group had an increased prevalence of thyroid cancer

  20. Depression, Suicide Ideation, and Thyroid Tumors Among Ukrainian Adolescents Exposed as Children to Chernobyl Radiation

    Science.gov (United States)

    Contis, George; Foley, Thomas P.

    2015-01-01

    Background The Chernobyl Childhood Illness Program (CCIP) was a humanitarian assistance effort funded by the United States Congress. Its purpose was to assist the Ukrainian Government to identify and treat adolescents who developed mental and physical problems following their exposure as young children to Chernobyl radiation. Thirteen years after the Chernobyl nuclear plant accident in 1986, the CCIP examined 116,655 Ukrainian adolescents for thyroid diseases. Of these, 115,191 were also screened for depression, suicide ideation, and psychological problems. The adolescents lived in five of Ukraine’s seven most Chernobyl radiation contaminated provinces. They were up to 6 years of age or in utero when exposed to nuclear fallout, or were born up to 45 months after Chernobyl. Methods Ukrainian endocrinologist and ultrasonographers used physical examination and ultrasonography of the neck to evaluate the adolescents for thyroid tumors. The adolescents were then screened for depression by the Children’s Depression Inventory (CDI). After this, Ukrainian psychologists conducted individual psychological interviews to corroborate the adolescents’ CDI responses. Results Papillary thyroid carcinoma was diagnosed in eight adolescents, a high prevalence rate similar to that reported by other studies from the Soviet Union. Screening identified thyroid nodules in 1,967 adolescents (1.7%). Depression was diagnosed in 15,399 adolescents (13.2%), suicide ideation in 813 (5.3%), and attempted suicide in 354 (2.3%). Underlying components of the participants’ depression were negative mood, interpersonal difficulties, negative self-esteem, ineffectiveness, and anhedonia. Depression was greater in females (77%). Those with thyroid and psychological problems were referred for treatment. Conclusions The adolescents screened by CCIP represent the largest Ukrainian cohort exposed to Chernobyl radiation as children who were evaluated for both thyroid tumors and depression. The group

  1. Studies on the influence of radiation and chemotherapy on pituitary-testicular axis in patients with testicular tumor

    Energy Technology Data Exchange (ETDEWEB)

    Ogawa, Katsuaki (Yokohama City Univ. (Japan). Faculty of Medicine)

    1982-02-01

    Radiation and chemotherapy have been known as the highly effective treatment of patients with testicular tumor. To evaluate the influences of the therapies on pituitary-testicular axis, plasma FSH, LH and testosterone were determined by radioimmunoassay in 60 patients with testicular tumor before and after 1 to 102 months in the completion of radiation and chemotherapy. The results were summarized as follows: 1) In 10 out of 24 patients, plasma FSH and LH levels significantly increased within 20 months after 2,100 - 4,500 rad/3 - 6 weeks of radiation therapy. 2) In combination chromotherapy popularly used for testicular tumor, plasma FSH and LH in 8 of 22 patients markedly elevated within 20 months after the treatment. 3) The elevated gonadotropins returned to normal levels in approximately 50 months in patients received radiation or chemotherapy. 4) Plasma testosterone revealed normal levels in any therapeutic programs employed in the present study. 5) From the results of Gn-RH test, the pituitary gland seemed to have normal function. 6) Plasma testosterone showed incomplete response to hCG stimulation after 1 to 35 months of radiation or chemotherapy. Therefore, it was suggested that radiation and chemotherapy for the treatment of testicular tumor may impair not only seminiferous tubules but also Leydig cell for a couple of years.

  2. Early Clinical Outcomes Using Proton Radiation for Children With Central Nervous System Atypical Teratoid Rhabdoid Tumors

    Energy Technology Data Exchange (ETDEWEB)

    De Amorim Bernstein, Karen; Sethi, Roshan; Trofimov, Alexei; Zeng, Chuan [Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (United States); Fullerton, Barbara [Department of Otology and Laryngology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts (United States); Yeap, Beow Y. [Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (United States); Ebb, David [Department of Pediatric Hematology-Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (United States); Tarbell, Nancy J.; Yock, Torunn I. [Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (United States); MacDonald, Shannon M., E-mail: smacdonald@partners.org [Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (United States)

    2013-05-01

    Purpose: Atypical teratoid/rhabdoid tumor (AT/RT) is an uncommon and aggressive tumor that often affects infants. Irradiation improves survival but has traditionally been avoided in patients under the age of 3 due to the increasing risk of neurocognitive side effects. We report the first cohort of AT/RT patients treated with proton therapy. Methods and Materials: All patients with AT/RT treated at Massachusetts General Hospital (MGH) Frances H. Burr Proton Beam Therapy Benter between July 2004 and November 2011 were included in this study. All patients were treated with 3-dimensional conformal proton therapy (3D-CPT). Results: Ten consecutive patients of a median 2.3 years of age and with a median follow-up of 27.3 months (range, 11.3-99.4 months) were identified. Two patients suffered distant relapse; 1 patient was successfully treated with involved field irradiation and chemotherapy, while the second patient died of disease. At last follow-up, 9 patients were alive without evidence of disease. Proton radiation demonstrated increasing sparing of the cerebrum, temporal lobe, cochlea, and hypothalamus. Conclusions: Initial clinical outcomes with proton therapy are favorable. The advantages of proton therapy are particularly suited to the treatment of AT/RT, a tumor that often requires irradiation treatment at an age when avoiding irradiation to healthy tissues is most desirable.

  3. Role of autophagy in high linear energy transfer radiation-induced cytotoxicity to tumor cells

    Science.gov (United States)

    Jin, Xiaodong; Liu, Yan; Ye, Fei; Liu, Xiongxiong; Furusawa, Yoshiya; Wu, Qingfeng; Li, Feifei; Zheng, Xiaogang; Dai, Zhongying; Li, Qiang

    2014-01-01

    Heavy-ion radiotherapy has a potential advantage over conventional radiotherapy due to improved dose distribution and a higher biological effectiveness in cancer therapy. However, there is a little information currently available on the cellular and molecular basis for heavy-ion irradiation-induced cell death. Autophagy, as a novel important target to improve anticancer therapy, has recently attracted considerable attention. In this study, the effect of autophagy induced by high linear energy transfer (LET) carbon ions was examined in various tumor cell lines. To our knowledge, our study is the first to reveal that high-LET carbon ions could induce autophagy in various tumor cells effectively, and the autophagic level in the irradiated cells increased in a dose- and LET-dependent manner. The ability of carbon ions to inhibit the activation of the PI3K/Akt pathway rose with increasing their LET. Moreover, modulation of autophagy in tumor cells could modify their sensitivity to high-LET radiation, and inhibiting autophagy accelerated apoptotic cell death, resulting in an increase in radiosensitivity. Our data imply that targeting autophagy might enhance the effectiveness of heavy-ion radiotherapy. PMID:24731006

  4. Induction of hypoxia and necrosis in multicellular tumor spheroids is associated with resistance to chemotherapy treatment.

    Science.gov (United States)

    Däster, Silvio; Amatruda, Nunzia; Calabrese, Diego; Ivanek, Robert; Turrini, Eleonora; Droeser, Raoul A; Zajac, Paul; Fimognari, Carmela; Spagnoli, Giulio C; Iezzi, Giandomenica; Mele, Valentina; Muraro, Manuele G

    2017-01-03

    Culture of cancerous cells in standard monolayer conditions poorly mirrors growth in three-dimensional architectures typically observed in a wide majority of cancers of different histological origin. Multicellular tumor spheroid (MCTS) culture models were developed to mimic these features. However, in vivo tumor growth is also characterized by the presence of ischemic and necrotic areas generated by oxygenation gradients and differential access to nutrients. Hypoxia and necrosis play key roles in tumor progression and resistance to treatment. To provide in vitro models recapitulating these events in highly controlled and standardized conditions, we have generated colorectal cancer (CRC) cell spheroids of different sizes and analyzed their gene expression profiles and sensitivity to treatment with 5FU, currently used in therapeutic protocols. Here we identify three MCTS stages, corresponding to defined spheroid sizes, characterized by normoxia, hypoxia, and hypoxia plus necrosis, respectively. Importantly, we show that MCTS including both hypoxic and necrotic areas most closely mimic gene expression profiles of in vivo-developing tumors and display the highest resistance to 5FU. Taken together, our data indicate that MCTS may mimic in vitro generation of ischemic and necrotic areas in highly standardized and controlled conditions, thereby qualifying as relevant models for drug screening purposes.

  5. Prostate cancer immunotherapy, particularly in combination with androgen deprivation or radiation treatment. Customized pharmacogenomic approaches to overcome immunotherapy cancer resistance.

    Science.gov (United States)

    Alberti, C

    2017-01-01

    Conventional therapeutic approaches for advanced prostate cancer - such as androgen deprivation, chemotherapy, radiation - come up often against lack of effectiveness because of possible arising of correlative cancer cell resistance and/or inadequate anti-tumor immune conditions. Whence the timeliness of resorting to immune-based treatment strategies including either therapeutic vaccination-based active immunotherapy or anti-tumor monoclonal antibody-mediated passive immunotherapy. Particularly attractive, as for research studies and clinical applications, results to be the cytotoxic T-lymphocyte check point blockade by the use of anti-CTLA-4 and PD-1 monoclonal antibodies, particularly when combined with androgen deprivation therapy or radiation. Unlike afore said immune check point inhibitors, both cell-based (by the use of prostate specific antigen carriers autologous dendritic cells or even whole cancer cells) and recombinant viral vector vaccines are able to induce immune-mediated focused killing of specific antigen-presenting prostate cancer cells. Such vaccines, either used alone or concurrently/sequentially combined with above-mentioned conventional therapies, led to generally reach, in the field of various clinical trials, reasonable results particularly as regards the patient's overall survival. Adoptive trasferred T-cells, as adoptive T-cell passive immunotherapy, and monoclonal antibodies against specific antigen-endowed prostate cancer cells can improve immune micro-environmental conditions. On the basis of a preliminary survey about various immunotherapy strategies, are here also outlined their effects when combined with androgen deprivation therapy or radiation. What's more, as regard the immune-based treatment effectiveness, it has to be pointed out that suitable personalized epigenetic/gene profile-achieved pharmacogenomic approaches to target identified gene aberrations, may lead to overcome - as well as for conventional therapies - possible

  6. Present status and prospects of R&D of radiation-resistant semiconductor devices at JAEA

    Science.gov (United States)

    Itoh, H.

    2013-05-01

    Research and development of radiation resistant semiconductor devices have been performed at Japan Atomic Energy Agency (JAEA) for their application to electronic system used in harsh environments like space, accelerator and nuclear facilities. Such devices are also indispensable for robots and equipment necessary for decommissioning of the damaged reactors at Fukushima Daiichi Nuclear Power Plants. For this purpose, we have fabricated transistors based on a wide band-gap semiconductor SiC and examined their radiation degradation. As a result, SiC-based transistors exhibited no significant degradation up to 1MGy, indicating their excellent radiation resistance. Recent our R&Ds of radiation resistant devices based on SiC are summarized and reviewed.

  7. Transformation Resistance in a Premature Aging Disorder Identifies a Tumor-Protective Function of BRD4

    Directory of Open Access Journals (Sweden)

    Patricia Fernandez

    2014-10-01

    Full Text Available Advanced age and DNA damage accumulation are prominent risk factors for cancer. The premature aging disorder Hutchinson-Gilford progeria syndrome (HGPS provides a unique opportunity for studying the interplay between DNA damage and aging-associated tumor mechanisms, given that HGPS patients do not develop tumors despite elevated levels of DNA damage. Here, we have used HGPS patient cells to identify a protective mechanism to oncogenesis. We find that HGPS cells are resistant to neoplastic transformation. Resistance is mediated by the bromodomain protein BRD4, which exhibits altered genome-wide binding patterns in transformation-resistant cells, leading to inhibition of oncogenic dedifferentiation. BRD4 also inhibits, albeit to a lower extent, the tumorigenic potential of transformed cells from healthy individuals. BRD4-mediated tumor protection is clinically relevant given that a BRD4 gene signature predicts positive clinical outcome in breast and lung cancer. Our results demonstrate a protective function for BRD4 and suggest tissue-specific roles for BRD4 in tumorigenesis.

  8. Fractionated stereotactic radiation therapy for intracranial benign tumor : preliminary results of clinical application

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Dae Yong; Ahn, Yong Chan; Huh, Seung Jae [Samsung Medical Center, Syungkyunkwan Univ. College of Medicine, Seoul (Korea, Republic of)] (and others)

    1998-06-01

    With the development of stereotactic immobilization systems capable of reliable serial repositioning, fractionated stereotactic radiation therapy(FSRT) offers the potential for an improved treatment outcome by excellent dose delivery, and dose distribution characteristics with the favorable radio-biological properties of fractionated irradiation. We describe our initial experience using FSRT for the treatment of intracranial benign tumor. Between August 1995 and December 1996, 15 patients(7 males and 8 females aged 6-70 years) were treated with FSRT. The patients had the following diagnosis : pituitary adenoma(10) including one patient who previously had received radiotherapy, craniopharyngioma(2), acoustic neurinoma(1), meningioma(2). Using the Gill-Thomas-Cos-man relocatable head frame and multiple non-coplanar therapy, the daily dose of 2Gy was irradiated at 90% to 100% isodose surface of the isocenter. The collimator sizes ranged from 26mm to 70mm. In all patients except one follow-up lost, disease was well-controlled. Acute complication was negligible and no patient experienced cranial nerve neuropathies and radiation necrosis. In overall patient setup with scalp measurements, reproducibility was found to have mean of 1.1{+-}0.6mm from the baseline reading. Relocatable stereotactic system for FSRT is highly reproducible and comfortable. Although the follow-up period was relatively short, FSRT is considered to be a safe an effective radiation technique as the treatment of intracranial tumor. But the fractionation schedule(fraction size, overall treatment time and total dose) still remains to be solved by further clinical trials.

  9. A benchmark analysis of radiation flux distribution for Boron Neutron Capture Therapy of canine brain tumors

    Energy Technology Data Exchange (ETDEWEB)

    Moran, J.M.

    1992-02-01

    Calculations of radiation flux and dose distributions for Boron Neutron Capture Therapy (BNCT) of brain tumors are typically performed using sophisticated three-dimensional analytical models based on either a homogeneous approximation or a simplified few-region approximation to the actual highly-heterogeneous geometry of the irradiation volume. Such models should be validated by comparison with calculations using detailed models in which all significant macroscopic tissue heterogeneities and geometric structures are explicitly represented as faithfully as possible. This work describes a validation exercise for BNCT of canine brain tumors. Geometric measurements of the canine anatomical structures of interest for this work were performed by dissecting and examining two essentially identical Labrador Retriever heads. Chemical analyses of various tissue samples taken during the dissections were conducted to obtain measurements of elemental compositions for tissues of interest. The resulting geometry and tissue composition data were then used to construct a detailed heterogeneous calculational model of the Labrador Retriever head. Calculations of three-dimensional radiation flux distributions pertinent to BNCT were performed for the model using the TORT discrete-ordinates radiation transport code. The calculations were repeated for a corresponding volume-weighted homogeneous tissue model. Comparison of the results showed that the peak neutron and photon flux magnitudes were quite similar for the two models (within 5%), but that the spatial flux profiles were shifted in the heterogeneous model such that the fluxes in some locations away from the peak differed from the corresponding fluxes in the homogeneous model by as much as 10-20%. Differences of this magnitude can be therapeutically significant, emphasizing the need for proper validation of simplified treatment planning models.

  10. Comparing Intelligence Quotient Change After Treatment With Proton Versus Photon Radiation Therapy for Pediatric Brain Tumors.

    Science.gov (United States)

    Kahalley, Lisa S; Ris, M Douglas; Grosshans, David R; Okcu, M Fatih; Paulino, Arnold C; Chintagumpala, Murali; Moore, Bartlett D; Guffey, Danielle; Minard, Charles G; Stancel, Heather H; Mahajan, Anita

    2016-04-01

    Compared with photon radiation (XRT), proton beam radiation therapy (PBRT) reduces dose to normal tissues, which may lead to better neurocognitive outcomes. We compared change in intelligence quotient (IQ) over time in pediatric patients with brain tumors treated with PBRT versus XRT. IQ scores were available for 150 patients (60 had received XRT, 90 had received PBRT). Linear mixed models examined change in IQ over time since radiation therapy (RT) by RT group, controlling for demographic/clinical characteristics. Craniospinal and focal RT subgroups were also examined. In the PBRT group, no change in IQ over time was identified (P = .130), whereas in the XRT group, IQ declined by 1.1 points per year (P = .004). IQ slopes did not differ between groups (P = .509). IQ was lower in the XRT group (by 8.7 points) versus the PBRT group (P = .011). In the craniospinal subgroup, IQ remained stable in both the PBRT (P = .203) and XRT groups (P = .060), and IQ slopes did not differ (P = .890). IQ was lower in the XRT group (by 12.5 points) versus the PBRT group (P = .004). In the focal subgroup, IQ scores remained stable in the PBRT group (P = .401) but declined significantly in the XRT group by 1.57 points per year (P = .026). IQ slopes did not differ between groups (P = .342). PBRT was not associated with IQ decline or impairment, yet IQ slopes did not differ between the PBRT and XRT groups. It remains unclear if PBRT results in clinically meaningful cognitive sparing that significantly exceeds that of modern XRT protocols. Additional long-term data are needed to fully understand the neurocognitive impact of PBRT in survivors of pediatric brain tumors. © 2016 by American Society of Clinical Oncology.

  11. Radiation therapy for patients of malignant salivary gland tumors with positive surgical margins

    Energy Technology Data Exchange (ETDEWEB)

    Sakata, K. (Tokyo Univ. School of Medicine (Japan). Dept. of Radiology); Aoki, Y. (Tokyo Univ. School of Medicine (Japan). Dept. of Radiology); Karasawa, K. (Tokyo Univ. School of Medicine (Japan). Dept. of Radiology); Nakagawa, K. (Tokyo Univ. School of Medicine (Japan). Dept. of Radiology); Hasezawa, K. (Tokyo Univ. School of Medicine (Japan). Dept. of Radiology); Muta, N. (Tokyo Univ. School of Medicine (Japan). Dept. of Radiology); Terahara, A. (Tokyo Univ. School of Medicine (Japan). Dept. of Radiology); Onogi, Y. (Tokyo Univ. School of Medicine (Japan). Dept. of Radiology); Sasaki, Y. (Tokyo Univ. School of Medicine (Japan). Dept. of Radiology); Akanuma, A. (Japanese Inst. of Radiological Sciences, Chiba (Japan)); Mohri, N. (Kyorin Univ. School of Medicine, Tokyo (Japan). 2. Dept. of Pathology)

    1994-06-01

    Purpose: Surgery is an essential part of treatment for tumors of the salivary gland, yet there is increasing evidence in the literature supporting the necessity of adjuvant radiation therapy. The patients described in this report were selected to receive postoperative radiation therapy because they were found to have positive margins. We have reviewed their records to identify factors influencing the control of local disease, the development of distant metastases and overall survival, and to define the role of postoperative radiation therapy in patients with postive surgical margins. A total of 17 patients with malignant tumors originating from the major salivary glands seen between 1970 and 1988 who were treated with surgery and postoperative radiation therapy were reviewed. Overall local control at five years was 65%. Classified by T-stage, local control was obtained in all two patients for T1 disease, in five of six for T2, in four of six for T3, and in none of three for T4. At five years, the ratio of patients free of distant metastases was two of two for T1 lesion, four of six for T2, three of six for T3, and none of three for T4. Five-year survival was obtained in all eight patients with T1 and T2 lesions, four of six for T3, and one of three for T4. Patients with neck nodal metastases did worse than those with negative nodes, with 0% (none of three patients) free of locoregional recurrence vs. 71% (eleven of 14), 0% (none of three) free of distant metastases vs. 63% (nine of 14), and 0% (none of three) survival at five years vs. 93% (13 of 14). Phostoperative radiation therapy for patients with positive surgical margins was found effective for T1 and T2 disease. However, patients with T3 and T4 disease require more aggressive therapy. Patients with nodal metastases in the neck at admission tended to have distant metastases and had poor prognoses. Further therapeutic measures using adjuvant chemotherapy might be explored.

  12. In vitro effect of αVβ3 and αVβ5 integrin inhibitor cilengitide combined with ionizing radiation on human malignant tumor cells

    Energy Technology Data Exchange (ETDEWEB)

    Silva, Felipe H.S.; Sanchez, Eládio O.F.; Santos, Raquel G., E-mail: felipehssilva@gmail.com, E-mail: santosr@cdtn.br, E-mail: eladio.flores@funed.mg.gov.br [Centro de Desenvolvimento da Tecnologia Nuclear (CDTN/CNEN-MG), Belo Horizonte, MG (Brazil); Fundação Ezequiel Dias (FUNED), Belo Horizonte,MG (Brazil)

    2017-11-01

    Integrin play a role in growth, motility, regulating adhesion and survival, leading to the increase of the proliferation capacity, invasion and metastasis of the tumors. Cilengitide inhibits the integrin αVβ3 and αVβ5 and its effect is in clinical evaluation in gliomas, being promising based on its great anticancer potential. Thus, the combination of ionizing radiation with Cilengitide is an alternative therapeutic strategy. Studies have shown the effect of combined therapy on tumor lines, which may lead to a radiosensitization effect by inhibiting the interaction of matrix proteins with integrin receptors, increasing the cytotoxic effect of ionizing radiation. Therefore, in this study we determined the radiosensitizing effect of cilengitide in the treatment of resistant tumors and compare to the effect of combination therapy with cisplatin, a molecule already used in clinical practice. The radiosensitizing effect of the cilengitide was evaluated by the quantification of metabolic cell viability through the MTT assay. Inhibition of colony formation was investigated in clonogenic assays. Flow cytometer was used to investigate the induction the generation of ROS in monotherapy and combined treatments. We observed that in cell line examined, cilengitide promoted detachment, metabolic alterations and reduced proliferation, but also induced the generation of ROS. Combined treatment with cilengitide and ionizing radiation showed an synergistic effect further reducing proliferation and metabolism compared to the both monotherapies (Cilengitide and Cisplatin), but also potentiated the induction of the generation of ROS. Combined therapy with cilengitide was more potent than with cisplatin, evidencing that therapies with anti-integrin are excellent therapeutic strategies to radiosensitize tumors. (author)

  13. Role of radiation therapy in the management of plasma cell tumors. [Incidence of complications

    Energy Technology Data Exchange (ETDEWEB)

    Mill, W.B.; Griffith, R.

    1980-02-15

    A retrospective review is reported of 128 patients presenting with multiple myeloma and 16 patients presenting with solitary plasmacytoma. Ninety-one percent of 116 evaluable patients treated for palliation of painful bone disease received some degree of subjective pain relief. The radiation dose most frequently prescribed was between 1500 and 2000 rad. Of the 278 ports treated, only 17 (6.1%) were re-treated to the same area at a later date. There was no increase in incidence of re-treatment with lower radiation doses. Ten of the 13 patients treated for a solitary plasmacytoma with a minimum follow-up period of three years have local tumor control. The median survival in the solitary plasmacytomas is five and one-half years. Data from the literature on 27 additional solitary plasmacytomas combined with our data suggest an improved local control and a decrease in dissemination with doses greater than 5000 rad. It is concluded that low doses of radiation are usually adequate to treat painful bone lesions of multiple myeloma and doses of 5000 to 6500 rad in six to seven weeks are recommended for solitary plasmacytomas.

  14. Glycolysis-related gene induction and ATP reduction during fractionated irradiation. Markers for radiation responsiveness of human tumor xenografts

    Energy Technology Data Exchange (ETDEWEB)

    Goetze, K.; Meyer, S.S.; Mueller-Klieser, W. [University Medical Center Mainz Univ. (Germany). Inst. of Physiology and Pathophysiology; Yaromina, A. [Technical Univ. Dresden (Germany). OncoRay - National Center for Radiation Research in Oncology; Zips, D. [University Hospital Tuebingen (Germany). Dept. of Radiation Oncology; Baumann, M. [Technical Univ. Dresden (Germany). OncoRay - National Center for Radiation Research in Oncology; University Hospital Dresden Technical Univ. Dresden (Germany). Dept. of Radiation Oncology

    2013-09-15

    Background and purpose: Lactate was previously shown to be a prognostic but not a predictive pre-therapeutic marker for radiation response of tumor xenografts. We hypothesize that metabolic changes during fractionated irradiation may restrict the predictiveness of lactate regarding tumor radiosensitivity. Materials and methods: Tumor xenografts were generated in nude mice by implanting 4 head and neck squamous cell carcinoma lines with different sensitivities to fractionated irradiation. Tumors were irradiated with up to 15 fractions of 2 Gy over a period of 3 weeks, and ATP and lactate levels were measured in vital tumor areas with induced metabolic bioluminescence imaging. Corresponding changes in mRNA expression of glycolysis-related genes were determined by quantitative RT-PCR. Results: Lactate content decreased significantly in 3 out of 4 cell lines in the course of irradiation showing no correlation with cell line-specific radiosensitivity. Radiation-induced changes in ATP levels and glycolysis-related mRNA expression, however, only occurred in radiosensitive or intermediately radioresistant xenografts, whereas these parameters remained unchanged in radioresistant tumors. Conclusion: Sensitivity-related differences in the transcriptional response of tumors to radiotherapy may be exploited in the clinic for better individualization of tumor treatment. (orig.)

  15. Indirect Tumor Cell Death After High-Dose Hypofractionated Irradiation: Implications for Stereotactic Body Radiation Therapy and Stereotactic Radiation Surgery

    Energy Technology Data Exchange (ETDEWEB)

    Song, Chang W., E-mail: songx001@umn.edu [Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota Medical School, Minneapolis, Minnesota (United States); Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Lee, Yoon-Jin [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Griffin, Robert J. [Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas (United States); Park, Inhwan [Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota Medical School, Minneapolis, Minnesota (United States); Koonce, Nathan A. [Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas (United States); Hui, Susanta [Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota Medical School, Minneapolis, Minnesota (United States); Kim, Mi-Sook [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Dusenbery, Kathryn E. [Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota Medical School, Minneapolis, Minnesota (United States); Sperduto, Paul W. [Minneapolis Radiation Oncology and Gamma Knife Center, University of Minnesota, Minneapolis, Minnesota (United States); Cho, L. Chinsoo [Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota Medical School, Minneapolis, Minnesota (United States)

    2015-09-01

    Purpose: The purpose of this study was to reveal the biological mechanisms underlying stereotactic body radiation therapy (SBRT) and stereotactic radiation surgery (SRS). Methods and Materials: FSaII fibrosarcomas grown subcutaneously in the hind limbs of C3H mice were irradiated with 10 to 30 Gy of X rays in a single fraction, and the clonogenic cell survival was determined with in vivo–in vitro excision assay immediately or 2 to 5 days after irradiation. The effects of radiation on the intratumor microenvironment were studied using immunohistochemical methods. Results: After cells were irradiated with 15 or 20 Gy, cell survival in FSaII tumors declined for 2 to 3 days and began to recover thereafter in some but not all tumors. After irradiation with 30 Gy, cell survival declined continuously for 5 days. Cell survival in some tumors 5 days after 20 to 30 Gy irradiation was 2 to 3 logs less than that immediately after irradiation. Irradiation with 20 Gy markedly reduced blood perfusion, upregulated HIF-1α, and increased carbonic anhydrase-9 expression, indicating that irradiation increased tumor hypoxia. In addition, expression of VEGF also increased in the tumor tissue after 20 Gy irradiation, probably due to the increase in HIF-1α activity. Conclusions: Irradiation of FSaII tumors with 15 to 30 Gy in a single dose caused dose-dependent secondary cell death, most likely by causing vascular damage accompanied by deterioration of intratumor microenvironment. Such indirect tumor cell death may play a crucial role in the control of human tumors with SBRT and SRS.

  16. Down-regulation of HSP27 sensitizes TRAIL-resistant tumor cell to TRAIL-induced apoptosis

    DEFF Research Database (Denmark)

    Zhuang, Hongqin; Jiang, Weiwei; Cheng, Wei

    2010-01-01

    Tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL) has recently emerged as a cancer therapeutic agent because it preferentially induces apoptosis in human cancer over normal cells. Most tumor cells, including lung cancer cell line A549, unfortunately, are resistant to TRAIL...... treatment even at high dose. Recent studies indicated that TRAIL-resistant cancer cells could be sensitized to TRAIL by combination therapy. Stress and heat shock proteins such as HSP90, HSP70 and HSP27 are induced in response to a wide variety of physiological environmental insults including heat, reactive...... oxygen species or anticancer drugs. Their elevated expressions facilitate cells to survive in stress circumstances. The HSP27 expression is enhanced in many tumor cells, implying that it is involved in tumor progression and the development of treatment resistance in various tumors, including lung cancer...

  17. Periostin in tumor microenvironment is associated with poor prognosis and platinum resistance in epithelial ovarian carcinoma

    Science.gov (United States)

    Sung, Pi-Lin; Jan, Yi-Hua; Lin, Shih-Chieh; Huang, Chao-Cheng; Lin, Hao; Wen, Kuo-Chang; Chao, Kuan-Chong; Lai, Chiung-Ru; Wang, Peng-Hui; Chuang, Chi-Mu; Wu, Hua-Hsi; Twu, Nae-Fang; Yen, Ming-Shyen; Hsiao, Michael; Huang, Chi-Ying F.

    2016-01-01

    The interplay between tumor microenvironment and cancer that causes chemoresistance remains unclear. By analyzing public available microarray datasets, we identified that periostin (POSTN) was overexpressed in cancer stroma in epithelial ovarian cancer (EOC) patients. Immunohistochemistry analysis showed overexpression of stromal POSTN is a powerful independent poor prognostic predictor for EOC patients. Furthermore, patients with high levels of stromal POSTN tend to have higher percentage of cisplatin resistance compared to those with low levels of stromal POSTN. Moreover, we found POSTN treatment can induce cisplatin resistant and activate AKT pathway in A2780 cells in vitro. Inhibition of AKT activity by AKT inhibitor MK-2206 abolished POSTN-induced AKT activation and cisplatin resistance in vitro. Taken together, we found high POSTN expression in cancer microenvironment is correlated with poor prognosis in EOC patients and associated with platinum resistance. The effect of POSTN in cancer stroma cells may activate AKT pathway in tumor and AKT inhibitor can be beneficial to augment the efficacy of existing cancer therapeutics. PMID:26716408

  18. Radiation-induced changes in nucleoid halo diameteres of aerobic and hypoxic SF-126 human brain tumor cells

    Energy Technology Data Exchange (ETDEWEB)

    Wang, J.; Basu, H.S.; Hu, L.; Feuerstein, B.G.; Deen, D.F. [Univ. of California, San Francisco, CA (United States)] [and others

    1995-02-01

    Nucleoid halo diameters were measured to assay changes in DNA supercoiling in human brain tumor cell line SF-126 after irradiation under aerobic or hypoxic conditions. In unirradiated aerobic cells, a typical propidium iodide titration curve showed that with increasing concentrations of propodium iodide, the halo diameter increased and then decreased with the unwinding and subsequent rewinding of DNA supercoils. In irradiated cells, the rewinding of DNA supercoils was inhibited, resulting in an increased halo diameter, in a radiation dose-dependent manner. To produce equal increases in halo diameter required about a threefold higher radiation dose in hypoxic cells than in aerobic cells. Quantitatively similiar differences in the radiation sensitivities of hypoxic and aerobic cells were demonstrated by a colony-forming efficiency assay. These findings suggest that the nucleoid halo assay may be used as a rapid measure of the inherent radiation sensitivity of human tumors. 22 refs., 5 figs.

  19. Treatment of a Solid Tumor Using Engineered Drug-Resistant Immunocompetent Cells and Cytotoxic Chemotherapy

    Science.gov (United States)

    Dasgupta, Anindya; Shields, Jordan E.

    2012-01-01

    Abstract Multimodal therapy approaches, such as combining chemotherapy agents with cellular immunotherapy, suffers from potential drug-mediated toxicity to immune effector cells. Overcoming such toxic effects of anticancer cellular products is a potential critical barrier to the development of combined therapeutic approaches. We are evaluating an anticancer strategy that focuses on overcoming such a barrier by genetically engineering drug-resistant variants of immunocompetent cells, thereby allowing for the coadministration of cellular therapy with cytotoxic chemotherapy, a method we refer to as drug-resistant immunotherapy (DRI). The strategy relies on the use of cDNA sequences that confer drug resistance and recombinant lentiviral vectors to transfer nucleic acid sequences into immunocompetent cells. In the present study, we evaluated a DRI-based strategy that incorporates the immunocompetent cell line NK-92, which has intrinsic antitumor properties, genetically engineered to be resistant to both temozolomide and trimetrexate. These immune effector cells efficiently lysed neuroblastoma cell lines, which we show are also sensitive to both chemotherapy agents. The antitumor efficacy of the DRI strategy was demonstrated in vivo, whereby neuroblastoma-bearing NOD/SCID/γ-chain knockout (NSG) mice treated with dual drug-resistant NK-92 cell therapy followed by dual cytotoxic chemotherapy showed tumor regression and significantly enhanced survival compared with animals receiving either nonengineered cell-based therapy and chemotherapy, immunotherapy alone, or chemotherapy alone. These data show there is a benefit to using drug-resistant cellular therapy when combined with cytotoxic chemotherapy approaches. PMID:22397715

  20. Basal DNA repair machinery is subject to positive selection in ionizing-radiation-resistant bacteria

    Directory of Open Access Journals (Sweden)

    Barkallah Insaf

    2008-06-01

    Full Text Available Abstract Background Ionizing-radiation-resistant bacteria (IRRB show a surprising capacity for adaptation to ionizing radiation and desiccation. Positive Darwinian selection is expected to play an important role in this trait, but no data are currently available regarding the role of positive adaptive selection in resistance to ionizing-radiation and tolerance of desiccation. We analyzed the four known genome sequences of IRRB (Deinococcus geothermalis, Deinococcus radiodurans, Kineococcus radiotolerans, and Rubrobacter xylanophilus to determine the role of positive Darwinian selection in the evolution of resistance to ionizing radiation and tolerance of desiccation. Results We used the programs MultiParanoid and DnaSP to deduce the sets of orthologs that potentially evolved due to positive Darwinian selection in IRRB. We find that positive selection targets 689 ortholog sets of IRRB. Among these, 58 ortholog sets are absent in ionizing-radiation-sensitive bacteria (IRSB: Escherichia coli and Thermus thermophilus. The most striking finding is that all basal DNA repair genes in IRRB, unlike many of their orthologs in IRSB, are subject to positive selection. Conclusion Our results provide the first in silico prediction of positively selected genes with potential roles in the molecular basis of resistance to γ-radiation and tolerance of desiccation in IRRB. Identification of these genes provides a basis for future experimental work aimed at understanding the metabolic networks in which they participate.

  1. Down-regulation of PERK enhances resistance to ionizing radiation

    Energy Technology Data Exchange (ETDEWEB)

    Oommen, Deepu, E-mail: oommen1978@gmail.com; Prise, Kevin M.

    2013-11-08

    Highlights: •PERK enhances the sensitivity of cancer cells to ionizing radiation. •Down-regulation of PERK results in enhanced DNA repair. •Ionizing radiation-induced apoptosis is inhibited in PERK-down regulated cancer cells. -- Abstract: Although, ionizing radiation (IR) has been implicated to cause stress in endoplasmic reticulum (ER), how ER stress signaling and major ER stress sensors modulate cellular response to IR is unclear. Protein kinase RNA-like endoplasmic reticulum kinase (PERK) is an ER transmembrane protein which initiates unfolded protein response (UPR) or ER stress signaling when ER homeostasis is disturbed. Here, we report that down-regulation of PERK resulted in increased clonogenic survival, enhanced DNA repair and reduced apoptosis in irradiated cancer cells. Our study demonstrated that PERK has a role in sensitizing cancer cells to IR.

  2. Role of Mn2+ and Compatible Solutes in the Radiation Resistance of Thermophilic Bacteria and Archaea

    Directory of Open Access Journals (Sweden)

    Kimberly M. Webb

    2012-01-01

    Full Text Available Radiation-resistant bacteria have garnered a great deal of attention from scientists seeking to expose the mechanisms underlying their incredible survival abilities. Recent analyses showed that the resistance to ionizing radiation (IR in the archaeon Halobacterium salinarum is dependent upon Mn-antioxidant complexes responsible for the scavenging of reactive oxygen species (ROS generated by radiation. Here we examined the role of the compatible solutes trehalose, mannosylglycerate, and di-myo-inositol phosphate in the radiation resistance of aerobic and anaerobic thermophiles. We found that the IR resistance of the thermophilic bacteria Rubrobacter xylanophilus and Rubrobacter radiotolerans was highly correlated to the accumulation of high intracellular concentration of trehalose in association with Mn, supporting the model of Mn2+-dependent ROS scavenging in the aerobes. In contrast, the hyperthermophilic archaea Thermococcus gammatolerans and Pyrococcus furiosus did not contain significant amounts of intracellular Mn, and we found no significant antioxidant activity from mannosylglycerate and di-myo-inositol phosphate in vitro. We therefore propose that the low levels of IR-generated ROS under anaerobic conditions combined with highly constitutively expressed detoxification systems in these anaerobes are key to their radiation resistance and circumvent the need for the accumulation of Mn-antioxidant complexes in the cell.

  3. Effects of low dose gamma radiation on the early growth of red pepper and the resistance to subsquent high dose of radiation

    Energy Technology Data Exchange (ETDEWEB)

    Kim, J. S.; Baek, M. H.; Kim, D. H.; Lee, Y. K. [KAERI, Taejon (Korea, Republic of); Lee, Y. B. [Chungnam National Univ., Taejon (Korea, Republic of)

    2001-05-01

    Red pepper (capsicum annuum L. cv. Jokwang and cv. Johong) seeds were irradiated with the dose of 0{approx}50 Gy to investigated the effect of the low dose gamma radiation on the early growth and resistance to subsequent high dose of radiation. The effect of the low dose gamma radiation on the early growth and resistance to subsequenct high dose of radiation were enhanced in Johong cultivar but not in Jokwang cultivar. Germination rate and early growth of Johong cultivar were noticeably increased at 4 Gy-, 8 Gy- and 20 Gy irradiation group. Resistance to subsequent high dose of radiation of Johong cultivar were increased at almost all of the low dose irradiation group. Especially it was highest at 4 Gy irradiation group. The carotenoid contents and enzyme activity on the resistance to subsequent high dose of radiation of Johong cultivar were increased at the 4 Gy and 8 Gy irradiation group.

  4. Image-Guided Robotic Stereotactic Radiation Therapy with Fiducial-Free Tumor Tracking for Lung Cancer

    Directory of Open Access Journals (Sweden)

    Bibault Jean-Emmanuel

    2012-06-01

    Full Text Available Abstract Purpose Stereotactic body radiation therapy (SBRT for early-stage lung cancer can be achieved with several methods: respiratory gating, body frame, or real-time target and motion tracking. Two target tracking methods are currently available with the CyberKnife® System: the first one, fiducial tracking, requires the use of radio-opaque markers implanted near or inside the tumor, while the other, Xsight® Lung Tracking System, (XLTS is fiducial-free. With XLTS, targeting is synchronized directly with target motion, which occurs due to respiration. While the former method (fiducial tracking is well documented, the clinical relevance of the latter (tracking without fiducials has never been well described to this date. Patients and Methods A study was performed at our department for each patient treated for lung cancer with CyberKnife using XLTS. Selection criteria were: primary or recurring T1 or T2 stage non-small-cell lung cancer (NSCLC with 15–60 mm tumor size. Initial staging included CT-Scan and FDG-PET. Results Fifty-one patients not amenable to surgery were treated with XLTS. Median follow-up was 15 months (range, 5–30 months. Median tumor size was 24 mm (range, 15–60 mm. Median total dose was 60 Gy (36–60 Gy in three fractions. Actuarial overall survival was 85.5% (95% CI = 74.5–96% at 1 year and 79.4% (95% CI = 64–94.8% at 2 years. Actuarial local control rate was 92% (95% CI = 84–99% at one1 year and 86% (95% CI = 75–97% at 2 years. Conclusion Local control and overall survival rates were similar to previous reports that used fiducials for tumor tracking. Toxicity was lower than most studies since tumor tracking did not require fiducial implantion. This fiducial-free method for respiratory motion tracking is a valid option for the most fragile patients.

  5. TU-CD-303-04: Radiation-Induced Long Distance Tumor Cell Migration Into and Out of the Radiation Field and Its Clinical Implication

    Energy Technology Data Exchange (ETDEWEB)

    Graves, E. [Stanford University (United States)

    2015-06-15

    Recent advances in cancer research have shed new light on the complex processes of how therapeutic radiation initiates changes at cellular, tissue, and system levels that may lead to clinical effects. These new advances may transform the way we use radiation to combat certain types of cancers. For the past two decades many technological advancements in radiation therapy have been largely based on the hypothesis that direct radiation-induced DNA double strand breaks cause cell death and thus tumor control and normal tissue damage. However, new insights have elucidated that in addition to causing cellular DNA damage, localized therapeutic radiation also initiates cascades of complex downstream biological responses in tissue that extend far beyond where therapeutic radiation dose is directly deposited. For instance, studies show that irradiated dying tumor cells release tumor antigens that can lead the immune system to a systemic anti-cancer attack throughout the body of cancer patient; targeted irradiation to solid tumor also increases the migration of tumor cells already in bloodstream, the seeds of potential metastasis. Some of the new insights may explain the long ago discovered but still unexplained non-localized radiation effects (bystander effect and abscopal effect) and the efficacy of spatially fractionated radiation therapy (microbeam radiation therapy and GRID therapy) where many “hot” and “cold” spots are intentionally created throughout the treatment volume. Better understanding of the mechanisms behind the non-localized radiation effects creates tremendous opportunities to develop new and integrated cancer treatment strategies that are based on radiotherapy, immunology, and chemotherapy. However, in the multidisciplinary effort to advance new radiobiology, there are also tremendous challenges including a lack of multidisciplinary researchers and imaging technologies for the microscopic radiation-induced responses. A better grasp of the essence of

  6. Micro-RNA expression in cisplatin resistant germ cell tumor cell lines

    Directory of Open Access Journals (Sweden)

    Meineke Viktor

    2011-05-01

    Full Text Available Abstract Background We compared microRNA expression patterns in three cisplatin resistant sublines derived from paternal cisplatin sensitive germ cell tumor cell lines in order to improve our understanding of the mechanisms of cisplatin resistance. Methods Three cisplatin resistant sublines (NTERA-2-R, NCCIT-R, 2102EP-R showing 2.7-11.3-fold increase in drug resistance after intermittent exposure to increasing doses of cisplatin were compared to their parental counterparts, three well established relatively cisplatin sensitive germ cell tumor cell lines (NTERA-2, NCCIT, 2102EP. Cells were cultured and total RNA was isolated from all 6 cell lines in three independent experiments. RNA was converted into cDNA and quantitative RT-PCR was run using 384 well low density arrays covering almost all (738 known microRNA species of human origin. Results Altogether 72 of 738 (9.8% microRNAs appeared differentially expressed between sensitive and resistant cell line pairs (NTERA-2R/NTERA-2 = 43, NCCIT-R/NCCIT = 53, 2102EP-R/2102EP = 15 of which 46.7-95.3% were up-regulated (NTERA-2R/NTERA-2 = 95.3%, NCCIT-R/NCCIT = 62.3%, 2102EP-R/2102EP = 46.7%. The number of genes showing differential expression in more than one of the cell line pairs was 34 between NTERA-2R/NTERA-2 (79% and NCCIT-R/NCCIT (64%, and 3 and 4, respectively, between these two cell lines and 2102EP-R/2102EP (about 27%. Only the has-miR-10b involved in breast cancer invasion and metastasis and has-miR-512-3p appeared to be up-regulated (2-3-fold in all three cell lines. The hsa-miR-371-373 cluster (counteracting cellular senescence and linked with differentiation potency, as well as hsa-miR-520c/-520h (inhibiting the tumor suppressor p21 were 3.9-16.3 fold up-regulated in two of the three cisplatin resistant cell lines. Several new micro-RNA species missing an annotation towards cisplatin resistance could be identified. These were hsa-miR-512-3p/-515/-517/-518/-525 (up to 8.1-fold up

  7. Micro-RNA expression in cisplatin resistant germ cell tumor cell lines.

    Science.gov (United States)

    Port, Matthias; Glaesener, Stephanie; Ruf, Christian; Riecke, Armin; Bokemeyer, Carsten; Meineke, Viktor; Honecker, Friedemann; Abend, Michael

    2011-05-15

    We compared microRNA expression patterns in three cisplatin resistant sublines derived from paternal cisplatin sensitive germ cell tumor cell lines in order to improve our understanding of the mechanisms of cisplatin resistance. Three cisplatin resistant sublines (NTERA-2-R, NCCIT-R, 2102EP-R) showing 2.7-11.3-fold increase in drug resistance after intermittent exposure to increasing doses of cisplatin were compared to their parental counterparts, three well established relatively cisplatin sensitive germ cell tumor cell lines (NTERA-2, NCCIT, 2102EP). Cells were cultured and total RNA was isolated from all 6 cell lines in three independent experiments. RNA was converted into cDNA and quantitative RT-PCR was run using 384 well low density arrays covering almost all (738) known microRNA species of human origin. Altogether 72 of 738 (9.8%) microRNAs appeared differentially expressed between sensitive and resistant cell line pairs (NTERA-2R/NTERA-2 = 43, NCCIT-R/NCCIT = 53, 2102EP-R/2102EP = 15) of which 46.7-95.3% were up-regulated (NTERA-2R/NTERA-2 = 95.3%, NCCIT-R/NCCIT = 62.3%, 2102EP-R/2102EP = 46.7%). The number of genes showing differential expression in more than one of the cell line pairs was 34 between NTERA-2R/NTERA-2 (79%) and NCCIT-R/NCCIT (64%), and 3 and 4, respectively, between these two cell lines and 2102EP-R/2102EP (about 27%). Only the has-miR-10b involved in breast cancer invasion and metastasis and has-miR-512-3p appeared to be up-regulated (2-3-fold) in all three cell lines. The hsa-miR-371-373 cluster (counteracting cellular senescence and linked with differentiation potency), as well as hsa-miR-520c/-520h (inhibiting the tumor suppressor p21) were 3.9-16.3 fold up-regulated in two of the three cisplatin resistant cell lines. Several new micro-RNA species missing an annotation towards cisplatin resistance could be identified. These were hsa-miR-512-3p/-515/-517/-518/-525 (up to 8.1-fold up-regulated) and hsa-miR-99a/-100/-145 (up to 10-fold

  8. Radiation therapy for malignant lid tumor; Effectiveness of racket-shaped lead protector

    Energy Technology Data Exchange (ETDEWEB)

    Totsuka, Seiichi; Itsuno, Hajime (Shinshu Univ., Matsumoto, Nagano (Japan). Faculty of Medicine)

    1991-04-01

    The case of a 42-year-old man with Meibomian gland carcinoma in his right lower lid is reported. The tumor found in the nasal part of the lower lid, was 12 mm x 13 mm in size. First, surgical resection was performed. The pathological diagnosis of the frozen section was 'undifferentiated basal cell epithelioma'. Second, cryotherapy was performed all over the cut surface. Later, the permanent section was pathologically diagnosed as 'undifferentiated Meibomian gland carcinoma'. Total 50 Gy irradiation therapy was therefore performed using a 9 Mev Linac electron beam, 25 x 20 mm field, with a lead protector for the cornea and lens. A lead contact lens did not afford good results because it was too easily shifted on the cornea, owing to its weight. Therefore, we made a racket-shaped lead protector. Fixed well with tape, this protector afforded good protective effect. Three years after treatment, the patient has good visual function, with no recurrence. This racket-shaped lead protector is thought to be useful in radiation therapy for malignant lid tumors. (author).

  9. Determination of Radiation Absorbed Dose to Primary Liver Tumors and Normal Liver Tissue Using Post Radioembolization 90Y PET

    Directory of Open Access Journals (Sweden)

    Shyam Mohan Srinivas

    2014-10-01

    Full Text Available Background: Radioembolization with Yttrium-90 (90Y microspheres is becoming a more widely used transcatheter treatment for unresectable hepatocellular carcinoma (HCC. Using post-treatment 90Y PET/CT scans,the distribution of microspheres within the liver can be determined and quantitatively assessesed . We studied the radiation dose of 90Y delivered to liver and treated tumors.Methods: This retrospective study of 56 patients with HCC, including analysis of 98 liver tumors, measured and correlated the dose of radiation delivered to liver tumors and normal liver tissue using glass microspheres (TheraSpheres® to the frequency of complications with mRECIST. 90Y PET/CT and triphasic liver CT scans were used to contour treated tumor and normal liver regions and determine their respective activity concentrations. An absorbed dose factor was used to convert the measured activity concentration (Bq/mL to an absorbed dose (Gy.Results: The 98 studied tumors received a mean dose of 169 Gy (mode 90-120 Gy;range 0-570 Gy. Tumor response by mRECIST criteria was performed for 48 tumors that had follow up scans. There were 21 responders (mean dose 215 Gy and 27 nonresponders (mean dose 167 Gy. The association between mean tumor absorbed dose and response suggests a trend but did not reach statistical significance (p=0.099. Normal liver tissue received a mean dose of 67 Gy (mode 60-70 Gy; range 10-120 Gy. There was a statistically significant association between absorbed dose to normal liver and the presence of two or more severe complications (p=0.036.Conclusion: Our cohort of patients showed a possible dose response trend for the tumors. Collateral dose to normal liver is nontrivial and can have clinical implications. These methods help us understand whether patient adverse events, treatment success, or treatment failure can be attributed to the dose which the tumor or normal liver received.

  10. Stereotactic body radiation therapy for liver oligo-recurrence and oligo-progression from various tumors

    Energy Technology Data Exchange (ETDEWEB)

    Cha, Yu Jin; Kim, Mi Sook; Jang, Won Il; Seo, Young Seok; Cho, Chul Koo; Yoo, Hyung Jun; Paik, Eun Kyung [Dept. of Radiation Oncology, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

    2017-06-15

    To evaluate the outcomes of stereotactic body radiation therapy (SBRT) for patients with liver oligo-recurrence and oligo-progression from various primary tumors. Between 2002 and 2013, 72 patients with liver oligo-recurrence (oligo-metastasis with a controlled primary tumor) and oligo-progression (contradictory progression of a few sites of disease despite an overall tumor burden response to therapy) underwent SBRT. Of these, 9 and 8 patients with uncontrollable distant metastases and patients immediate loss to follow-up, respectively, were excluded. The total planning target volume was used to select the SBRT dose (median, 48 Gy; range, 30 to 60 Gy, 3–4 fractions). Toxicity was evaluated using the Common Toxicity Criteria for Adverse Events v4.0. We evaluated 55 patients (77 lesions) treated with SBRT for liver metastases. All patients had controlled primary lesions, and 28 patients had stable lesions at another site (oligo-progression). The most common primary site was the colon (36 patients), followed by the stomach (6 patients) and other sites (13 patients). The 2-year local control and progression-free survival rates were 68% and 22%, respectively. The 2- and 5-year overall survival rates were 56% and 20%, respectively. The most common adverse events were grade 1–2 fatigue, nausea, and vomiting; no grade ≥3 toxicities were observed. Univariate analysis revealed that oligo-progression associated with poor survival. SBRT for liver oligo-recurrence and oligo-progression appears safe, with similar local control rates. For liver oligo-progression, criteria are needed to select patients in whom improved overall survival can be expected through SBRT.

  11. SU-E-J-273: Simulation of the Radiation Response of Hypoxic Tumors

    Energy Technology Data Exchange (ETDEWEB)

    Espinoza, I [Pontificia Universidad Catolica de Chile, Santiago (Chile); Peschke, P; Karger, C [German Cancer Research Center (DKFZ), Heidelberg (Germany)

    2014-06-01

    Purpose: In radiotherapy, it is important to predict the response of tumour to irradiation prior to the treatment. Mathematical modelling of tumour control probability (TCP) based on the dose distribution, medical imaging and other biological information may help to improve this prediction and to optimize the treatment plan. The aim of this work is to develop an image based 3D multiscale radiobiological model, which describes the growth and the response to radiotherapy of hypoxic tumors. Methods: The computer model is based on voxels, containing tumour, normal (including capillary) and dead cells. Killing of tumour cells due to irradiation is calculated by the Linear Quadratic Model (extended for hypoxia), and the proliferation and resorption of cells are modelled by exponential laws. The initial shape of the tumours is taken from CT images and the initial vascular and cell density information from PET and/or MR images. Including the fractionation regime and the physical dose distribution of the radiation treatment, the model simulates the spatial-temporal evolution of the tumor. Additionally, the dose distribution may be biologically optimized. Results: The model describes the appearance of hypoxia during tumour growth and the reoxygenation processes during radiotherapy. Among other parameters, the TCP is calculated for different dose distributions. The results are in accordance with published results. Conclusion: The simulation model may contribute to the understanding of the influence of biological parameters on tumor response during treatment, and specifically on TCP. It may be used to implement dose-painting approaches. Experimental and clinical validation is needed. This study is supported by a grant from the Ministry of Education of Chile, Programa Mece Educacion Superior (2)

  12. Near future of tumor immunology: Anticipating resistance mechanisms to immunotherapies, a big challenge for clinical trials.

    Science.gov (United States)

    Catani, João Paulo Portela; Riechelmann, Rachel P; Adjemian, Sandy; Strauss, Bryan E

    2017-05-04

    The success of immunotherapies brings hope for the future of cancer treatment. Even so, we are faced with a new challenge, that of understanding which patients will respond initially and, possibly, develop resistance. The examination of the immune profile, especially approaches related to the immunoscore, may foretell which tumors will have a positive initial response. Ideally, the mutation load would also be analyzed, helping to reveal tumor associated antigens that are predictive of an effective cytolytic attack. However, the response may be hindered by changes induced in the tumor and its microenvironment during treatment, perhaps stemming from the therapy itself. To monitor such alterations, we suggest that minimally invasive approaches should be explored, such as the analysis of circulating tumor DNA. When testing new drugs, the data collected from each patient would initially represent an N of 1 clinical trial that could then be deposited in large databases and mined retrospectively for trends and correlations between genetic alterations and response to therapy. We expect that the investment in personalized approaches that couple molecular analysis during clinical trials will yield critical data that, in the future, may be used to predict the outcome of novel immunotherapies.

  13. USE OF PROTON MAGNETIC RESONANCE SPECTROSCOPIC IMAGING DATA IN PLANNING FOCAL RADIATION THERAPIES FOR BRAIN TUMORS

    Directory of Open Access Journals (Sweden)

    Edward E Graves

    2011-05-01

    Full Text Available Advances in radiation therapy for malignant neoplasms have produced techniques such as Gamma Knife radiosurgery, capable of delivering an ablative dose to a specific, irregular volume of tissue. However, efficient use of these techniques requires the identification of a target volume that will produce the best therapeutic response while sparing surrounding normal brain tissue. Accomplishing this task using conventional computed tomography (CT and contrast-enhanced magnetic resonance imaging (MRI techniques has proven difficult because of the difficulties in identifying the effective tumor margin. Magnetic resonance spectroscopic imaging (MRSI has been shown to offer a clinically-feasible metabolic assessment of the presence and extent of neoplasm that can complement conventional anatomic imaging. This paper reviews current Gamma Knife protocols and MRSI acquisition, reconstruction, and interpretation techniques, and discusses the motivation for including magnetic resonance spectroscopy findings while planning focal radiation therapies. A treatment selection and planning strategy incorporating MRSI is then proposed, which can be used in the future to assess the efficacy of spectroscopy-based therapy planning.

  14. Radiation sparing of cerebral cortex in brain tumor patients using quantitative neuroimaging.

    Science.gov (United States)

    Karunamuni, Roshan A; Moore, Kevin L; Seibert, Tyler M; Li, Nan; White, Nathan S; Bartsch, Hauke; Carmona, Ruben; Marshall, Deborah; McDonald, Carrie R; Farid, Nikdokht; Krishnan, Anithapriya; Kuperman, Joshua; Mell, Loren K; Brewer, James; Dale, Anders M; Moiseenko, Vitali; Hattangadi-Gluth, Jona A

    2016-01-01

    Neurocognitive decline in brain tumor patients treated with radiotherapy (RT) may be linked to cortical atrophy. We developed models to determine radiation treatment-planning objectives for cortex, which were tested on a sample population to identify the dosimetric cost of cortical sparing. The relationship between the probability of cortical atrophy in fifteen high-grade glioma patients at 1-year post-RT and radiation dose was fit using logistic mixed effects modeling. Cortical sparing was implemented using two strategies: region-specific sparing using model parameters, and non-specific sparing of all normal brain tissue. A dose threshold of 28.6 Gy was found to result in a 20% probability of severe atrophy. Average cortical sparing at 30 Gy was greater for region-specific dose avoidance (4.6%) compared to non-specific (3.6%). Cortical sparing resulted in an increase in heterogeneity index of the planning target volume (PTV) with an average increase of 1.9% (region-specific) and 0.9% (non-specific). We found RT doses above 28.6 Gy resulted in a greater than 20% probability of cortical atrophy. Cortical sparing can be achieved using region-specific or non-specific dose avoidance strategies at the cost of an increase in the dose heterogeneity of the PTV. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  15. Materials That Enhance Efficiency and Radiation Resistance of Solar Cells

    Science.gov (United States)

    Sun, Xiadong; Wang, Haorong

    2012-01-01

    A thin layer (approximately 10 microns) of a novel "transparent" fluorescent material is applied to existing solar cells or modules to effectively block and convert UV light, or other lower solar response waveband of solar radiation, to visible or IR light that can be more efficiently used by solar cells for additional photocurrent. Meanwhile, the layer of fluorescent coating material remains fully "transparent" to the visible and IR waveband of solar radiation, resulting in a net gain of solar cell efficiency. This innovation alters the effective solar spectral power distribution to which an existing cell gets exposed, and matches the maximum photovoltaic (PV) response of existing cells. By shifting a low PV response waveband (e.g., UV) of solar radiation to a high PV response waveband (e.g. Vis-Near IR) with novel fluorescent materials that are transparent to other solar-cell sensitive wavebands, electrical output from solar cells will be enhanced. This approach enhances the efficiency of solar cells by converting UV and high-energy particles in space that would otherwise be wasted to visible/IR light. This innovation is a generic technique that can be readily implemented to significantly increase efficiencies of both space and terrestrial solar cells, without incurring much cost, thus bringing a broad base of economical, social, and environmental benefits. The key to this approach is that the "fluorescent" material must be very efficient, and cannot block or attenuate the "desirable" and unconverted" waveband of solar radiation (e.g. Vis-NIR) from reaching the cells. Some nano-phosphors and novel organometallic complex materials have been identified that enhance the energy efficiency on some state-of-the-art commercial silicon and thin-film-based solar cells by over 6%.

  16. Assessment of Gamma Radiation Resistance of Spores Isolated from the Spacecraft Assembly Facility During MSL Assembly

    Science.gov (United States)

    Chopra, Arsh; Ramirez, Gustavo A.; Vaishampayan, Parag A.; Venkateswaran, Kasthuri J.

    2011-01-01

    Spore forming bacteria, a common inhabitant of spacecraft assembly facilities, are known to tolerate extreme environmental conditions such as radiation, desiccation, and high temperatures. Since the Viking era (early 1970's), spores have been utilized to assess the degree and level of microbiological contamination on spacecraft and their associated spacecraft assembly facilities. There is a growing concern that desiccation and extreme radiation resistant spore forming microorganisms associated with spacecraft surfaces can withstand space environmental conditions and subsequently proliferate on another solar body. Such forward contamination would certainly jeopardize future life detection or sample return technologies. It is important to recognize that different classes of organisms are critical while calculating the probability of contamination, and methods must be devised to estimate their abundances. Microorganisms can be categorized based on radiation sensitivity as Type A, B, C, and D. Type C represents spores resistant to radiation (10% or greater survival above 0.8 Mrad gamma radiation). To address these questions we have purified 96 spore formers, isolated during planetary protection efforts of Mars Science Laboratory assembly for gamma radiation resistance. The spores purified and stored will be used to generate data that can be used further to model and predict the probability of forward contamination.

  17. An in vitro assessment of liposomal topotecan simulating metronomic chemotherapy in combination with radiation in tumor-endothelial spheroids.

    Science.gov (United States)

    Jyoti, Amar; Fugit, Kyle D; Sethi, Pallavi; McGarry, Ronald C; Anderson, Bradley D; Upreti, Meenakshi

    2015-10-15

    Low dose metronomic chemotherapy (LDMC) refers to prolonged administration of low dose chemotherapy designed to minimize toxicity and target the tumor endothelium, causing tumor growth inhibition. Topotecan (TPT) when administered at its maximum tolerated dose (MTD) is often associated with systemic hematological toxicities. Liposomal encapsulation of TPT enhances efficacy by shielding it from systemic clearance, allowing greater uptake and extended tissue exposure in tumors. Extended release of TPT from liposomal formulations also has the potential to mimic metronomic therapies with fewer treatments. Here we investigate potential toxicities of equivalent doses of free and actively loaded liposomal TPT (LTPT) and compare them to a fractionated low dose regimen of free TPT in tumor-endothelial spheroids (TES) with/without radiation exposure for a prolonged period of 10 days. Using confocal microscopy, TPT fluorescence was monitored to determine the accumulation of drug within TES. These studies showed TES, being more reflective of the in vivo tumor microenvironment, were more sensitive to LTPT in comparison to free TPT with radiation. More importantly, the response of TES to low-dose metronomic TPT with radiation was comparable to similar treatment with LTPT. This TES study suggests nanoparticle formulations designed for extended release of drug can simulate LDMC in vivo.

  18. EVALUATION OF THE CLINICAL USE OF HYPOXIC CELL SENSITIZERS IN RADIATION THERAPY OF MALIGNANT EPITHELIAL SKIN TUMORS

    Directory of Open Access Journals (Sweden)

    P. Yu. Polyakov

    2015-01-01

    Full Text Available Aim: To increase the efficacy of radiation therapy of malignant epithelial cell skin neoplasms with the use of radiation sensitizers of hypoxic tumor cells.Materials and methods: The study was performed in 517 patients with basal cell (n = 361 and squamous cell (n = 156 skin cancer, 274 (53% of whom had T2 and 243 (47%, T3 tumors. Patients with locally advanced and metastatic tumors were excluded from the study. The following treatment modalities were used: distant gamma-therapy, short-distance radiation therapy and combined radiation therapy with the use of non-conventional dose fractioning at total local doses equal to 72–73 Gr. The sensibilization of hypoxic tumor cells to radiation therapy with metronidazole was done by targeted delivery of the drug to the tumor by means of topical application of Coletex-M drapes impregnated with metronidazole in a high concentration (up to 20 mcg/cm². The second method of radiosensibilization of hypoxic tumor cells was based on a preliminary use of low intensity laser radiation onto the tumor. As a source this radiation, a helium neon laser was used with the power of up to 12 mVt and the wave length of 0.63 to 0.89 mcm, duration of sessions from 3 to 15 minutes. The control group comprised 192 skin cancer patients who underwent radiation therapy without the use of radiation sensitizers. Results: The use of metronidazole and low intensity laser radiation within the radiation therapy of T3 skin cancer patients, compared to the treatment without the radiation modifiers, significantly improved the immediate cure rates (full tumor regression at 1 to 1.5 months after completion of radiation from 75.5 ± 3.1% to 89.2 ± 1.9% (р < 0.05. In the group with basal cell skin cancer that underwent radiation therapy combined with metronidazole, there was an association of its radio-modifying effect and tumor size. Short-distance roentgenotherapy of patients with T2 basal cell skin cancer and tumor size of < 4 cm was

  19. Characterization of Adriamycin-resistant and radiation-sensitive Chinese hamster cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Sognier, M.A.; Yin Zhang; Eberle, R.L.; Belli, J.A. (Texas Univ., Galveston, TX (United States). Medical Branch)

    1992-11-03

    A series of cell lines derived from Chinese hamster V79 cells by selection in increasing concentrations of Adriamycin (ADRM) was developed to study the mechanism of drug resistance and its relationship to radiation response. Survival studies revealed that selection in increasingly higher concentrations of ADRM positively correlated with increased cellular drug resistance. Increased cellular resistance correlated positively with amplification of the hamster multidrug-resistance gene (pgp 1) as detected with dot blot analysis using the pCHP1 probe. Southern blot analysis of restriction endonuclease digested DNA showed that (1) some fragments were preferentially amplified compared to others in the ADRM-resistant; and (2) no major gene rearrangement appeared to have occurred during the selection for greater ADRM resistance. (author).

  20. Synchrotron microbeam radiation therapy for rat brain tumor palliation-influence of the microbeam width at constant valley dose

    Energy Technology Data Exchange (ETDEWEB)

    Serduc, Raphael; Fonta, Caroline; Renaud, Luc [Universite de Toulouse, UPS, Centre de Recherche Cerveau et Cognition (France); Bouchet, Audrey; Braeuer-Krisch, Elke; Sarun, Sukhena; Bravin, Alberto; Le Duc, Geraldine [European Synchrotron Radiation Facility, F38043 Grenoble (France); Laissue, Jean A [Institute of Pathology, University of Bern (Switzerland); Spiga, Jenny [Department of Physics, University of Cagliari, s.p. Monserrato-Sestu, Monserrato (Canada) 09042 (Italy); Boutonnat, Jean [TIMC lab, UMR CNRS 5525, Univ Joseph Fourier, CHU, Grenoble (France); Siegbahn, Erik Albert [Department of Medical Physics, Karolinska Universitetssjukhuset, 17176 Stockholm (Sweden); Esteve, Francois [INSERM U836, Equipe 6, Institut des Neurosciences de Grenoble, 38043 Grenoble Cedex (France)], E-mail: raph.serduc@gmail.com

    2009-11-07

    To analyze the effects of the microbeam width (25, 50 and 75 {mu}m) on the survival of 9L gliosarcoma tumor-bearing rats and on toxicity in normal tissues in normal rats after microbeam radiation therapy (MRT), 9L gliosarcomas implanted in rat brains, as well as in normal rat brains, were irradiated in the MRT mode. Three configurations (MRT25, MRT50, MRT75), each using two orthogonally intersecting arrays of either 25, 50 or 75 {mu}m wide microbeams, all spaced 211 {mu}m on center, were tested. For each configuration, peak entrance doses of 860, 480 and 320 Gy, respectively, were calculated to produce an identical valley dose of 18 Gy per individual array at the center of the tumor. Two, 7 and 14 days after radiation treatment, 42 rats were killed to evaluate histopathologically the extent of tumor necrosis, and the presence of proliferating tumors cells and tumor vessels. The median survival times of the normal rats were 4.5, 68 and 48 days for MRT25, 50 and 75, respectively. The combination of the highest entrance doses (860 Gy per array) with 25 {mu}m wide beams (MRT25) resulted in a cumulative valley dose of 36 Gy and was excessively toxic, as it led to early death of all normal rats and of {approx}50% of tumor-bearing rats. The short survival times, particularly of rats in the MRT25 group, restricted adequate observance of the therapeutic effect of the method on tumor-bearing rats. However, microbeams of 50 {mu}m width led to the best median survival time after 9L gliosarcoma MRT treatment and appeared as the better compromise between tumor control and normal brain toxicity compared with 75 {mu}m or 25 {mu}m widths when used with a 211 {mu}m on-center distance. Despite very high radiation doses, the tumors were not sterilized; viable proliferating tumor cells remained present at the tumor margin. This study shows that microbeam width and peak entrance doses strongly influence tumor responses and normal brain toxicity, even if valley doses are kept constant in

  1. The tumor suppressive role of CAMK2N1 in castration-resistant prostate cancer

    OpenAIRE

    Wang, Tao; Liu, Zhuo; Guo, ShuiMing; Wu, Licheng; Li, Mingchao; Yang, Jun; Chen, Ruibao; Xu, Hua; Cai, Shaoxin; CHEN, Hui; LI, WEIYONG; Wang, Liang; Hu, Zhiquan; Zhuang, Qianyuan; Xu, Shaohua

    2014-01-01

    Prostate cancer at advanced stages including metastatic and castration-resistant cancer remains incurable due to the lack of effective therapies. The CAMK2N1 gene, cloned and characterized as an inhibitor of CaMKII (calcium/calmodulin-dependent protein kinase II), has been shown to affect tumorigenesis and tumor growth. However, it is still unknown whether CAMK2N1 plays a role in prostate cancer development. We first examined the protein and mRNA levels of CAMK2N1 and observed a significant d...

  2. Adipose Expression of Tumor Necrosis Factor-α: Direct Role in Obesity-Linked Insulin Resistance

    Science.gov (United States)

    Hotamisligil, Gokhan S.; Shargill, Narinder S.; Spiegelman, Bruce M.

    1993-01-01

    Tumor necrosis factor-α (TNF-α) has been shown to have certain catabolic effects on fat cells and whole animals. An induction of TNF-α messenger RNA expression was observed in adipose tissue from four different rodent models of obesity and diabetes. TNF-α protein was also elevated locally and systemically. Neutralization of TNF-α in obese fa/fa rats caused a significant increase in the peripheral uptake of glucose in response to insulin. These results indicate a role for TNF-α in obesity and particularly in the insulin resistance and diabetes that often accompany obesity.

  3. The role of cancer-associated fibroblasts, solid stress and other microenvironmental factors in tumor progression and therapy resistance.

    Science.gov (United States)

    Kharaishvili, Gvantsa; Simkova, Dana; Bouchalova, Katerina; Gachechiladze, Mariam; Narsia, Nato; Bouchal, Jan

    2014-01-01

    Tumors are not merely masses of neoplastic cells but complex tissues composed of cellular and noncellular elements. This review provides recent data on the main components of a dynamic system, such as carcinoma associated fibroblasts that change the extracellular matrix (ECM) topology, induce stemness and promote metastasis-initiating cells. Altered production and characteristics of collagen, hyaluronan and other ECM proteins induce increased matrix stiffness. Stiffness along with tumor growth-induced solid stress and increased interstitial fluid pressure contribute to tumor progression and therapy resistance. Second, the role of immune cells, cytokines and chemokines is outlined. We discuss other noncellular characteristics of the tumor microenvironment such as hypoxia and extracellular pH in relation to neoangiogenesis. Overall, full understanding of the events driving the interactions between tumor cells and their environment is of crucial importance in overcoming treatment resistance and improving patient outcome.

  4. CD47 in the tumor microenvironment limits cooperation between anti-tumor T cell immunity and radiation therapy

    Science.gov (United States)

    Soto-Pantoja, David R.; Terabe, Masaki; Ghosh, Arunima; Ridnour, Lisa A.; DeGraff, William G.; Wink, David A.; Berzofsky, Jay A.; Roberts, David D.

    2014-01-01

    While significant advances in radiotherapy have increased its effectiveness in many cancer settings, general strategies to widen the therapeutic window between normal tissue toxicity and malignant tumor destruction would still offer great value. CD47 blockade has been found to confer radioprotection to normal tissues while enhancing tumor radiosensitivity. Here we report that CD47 blockade directly enhances tumor immunosurveillance by CD8+ T cells. Combining CD47 blockade with irradiation did not affect fibrosarcoma growth in T cell-deficient mice, whereas adoptive transfer of tumor-specific CD8+ T cells restored combinatorial efficacy. Further, ablation of CD8+ T cells abolished radiotherapeutic response in immunocompetent syngeneic hosts. CD47 blockade in either target cells or effector cells was sufficient to enhance antigen-dependent CD8+ CTL-mediated tumor cell killing in vitro. In CD47-deficient syngeneic hosts, engrafted B16 melanomas were 50% more sensitive to irradiation, establishing that CD47 expression in the microenvironment was sufficient to limit tumor radiosensitivity. Mechanistic investigations revealed increased tumor infiltration by cytotoxic CD8+ T cells in a CD47-deficient microenvironment, with an associated increase in T cell-dependent intratumoral expression of granzyme B. Correspondingly, an inverse correlation between CD8+ T cell infiltration and CD47 expression was observed in human melanomas. Our findings establish that blocking CD47 in the context of radiotherapy enhances antitumor immunity by directly stimulating CD8+ cytotoxic T cells, with the potential to increase curative responses. PMID:25297630

  5. Clinical Implementation of Intrafraction Cone Beam Computed Tomography Imaging During Lung Tumor Stereotactic Ablative Radiation Therapy

    Science.gov (United States)

    Li, Ruijiang; Han, Bin; Meng, Bowen; Maxim, Peter G.; Xing, Lei; Koong, Albert C.; Diehn, Maximilian; Loo, Billy W.

    2013-01-01

    Purpose To develop and clinically evaluate a volumetric imaging technique for assessing intrafraction geometric and dosimetric accuracy of stereotactic ablative radiation therapy (SABR). Methods and Materials Twenty patients received SABR for lung tumors using volumetric modulated arc therapy (VMAT). At the beginning of each fraction, pretreatment cone beam computed tomography (CBCT) was used to align the soft-tissue tumor position with that in the planning CT. Concurrent with dose delivery, we acquired fluoroscopic radiograph projections during VMAT using the Varian on-board imaging system. Those kilovolt projections acquired during megavolt beam-on were automatically extracted, and intrafraction CBCT images were reconstructed using the filtered backprojection technique. We determined the time-averaged target shift during VMAT by calculating the center of mass of the tumor target in the intrafraction CBCT relative to the planning CT. To estimate the dosimetric impact of the target shift during treatment, we recalculated the dose to the GTV after shifting the entire patient anatomy according to the time-averaged target shift determined earlier. Results The mean target shift from intrafraction CBCT to planning CT was 1.6, 1.0, and 1.5 mm; the 95th percentile shift was 5.2, 3.1, 3.6 mm; and the maximum shift was 5.7, 3.6, and 4.9 mm along the anterior-posterior, left-right, and superior-inferior directions. Thus, the time-averaged intrafraction gross tumor volume (GTV) position was always within the planning target volume. We observed some degree of target blurring in the intrafraction CBCT, indicating imperfect breath-hold reproducibility or residual motion of the GTV during treatment. By our estimated dose recalculation, the GTV was consistently covered by the prescription dose (PD), that is, V100% above 0.97 for all patients, and minimum dose to GTV >100% PD for 18 patients and >95% PD for all patients. Conclusions Intrafraction CBCT during VMAT can provide

  6. Noninvasive referencing of intraocular tumors for external beam radiation therapy using optical coherence tomography: A proof of concept

    Energy Technology Data Exchange (ETDEWEB)

    Rüegsegger, Michael B.; Steiner, Patrick; Kowal, Jens H., E-mail: jens.kowal@artorg.unibe.ch [ARTORG Center for Biomedical Engineering Research, University of Bern, Bern 3010 (Switzerland); Geiser, Dominik [Berne University of Applied Sciences, HuCE OptoLab, 2501 (Switzerland); Pica, Alessia; Aebersold, Daniel M. [Department of Radiation Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3010 (Switzerland)

    2014-08-15

    Purpose: External beam radiation therapy is currently considered the most common treatment modality for intraocular tumors. Localization of the tumor and efficient compensation of tumor misalignment with respect to the radiation beam are crucial. According to the state of the art procedure, localization of the target volume is indirectly performed by the invasive surgical implantation of radiopaque clips or is limited to positioning the head using stereoscopic radiographies. This work represents a proof-of-concept for direct and noninvasive tumor referencing based on anterior eye topography acquired using optical coherence tomography (OCT). Methods: A prototype of a head-mounted device has been developed for automatic monitoring of tumor position and orientation in the isocentric reference frame for LINAC based treatment of intraocular tumors. Noninvasive tumor referencing is performed with six degrees of freedom based on anterior eye topography acquired using OCT and registration of a statistical eye model. The proposed prototype was tested based on enucleated pig eyes and registration accuracy was measured by comparison of the resulting transformation with tilt and torsion angles manually induced using a custom-made test bench. Results: Validation based on 12 enucleated pig eyes revealed an overall average registration error of 0.26 ± 0.08° in 87 ± 0.7 ms for tilting and 0.52 ± 0.03° in 94 ± 1.4 ms for torsion. Furthermore, dependency of sampling density on mean registration error was quantitatively assessed. Conclusions: The tumor referencing method presented in combination with the statistical eye model introduced in the past has the potential to enable noninvasive treatment and may improve quality, efficacy, and flexibility of external beam radiotherapy of intraocular tumors.

  7. Radiation sensitivity of Salmonella isolates relative to resistance to ampicillin, chloramphenicol or gentamicin

    Science.gov (United States)

    Niemira, Brendan A.; Lonczynski, Kelly A.; Sommers, Christopher H.

    2006-09-01

    Antibiotic resistance of inoculated bacteria is a commonly used selective marker. Bacteria resistant to the antibiotic nalidixic acid have been shown to have an increased sensitivity to irradiation. The purpose of this research was to screen a collection of Salmonella isolates for antibiotic resistance and determine the association, if any, of antibiotic resistance with radiation sensitivity. Twenty-four clinical isolates of Salmonella were screened for native resistance to multiple concentrations of ampicillin (Amp), chloramphenicol (Chl), or gentamicin (Gm). Test concentrations were chosen based on established clinical minimum inhibitory concentration (MIC) levels, and isolates were classified as either sensitive or resistant based on their ability to grow at or above the MIC. Salmonella cultures were grown overnight at (37 °C) in antibiotic-amended tryptic soy broth (TSB). Native resistance to Gm was observed with each of the 24 isolates (100%). Eight isolates (33%) were shown to be resistant to Amp, while seven isolates (29%) were shown to be resistant to Chl. In separate experiments, Salmonella cultures were grown overnight (37 °C) in TSB, centrifuged, and the cell pellets were re-suspended in phosphate buffer. The samples were then gamma irradiated at doses up to 1.0 kGy. The D10 values (the ionizing radiation dose required to reduce the viable number of microorganisms by 90%) were determined for the 24 isolates and they ranged from 0.181 to 0.359 kGy. No correlation was found between the D10 value of the isolate and its sensitivity or resistance to each of the three antibiotics. Resistance to Amp or Chl is suggested as appropriate resistance marker for Salmonella test strains to be used in studies of irradiation.

  8. Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine.

    Science.gov (United States)

    Geller, Leore T; Barzily-Rokni, Michal; Danino, Tal; Jonas, Oliver H; Shental, Noam; Nejman, Deborah; Gavert, Nancy; Zwang, Yaara; Cooper, Zachary A; Shee, Kevin; Thaiss, Christoph A; Reuben, Alexandre; Livny, Jonathan; Avraham, Roi; Frederick, Dennie T; Ligorio, Matteo; Chatman, Kelly; Johnston, Stephen E; Mosher, Carrie M; Brandis, Alexander; Fuks, Garold; Gurbatri, Candice; Gopalakrishnan, Vancheswaran; Kim, Michael; Hurd, Mark W; Katz, Matthew; Fleming, Jason; Maitra, Anirban; Smith, David A; Skalak, Matt; Bu, Jeffrey; Michaud, Monia; Trauger, Sunia A; Barshack, Iris; Golan, Talia; Sandbank, Judith; Flaherty, Keith T; Mandinova, Anna; Garrett, Wendy S; Thayer, Sarah P; Ferrone, Cristina R; Huttenhower, Curtis; Bhatia, Sangeeta N; Gevers, Dirk; Wargo, Jennifer A; Golub, Todd R; Straussman, Ravid

    2017-09-15

    Growing evidence suggests that microbes can influence the efficacy of cancer therapies. By studying colon cancer models, we found that bacteria can metabolize the chemotherapeutic drug gemcitabine (2',2'-difluorodeoxycytidine) into its inactive form, 2',2'-difluorodeoxyuridine. Metabolism was dependent on the expression of a long isoform of the bacterial enzyme cytidine deaminase (CDDL), seen primarily in Gammaproteobacteria. In a colon cancer mouse model, gemcitabine resistance was induced by intratumor Gammaproteobacteria, dependent on bacterial CDDL expression, and abrogated by cotreatment with the antibiotic ciprofloxacin. Gemcitabine is commonly used to treat pancreatic ductal adenocarcinoma (PDAC), and we hypothesized that intratumor bacteria might contribute to drug resistance of these tumors. Consistent with this possibility, we found that of the 113 human PDACs that were tested, 86 (76%) were positive for bacteria, mainly Gammaproteobacteria. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

  9. Enhancement by N-methylformamide of the effect of ionizing radiation on a human colon tumor xenografted in nude mice

    Energy Technology Data Exchange (ETDEWEB)

    Dexter, D.L.; Lee, E.S.; Bliven, S.F.; Glicksman, A.S.; Leith, J.T.

    1984-11-01

    Polar solvents, which induce differentiation in murine and human tumor cells, enhance the effect of ionizing radiation on cultured mouse mammary and human colon cancer cells. To determine whether this enhancement occurs in vivo, DLD-2 human colon carcinoma xenografts in nude mice were treated with combinations of 6 MV photon irradiation, the polar solvent N-methylformamide (NMF), or combinations of the two agents. Nude mice bearing 300-mg s.c. implants of DLD-2 tumors were treated i.p. with 150 mg NMF/kg daily for 19 days. Local tumor irradiations were administered as graded single doses or as fractionated doses, daily for 4 days, following the third NMF injection. The growth-inhibiting effect of the radiation treatment for both single dose and fractionation protocols was enhanced by the polar solvent. NMF alone increased the time required for a doubling of initial tumor volume by 1.7 days, compared to control tumors. Initial tumor volume doubling times compared to untreated controls were increased by 3.6 and 7.6 days by photon doses of 10.0 and 13.75 Gy, respectively, whereas NMF plus 10.0 or 13.75 Gy increased the DLD-2 regrowth delay time by 7.5 or 12.9 days. NMF caused essentially equivalent enhancements, whether split-dose schedules of 2.5 Gy daily for 4 days, and 3.44 Gy daily for 4 days, or single doses of 10.0 and 13.75 Gy were used; therefore, radiation enhancement was not due to effects on sublethal damage repair. The results support the use of NMF, currently in Phase 1-Phase 2 clinical trials, with radiation in the therapy of selected human neoplasms.

  10. Pirfenidone enhances the efficacy of combined radiation and sunitinib therapy

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Seo-Hyun; Nam, Jae-Kyung; Jang, Junho; Lee, Hae-June, E-mail: hjlee@kcch.re.kr; Lee, Yoon-Jin, E-mail: yjlee8@kcch.re.kr

    2015-06-26

    Radiotherapy is a widely used treatment for many tumors. Combination therapy using anti-angiogenic agents and radiation has shown promise; however, these combined therapies are reported to have many limitations in clinical trials. Here, we show that radiation transformed tumor endothelial cells (ECs) to fibroblasts, resulting in reduced vascular endothelial growth factor (VEGF) response and increased Snail1, Twist1, Type I collagen, and transforming growth factor (TGF)-β release. Irradiation of radioresistant Lewis lung carcinoma (LLC) tumors greater than 250 mm{sup 3} increased collagen levels, particularly in large tumor vessels. Furthermore, concomitant sunitinib therapy did not show a significant difference in tumor inhibition versus radiation alone. Thus, we evaluated multimodal therapy that combined pirfenidone, an inhibitor of TGF-induced collagen production, with radiation and sunitinib treatment. This trimodal therapy significantly reduced tumor growth, as compared to radiation alone. Immunohistochemical analysis revealed that radiation-induced collagen deposition and tumor microvessel density were significantly reduced with trimodal therapy, as compared to radiation alone. These data suggest that combined therapy using pirfenidone may modulate the radiation-altered tumor microenvironment, thereby enhancing the efficacy of radiation therapy and concurrent chemotherapy. - Highlights: • Radiation changes tumor endothelial cells to fibroblasts. • Radio-resistant tumors contain collagen deposits, especially in tumor vessels. • Pirfenidone enhances the efficacy of combined radiation and sunitinib therapy. • Pirfenidone reduces radiation-induced collagen deposits in tumors.

  11. Differentiating Radiation-Induced Necrosis from Recurrent Brain Tumor Using MR Perfusion and Spectroscopy: A Meta-Analysis.

    Science.gov (United States)

    Chuang, Ming-Tsung; Liu, Yi-Sheng; Tsai, Yi-Shan; Chen, Ying-Chen; Wang, Chien-Kuo

    2016-01-01

    This meta-analysis examined roles of several metabolites in differentiating recurrent tumor from necrosis in patients with brain tumors using MR perfusion and spectroscopy. Medline, Cochrane, EMBASE, and Google Scholar were searched for studies using perfusion MRI and/or MR spectroscopy published up to March 4, 2015 which differentiated between recurrent tumor vs. necrosis in patients with primary brain tumors or brain metastasis. Only two-armed, prospective or retrospective studies were included. A meta-analysis was performed on the difference in relative cerebral blood volume (rCBV), ratios of choline/creatine (Cho/Cr) and/or choline/N-acetyl aspartate (Cho/NAA) between participants undergoing MRI evaluation. A χ2-based test of homogeneity was performed using Cochran's Q statistic and I2. Of 397 patients in 13 studies who were analyzed, the majority had tumor recurrence. As there was evidence of heterogeneity among 10 of the studies which used rCBV for evaluation (Q statistic = 31.634, I2 = 97.11%, P tumor recurrence compared with radiation injury (P = 0.001). Based on a fixed-effect model of analysis encompassing the six studies which used Cho/Cr ratios for evaluation (Q statistic = 8.388, I2 = 40.39%, P = 0.137), the pooled difference in means (0.77, 95%CI = 0.57 to 0.98) of the average Cho/Cr ratio was significantly higher in tumor recurrence than in tumor necrosis (P = 0.001). There was significant difference in ratios of Cho to NAA between recurrent tumor and necrosis (1.02, 95%CI = 0.03 to 2.00, P = 0.044). MR spectroscopy and MR perfusion using Cho/NAA and Cho/Cr ratios and rCBV may increase the accuracy of differentiating necrosis from recurrent tumor in patients with primary brain tumors or metastases.

  12. Sigma-2 receptor agonists as possible antitumor agents in resistant tumors: hints for collateral sensitivity.

    Science.gov (United States)

    Niso, Mauro; Abate, Carmen; Contino, Marialessandra; Ferorelli, Savina; Azzariti, Amalia; Perrone, Roberto; Colabufo, Nicola Antonio; Berardi, Francesco

    2013-12-01

    With the aim of contributing to the development of novel antitumor agents, high-affinity σ2 receptor agonists were developed, with 6,7-dimethoxy-2-[4-[1-(4-fluorophenyl)-1H-indol-3-yl]butyl]-1,2,3,4-tetrahydroisoquinoline (15) and 9-[4-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)butyl]-9H-carbazole (25) showing exceptional selectivity for the σ2 subtype. Most of the compounds displayed notable antiproliferative activity in human MCF7 breast adenocarcinoma cells, with similar activity in the corresponding doxorubicin-resistant MCF7adr cell line. Surprisingly, a few compounds, including 25, displayed enhanced activity in MCF7adr cells over parent cells, recalling the phenomenon of collateral sensitivity, which is under study for the treatment of drug-resistant tumors. All of the compounds showed interaction with P-glycoprotein (P-gp), and 15 and 25, with the greatest activity, were able to revert P-gp-mediated resistance and reestablish the antitumor effect of doxorubicin in MCF7adr cells. We therefore identified a series of σ2 receptor agonists endowed with intriguing antitumor properties; these compounds deserve further investigation for the development of alternate strategies against multidrug- resistant cancers. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  13. Diet-induced obesity and insulin resistance spur tumor growth and cancer cachexia in rats bearing the Yoshida sarcoma.

    Science.gov (United States)

    Honors, Mary Ann; Kinzig, Kimberly P

    2014-01-01

    Obesity and insulin resistance are associated with increased risk of cancer and cancer mortality. However, it is currently unknown whether they contribute to the development of cancer cachexia, a syndrome that contributes significantly to morbidity and mortality in individuals with cancer. The present experiment addresses the question of whether preexisting obesity and insulin resistance alter tumor growth and cancer cachexia symptoms in Yoshida sarcoma bearing male rats. Obesity and insulin resistance were induced through 5 weeks of high-fat (HF) diet feeding and insulin resistance was confirmed by intraperitoneal glucose tolerance testing. Chow-fed animals were used as a control group. Following the establishment of insulin resistance, HF- and chow-fed animals were implanted with fragments of the Yoshida sarcoma or received a sham surgery. Tumor growth rate was greater in HF-fed animals, resulting in larger tumors. In addition, cancer cachexia symptoms developed in HF-fed animals but not chow-fed animals during the 18-day experiment. These results support a stimulatory effect of obesity and insulin resistance on tumor growth and cancer cachexia development in Yoshida sarcoma-bearing rats. Future research should investigate the relationship between obesity, insulin resistance, and cancer cachexia in human subjects.

  14. The effect of ultraviolet radiation on water-logging resistance in ...

    African Journals Online (AJOL)

    The effect of ultraviolet (UV) radiation on the water-logging resistance of Tibetan peach (Amygdalus mira Koehne) remains unclear. In this study, Tibetan peach seedlings were subjected to 9-days of UV-B (280 - 320 nm) supplementation, water-logging or the combination of both, and the growth indicated by leaf number, net ...

  15. Identifying the Proteins that Mediate the Ionizing Radiation Resistance of Deinococcus Radiodurans R1

    Energy Technology Data Exchange (ETDEWEB)

    Battista, John R

    2010-02-22

    The primary objectives of this proposal was to define the subset of proteins required for the ionizing radiation (IR) resistance of Deinococcus radiodurans R1, characterize the activities of those proteins, and apply what was learned to problems of interest to the Department of Energy.

  16. Neuroplastic Response After Radiation Therapy for Pediatric Brain Tumors: A Pilot Study

    Energy Technology Data Exchange (ETDEWEB)

    Armstrong, Carol L., E-mail: armstrongc@email.chop.edu [Neuro-Oncology Section, Children' s Hospital of Philadelphia, and Department of Pediatrics, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania (United States); Fisher, Michael J. [Neuro-Oncology Section, Children' s Hospital of Philadelphia, and Department of Pediatrics, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania (United States); Li, Yimei [Oncology Division, Children' s Hospital of Philadelphia, and Department of Biostatistics and Epidemiology, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania (United States); Lustig, Robert A. [Department of Radiation Oncology, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania (United States); Belasco, Jean B.; Minturn, Jane E. [Neuro-Oncology Section, Children' s Hospital of Philadelphia, and Department of Pediatrics, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania (United States); Hill-Kayser, Christine E.; Batra, Sonny [Department of Radiation Oncology, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania (United States); Phillips, Peter C. [Neuro-Oncology Section, Children' s Hospital of Philadelphia, and Department of Pediatrics, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania (United States)

    2016-07-01

    Purpose: Clinically effective measurement of cognitive toxicity from photon radiation therapy (XRT) should be accurate, sensitive, and specific. This pilot study tested translational findings on phasic changes in children's memory systems that are sensitive and insensitive to toxic XRT effects to identify a possible neuroplastic effect. Methods and Materials: Memory processes were prospectively tested before XRT and at 3 later time points up to 2 years in 35 children with mixed primary brain tumors who had not experienced recurrence. Memory processes were verbal-semantic, visual-semantic, and visual-perceptual, including accuracy, speed to recall, encoding, retrieval, and recognition. The mixed-effects model included time (to estimate slope), covariates (age, tumor locus, XRT field, and medications) as fixed effects, and individual random intercepts. A sensitivity analysis examined the influence of XRT dose to the hippocampi on memory. Results: Retrieval from long-term verbal-semantic memory declined 2 months after completing XRT, as seen in adults, and was lowest at 1 year, which was delayed in comparison with adults. Double dissociation from visual-perceptual memory at baseline and 2 months was found, consistent with adults. Recovery was demonstrated 2 years after XRT. Patterns were unchanged when dose to hippocampus was included in the model. Conclusions: Verbal and semantic long-term retrieval is specifically sensitive to XRT-related cognitive dysfunction, without effect on visual-perceptual memory. Children reached nadir in XRT-sensitive memory 1 year after XRT and recovered by 2 years, which is later than that observed in adults. The protracted period of post-XRT injury may represent the maturation of the human hippocampus and white matter into late adolescence.

  17. Neuroplastic Response After Radiation Therapy for Pediatric Brain Tumors: A Pilot Study.

    Science.gov (United States)

    Armstrong, Carol L; Fisher, Michael J; Li, Yimei; Lustig, Robert A; Belasco, Jean B; Minturn, Jane E; Hill-Kayser, Christine E; Batra, Sonny; Phillips, Peter C

    2016-07-01

    Clinically effective measurement of cognitive toxicity from photon radiation therapy (XRT) should be accurate, sensitive, and specific. This pilot study tested translational findings on phasic changes in children's memory systems that are sensitive and insensitive to toxic XRT effects to identify a possible neuroplastic effect. Memory processes were prospectively tested before XRT and at 3 later time points up to 2 years in 35 children with mixed primary brain tumors who had not experienced recurrence. Memory processes were verbal-semantic, visual-semantic, and visual-perceptual, including accuracy, speed to recall, encoding, retrieval, and recognition. The mixed-effects model included time (to estimate slope), covariates (age, tumor locus, XRT field, and medications) as fixed effects, and individual random intercepts. A sensitivity analysis examined the influence of XRT dose to the hippocampi on memory. Retrieval from long-term verbal-semantic memory declined 2 months after completing XRT, as seen in adults, and was lowest at 1 year, which was delayed in comparison with adults. Double dissociation from visual-perceptual memory at baseline and 2 months was found, consistent with adults. Recovery was demonstrated 2 years after XRT. Patterns were unchanged when dose to hippocampus was included in the model. Verbal and semantic long-term retrieval is specifically sensitive to XRT-related cognitive dysfunction, without effect on visual-perceptual memory. Children reached nadir in XRT-sensitive memory 1 year after XRT and recovered by 2 years, which is later than that observed in adults. The protracted period of post-XRT injury may represent the maturation of the human hippocampus and white matter into late adolescence. Copyright © 2016 Elsevier Inc. All rights reserved.

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

    Science.gov (United States)

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

    2013-04-01

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

  19. Improved Tumor-Specific Drug Accumulation by Polymer Therapeutics with pH-Sensitive Drug Release Overcomes Chemotherapy Resistance.

    Science.gov (United States)

    Heinrich, Anne-Kathrin; Lucas, Henrike; Schindler, Lucie; Chytil, Petr; Etrych, Tomáš; Mäder, Karsten; Mueller, Thomas

    2016-05-01

    The success of chemotherapy is limited by poor selectivity of active drugs combined with occurrence of tumor resistance. New star-like structured N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-based drug delivery systems containing doxorubicin attached via a pH-sensitive hydrazone bond were designed and investigated for their ability to overcome chemotherapy resistance. These conjugates combine two strategies to achieve a high drug concentration selectively at the tumor site: (I) high accumulation by passive tumor targeting based on enhanced permeability and retention effect and (II) pH-sensitive site-specific drug release due to an acidic tumor microenvironment. Mice bearing doxorubicin-resistant xenograft tumors were treated with doxorubicin, PBS, poly HPMA (pHPMA) precursor or pHPMA-doxorubicin conjugate at different equivalent doses of 5 mg/kg bodyweight doxorubicin up to a 7-fold total dose using different treatment schedules. Intratumoral drug accumulation was analyzed by fluorescence imaging utilizing intrinsic fluorescence of doxorubicin. Free doxorubicin induced significant toxicity but hardly any tumor-inhibiting effects. Administering at least a 3-fold dose of pHPMA-doxorubicin conjugate was necessary to induce a transient response, whereas doses of about 5- to 6-fold induced strong regressions. Tumors completely disappeared in some cases. The onset of response was differential delayed depending on the tumor model, which could be ascribed to distinct characteristics of the microenvironment. Further fluorescence imaging-based analyses regarding underlying mechanisms of the delayed response revealed a related switch to a more supporting intratumoral microenvironment for effective drug release. In conclusion, the current study demonstrates that the concept of tumor site-restricted high-dose chemotherapy is able to overcome therapy resistance. Mol Cancer Ther; 15(5); 998-1007. ©2016 AACR. ©2016 American Association for Cancer Research.

  20. ETS Gene Fusions as Predictive Biomarkers of Resistance to Radiation Therapy for Prostate Cancer

    Science.gov (United States)

    2016-05-01

    Award  Number:    W81XWH-10-1-0582 TITLE:      ETS Gene Fusions as Predictive Biomarkers of Resistance to Radiation Therapy for Prostate Cancer...5a.  CONTRACT  NUMBER   ETS Gene Fusions as Predictive Biomarkers of Resistance to Radiation Therapy for Prostate Cancer 5b.  GRANT  NUMBER   W81XWH...ramifications,  particularly  in  the  context  of   radiation   therapy ,   which  represents  a  primary  treatment  modality  for  localized  prostate

  1. The efficiency of adjusted-da-chai-ling-tang in radiation-induced brain edema in patients with brain tumors

    Directory of Open Access Journals (Sweden)

    Da-Tong Ju

    2015-01-01

    Full Text Available Background: Brain edema induced by radiotherapy is a common complication in patients with brain tumors, for which medical treatment is the treatment of choice. Adjusted-Da-Chai-Ling-Tang, a Chinese herbal formulation, has been confirmed to be protective against the radiation-induced edema. In this study, we investigated the efficiency of adjusted-Da-Chai-Ling-Tang in radiation-induced brain edema in patients with brain tumors. Materials and Methods: A total of 46 patients with brain tumors treated with radiotherapy alone or combined with surgery were enrolled. These patients were divided into two groups: The experimental group with adjusted-Da-Chai-Ling-Tang and the control group with conventional medical treatment. Clinical data including symptoms and serologic results were collected pretreatment and on the 4 th , 7 th and 10 th day posttreatment. Magnetic resonance imaging of the brain was performed to investigate changes in brain edema. Results: Clinical symptoms including headache, dizziness, nausea/vomiting and fatigue significantly improved in the experimental group (P < 0.05. No difference in serological results was observed. Brain edema was significantly reduced in the experimental group in magnetic resonance imaging (P < 0.05. Conclusion: Adjusted-Da-Chai-Ling-Tang is effective in the treatment of radiation-induced brain edema in patients with brain tumors. No obvious side effects were observed.

  2. Stereotactic Radiation Therapy Augments Antigen-Specific PD-1-Mediated Antitumor Immune Responses via Cross-Presentation of Tumor Antigen.

    Science.gov (United States)

    Sharabi, Andrew B; Nirschl, Christopher J; Kochel, Christina M; Nirschl, Thomas R; Francica, Brian J; Velarde, Esteban; Deweese, Theodore L; Drake, Charles G

    2015-04-01

    The immune-modulating effects of radiotherapy (XRT) have gained considerable interest recently, and there have been multiple reports of synergy between XRT and immunotherapy. However, additional preclinical studies are needed to demonstrate the antigen-specific nature of radiation-induced immune responses and elucidate potential mechanisms of synergy with immunotherapy. Here, we demonstrate the ability of stereotactic XRT to induce endogenous antigen-specific immune responses when it is combined with anti-PD-1 checkpoint blockade immunotherapy. Using the small animal radiation research platform (SARRP), image-guided stereotactic XRT delivered to B16-OVA melanoma or 4T1-HA breast carcinoma tumors resulted in the development of antigen-specific T cell- and B cell-mediated immune responses. These immune-stimulating effects of XRT were significantly increased when XRT was combined with either anti-PD-1 therapy or regulatory T cell (Treg) depletion, resulting in improved local tumor control. Phenotypic analyses of antigen-specific CD8 T cells revealed that XRT increased the percentage of antigen-experienced T cells and effector memory T cells. Mechanistically, we found that XRT upregulates tumor-associated antigen-MHC complexes, enhances antigen cross-presentation in the draining lymph node, and increases T-cell infiltration into tumors. These findings demonstrate the ability of XRT to prime an endogenous antigen-specific immune response and provide an additional mechanistic rationale for combining radiation with PD-1 blockade in the clinic. ©2014 American Association for Cancer Research.

  3. Radiation-resistant acquired immunity of vaccinated mice to Schistosoma mansoni

    Energy Technology Data Exchange (ETDEWEB)

    Aitken, R.; Coulson, P.S.; Dixon, B.; Wilson, R.A.

    1987-11-01

    Vaccination of mice with attenuated cercariae of Schistosoma mansoni induces specific acquired resistance to challenge infection. This resistance is immunologically-mediated, possibly via a delayed-type hypersensitivity. Studies of parasite migration have shown that the protective mechanism operates most effectively in the lungs of vaccinated mice. We have probed the mechanism by exposing mice to 500 rads of gamma radiation before challenge infection. Our results show that the effector mechanism operative against challenge larvae is resistant to radiation. In contrast, classical immune responses are markedly suppressed by the same treatment. While leukocyte populations in the blood fall dramatically after irradiation, numbers of cells recoverable by bronchoalveolar lavage are unaffected. We suggest that vaccination with attenuated cercariae establishes populations of sensitized cells in the lungs which trigger the mechanism of resistance when challenge schistosomula migrate through pulmonary capillary beds. Although the cells may be partially disabled by irradiation, they remain responsive to worm antigens and thereby capable of initiating the elimination mechanism. This hypothesis would explain the radiation resistance of vaccine-induced immunity to S. mansoni.

  4. Radiation therapy combined with intracerebral administration of carboplatin for the treatment of brain tumors

    Science.gov (United States)

    2014-01-01

    Background In this study we determined if treatment combining radiation therapy (RT) with intracerebral (i.c.) administration of carboplatin to F98 glioma bearing rats could improve survival over that previously reported by us with a 15 Gy dose (5 Gy × 3) of 6 MV photons. Methods First, in order to reduce tumor interstitial pressure, a biodistribution study was carried out to determine if pretreatment with dexamethasone alone or in combination with mannitol and furosemide (DMF) would increase carboplatin uptake following convection enhanced delivery (CED). Next, therapy studies were carried out in rats that had received carboplatin either by CED over 30 min (20 μg) or by Alzet pumps over 7 d (84 μg), followed by RT using a LINAC to deliver either 20 Gy (5 Gy × 4) or 15 Gy (7.5 Gy × 2) dose at 6 or 24 hrs after drug administration. Finally, a study was carried out to determine if efficacy could be improved by decreasing the time interval between drug administration and RT. Results Tumor carboplatin values for D and DMF-treated rats were 9.4 ±4.4 and 12.4 ±3.2 μg/g, respectively, which were not significantly different (P = 0.14). The best survival data were obtained by combining pump delivery with 5 Gy × 4 of X-irradiation with a mean survival time (MST) of 107.7 d and a 43% cure rate vs. 83.6 d with CED vs. 30-35 d for RT alone and 24.6 d for untreated controls. Treatment-related mortality was observed when RT was initiated 6 h after CED of carboplatin and RT was started 7 d after tumor implantation. Dividing carboplatin into two 10 μg doses and RT into two 7.5 Gy fractions, administered 24 hrs later, yielded survival data (MST 82.1 d with a 25% cure rate) equivalent to that previously reported with 5 Gy × 3 and 20 μg of carboplatin. Conclusions Although the best survival data were obtained by pump delivery, CED was highly effective in combination with 20 Gy, or as previously reported, 15 Gy, and the latter would be preferable since it would produce less

  5. Lung Volume Reduction After Stereotactic Ablative Radiation Therapy of Lung Tumors: Potential Application to Emphysema

    Energy Technology Data Exchange (ETDEWEB)

    Binkley, Michael S. [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California (United States); Shrager, Joseph B. [Division of Thoracic Surgery, Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, California (United States); Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California (United States); Leung, Ann N. [Department of Radiology, Stanford University School of Medicine, Stanford, California (United States); Popat, Rita [Department of Health Research and Policy, Stanford University School of Medicine, Stanford, California (United States); Trakul, Nicholas [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California (United States); Department of Radiation Oncology, University of Southern California Keck School of Medicine, Los Angeles, California (United States); Atwood, Todd F.; Chaudhuri, Aadel [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California (United States); Maxim, Peter G. [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California (United States); Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California (United States); Diehn, Maximilian, E-mail: Diehn@Stanford.edu [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California (United States); Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California (United States); Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California (United States); Loo, Billy W., E-mail: BWLoo@Stanford.edu [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California (United States); Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California (United States)

    2014-09-01

    Purpose: Lung volume reduction surgery (LVRS) improves dyspnea and other outcomes in selected patients with severe emphysema, but many have excessive surgical risk for LVRS. We analyzed the dose-volume relationship for lobar volume reduction after stereotactic ablative radiation therapy (SABR) of lung tumors, hypothesizing that SABR could achieve therapeutic volume reduction if applied in emphysema. Methods and Materials: We retrospectively identified patients treated from 2007 to 2011 who had SABR for 1 lung tumor, pre-SABR pulmonary function testing, and ≥6 months computed tomographic (CT) imaging follow-up. We contoured the treated lobe and untreated adjacent lobe(s) on CT before and after SABR and calculated their volume changes relative to the contoured total (bilateral) lung volume (TLV). We correlated lobar volume reduction with the volume receiving high biologically effective doses (BED, α/β = 3). Results: 27 patients met the inclusion criteria, with a median CT follow-up time of 14 months. There was no grade ≥3 toxicity. The median volume reduction of the treated lobe was 4.4% of TLV (range, −0.4%-10.8%); the median expansion of the untreated adjacent lobe was 2.6% of TLV (range, −3.9%-11.6%). The volume reduction of the treated lobe was positively correlated with the volume receiving BED ≥60 Gy (r{sup 2}=0.45, P=.0001). This persisted in subgroups determined by high versus low pre-SABR forced expiratory volume in 1 second, treated lobe CT emphysema score, number of fractions, follow-up CT time, central versus peripheral location, and upper versus lower lobe location, with no significant differences in effect size between subgroups. Volume expansion of the untreated adjacent lobe(s) was positively correlated with volume reduction of the treated lobe (r{sup 2}=0.47, P<.0001). Conclusions: We identified a dose-volume response for treated lobe volume reduction and adjacent lobe compensatory expansion after lung tumor SABR, consistent across

  6. Lung volume reduction after stereotactic ablative radiation therapy of lung tumors: potential application to emphysema.

    Science.gov (United States)

    Binkley, Michael S; Shrager, Joseph B; Leung, Ann N; Popat, Rita; Trakul, Nicholas; Atwood, Todd F; Chaudhuri, Aadel; Maxim, Peter G; Diehn, Maximilian; Loo, Billy W

    2014-09-01

    Lung volume reduction surgery (LVRS) improves dyspnea and other outcomes in selected patients with severe emphysema, but many have excessive surgical risk for LVRS. We analyzed the dose-volume relationship for lobar volume reduction after stereotactic ablative radiation therapy (SABR) of lung tumors, hypothesizing that SABR could achieve therapeutic volume reduction if applied in emphysema. We retrospectively identified patients treated from 2007 to 2011 who had SABR for 1 lung tumor, pre-SABR pulmonary function testing, and ≥6 months computed tomographic (CT) imaging follow-up. We contoured the treated lobe and untreated adjacent lobe(s) on CT before and after SABR and calculated their volume changes relative to the contoured total (bilateral) lung volume (TLV). We correlated lobar volume reduction with the volume receiving high biologically effective doses (BED, α/β = 3). 27 patients met the inclusion criteria, with a median CT follow-up time of 14 months. There was no grade ≥3 toxicity. The median volume reduction of the treated lobe was 4.4% of TLV (range, -0.4%-10.8%); the median expansion of the untreated adjacent lobe was 2.6% of TLV (range, -3.9%-11.6%). The volume reduction of the treated lobe was positively correlated with the volume receiving BED ≥60 Gy (r(2)=0.45, P=.0001). This persisted in subgroups determined by high versus low pre-SABR forced expiratory volume in 1 second, treated lobe CT emphysema score, number of fractions, follow-up CT time, central versus peripheral location, and upper versus lower lobe location, with no significant differences in effect size between subgroups. Volume expansion of the untreated adjacent lobe(s) was positively correlated with volume reduction of the treated lobe (r(2)=0.47, Pvolume response for treated lobe volume reduction and adjacent lobe compensatory expansion after lung tumor SABR, consistent across multiple clinical parameters. These data serve to inform our ongoing prospective trial of stereotactic

  7. Temperature mapping and thermal dose calculation in combined radiation therapy and 13.56 MHz radiofrequency hyperthermia for tumor treatment

    Science.gov (United States)

    Kim, Jung Kyung; Prasad, Bibin; Kim, Suzy

    2017-02-01

    To evaluate the synergistic effect of radiotherapy and radiofrequency hyperthermia therapy in the treatment of lung and liver cancers, we studied the mechanism of heat absorption and transfer in the tumor using electro-thermal simulation and high-resolution temperature mapping techniques. A realistic tumor-induced mouse anatomy, which was reconstructed and segmented from computed tomography images, was used to determine the thermal distribution in tumors during radiofrequency (RF) heating at 13.56 MHz. An RF electrode was used as a heat source, and computations were performed with the aid of the multiphysics simulation platform Sim4Life. Experiments were carried out on a tumor-mimicking agar phantom and a mouse tumor model to obtain a spatiotemporal temperature map and thermal dose distribution. A high temperature increase was achieved in the tumor from both the computation and measurement, which elucidated that there was selective high-energy absorption in tumor tissue compared to the normal surrounding tissues. The study allows for effective treatment planning for combined radiation and hyperthermia therapy based on the high-resolution temperature mapping and high-precision thermal dose calculation.

  8. Cancer stem cell overexpression of nicotinamide N-methyltransferase enhances cellular radiation resistance

    DEFF Research Database (Denmark)

    D’Andrea, Filippo P.; Safwat, Akmal; Kassem, Moustapha

    2011-01-01

    validated with q-RT-PCR using TaqMan probes. ResultsThe CE8 clone was more radiation resistant than the BB3 clone. From a pool of 15 validated genes with altered expression in the CE8 clone, we found the enzyme nicotinamide N-methyltransferase (NNMT) more than 5-fold upregulated. In-depth pathway analysis...... found the genes involved in cancer, proliferation, DNA repair and cell death. ConclusionsThe higher radiation resistance in clone CE8 is likely due to NNMT overexpression. The higher levels of NNMT could affect the cellular damage resistance through depletion of the accessible amounts of nicotinamide......, which is a known inhibitor of cellular DNA repair mechanisms....

  9. Tumor Response After Stereotactic Body Radiation Therapy to Nonspine Bone Metastases: An Evaluation of Response Criteria

    Energy Technology Data Exchange (ETDEWEB)

    McDonald, Rachel [Department of Radiation Oncology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario (Canada); Probyn, Linda [Department of Medical Imaging, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario (Canada); Poon, Ian; Erler, Darby; Brotherston, Drew; Soliman, Hany; Cheung, Patrick; Chung, Hans; Chu, William; Loblaw, Andrew; Thavarajah, Nemica [Department of Radiation Oncology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario (Canada); Lang, Catherine [Department of Medical Imaging, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario (Canada); Chin, Lee [Department of Physics, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario (Canada); Chow, Edward, E-mail: Edward.Chow@sunnybrook.ca [Department of Radiation Oncology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario (Canada); Sahgal, Arjun [Department of Radiation Oncology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario (Canada)

    2015-11-15

    Purpose: To evaluate the applicability of the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and University of Texas MD Anderson (MDA) Cancer Center criteria in the setting of stereotactic body radiation therapy (SBRT) to nonspine bone metastases. Methods: Patients who were treated with SBRT to nonspine bone metastases were identified by retrospective chart review. An independent musculoskeletal radiologist evaluated response to treatment using computed tomography (CT) scans. Results: Thirty-three patients were treated to 42 nonspine bone metastases. The most common primary cancer cites were renal cell carcinoma (RCC) (33.3%), lung (24.2%), and prostate (18.2%). Bone metastases were either mainly lytic (57.1%), mainly sclerotic (28.6%), or mixed (14.3%). When lytic and sclerotic lesions were evaluated according to RECIST 1.1, local control (LC) was 83%, 85%, 88%, and 80% for those with CT imaging between months 1 to 3, 4 to 6, 7 to 9, and 10 to 12, respectively. When evaluated by the MDA criteria by density, LC within each time period was slightly greater. Overall LC decreased considerably when evaluated by MDA in terms of size. Conclusions: Consensus definitions of response are required as they have implications on clinical trials and disease management. Without consistent response criteria, outcomes from clinical trials cannot be compared and treatment efficacy remains undetermined.

  10. Radiation resistance of wide-gap materials as exemplified by SiC nuclear radiation detectors

    Science.gov (United States)

    Ivanov, A. M.; Strokan, N. B.; Lebedev, A. A.

    2012-04-01

    In wide-gap materials used in nuclear detectors, the polarization effect is typically observed when the concentration of radiation-induced defects is high. An emf arising in the detector is associated with long-term trapping of charge carries by deep radiation-induced levels (centers). The polarization kinetics and the polarization field strength are determined experimentally. The trapping efficiency can be controlled by varying the temperature, and a tradeoff can be reached at an "optimal" temperature between the generation current and the position of the deepest level, which has a negligible effect on charge losses via trapping. It is found that the ratio between the depth of this level and the bandgap is about 1/3 irrespective of the material but the optimal temperature is material-specific.

  11. Tumor heterogeneity and plasticity as elusive drivers for resistance to MAPK pathway inhibition in melanoma.

    Science.gov (United States)

    Roesch, A

    2015-06-04

    Despite the recent success of MAPK signaling-targeted drugs in melanoma, the majority of patients with metastatic melanoma still undergo disease progression after initial tumor shrinkage indicating gradually developing therapy resistance. This review will give an overview on currently suggested concepts of resistance to MAPK pathway inhibitors in melanoma with particular focus on inter- and intraindividual as well as intratumor heterogeneity. The high plasticity of melanoma cells promotes both the clonal evolution of genetic resistance, for example, because of mutations in the MAPK or PI3K/AKT/PTEN pathways, and the emergence of cell phenotypes that functionally and metabolically overcome MAPK inhibition. Like a 'moving target', melanoma cells are shifting between different metabolic, cell cycle and differentiation states reflecting a highly dynamic potential to adapt to exogenous stressors including drugs. The introduction of MAPK inhibitors into the clinics has tremendously pushed the field of melanoma research not just because of the historic therapeutic success but also by providing a new tool to study human melanoma in its natural microenvironment.

  12. Cyclin-dependent kinase inhibitor, flavopiridol, induces apoptosis and inhibits tumor growth in drug-resistant osteosarcoma and Ewing's family tumor cells.

    Science.gov (United States)

    Li, Yan; Tanaka, Kazuhiro; Li, Xu; Okada, Takamitsu; Nakamura, Tomoyuki; Takasaki, Minoru; Yamamoto, Shunsaku; Oda, Yoshinao; Tsuneyoshi, Masazumi; Iwamoto, Yukihide

    2007-09-15

    Multimodal therapies play important roles in the treatment of osteosarcoma (OS) and Ewing's family of tumors (EFTs), two most frequent malignant bone tumors. Although the clinical outcome of primary OS and EFTs is greatly improved, the relapsed cases often are associated with multidrug resistance of the tumors and the prognosis of these patients is still poor. Flavopiridol, a pan cyclin-dependent kinase (CDK) inhibitor is a novel antitumor agent that can induce cell cycle arrest and apoptosis in many cancer cells. However, there have been no studies about the effects of flavopiridol on drug-resistant OS and EFTs. Here, we demonstrated that flavopiridol induced the cleavage of poly-ADP-ribose polymerase (PARP) in a time and dose dependent manner in adriamycin-resistant OS and EFTs cells expressing P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP(1)) as effectively as in their parental cells. Our data also showed that flavopiridol caused the release of mitochondrial cytochrome c and the activation of caspase-9, caspase-8 and caspase-3, with an increase ratio of the proapoptotic protein level (Bax) to the antiapoptotic protein level (Bcl-2 and Bcl-X(L)), while apoptosis was inhibited by pan caspase inhibitor (Z-VAD-FMK) and caspase-3 inhibitor (Z-DEVD-FMK), not by caspase-8 inhibitor (Z-IETD-FMK). The treatment with flavopiridol further inhibited the tumor growth in mouse models of the drug-resistant OS and EFTs. These results suggest that flavopiridol might be promising in clinical therapy for the relapsed OS and EFTs. (c) 2007 Wiley-Liss, Inc.

  13. Predicting oropharyngeal tumor volume throughout the course of radiation therapy from pretreatment computed tomography data using general linear models

    Science.gov (United States)

    Yock, Adam D.; Rao, Arvind; Dong, Lei; Beadle, Beth M.; Garden, Adam S.; Kudchadker, Rajat J.; Court, Laurence E.

    2014-01-01

    Purpose: The purpose of this work was to develop and evaluate the accuracy of several predictive models of variation in tumor volume throughout the course of radiation therapy. Methods: Nineteen patients with oropharyngeal cancers were imaged daily with CT-on-rails for image-guided alignment per an institutional protocol. The daily volumes of 35 tumors in these 19 patients were determined and used to generate (1) a linear model in which tumor volume changed at a constant rate, (2) a general linear model that utilized the power fit relationship between the daily and initial tumor volumes, and (3) a functional general linear model that identified and exploited the primary modes of variation between time series describing the changing tumor volumes. Primary and nodal tumor volumes were examined separately. The accuracy of these models in predicting daily tumor volumes were compared with those of static and linear reference models using leave-one-out cross-validation. Results: In predicting the daily volume of primary tumors, the general linear model and the functional general linear model were more accurate than the static reference model by 9.9% (range: −11.6%–23.8%) and 14.6% (range: −7.3%–27.5%), respectively, and were more accurate than the linear reference model by 14.2% (range: −6.8%–40.3%) and 13.1% (range: −1.5%–52.5%), respectively. In predicting the daily volume of nodal tumors, only the 14.4% (range: −11.1%–20.5%) improvement in accuracy of the functional general linear model compared to the static reference model was statistically significant. Conclusions: A general linear model and a functional general linear model trained on data from a small population of patients can predict the primary tumor volume throughout the course of radiation therapy with greater accuracy than standard reference models. These more accurate models may increase the prognostic value of information about the tumor garnered from pretreatment computed tomography

  14. Predicting oropharyngeal tumor volume throughout the course of radiation therapy from pretreatment computed tomography data using general linear models

    Energy Technology Data Exchange (ETDEWEB)

    Yock, Adam D., E-mail: ADYock@mdanderson.org; Kudchadker, Rajat J. [Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 and The Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, Texas 77030 (United States); Rao, Arvind [Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 and the Graduate School of Biomedical Sciences, the University of Texas Health Science Center at Houston, Houston, Texas 77030 (United States); Dong, Lei [Scripps Proton Therapy Center, San Diego, California 92121 and The Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, Texas 77030 (United States); Beadle, Beth M.; Garden, Adam S. [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 (United States); Court, Laurence E. [Department of Radiation Physics and Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 and The Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, Texas 77030 (United States)

    2014-05-15

    Purpose: The purpose of this work was to develop and evaluate the accuracy of several predictive models of variation in tumor volume throughout the course of radiation therapy. Methods: Nineteen patients with oropharyngeal cancers were imaged daily with CT-on-rails for image-guided alignment per an institutional protocol. The daily volumes of 35 tumors in these 19 patients were determined and used to generate (1) a linear model in which tumor volume changed at a constant rate, (2) a general linear model that utilized the power fit relationship between the daily and initial tumor volumes, and (3) a functional general linear model that identified and exploited the primary modes of variation between time series describing the changing tumor volumes. Primary and nodal tumor volumes were examined separately. The accuracy of these models in predicting daily tumor volumes were compared with those of static and linear reference models using leave-one-out cross-validation. Results: In predicting the daily volume of primary tumors, the general linear model and the functional general linear model were more accurate than the static reference model by 9.9% (range: −11.6%–23.8%) and 14.6% (range: −7.3%–27.5%), respectively, and were more accurate than the linear reference model by 14.2% (range: −6.8%–40.3%) and 13.1% (range: −1.5%–52.5%), respectively. In predicting the daily volume of nodal tumors, only the 14.4% (range: −11.1%–20.5%) improvement in accuracy of the functional general linear model compared to the static reference model was statistically significant. Conclusions: A general linear model and a functional general linear model trained on data from a small population of patients can predict the primary tumor volume throughout the course of radiation therapy with greater accuracy than standard reference models. These more accurate models may increase the prognostic value of information about the tumor garnered from pretreatment computed tomography

  15. Sunlight-exposed biofilm microbial communities are naturally resistant to chernobyl ionizing-radiation levels.

    Science.gov (United States)

    Ragon, Marie; Restoux, Gwendal; Moreira, David; Møller, Anders Pape; López-García, Purificación

    2011-01-01

    The Chernobyl accident represents a long-term experiment on the effects of exposure to ionizing radiation at the ecosystem level. Though studies of these effects on plants and animals are abundant, the study of how Chernobyl radiation levels affect prokaryotic and eukaryotic microbial communities is practically non-existent, except for a few reports on human pathogens or soil microorganisms. Environments enduring extreme desiccation and UV radiation, such as sunlight exposed biofilms could in principle select for organisms highly resistant to ionizing radiation as well. To test this hypothesis, we explored the diversity of microorganisms belonging to the three domains of life by cultivation-independent approaches in biofilms developing on concrete walls or pillars in the Chernobyl area exposed to different levels of radiation, and we compared them with a similar biofilm from a non-irradiated site in Northern Ireland. Actinobacteria, Alphaproteobacteria, Bacteroidetes, Acidobacteria and Deinococcales were the most consistently detected bacterial groups, whereas green algae (Chlorophyta) and ascomycete fungi (Ascomycota) dominated within the eukaryotes. Close relatives to the most radio-resistant organisms known, including Rubrobacter species, Deinococcales and melanized ascomycete fungi were always detected. The diversity of bacteria and eukaryotes found in the most highly irradiated samples was comparable to that of less irradiated Chernobyl sites and Northern Ireland. However, the study of mutation frequencies in non-coding ITS regions versus SSU rRNA genes in members of a same actinobacterial operational taxonomic unit (OTU) present in Chernobyl samples and Northern Ireland showed a positive correlation between increased radiation and mutation rates. Our results show that biofilm microbial communities in the most irradiated samples are comparable to non-irradiated samples in terms of general diversity patterns, despite increased mutation levels at the single

  16. Texture descriptors to distinguish radiation necrosis from recurrent brain tumors on multi-parametric MRI

    Science.gov (United States)

    Tiwari, Pallavi; Prasanna, Prateek; Rogers, Lisa; Wolansky, Leo; Badve, Chaitra; Sloan, Andrew; Cohen, Mark; Madabhushi, Anant

    2014-03-01

    Di erentiating radiation necrosis (a radiation induced treatment e ect) from recurrent brain tumors (rBT) is currently one of the most clinically challenging problems in care and management of brain tumor (BT) patients. Both radiation necrosis (RN), and rBT exhibit similar morphological appearance on standard MRI making non-invasive diagnosis extremely challenging for clinicians, with surgical intervention being the only course for obtaining de nitive ground truth". Recent studies have reported that the underlying biological pathways de n- ing RN and rBT are fundamentally di erent. This strongly suggests that there might be phenotypic di erences and hence cues on multi-parametric MRI, that can distinguish between the two pathologies. One challenge is that these di erences, if they exist, might be too subtle to distinguish by the human observer. In this work, we explore the utility of computer extracted texture descriptors on multi-parametric MRI (MP-MRI) to provide alternate representations of MRI that may be capable of accentuating subtle micro-architectural di erences between RN and rBT for primary and metastatic (MET) BT patients. We further explore the utility of texture descriptors in identifying the MRI protocol (from amongst T1-w, T2-w and FLAIR) that best distinguishes RN and rBT across two independent cohorts of primary and MET patients. A set of 119 texture descriptors (co-occurrence matrix homogeneity, neighboring gray-level dependence matrix, multi-scale Gaussian derivatives, Law features, and histogram of gradient orientations (HoG)) for modeling di erent macro and micro-scale morphologic changes within the treated lesion area for each MRI protocol were extracted. Principal component analysis based variable importance projection (PCA-VIP), a feature selection method previously developed in our group, was employed to identify the importance of every texture descriptor in distinguishing RN and rBT on MP-MRI. PCA-VIP employs regression analysis to provide

  17. Diffusion-weighted and PET/MR Imaging after Radiation Therapy for Malignant Head and Neck Tumors.

    Science.gov (United States)

    Varoquaux, Arthur; Rager, Olivier; Dulguerov, Pavel; Burkhardt, Karim; Ailianou, Angeliki; Becker, Minerva

    2015-01-01

    Interpreting imaging studies of the irradiated neck constitutes a challenge because of radiation therapy-induced tissue alterations, the variable appearances of recurrent tumors, and functional and metabolic phenomena that mimic disease. Therefore, morphologic magnetic resonance (MR) imaging, diffusion-weighted (DW) imaging, positron emission tomography with computed tomography (PET/CT), and software fusion of PET and MR imaging data sets are increasingly used to facilitate diagnosis in clinical practice. Because MR imaging and PET often yield complementary information, PET/MR imaging holds promise to facilitate differentiation of tumor recurrence from radiation therapy-induced changes and complications. This review focuses on clinical applications of DW and PET/MR imaging in the irradiated neck and discusses the added value of multiparametric imaging to solve diagnostic dilemmas. Radiologists should understand key features of radiation therapy-induced tissue alterations and potential complications seen at DW and PET/MR imaging, including edema, fibrosis, scar tissue, soft-tissue necrosis, bone and cartilage necrosis, cranial nerve palsy, and radiation therapy-induced arteriosclerosis, brain necrosis, and thyroid disorders. DW and PET/MR imaging also play a complementary role in detection of residual and recurrent disease. Interpretation pitfalls due to technical, functional, and metabolic phenomena should be recognized and avoided. Familiarity with DW and PET/MR imaging features of expected findings, potential complications, and treatment failure after radiation therapy increases diagnostic confidence when interpreting images of the irradiated neck. Online supplemental material is available for this article. (©)RSNA, 2015.

  18. RNA Nanoparticles Derived from Three-Way Junction of Phi29 Motor pRNA Are Resistant to I-125 and Cs-131 Radiation

    Science.gov (United States)

    Li, Hui; Rychahou, Piotr G.; Cui, Zheng; Pi, Fengmei; Evers, B. Mark; Shu, Dan

    2015-01-01

    Radiation reagents that specifically target tumors are in high demand for the treatment of cancer. The emerging field of RNA nanotechnology might provide new opportunities for targeted radiation therapy. This study investigates whether chemically modified RNA nanoparticles derived from the packaging RNA (pRNA) three-way junction (3WJ) of phi29 DNA-packaging motor are resistant to potent I-125 and Cs-131 radiation, which is a prerequisite for utilizing these RNA nanoparticles as carriers for targeted radiation therapy. pRNA 3WJ nanoparticles were constructed and characterized, and the stability of these nanoparticles under I-125 and Cs-131 irradiation with clinically relevant doses was examined. RNA nanoparticles derived from the pRNA 3WJ targeted tumors specifically and they were stable under irradiation of I-125 and Cs-131 with clinically relevant doses ranging from 1 to 90 Gy over a significantly long time up to 20 days, while control plasmid DNA was damaged at 20 Gy or higher. PMID:26017686

  19. Diffuse optical measurements of head and neck tumor hemodynamics for early prediction of radiation therapy (Conference Presentation)

    Science.gov (United States)

    Dong, Lixin; Kudrimoti, Mahesh; Irwin, Daniel; Chen, Li; Shang, Yu; Li, Xingzhe; Stevens, Scott D.; Shelton, Brent J.; Yu, Guoqiang

    2016-03-01

    Radiation therapy is a principal modality for head and neck cancers and its efficacy depends on tumor hemodynamics. Our laboratory developed a hybrid diffuse optical instrument allowing for simultaneous measurements of tumor blood flow and oxygenation. In this study, the clinically involved cervical lymph node was monitored by the hybrid instrument once a week over the treatment period of seven weeks. Based on treatment outcomes within one year, patients were classified into a complete response group (CR) and an incomplete response group (IR) with remote metastasis and/or local recurrence. A linear mixed models was used to compare tumor hemodynamic responses to the treatment between the two groups. Interestingly, we found that human papilloma virus (HPV-16) status largely affected tumor hemodynamic responses. For HPV-16 negative tumors, significant differences in blood flow index (BFI, p = 0.007) and reduced scattering coefficient (μs', p = 0.0005) were observed between the two groups; IR tumors exhibited higher μs' values and a continuous increase in BFI over the treatment period. For HPV-16 positive tumors, oxygenated hemoglobin concentration ([HbO2]) and blood oxygen saturation (StO2) were significant different (p = 0.003 and 0.01, respectively); IR group showed lower [HbO2] and StO2. Our results imply HPV-16 negative tumors with higher density of vasculature (μs') and higher blood flow show poor responses to radiotherapy and HPV-16 positive tumors with lower tissue oxygenation level (lower StO2 and [HbO2]) exhibit poor treatment outcomes. Our diffuse optical measurements show the great potential for early prediction of radiotherapy in head and neck cancers.

  20. Radiation therapy for glomus tumors of the temporal bone; Tratamento radioterapico dos tumores glomicos do osso temporal

    Energy Technology Data Exchange (ETDEWEB)

    Dall' Igna, Celso; Antunes, Marcelo B. [Rio Grande do Sul Univ., Porto Alegre, RS (Brazil). Hospital das Clinicas. Servico de Otorrinolaringologia e Cirurgia da Cabeca e Pescoco; Dall' Igna, Daniela Pernigotti [Parana Univ., Curitiba, PR (Brazil)

    2005-11-15

    The treatment of glomic tumors has been controversial since its first description. It can be done with surgery, radiotherapy or just expectation. Aim: the objective of this paper was to evaluate the effectiveness and complications of radiotherapy.Study Design: clinical with transversal cohort. Material and method: it was made a retrospective review in the charts of the patients with glomus jugular tumors treated with radiotherapy. Disease control was determined by (1) no progression of symptoms or cranial nerve dysfunction or (2) no progression of the lesion in radiological follow-up. It was also evaluated the follow-up period and the sequelae of the treatment. Results: twelve patients were included, 8 of then women. The follow-up period was from 3 to 35 years, with a media of 11,6 years. The main symptoms were: hearing loss, pulsate tinnitus, dizziness and vertigo. The signs were pulsate retrotympanic mass, facial palsy and cofosis. The tumors were staged using Fischs classification. The radiotherapy was performed with linear accelerator with dose ranging from 4500-5500 in 4-6 weeks. In the follow-up period were possible to identify sequelaes like dermatitis, meatal stenosis, cofosis and facial palsy. Discussion: the signs and symptoms were the same found in the medical literature. The type and dosages of the radiotherapy were also the same of others reports. All patients had improvement of the symptoms and only one was not considered as having disease controlled. Complications were, in general, minor complications, with exception of the cofosis and facial palsy. Conclusion: radiotherapy is a viable alternative to treatment of these tumors because their good response and low level of complications. It should be considered specially in advanced tumors where a surgical procedure could bring a high level of morbidity. (author)

  1. Comments on ‘The influence of dose heterogeneity on tumor control probability in fractionated radiation therapy’

    Science.gov (United States)

    Grusell, Erik

    2013-09-01

    By analyzing the radiobiological model, and the equations derived from the model, it is shown that the main results of the article ‘The influence of dose heterogeneity on tumor control probability in fractionated radiation therapy’ by Wiklund et al (2011 Phys. Med. Biol. 56 7585-600) are valid only under the condition that the dose to any cell is statistically independent of the dose to any other cell in the same fraction. This condition is in practice not fulfilled for radiotherapy. Hence the main results and most of the discussion are not applicable to fractionated radiation therapy.

  2. Studies on genetic and vaccination-induced resistance of chickens to lymphoid tumor transplants 2. Transmissible lymphoid tumor of Olson.

    Science.gov (United States)

    Spencer, J L; Gavora, J S; Grunder, A A; Robertson, A; Speckmann, G W

    1976-01-01

    Transmissible lymphoid tumor (TLT) was inoculated in wing webs of five-week-old chickens of 6 strains. About half of the chickens of each strain had been vaccinated with turkey herpesvirus (HVT) one week before challenge in the wing web with TLT. Tumors which developed at the site of inoculation usually reached maximum size within 2 weeks and then regressed. In some chickens, however, tumors developed in visceral organs and caused death in the 2nd through 5th weeks postinoculation. Comparisons among strains of chickens in Expt. 1 revealed no differences in mortality. Vaccination with HVT reduced mortality and also the incidence of wing-web tumors (WWT) in all strains of chickens. A lymphoid leukosis virus and a Marek's disease (MD) virus of low virulence were detected in preparations of TLT, and it is suggested that the immunity induced by vaccination may have been directed against tumor antigens associated with MD virus.

  3. Assessment of Resistance of Bacillus Horneckiae Endospores to UV Radiation and Function of Their Extraneous Layer in Resistance

    Science.gov (United States)

    Zachariah, Malcolm M.; Vaishampayan, Parag

    2011-01-01

    Spore-forming microbes are highly resistant to various physical and chemical conditions, which include ionizing and UV radiation, desiccation and oxidative stress, and the harsh environment of outer space or planetary surfaces. The spore's resistance might be due to their metabolically dormant state, and/or by the presence of a series of protective structures that encase the interior-most compartment, the core, which houses the spore chromosome. These spores have multiple layers surrounding the cell that are not found in vegetative cells, and some species have an outer layer of proteins and glycoproteins termed the "exosporium" or a fibrous "extraneous layer" (EL). Bacillus horneckiae is an EL-producing novel sporeformer isolated from a Phoenix spacecraft assembly clean room, and it has previously demonstrated resistance to UV radiation up to 1000 J/m(sup 2). The EL appears to bind B. horneckiae spores into large aggregations, or biofilms, and may confer some UV resistance to the spores. Multiple culturing and purification schemes were tried to achieve high purity spores because vegetative cells would skew UV resistance results. An ethanol-based purification scheme produced high purity spores. Selective removal of the EL from spores was attempted with two schemes: a chemical extraction method and physical extraction (sonication). Results from survival rates in the presence and absence of the external layer will provide a new understanding of the role of biofilms and passive resistance that may favor survival of biological systems in aggressive extra-terrestrial environments. The chemical extraction method decreased viable counts of spores and lead to an inconclusive change UV resistance relative to non-extracted spores. The physical extraction method lead to non-aggregated spores and did not alter viability; however, it produced UV resistance profiles similar to non-extracted spores. In addition to the EL-removal study, samples of B. horneckiae spores dried on

  4. Celecoxib enhances radiation response of secondary bone tumors of a human non-small cell lung cancer via antiangiogenesis in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Klenke, Frank Michael [Bern Univ. (Switzerland). Dept. of Orthopedic Surgery; Abdollahi, Amir [Deutsches Krebsforschungszentrum, Heidelberg (Germany). Dept. of Radiation Oncology; Tufts Univ. School of Medicine, Boston, MA (United States). Center of Cancer Systems Biology; Bischof, Marc; Huber, Peter E. [Deutsches Krebsforschungszentrum, Heidelberg (Germany). Dept. of Radiation Oncology; Gebhard, Martha-Maria [Heidelberg Univ. (Germany). Dept. of Experimental Surgery; Ewerbeck, Volker [Heidelberg Univ. (Germany). Dept. of Orthopedic Surgery; Sckell, Axel [Charite Univ. Medical Center, Berlin (Germany). Dept. of Orthopedic, Trauma and Reconstructive Surgery

    2011-01-15

    Purpose: Cyclooxygenase-2 (COX-2) inhibitors mediate a systemic antitumor activity via antiangiogenesis and seem to enhance the response of primary tumors to radiation. Radiosensitizing effects of COX-2 inhibition have not been reported for bone metastases. Therefore, the aim of this study was the investigation of the radiosensitizing effects of the selective COX-2 inhibitor celecoxib in secondary bone tumors of a non-small cell lung carcinoma in vivo. Materials and Methods: Human A549 lung carcinomas were implanted into a cranial window preparation in male SCID mice (n = 24). Animals were treated with either celecoxib or radiation (7 Gy single photon dose) alone or a combination of celecoxib and radiation, respectively. Untreated animals served as controls. The impact of radiation and COX-2 inhibition on angiogenesis, microcirculation, and tumor growth was analyzed over 28 days by means of intravital microscopy and histological methods. Results: Monotherapies with radiation as well as celecoxib had significant antitumor effects compared to untreated controls. Both therapies reduced tumor growth and vascularization to a similar extent. The simultaneous administration of celecoxib and radiation further enhanced the antitumor and antiangiogenic effects of single-beam radiation. With the combined treatment approach, tumor vascularization and tumor size were decreased by 57% and 51%, respectively, as compared to monotherapy with radiation. Conclusion: The combined application of radiation therapy and COX-2 inhibition showed synergistic effects concerning the inhibition of tumor growth and tumor angiogenesis. Therefore, the combination of radiation with COX-2 inhibitor therapy represents a promising approach to improve the therapeutic efficacy of radiotherapy of bone metastases. (orig.)

  5. Increasing the radiation resistance of single-crystal silicon epitaxial layers

    Directory of Open Access Journals (Sweden)

    Kurmashev Sh. D.

    2014-12-01

    Full Text Available The authors investigate the possibility of increasing the radiation resistance of silicon epitaxial layers by creating radiation defects sinks in the form of dislocation networks of the density of 109—1012 m–2. Such networks are created before the epitaxial layer is applied on the front surface of the silicon substrate by its preliminary oxidation and subsequent etching of the oxide layer. The substrates were silicon wafers KEF-4.5 and KDB-10 with a diameter of about 40 mm, grown by the Czochralski method. Irradiation of the samples was carried out using electron linear accelerator "Electronics" (ЭЛУ-4. Energy of the particles was 2,3—3,0 MeV, radiation dose 1015—1020 m–2, electron beam current 2 mA/m2. It is shown that in structures containing dislocation networks, irradiation results in reduction of the reverse currents by 5—8 times and of the density of defects by 5—10 times, while the mobility of the charge carriers is increased by 1,2 times. Wafer yield for operation under radiation exposure, when the semiconductor structures are formed in the optimal mode, is increased by 7—10% compared to the structures without dislocation networks. The results obtained can be used in manufacturing technology for radiation-resistant integrated circuits (bipolar, CMOS, BiCMOS, etc..

  6. Low-Temperature Ionizing Radiation Resistance of Deinococcus radiodurans and Antarctic Dry Valley Bacteria

    Science.gov (United States)

    Dartnell, Lewis R.; Hunter, Stephanie J.; Lovell, Keith V.; Coates, Andrew J.; Ward, John M.

    2010-09-01

    The high flux of cosmic rays onto the unshielded surface of Mars poses a significant hazard to the survival of martian microbial life. Here, we determined the survival responses of several bacterial strains to ionizing radiation exposure while frozen at a low temperature characteristic of the martian near-subsurface. Novel psychrotolerant bacterial strains were isolated from the Antarctic Dry Valleys, an environmental analogue of the martian surface, and identified by 16S rRNA gene phylogeny as representatives of Brevundimonas, Rhodococcus, and Pseudomonas genera. These isolates, in addition to the known radioresistant extremophile Deinococcus radiodurans, were exposed to gamma rays while frozen on dry ice (-79°C). We found D. radiodurans to exhibit far greater radiation resistance when irradiated at -79°C than was observed in similar studies performed at higher temperatures. This greater radiation resistance has important implications for the estimation of potential survival times of microorganisms near the martian surface. Furthermore, the most radiation resistant of these Dry Valley isolates, Brevundimonas sp. MV.7, was found to show 99% 16S rRNA gene similarity to contaminant bacteria discovered in clean rooms at both Kennedy and Johnson Space Centers and so is of prime concern to efforts in the planetary protection of Mars from our lander probes. Results from this experimental irradiation, combined with previous radiation modeling, indicate that Brevundimonas sp. MV.7 emplaced only 30 cm deep in martian dust could survive the cosmic radiation for up to 100,000 years before suffering 106 population reduction.

  7. Low-temperature ionizing radiation resistance of Deinococcus radiodurans and Antarctic Dry Valley bacteria.

    Science.gov (United States)

    Dartnell, Lewis R; Hunter, Stephanie J; Lovell, Keith V; Coates, Andrew J; Ward, John M

    2010-09-01

    The high flux of cosmic rays onto the unshielded surface of Mars poses a significant hazard to the survival of martian microbial life. Here, we determined the survival responses of several bacterial strains to ionizing radiation exposure while frozen at a low temperature characteristic of the martian near-subsurface. Novel psychrotolerant bacterial strains were isolated from the Antarctic Dry Valleys, an environmental analogue of the martian surface, and identified by 16S rRNA gene phylogeny as representatives of Brevundimonas, Rhodococcus, and Pseudomonas genera. These isolates, in addition to the known radioresistant extremophile Deinococcus radiodurans, were exposed to gamma rays while frozen on dry ice (-79°C). We found D. radiodurans to exhibit far greater radiation resistance when irradiated at -79°C than was observed in similar studies performed at higher temperatures. This greater radiation resistance has important implications for the estimation of potential survival times of microorganisms near the martian surface. Furthermore, the most radiation resistant of these Dry Valley isolates, Brevundimonas sp. MV.7, was found to show 99% 16S rRNA gene similarity to contaminant bacteria discovered in clean rooms at both Kennedy and Johnson Space Centers and so is of prime concern to efforts in the planetary protection of Mars from our lander probes. Results from this experimental irradiation, combined with previous radiation modeling, indicate that Brevundimonas sp. MV.7 emplaced only 30 cm deep in martian dust could survive the cosmic radiation for up to 100,000 years before suffering 10⁶ population reduction.

  8. Synthetic paclitaxel-octreotide conjugate reversing the resistance of A2780/Taxol to paclitaxel in xenografted tumor in nude mice.

    Science.gov (United States)

    Chen, Xi; Zhang, Xiao-Yu; Shen, Yang; Fan, Li-Li; Ren, Mu-Lan; Wu, Yong-Ping

    2016-12-13

    Peptide hormone-based targeted therapy to tumors has been studied extensively. Our previous study shows that somatostatin receptor expresses high level on drug-resistant human ovarian cancer. The paclitaxel-octreotide conjugate (POC) exhibits enhanced growth inhibition, as well as reduced toxicity, in paclitaxel-resistant human ovarian cancer cells. The aim of this study was to investigate the effect of targeted cytotoxicity and potential reversal mechanism of resistance in paclitaxel-resistant human ovarian cancer cells xenografted into nude mice. The SSTR2 shows higher expression levels in tumor tissue. Moreover, fluorescein-labeled POC displays favorable targeting in tumor cells. POC presents the perfect efficacy in inhibiting tumor growth and exerts lower or no toxic effects on normal tissues. Real-time PCR and Western Blotting has demonstrated that the mRNA and protein expressions of SSTR2 in POC group were significantly higher, while MDR1, α-tubulin, βIII-tubulin, VEGF and MMP-9 were significantly lower than in the other treatment groups and controls. Combined with the previous study in vitro, this study evaluates an effective approach on the treatment of paclitaxel-resistant ovarian cancer which expresses somatostatin receptor SSTR. Our investigation has also revealed the possible molecular mechanism of POC in treating the ovarian cancer, and therefore, provided a theoretical basis for the clinical application of this newly-invented compound.

  9. Some resistance mechanisms to ultraviolet radiation; Algunos mecanismos de resistencia a radiacion ultravioleta

    Energy Technology Data Exchange (ETDEWEB)

    Alcantara D, D. [ININ, 52045 Ocoyoacac, Estado de Mexico (Mexico)

    2002-12-15

    The cyclical exposure of bacterial cells to the ultraviolet light (UV) it has as consequence an increment in the resistance to the lethal effects of this type of radiation, increment that happens as a result of a selection process of favorable genetic mutations induced by the same UV light. With object to study the reproducibility of the genetic changes and the associate mechanisms to the resistance to UV in the bacteria Escherichia coli, was irradiated cyclically with UV light five different derived cultures of a single clone, being obtained five stumps with different resistance grades. The genetic mapping Hfr revealed that so much the mutation events like of selection that took place during the adaptation to the UV irradiation, happened of random manner, that is to say, each one of the resistant stumps it is the result of the unspecified selection of mutations arisen at random in different genes related with the repair and duplication of the DNA. (Author)

  10. JNK inhibition sensitizes tumor cells to radiation-induced premature senescence via Bcl-2/ROS/DDR signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Jae Seon; Lee, Je Jung [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

    2009-05-15

    Premature senescence is considered as a cellular defense mechanism to prevent tumorigenesis. Although recent evidences demonstrate that c-Jun N-terminal kinase (JNK) is involved in the senescence process, the target and exact mechanism of JNK signaling in the regulation of cell proliferation has yet to be defined. In this study, we investigated the role of JNK in premature senescence and demonstrated JNK inhibition sensitized tumor cells to radiation-induced premature senescence.

  11. Combined effect of tumor necrosis factor-related apoptosis-inducing ligand and ionizing radiation in breast cancer therapy

    OpenAIRE

    Chinnaiyan, Arul M; Prasad, Uttara; Shankar, Sunita; Hamstra, Daniel A.; Shanaiah, Murthy; Chenevert, Thomas L.; Ross, Brian D.; Rehemtulla, Alnawaz

    2000-01-01

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent endogenous activator of the cell death pathway and functions by activating the cell surface death receptors 4 and 5 (DR4 and DR5). TRAIL is nontoxic in vivo and preferentially kills neoplastically transformed cells over normal cells by an undefined mechanism. Radiotherapy is a common treatment for breast cancer as well as many other cancers. Here we demonstrate that ionizing radiation can sensitize breast carcinoma ce...

  12. Unusual resistance to ionizing radiation of the viruses of kuru, Creutzfeldt-Jakob disease, and scrapie.

    Science.gov (United States)

    Gibbs, C J; Gajdusek, D C; Latarjet, R

    1978-01-01

    The titers of several preparations of kuru. Creutzfeldt-Jacob disease, and scrapie viruses were reduced by only 1/10th or less by high doses of gamma radiation of 50 kGy and by only 1/10th-1/1000th or less for 200 kGy. This unusual radiation resistance of the two human viruses further links them with the scrapie virus and suggests that the genetic information of all three viruses is considerably smaller than that of any other known viruses of mammals. PMID:104301

  13. Structure-activity relationships of diverse xanthones against multidrug resistant human tumor cells.

    Science.gov (United States)

    Wang, Qiwen; Ma, Chenyao; Ma, Yun; Li, Xiang; Chen, Yong; Chen, Jianwei

    2017-02-01

    Thirteen xanthones were isolated naturally from the stem of Securidaca inappendiculata Hassk, and structure-activity relationships (SARs) of these compounds were comparatively predicted for their cytotoxic activity against three human multidrug resistant (MDR) cell lines MCF-7/ADR, SMMC-7721/Taxol, and A549/Taxol cells. The results showed that the selected xanthones exhibited different potent cytotoxic activity against the growth of different human tumor cell lines, and most of the xanthones exhibited selective cytotoxicity against SMMC-7721/Taxol cells. Furthermore, some tested xanthones showed stronger cytotoxicity than Cisplatin, which has been used in clinical application extensively. The SARs analysis revealed that the cytotoxic activities of diverse xanthones were affected mostly by the number and position of methoxyl and hydroxyl groups. Xanthones with more free hydroxyl and methoxyl groups increased the cytotoxic activity significantly, especially for those with the presence of C-3 hydroxyl and C-4 methoxyl groups. Copyright © 2016 Elsevier Ltd. All rights reserved.

  14. Clinical characteristics, surgical and neuropsychological outcomes in drug resistant tumoral temporal lobe epilepsy.

    Science.gov (United States)

    Ravat, Sangeeta; Iyer, Vivek; Muzumdar, Dattatraya; Shah, Urvashi; Pradhan, Pranjali; Jain, Neeraj; Godge, Yogesh

    2016-12-01

    Glioneuronal tumors are found in nearly one third patients who undergo surgery for pharmacoresistant epilepsy with temporal lobe being the most common location. Few studies, however have concentrated on the neurological and neuropsychological outcomes after surgery, hitherto none from India. We studied 34 patients with temporal lobe tumors and drug resistant epilepsy. These patients underwent anterior temporal lobectomy or lesionectomy based on the involvement of the hippocampus and mesial temporal structures. The clinical history, EEG, neuropsychology profile and MRI were compared. Seizure outcome was categorized using Engel's classification. At a mean follow up of 62 months, 85.29% of the patients were seizure free (Engel's Class I). All 8 patients with intraoperative electrocorticography (ECoG) guided resection were seizure free. Presence of a residual lesion was significantly associated with persistence of seizures post surgery (p = 0.002). Group analysis revealed no significant shifts in IQ and memory scores postoperatively. There was a significant improvement in the quality of life scores (total and across all subdomains) in all patients (p temporal lobe tumors and refractory epilepsy offers complete seizure freedom in majority. Complete surgical excision of the epileptogenic zone is of paramount importance in achieving seizure freedom. Intraoperative electrocorticography (EcoG) is a useful adjunct to ensure complete removal of epileptogenic zone, thus achieving optimal seizure freedom. There is a significant improvement in the quality of life scores (p < 0.001) with no negative impact of surgery on memory and intelligence. Even the patients who are not seizure free can achieve worthwhile improvement post surgery. Copyright © 2015 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.

  15. Role of Adjuvant Radiation Therapy After Surgery for Abdominal Desmoplastic Small Round Cell Tumors

    Energy Technology Data Exchange (ETDEWEB)

    Atallah, Vincent [Department of Radiation Oncology, Bergonie Institute, Bordeaux (France); Honore, Charles [Department of Digestive Surgery, Gustave-Roussy Institute, Paris (France); Orbach, Daniel; Helfre, Sylvie [Department of Pediatric Oncology, Curie Institute, Paris (France); Ducassou, Anne [Department of Radiation Oncology, Universitary Cancer Institute, Toulouse (France); Thomas, Laurence [Department of Radiation Oncology, Bergonie Institute, Bordeaux (France); Levitchi, Mihai-Barbu [Department of Radiation Oncology, Alexis-Vautrin Center, Nancy (France); Mervoyer, Augustin [Department of Radiation Oncology, Cancerologie de l' ouest Institute, Nantes (France); Naji, Salem [Department of Radiation Oncology, Paoli-Calmette Institute, Marseille (France); Dupin, Charles [Department of Radiation Oncology, Universitary Hospital, Bordeaux (France); Bosco-Levy, Pauline J. [Department of Radiation Oncology, Bergonie Institute, Bordeaux (France); Philippe-Chomette, Pascale [Department of Pediatric Surgery, University Paris 7 Denis Diderot, Hôpital Robert Debré, Assistance Publique-Hôpitaux de Paris, Paris (France); Kantor, Guy; Henriques de Figueiredo, Benedicte [Department of Radiation Oncology, Bergonie Institute, Bordeaux (France); Sunyach, Marie-Pierre [Department of Radiation Oncology, Leon-Berard Center, Lyon (France); Sargos, Paul, E-mail: p.sargos@bordeaux.unicancer.fr [Department of Radiation Oncology, Bergonie Institute, Bordeaux (France)

    2016-07-15

    Purpose: To identify the prognostic role of adjuvant abdominal radiation therapy (RT) on oncologic outcomes as a part of multimodal treatment in the management of desmoplastic small round cell tumor (DSRCT) and to determine its impact according to the quality of surgical resection. Methods and Materials: All patients treated for primary abdominal DSRCT in 8 French centers from 1991 to 2014 were included. Patients were retrospectively staged into 3 groups: group A treated with adjuvant RT after cytoreductive surgery, group B without RT after cytoreductive surgery, and group C by exclusive chemotherapy. Peritoneal progression-free survival (PPFS), progression-free survival (PFS), and overall survival (OS) were evaluated. We also performed a direct comparison between groups A and B to evaluate RT after cytoreductive surgery. Radiation therapy was also evaluated according to completeness of surgery: complete cytoreductive surgery (CCS) or incomplete cytoreductive surgery (ICS). Results: Thirty-seven (35.9%), thirty-six (34.9%), and thirty (28.0%) patients were included in groups A, B, and C, respectively. Three-year OS was 61.2% (range, 41.0%-76.0%), 37.6% (22.0%-53.1%), and 17.3% (6.3%-32.8%) for groups A, B, and C, respectively. Overall survival, PPFS, and PFS differed significantly among the 3 groups (P<.001, P<.001, and P<.001, respectively). Overall survival and PPFS were higher in group A (RT group) compared with group B (no RT group) (P=.045 and P=.006, respectively). Three-year PPFS was 23.8% (10.3%-40.4%) for group A and 12.51% (4.0%-26.2%) for group B. After CCS, RT improved PPFS (P=.024), but differences in OS and PFS were not significant (P=.40 and P=.30, respectively). After ICS, RT improved OS (P=.044). A trend of PPFS and PFS increase was observed, but the difference was not statistically significant (P=.073 and P=.076). Conclusions: Adjuvant RT as part of multimodal treatment seems to confer oncologic benefits for patients treated for abdominal DSRCT

  16. A patient with Moyamoya-like vessels after radiation therapy for a tumor in the basal ganglia

    Energy Technology Data Exchange (ETDEWEB)

    Ishiyama, Koichi; Tomura, Noriaki; Kato, Koki; Takahashi, Satoshi; Watarai, Jiro; Sasajima, Toshio; Mizoi, Kazuo [Akita Univ. (Japan). School of Medicine

    2001-10-01

    A patient with Moyamoya-like vessels after radiation therapy for treatment of a tumor in the basal ganglia is reported. He was diagnosed as Down syndrome at birth. He had a tumor in the left basal ganglionic region at 12 years of the age. The tumor increased in size at age 14. He underwent cerebral angiography, which did not show a stenosis nor occlusion of the internal carotid artery, anterior cerebral artery, nor the middle cerebral artery. He received radiation therapy with a total dose of 56 Gy. He presented a dressing apraxia at age 19. MRI showed cerebral infarction in the left temporo-occipital region. Right internal carotid angiography revealed a severe stenosis of the internal carotid artery and anterior cerebral artery as well as a severe stenosis of the middle cerebral artery on the right side. Moyamoya-like vessels were seen in the basal ganglionic region. Left internal carotid angiography also showed a stenosis of the internal carotid artery and anterior cerebral artery as well as a severe stenosis of the middle cerebral artery on the left side. Moyamoya-like vessels were seen in the basal ganglionic region. Leptomeningeal anastomose and transdural anastomose were bilaterally seen. These arterial occlusion and stenotic phenomenon corresponded to a previous radiation field. These Moyamoya-like vessels with arterial stenosis and occlusion were thought to be due to radiation-induced vasculopathy, because a previous cerebral angiography showed a normal caliber of cerebral arteries. This patient showed that patients with radiation therapy in their early childhood should be carefully observed considering the possibility of the phenomenon. (author)

  17. Oncogene amplification detected by in situ hybridization in radiation induced rat skin tumors. [C-myc:a3

    Energy Technology Data Exchange (ETDEWEB)

    Yi Jin.

    1991-02-01

    Oncogene activation may play an important role in radiation induced carcinogenesis. C-myc oncogene amplification was detected by in situ hybridization in radiation-induced rat skin tumors, including squamous and basal cell carcinomas. In situ hybridization was performed with a biotinylated human c-myc third exon probe, visualized with an avidin-biotinylated alkaline phosphate detection system. No c-myc oncogene amplification was detected in normal rat skin at very early times after exposure to ionizing radiation, which is consistent with the view that c-myc amplification is more likely to be related to carcinogenesis than to normal cell proliferation. The incorporation of tritiated thymidine into the DNA of rat skin cells showed that the proliferation of epidermal cells reached a peak on the seventh day after exposure to ionizing radiation and then decreased. No connection between the proliferation of epidermal cell and c-myc oncogene amplification in normal or irradiated rat skin was found. The results indicated that c-myc amplification as measured by in situ hybridization was correlated with the Southern bolt results, but only some of the cancer cells were amplified. The c-myc positive cells were distributed randomly within regions of the tumor and exhibited a more uniform nuclear structure in comparison to the more vacuolated c-myc negative cells. No c-myc signal was detected in unirradiated normal skin or in irradiated skin cells near the tumors. C-myc amplification appears to be cell or cell cycle specific within radiation-induced carcinomas. 28 refs., 3 figs., 3 tabs.

  18. (90) Y radiation lobectomy: Outcomes following surgical resection in patients with hepatic tumors and small future liver remnant volumes.

    Science.gov (United States)

    Lewandowski, Robert J; Donahue, Larry; Chokechanachaisakul, Attasit; Kulik, Laura; Mouli, Samdeep; Caicedo, Juan; Abecassis, Michael; Fryer, Jonathan; Salem, Riad; Baker, Talia

    2016-07-01

    The purpose of this study is to assess operative, post-operative, and long-term outcomes in patients who underwent radiation lobectomy (RL) for tumor control and/or hypertrophy of small future liver remnant (FLR) prior to resection. Right lobar +/- segment 4 radioembolization was performed prior to lobectomy/tri-segmentectomy in patients with hepatic tumor but inadequate FLR. Parenchymal/tumor volumes were calculated from pre/post-RL imaging; FLR/%FLR hypertrophy were determined. Complications were graded by the Clavien-Dindo classification. Thirteen patients (HCC n = 10, cholangiocarcinoma n = 2, mCRC n = 1) underwent RL prior to resection. The median time between RL and post-RL imaging was 40 days (23-190 days); the median time to resection was 86 days (30-210 days). Median FLR increased significantly [pre: 33% (22-43%); post: 43% (29-69%), P 50% pathologic necrosis. Median follow up time after surgery was 604 days (144-1,416 days); one death occurred. In this preliminary study, radiation lobectomy was a safe and effective method to achieve remnant liver hypertrophy while providing tumor control. This approach may facilitate safe resection and favorable post-operative outcomes.J. Surg. Oncol. 2016;114:99-105. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  19. The anti-tumor effects, immuno-activity and radiation protection of beta-1,3D glucan from yeast

    Energy Technology Data Exchange (ETDEWEB)

    Fukuyama, Atsushi; Hasegawa, Takeo; Takahashi, Tohru [Graduate School of Health Science, Suzuka (Japan)] [and others

    2002-07-01

    In this study, we evaluated the immunological activity, the anti-tumor effect and the radiation protection of the Beta-1,3D glucan (Macroglucan) from baker's yeast (Saccharomyces cerevisiae). We used animals were C3H mice. The animals were divided into following group, 1) control group, 2) 200mg/kg of Macroglucan group, 3) 400mg/kg of Macroglucan group, 4) 800mg/kg of Macroglucan group. After intraperitoneal injection of Macroglucan each concentration, we measured blood cells, NK-cell, LAK-cell activity, tumor growth, and charge of the body weight, surviving fraction, and examination of small intestines using microscope after irradiation. The white blood cell was increased to 1.2 times and the lymphocyte was increased to 1.7 times after injection of Macroglucan. The tumor growth delay was observed after injection of Macroglucan. Inhabitation of body weight loss, increase of surviving fraction and protect of small intestines was observed after injection of Macroglucan. These results demonstrated the immunological activity, the anti-tumor effects and the radiation protection after injection of Macroglucan.

  20. Resistance of radiation-induced tropical wood-polymer composites to fungal degradation

    Energy Technology Data Exchange (ETDEWEB)

    Chia, L.H.L.; Lim, V.S.L.; Yap, M.G.S.

    1987-01-01

    The resistance of six tropical hardwoods to fungal degradation by two wild-type strains of Phanerochaete chrysosporium Burdsall was investigated using vermiculite burial and wood-block weight loss techniques. Radiation-induced wood-polymer composites (WPC), based on two hardwoods Ramin and Rubberwood with methyl methacrylate, were prepared, and samples were also exposed to the wood-rotting fungus. A significant improvement in resistance to fungal decay was observed in the WPC. Scanning-electron micrographs of the two woods and their composites after fungal degradation are presented and discussed.

  1. Electrophysiological Monitoring in Patients With Tumors of the Skull Base Treated by Carbon-12 Radiation Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Carozzo, Simone [Department of Neuroscience, Ophthalmology, and Genetics, University of Genova, Genova (Italy); Schardt, Dieter [Department of Biophysics, GSI Helmholtzzentrum für Schwerionenforschung, Darmstadt (Germany); Narici, Livio [Department of Physics, University of Rome Tor Vergata, Rome (Italy); Combs, Stephanie E.; Debus, Jürgen [Department of Radiation Oncology, University of Heidelberg, Heidelberg (Germany); Sannita, Walter G., E-mail: wgs@dism.unige.it [Department of Neuroscience, Ophthalmology, and Genetics, University of Genova, Genova (Italy); Department of Psychiatry, State University of New York, Stony Brook, New York (United States)

    2013-03-15

    Purpose: To report the results of short-term electrophysiologic monitoring of patients undergoing {sup 12}C therapy for the treatment of skull chordomas and chondrosarcomas unsuitable for radical surgery. Methods and Materials: Conventional electroencephalogram (EEG) and retinal and cortical electrophysiologic responses to contrast stimuli were recorded from 30 patients undergoing carbon ion radiation therapy, within a few hours before the first treatment and after completion of therapy. Methodologies and procedures were compliant with the guidelines of the International Federation for Clinical Neurophysiology and International Society for Clinical Electrophysiology of Vision. Results: At baseline, clinical signs were reported in 56.6% of subjects. Electrophysiologic test results were abnormal in 76.7% (EEG), 78.6% (cortical evoked potentials), and 92.8% (electroretinogram) of cases, without correlation with neurologic signs, tumor location, or therapy plan. Results on EEG, but not electroretinograms and cortical responses, were more often abnormal in patients with reported clinical signs. Abnormal EEG results and retinal/cortical responses improved after therapy in 40% (EEG), 62.5% (cortical potentials), and 70% (electroretinogram) of cases. Results on EEG worsened after therapy in one-third of patients whose recordings were normal at baseline. Conclusions: The percentages of subjects whose EEG results improved or worsened after therapy and the improvement of retinal/cortical responses in the majority of patients are indicative of a limited or negligible (and possibly transient) acute central nervous system toxicity of carbon ion therapy, with a significant beneficial effect on the visual pathways. Research on large samples would validate electrophysiologic procedures as a possible independent test for central nervous system toxicity and allow investigation of the correlation with clinical signs; repeated testing over time after therapy would demonstrate, and may

  2. Acoustic radiation force impulse shear wave elastography (ARFI) of acute and chronic pancreatitis and pancreatic tumor.

    Science.gov (United States)

    Goertz, Ruediger S; Schuderer, Johanna; Strobel, Deike; Pfeifer, Lukas; Neurath, Markus F; Wildner, Dane

    2016-12-01

    Acoustic Radiation Force Impulse (ARFI) elastography evaluates tissue stiffness non-invasively and has rarely been applied to pancreas examinations so far. In a prospective and retrospective analysis, ARFI shear wave velocities of healthy parenchyma, pancreatic lipomatosis, acute and chronic pancreatitis, adenocarcinoma and neuroendocrine tumor (NET) of the pancreas were evaluated and compared. In 95 patients ARFI elastography of the pancreatic head, and also of the tail for a specific group, was analysed retrospectively. Additionally, prospectively in 100 patients ARFI was performed in the head and tail of the pancreas. A total of 195 patients were included in the study. Healthy parenchyma (n=21) and lipomatosis (n=30) showed similar shear wave velocities of about 1.3m/s. Acute pancreatitis (n=35), chronic pancreatitis (n=53) and adenocarcinoma (n=52) showed consecutively increasing ARFI values, respectively. NET (n=4) revealed the highest shear wave velocities amounting to 3.62m/s. ARFI elastography showed relevant differences between acute pancreatitis and chronic pancreatitis or adenocarcinoma. With a cut-off value of 1.74m/s for the diagnosis of a malignant disease the sensitivity was 91.1% whereas the specificity amounted to 60.4%. ARFI shear wave velocities present differences in various pathologies of the pancreas. Acute and chronic pancreatitis as well as neoplastic lesions show high ARFI values. Very high elasticity values may indicate malignant disease of the pancreas. However, there is a considerable overlap between the entities. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  3. Ovarian cancer spheroid cells with stem cell-like properties contribute to tumor generation, metastasis and chemotherapy resistance through hypoxia-resistant metabolism.

    Science.gov (United States)

    Liao, Jianqun; Qian, Feng; Tchabo, Nana; Mhawech-Fauceglia, Paulette; Beck, Amy; Qian, Zikun; Wang, Xinhui; Huss, Wendy J; Lele, Shashikant B; Morrison, Carl D; Odunsi, Kunle

    2014-01-01

    Cells with sphere forming capacity, spheroid cells, are present in the malignant ascites of patients with epithelial ovarian cancer (EOC) and represent a significant impediment to efficacious treatment due to their putative role in progression, metastasis and chemotherapy resistance. The exact mechanisms that underlie EOC metastasis and drug resistance are not clear. Understanding the biology of sphere forming cells may contribute to the identification of novel therapeutic opportunities for metastatic EOC. Here we generated spheroid cells from human ovarian cancer cell lines and primary ovarian cancer. Xenoengraftment of as few as 2000 dissociated spheroid cells into immune-deficient mice allowed full recapitulation of the original tumor, whereas >10(5) parent tumor cells remained non-tumorigenic. The spheroid cells were found to be enriched for cells with cancer stem cell-like characteristics such as upregulation of stem cell genes, self-renewal, high proliferative and differentiation potential, and high aldehyde dehydrogenase (ALDH) activity. Furthermore, spheroid cells were more aggressive in growth, migration, invasion, scratch recovery, clonogenic survival, anchorage-independent growth, and more resistant to chemotherapy in vitro. (13)C-glucose metabolic studies revealed that spheroid cells route glucose predominantly to anaerobic glycolysis and pentose cycle to the detriment of re-routing glucose for anabolic purposes. These metabolic properties of sphere forming cells appear to confer increased resistance to apoptosis and contribute to more aggressive tumor growth. Collectively, we demonstrated that spheroid cells with cancer stem cell-like characteristics contributed to tumor generation, progression and chemotherapy resistance. This study provides insight into the relationship between tumor dissemination and metabolic attributes of human cancer stem cells and has clinical implications for cancer therapy.

  4. Radiation-resistant erbium-doped-nanoparticles optical fiber for space applications.

    Science.gov (United States)

    Thomas, Jérémie; Myara, Mikhaël; Troussellier, Laurent; Burov, Ekaterina; Pastouret, Alain; Boivin, David; Mélin, Gilles; Gilard, Olivier; Sotom, Michel; Signoret, Philippe

    2012-01-30

    We demonstrate for the first time a radiation-resistant Erbium-Doped Fiber exhibiting performances that can fill the requirements of Erbium-Doped Fiber Amplifiers for space applications. This is based on an Aluminum co-doping atom reduction enabled by Nanoparticules Doping-Process. For this purpose, we developed several fibers containing very different erbium and aluminum concentrations, and tested them in the same optical amplifier configuration. This work allows to bring to the fore a highly radiation resistant Erbium-doped pure silica optical fiber exhibiting a low quenching level. This result is an important step as the EDFA is increasingly recognized as an enabling technology for the extensive use of photonic sub-systems in future satellites.

  5. Effect of nano-oxide particle size on radiation resistance of iron–chromium alloys

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Weizong; Li, Lulu [Department of Materials Science and Engineering, North Carolina State University, Raleigh, NC 27695 (United States); Valdez, James A. [Materials Science and Technology Division, Los Alamos National Laboratory, Los Alamos, NM 87545 (United States); Saber, Mostafa [Department of Mechanical and Materials Engineering, Portland State University, Portland, OR 97201 (United States); Zhu, Yuntian, E-mail: ytzhu@ncsu.edu [Department of Materials Science and Engineering, North Carolina State University, Raleigh, NC 27695 (United States); Koch, Carl C.; Scattergood, Ronald O. [Department of Materials Science and Engineering, North Carolina State University, Raleigh, NC 27695 (United States)

    2016-02-15

    Radiation resistance of Fe–14Cr alloys under 200 keV He irradiation at 500 °C was systematically investigated with varying sizes of nano oxide Zr, Hf and Cr particles. It is found that these nano oxide particles acted as effective sites for He bubble formation. By statistically analyzing 700–1500 He bubbles at the depth of about 150–700 nm from a series of HRTEM images for each sample, we established the variation of average He bubble size, He bubble density, and swelling percentage along the depth, and found them to be consistent with the He concentration profile calculated from the SIRM program. Oxide particles with sizes less than 3.5–4 nm are found most effective for enhancing radiation resistance in the studied alloy systems.

  6. Large-Scale Procurement of Radiation Resistant Single-Mode Optical Fibers for CERN

    CERN Document Server

    Guillermain, Elisa; Kuhnhenn, Jochen; Ricci, Daniel; Weinand, Udo

    2015-01-01

    2400 km of special radiation resistant optical fibres were procured by CERN (European Organization for Nuclear Research), for the installation of more than 55 km of optical fibre cables in the accelerator complex underground during the Long Shutdown 1 (LS1). In the frame of this large-scale industrial production, a thorough quality assurance plan (QAP) was put in place and followed at each step of the process. In-depth qualification of optical fibres preceded the 17-month procurement process. All supplied batches were tested for their resistance to radiation, leading to more than 65 quality control irradiation tests. During the cable assembly process and the installations works, a full traceability down to the optical fibre level was ensured. The actions put in place in the frame of the QAP led to successful installation works and to full respect of the LS1 planning.

  7. With me or against me: Tumor suppressor and drug resistance activities of SAMHD1.

    Science.gov (United States)

    Herold, Nikolas; Rudd, Sean G; Sanjiv, Kumar; Kutzner, Juliane; Myrberg, Ida Hed; Paulin, Cynthia B J; Olsen, Thale Kristin; Helleday, Thomas; Henter, Jan-Inge; Schaller, Torsten

    2017-08-01

    Sterile alpha motif and histidine/aspartic acid domain-containing protein 1 (SAMHD1) is a (deoxy)guanosine triphosphate (dGTP/GTP)-activated deoxyribonucleoside triphosphate (dNTP) triphosphohydrolase involved in cellular dNTP homoeostasis. Mutations in SAMHD1 have been associated with the hyperinflammatory disease Aicardi-Goutières syndrome (AGS). SAMHD1 also limits cells' permissiveness to infection with diverse viruses, including human immunodeficiency virus (HIV-1), and controls endogenous retroviruses. Increasing evidence supports the role of SAMHD1 as a tumor suppressor. However, SAMHD1 also can act as a resistance factor to nucleoside-based chemotherapies by hydrolyzing their active triphosphate metabolites, thereby reducing response of various malignancies to these anticancer drugs. Hence, informed cancer therapies must take into account the ambiguous properties of SAMHD1 as both an inhibitor of uncontrolled proliferation and a resistance factor limiting the efficacy of anticancer treatments. Here, we provide evidence that SAMHD1 is a double-edged sword for patients with acute myelogenous leukemia (AML). Our time-dependent analyses of The Cancer Genome Atlas (TCGA) AML cohort indicate that high expression of SAMHD1, even though it critically limits the efficacy of high-dose ara-C therapy, might be associated with more favorable disease progression. Copyright © 2017 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.

  8. Cancer systems biology in the genome sequencing era: part 2, evolutionary dynamics of tumor clonal networks and drug resistance.

    Science.gov (United States)

    Wang, Edwin; Zou, Jinfeng; Zaman, Naif; Beitel, Lenore K; Trifiro, Mark; Paliouras, Miltiadis

    2013-08-01

    A tumor often consists of multiple cell subpopulations (clones). Current chemo-treatments often target one clone of a tumor. Although the drug kills that clone, other clones overtake it and the tumor recurs. Genome sequencing and computational analysis allows to computational dissection of clones from tumors, while singe-cell genome sequencing including RNA-Seq allows profiling of these clones. This opens a new window for treating a tumor as a system in which clones are evolving. Future cancer systems biology studies should consider a tumor as an evolving system with multiple clones. Therefore, topics discussed in Part 2 of this review include evolutionary dynamics of clonal networks, early-warning signals (e.g., genome duplication events) for formation of fast-growing clones, dissecting tumor heterogeneity, and modeling of clone-clone-stroma interactions for drug resistance. The ultimate goal of the future systems biology analysis is to obtain a 'whole-system' understanding of a tumor and therefore provides a more efficient and personalized management strategies for cancer patients. Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.

  9. A DICOM-RT based ePR radiation therapy information system for managing brain tumor patients

    Science.gov (United States)

    Liu, Brent J.; Law, Maria; Huang, H. K.; Zee, C. S.; Chan, Lawrence

    2005-04-01

    The need for comprehensive clinical image data and relevant information in image-guided Radiation Therapy (RT) is becoming steadily apparent. Multiple standalone systems utilizing the most technological advancements in imaging, therapeutic radiation, and computerized treatment planning systems acquire key data during the RT treatment course of a patient. One example are patients treated for brain tumors of greater sizes and irregular shapes that utilize state-of-the-art RT technology to deliver pinpoint accurate radiation doses. One such system, the Cyberknife, is a radiation treatment system that utilizes image-guided information to control a multi-jointed, six degrees of freedom, robotic arm to deliver precise and required radiation dose to the tumor site of a cancer patient. The image-guided system is capable of tracking the lesion orientations with respect to the patient"s position throughout the treatment process. This is done by correlating live radiographic images with pre-operative, CT and MR imaging information to determine relative patient and tumor position repeatedly over the course of the treatment. The disparate and complex data generated by the Cyberknife system along with related data is scattered throughout the RT department compromising an efficient clinical workflow since the data crucial for a clinical decision may be time-consuming to retrieve, temporarily missing, or even lost. To address these shortcomings, the ACR-NEMA Standards Committee extended its DICOM (Digital Imaging & Communications in Medicine) Standard from Radiology to RT by ratifying seven DICOM RT objects starting in 1997. However, they are rarely used by the RT community in daily clinical operations. In the past, the research focus of an RT department has primarily been developing new protocols and devices to improve treatment process and outcomes of cancer patients with minimal effort dedicated to integration of imaging and information systems. Our research, tightly

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2014-04-01

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

  11. Topotecan distribution in an anephric infant with therapy resistant bilateral Wilms tumor with a novel germline WT1 gene mutation

    NARCIS (Netherlands)

    R.T. Lugtenberg (Rieneke); K. Cransberg (Karlien); W.J. Loos (Walter); A. Wagner (Anja); M. Alders (Mariëlle); M.M. van den Heuvel-Eibrink (Marry)

    2008-01-01

    textabstractThe therapeutic strategy for bilateral Wilms tumor (WT) remains a challenge. Especially in cases with chemotherapy resistant disease, bilateral nephrectomy is sometimes inevitable. For optimal cure rates stage V WT patients benefit from adjuvant treatment; however, there are limited data

  12. Unraveling Fungal Radiation Resistance Regulatory Networks through the Genome-Wide Transcriptome and Genetic Analyses of Cryptococcus neoformans.

    Science.gov (United States)

    Jung, Kwang-Woo; Yang, Dong-Hoon; Kim, Min-Kyu; Seo, Ho Seong; Lim, Sangyong; Bahn, Yong-Sun

    2016-11-29

    The basidiomycetous fungus Cryptococcus neoformans has been known to be highly radiation resistant and has been found in fatal radioactive environments such as the damaged nuclear reactor at Chernobyl. To elucidate the mechanisms underlying the radiation resistance phenotype of C. neoformans, we identified genes affected by gamma radiation through genome-wide transcriptome analysis and characterized their functions. We found that genes involved in DNA damage repair systems were upregulated in response to gamma radiation. Particularly, deletion of recombinase RAD51 and two DNA-dependent ATPase genes, RAD54 and RDH54, increased cellular susceptibility to both gamma radiation and DNA-damaging agents. A variety of oxidative stress response genes were also upregulated. Among them, sulfiredoxin contributed to gamma radiation resistance in a peroxiredoxin/thioredoxin-independent manner. Furthermore, we found that genes involved in molecular chaperone expression, ubiquitination systems, and autophagy were induced, whereas genes involved in the biosynthesis of proteins and fatty acids/sterols were downregulated. Most importantly, we discovered a number of novel C. neoformans genes, the expression of which was modulated by gamma radiation exposure, and their deletion rendered cells susceptible to gamma radiation exposure, as well as DNA damage insults. Among these genes, we found that a unique transcription factor containing the basic leucine zipper domain, named Bdr1, served as a regulator of the gamma radiation resistance of C. neoformans by controlling expression of DNA repair genes, and its expression was regulated by the evolutionarily conserved DNA damage response protein kinase Rad53. Taken together, the current transcriptome and functional analyses contribute to the understanding of the unique molecular mechanism of the radiation-resistant fungus C. neoformans IMPORTANCE: Although there are no natural environments under intense radiation, some living organisms

  13. Elimination of Listeria monocytogenes in sausage meat by combination treatment: Radiation and radiation-resistant bacteriocins

    Science.gov (United States)

    Turgis, Mélanie; Stotz, Viviane; Dupont, Claude; Salmieri, Stéphane; Khan, Ruhul A.; Lacroix, Monique

    2012-08-01

    Two new bacteria were isolated from human feces and were designated MT 104 and MT 162. They were able to produce bacteriocins that are active against five strains of Listeria monocytogenes. Bacteriocins produced by these isolated strains had 100% and 82.35% residual activity when they were treated by gamma radiation at doses of 4 and 40 kGy, respectively. A reduction of 1.0, 1.5 and 3 log CFU/g of L. monocytogenes was observed in sausage meat when treated with bacteriocins from MT 104, MT 162, and nisin, respectively. For synergic effect, the D10 value in presence of the bacteriocins produced by MT 104 showed a 1.08 fold increased relative sensitivity of L. monocytogenes as compared to control after 5 days. The highest synergic effect was observed in presence of nisin which led to 1.61 fold increased relative sensitivity. Combined treatments with nisin and γ-irradiation showed a synergic antimicrobial effect in meat after 24 h and 5 days of storage. A synergic effect was observed only after 5 days at 4 °C for the bacteriocin from MT 104, as compared to the bacteriocin produced by MT 162 that had only an additive antimicrobial effect in all conditions.

  14. Postoperative Stereotactic Radiosurgery Without Whole-Brain Radiation Therapy for Brain Metastases: Potential Role of Preoperative Tumor Size

    Energy Technology Data Exchange (ETDEWEB)

    Hartford, Alan C., E-mail: Alan.C.Hartford@Hitchcock.org [Section of Radiation Oncology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire (United States); Paravati, Anthony J. [Section of Radiation Oncology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire (United States); Spire, William J. [Section of Neurosurgery, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire (United States); Li, Zhongze [Biostatistics Shared Resource, Norris Cotton Cancer Center, Lebanon, New Hampshire (United States); Jarvis, Lesley A. [Section of Radiation Oncology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire (United States); Fadul, Camilo E. [Section of Hematology/Oncology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire (United States); Rhodes, C. Harker [Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire (United States); Erkmen, Kadir [Section of Neurosurgery, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire (United States); Friedman, Jonathan [Department of Surgery, Texas A and M College of Medicine, College Station, Texas (United States); Gladstone, David J. [Section of Radiation Oncology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire (United States); Hug, Eugen B. [ProCure, New York, New York (United States); Roberts, David W.; Simmons, Nathan E. [Section of Neurosurgery, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire (United States)

    2013-03-01

    Purpose: Radiation therapy following resection of a brain metastasis increases the probability of disease control at the surgical site. We analyzed our experience with postoperative stereotactic radiosurgery (SRS) as an alternative to whole-brain radiotherapy (WBRT), with an emphasis on identifying factors that might predict intracranial disease control and overall survival (OS). Methods and Materials: We retrospectively reviewed all patients through December 2008, who, after surgical resection, underwent SRS to the tumor bed, deferring WBRT. Multiple factors were analyzed for time to intracranial recurrence (ICR), whether local recurrence (LR) at the surgical bed or “distant” recurrence (DR) in the brain, for time to WBRT, and for OS. Results: A total of 49 lesions in 47 patients were treated with postoperative SRS. With median follow-up of 9.3 months (range, 1.1-61.4 months), local control rates at the resection cavity were 85.5% at 1 year and 66.9% at 2 years. OS rates at 1 and 2 years were 52.5% and 31.7%, respectively. On univariate analysis (preoperative) tumors larger than 3.0 cm exhibited a significantly shorter time to LR. At a cutoff of 2.0 cm, larger tumors resulted in significantly shorter times not only for LR but also for DR, ICR, and salvage WBRT. While multivariate Cox regressions showed preoperative size to be significant for times to DR, ICR, and WBRT, in similar multivariate analysis for OS, only the graded prognostic assessment proved to be significant. However, the number of intracranial metastases at presentation was not significantly associated with OS nor with other outcome variables. Conclusions: Larger tumor size was associated with shorter time to recurrence and with shorter time to salvage WBRT; however, larger tumors were not associated with decrements in OS, suggesting successful salvage. SRS to the tumor bed without WBRT is an effective treatment for resected brain metastases, achieving local control particularly for tumors up to

  15. Evaluation of dynamic contrast-enhanced T1-weighted perfusion MRI in the differentiation of tumor recurrence from radiation necrosis

    Energy Technology Data Exchange (ETDEWEB)

    Larsen, Vibeke A. [Glostrup University Hospital, Department of Radiology, Glostrup (Denmark); Glostrup University Hospital, Department of Radiology, Copenhagen Oe (Denmark); Simonsen, Helle J.; Larsson, Henrik B.W. [Glostrup University Hospital, Functional Imaging Unit, Glostrup (Denmark); Glostrup University Hospital, Department of Clinical Physiology, Glostrup (Denmark); Law, Ian [Nuclear Medicine and PET, Department of Clinical Physiology, Copenhagen Oe (Denmark); Hansen, Adam E. [Glostrup University Hospital, Department of Radiology, Glostrup (Denmark); Glostrup University Hospital, Functional Imaging Unit, Glostrup (Denmark)

    2013-03-15

    To investigate if perfusion measured with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can be used to differentiate radiation necrosis from tumor recurrence in patients with high-grade glioma. The study was approved by the institutional review board and informed consent was obtained from all subjects. 19 patients were recruited following surgery and radiation therapy for glioma. Patients had contrast enhancing lesions, which during the standard MRI examination could not be exclusively determined as recurrence or radiation necrosis. DCE-MRI was used to measure cerebral blood volume (CBV), blood-brain barrier (BBB) permeability and cerebral blood flow (CBF). Subjects also underwent FDG-PET and lesions were classified as either metabolically active or inactive. Follow-up clinical MRI and lesion histology in case of additional tissue resection was used to determine whether lesions were regressing or progressing. Fourteen enhancing lesions could be classified as progressing (11) or regressing (three). An empirical threshold of 2.0 ml/100 g for CBV allowed detection of regressing lesions with a sensitivity of 100 % and specificity of 100 %. FDG-PET and DCE-MRI agreed in classification of tumor status in 13 out of the 16 cases where an FDG-PET classification was obtained. In two of the remaining three patients, MRI follow-up and histology was available and both indicated that the DCE-MRI answer was correct. CBV measurements using DCE-MRI may predict the status of contrast enhancing lesions and give results very similar to FDG-PET with regards to differentiation between tumor recurrence and radiation necrosis. (orig.)

  16. Prostate tumor alignment and continuous, real-time adaptive radiation therapy using electromagnetic fiducials: clinical and cost-utility analyses.

    Science.gov (United States)

    Quigley, Martin M; Mate, Timothy P; Sylvester, John E

    2009-01-01

    To evaluate the accuracy, utility, and cost effectiveness of a new electromagnetic patient positioning and continuous, real-time monitoring system, which uses permanently implanted resonant transponders in the target (Calypso 4D Localization System and Beacon transponders, Seattle, WA) to continuously monitor tumor location and movement during external beam radiation therapy of the prostate. This clinical trial studied 43 patients at 5 sites. All patients were implanted with 3 transponders each. In 41 patients, the system was used for initial alignment at each therapy session. Thirty-five patients had continuous monitoring during their radiation treatment. Over 1,000 alignment comparisons were made to a commercially available kV X-ray positioning system (BrainLAB ExacTrac, Munich, Germany). Using decision analysis and Markov processes, the outcomes of patients were simulated over a 5-year period and measured in terms of costs from a payer's perspective and quality-adjusted life years (QALYs). All patients had satisfactory transponder implantations for monitoring purposes. In over 75% of the treatment sessions, the correction to conventional positioning (laser and tattoos) directed by an electromagnetic patient positioning and monitoring system was greater than 5 mm. Ninety-seven percent (34/35) of the patients who underwent continuous monitoring had target motion that exceeded preset limits at some point during the course of their radiation therapy. Exceeding preset thresholds resulted in user intervention at least once during the therapy in 80% of the patients (28/35). Compared with localization using ultrasound, electronic portal imaging devices (EPID), or computed tomography (CT), localization with the electromagnetic patient positioning and monitoring system yielded superior gains in QALYs at comparable costs. Most patients positioned with conventional tattoos and lasers for prostate radiation therapy were found by use of the electromagnetic patient positioning

  17. Structural Component Fabrication and Characterization of Advanced Radiation Resistant ODS Steel for Next Generation Nuclear Systems

    Energy Technology Data Exchange (ETDEWEB)

    Noh, Sang Hoon; Kim, Young Chun; Jin, Hyun Ju; Choi, Byoung Kwon; Kang, Suk Hoon; Kim, Tae Kyu [KAERI, Daejeon (Korea, Republic of)

    2016-05-15

    In a sodium-cooled fast reactor (SFR), the coolant outlet temperature and peak temperature of the fuel cladding tube will be about 545 .deg. C and 700 .deg. C with 250 dpa of a very high neutron dose rate. To realize this system, it is necessary to develop an advanced structural material having high creep and irradiation resistance at high temperatures. Austenitic stainless steel may be one of the candidates because of good strength and corrosion resistance at the high temperatures, however irradiation swelling severely occurred to 120dpa at high temperatures and this eventually leads to a decrease of the mechanical properties and dimensional stability. Advanced radiation resistant ODS steel (ARROS) has been newly developed for the in-core structural components in SFR, which has very attractive microstructures to achieve both superior creep and radiation resistances at high temperatures [4]. Nevertheless, the use of ARROS as a structural material essentially requires the fabrication technology development for component parts such as sheet, plate and tube. In this study, plates and tubes were tentatively fabricated with a newly developed alloy, ARROS. Microstructures as well as mechanical properties were also investigated to determine the optimized condition of the fabrication processes.

  18. Study of multidrug resistance and radioresistance

    Energy Technology Data Exchange (ETDEWEB)

    Kang, Yoon Koo; Yoo, Young Do

    1999-04-01

    We investigated the mechanism of 5-FU, adriamycin, radiation resistance in Korean gastric cancer cells. First we investigated the relation between Rb and multidrug resistance. Rb stable transfectants exhibited 5- to 10- fold more resistance to adriamycin than the control cells. These Rb transfectants showed increased MDR1 expression. We also investigated up-regulation in radiation-resistant tumor tissues. HSP27, MRP-8, GST, and NKEF-B were up-regulated in radiation resistant tumor. Expression of NKEF-B was also increased by radiation exposure in Head and Neck cells. These results demonstrated that NKEF-B is a stress response protein and it may have an important role in radiation resistance.

  19. Expression of P-glycoprotein and multidrug resistance associated protein in Ehrlich ascites tumor cells after fractionated irradiation

    DEFF Research Database (Denmark)

    Nielsen, D; Maare, C; Eriksen, J

    2001-01-01

    PURPOSE: To characterize irradiated murine tumor cells with respect to drug resistance, drug kinetics, and ATPase activity, and to evaluate the possible role of P-glycoprotein (PGP) and murine multidrug resistance associated protein (Mrp1) in the drug-resistant phenotype of these cells. METHODS...... AND MATERIALS: Sensitive Ehrlich ascites tumor cells (EHR2) were in vitro exposed to fractionated irradiation (60 Gy). Western blot analysis was performed for determination of PGP and Mrp1, reverse transcriptase-polymerase chain reaction (RT-PCR) for determination of mdr1a + b mRNA, and semiquantitative RT......-PCR for Mrp1 mRNA. The clonogenic assay was applied to investigate sensitivity, whereas the steady-state drug accumulation of daunorubicin (DNR), 3H-vincristine (VCR), and 3H-etoposide (VP16) was measured by spectrofluorometry and scintillation counting, respectively. For determining of ATPase activity...

  20. 4-1BB Aptamer-Based Immunomodulation Enhances the Therapeutic Index of Radiation Therapy in Murine Tumor Models

    Energy Technology Data Exchange (ETDEWEB)

    Benaduce, Ana Paula; Brenneman, Randall; Schrand, Brett; Pollack, Alan; Gilboa, Eli; Ishkanian, Adrian, E-mail: aishkanian@med.miami.edu

    2016-10-01

    Purpose: To report a novel strategy using oligonucleotide aptamers to 4-1BB as an alternate method for costimulation, and show that combinatorial therapy with radiation improves the therapeutic ratio over equivalent monoclonal antibodies. Methods and Materials: Subcutaneous 4T1 (mouse mammary carcinoma) tumors were established (approximately 100 mm{sup 3}), and a radiation therapy (RT) dose/fractionation schedule that optimally synergizes with 4-1BB monoclonal antibody (mAb) was identified. Comparable tumor control and animal survival was observed when either 4-1BB antibody or aptamer were combined with RT using models of breast cancer and melanoma (4T1 and B16-F10). Off-target CD8{sup +} T-cell toxicity was evaluated by quantification of CD8{sup +} T cells in livers and spleens of treated animals. Results: When combined with 4-1BB mAb, significant differences in tumor control were observed by varying RT dose and fractionation schedules. Optimal synergy between RT and 4-1BB mAb was observed at 5 Gy × 6. Testing 4-1BB mAb and aptamer independently using the optimal RT (5 Gy × 6 for 4T1/Balb/c and 12 Gy × 1 for B16/C57BL6J mouse models) revealed equivalent tumor control using 4-1BB aptamer and 4-1BB mAb. 4-1BB mAb, but not 4-1BB aptamer-treated animals, exhibited increased lymphocytic liver infiltrates and increased splenic and liver CD8{sup +} T cells. Conclusions: Radiation therapy synergizes with 4-1BB mAb, and this effect is dependent on RT dose and fractionation. Tumor control by 4-1BB aptamer is equivalent to 4-1BB mAb when combined with optimal RT dose, without eliciting off-target liver and spleen CD8{sup +} expansion. 4-1BB aptamer-based costimulation affords a comparable and less toxic strategy to augment RT-mediated tumor control.

  1. Considering the oxygen effect: Further development of a volumetric model of tumor response to radiation therapy for cervical cancer

    Science.gov (United States)

    Winkler, Stephanie S.

    Mathematical modeling of tumor response to radiation therapy (RT) has great potential for designing therapy plans that are more personalized, more adaptive, and more reliable for outcome predictions. A preexisting model of tumor response to radiation therapy for cervical cancer has been shown to generate model parameters that correlate strongly with both tumor local control and disease-specific survival. This model is further developed through incorporation of another effect of RT not previously accounted for: the oxygen effect. An easily obtainable form of input data, hemoglobin level, enables simulation of the oxygen effect simultaneously with the other major model effects. For the Local Control (LC) patient group, the changes in the model parameters caused by incorporation of the oxygen effect are found to significantly improve the agreement of those parameters with actual patient data. For the Local Failure (LF) group and the overall patient group, the oxygen effect is incorporated without significant change to the agreement between the model-simulated output parameters and the actual patient data. Also, a strategy is presented for solving the main model equations to obtain analytic expressions for surviving cell fraction and regression volume ratio as functions of time.

  2. The effect of X-ray and heavy ions radiations on chemotherapy refractory tumor cells

    Directory of Open Access Journals (Sweden)

    Zhan eYu

    2016-03-01

    Full Text Available Purpose: To link both numeric and structural chromosomal aberrations to the effectiveness of radiotherapy in chemotherapy refractory tumor cells.Materials and methods: Neuroblastoma (LAN-1 and 79HF6 glioblastoma cells derived from patients and their chemoresistant sublines were artificially cultured as neurospheres and irradiated by x-rays and heavy ions sources. All the cell lines were irradiated by Carbon-SIS with LET of 100 keV/µm. 79HF6 cells were also irradiated by Carbon-UNILAC with LET of 168 keV/µm, while LAN-1 cells were irradiated by Nickel ions with LET of 174 keV/µm. The effect of radiation on the survival and proliferation of cells was addressed by standards clonogenic assays. In order to analyze cell karyotype standard giemsa-staining, multicolor fluorescence in situ hybridization technique and multicolor banding technique were applied.Results: Relative biological effectiveness (RBE values of heavy ions beam relative to X-rays at the D10-values were found between 2.3-2.6 with Carbon-SIS and Nickel for LAN-1, while that were 2.5-3.4 with Carbon-SIS and Carbon-UNILAC for 79HF6 cells. Chemorefractory LAN-1RETO cells were found more radioresistant than untreated LAN-1WT cells. 79HF6RETO glioblastoma cells were found more radiosensitive than cytostatic sensitive cells 79HF6WT. Sphere formation assay showed LAN-1RETO cells were able to form spheres in serum-free culture whereas 79HF6 cells could not. Most of 79HF6WT cells revealed to content 71-90 chromosomes while 79HF6RETO revealed a numeric of 52-83 chromosomes. The majority of LAN-1WT cells revealed a number of 40-44 chromosomes. mFISH analysis showed some stable aberrations especially on chromosome 10 with as judged by the impossibility to label this region with specific probes. This was corroborated using mBAND analysis.Conclusions: Heavy ion irradiation were more effective than X-ray in both cytostatic naive cancer and chemoresistant cell lines. LAN-1RETO chemoresistant

  3. Sunlight-exposed biofilm microbial communities are naturally resistant to chernobyl ionizing-radiation levels.

    Directory of Open Access Journals (Sweden)

    Marie Ragon

    Full Text Available BACKGROUND: The Chernobyl accident represents a long-term experiment on the effects of exposure to ionizing radiation at the ecosystem level. Though studies of these effects on plants and animals are abundant, the study of how Chernobyl radiation levels affect prokaryotic and eukaryotic microbial communities is practically non-existent, except for a few reports on human pathogens or soil microorganisms. Environments enduring extreme desiccation and UV radiation, such as sunlight exposed biofilms could in principle select for organisms highly resistant to ionizing radiation as well. METHODOLOGY/PRINCIPAL FINDINGS: To test this hypothesis, we explored the diversity of microorganisms belonging to the three domains of life by cultivation-independent approaches in biofilms developing on concrete walls or pillars in the Chernobyl area exposed to different levels of radiation, and we compared them with a similar biofilm from a non-irradiated site in Northern Ireland. Actinobacteria, Alphaproteobacteria, Bacteroidetes, Acidobacteria and Deinococcales were the most consistently detected bacterial groups, whereas green algae (Chlorophyta and ascomycete fungi (Ascomycota dominated within the eukaryotes. Close relatives to the most radio-resistant organisms known, including Rubrobacter species, Deinococcales and melanized ascomycete fungi were always detected. The diversity of bacteria and eukaryotes found in the most highly irradiated samples was comparable to that of less irradiated Chernobyl sites and Northern Ireland. However, the study of mutation frequencies in non-coding ITS regions versus SSU rRNA genes in members of a same actinobacterial operational taxonomic unit (OTU present in Chernobyl samples and Northern Ireland showed a positive correlation between increased radiation and mutation rates. CONCLUSIONS/SIGNIFICANCE: Our results show that biofilm microbial communities in the most irradiated samples are comparable to non-irradiated samples in

  4. [Formula: see text]Working memory and attention in pediatric brain tumor patients treated with and without radiation therapy.

    Science.gov (United States)

    Raghubar, Kimberly P; Mahone, E Mark; Yeates, Keith Owen; Cecil, Kim M; Makola, Monwabisi; Ris, M Douglas

    2017-08-01

    Children are at risk for cognitive difficulties following the diagnosis and treatment of a brain tumor. Longitudinal studies have consistently demonstrated declines on measures of intellectual functioning, and recently it has been proposed that specific neurocognitive processes underlie these changes, including working memory, processing speed, and attention. However, a fine-grained examination of the affected neurocognitive processes is required to inform intervention efforts. Radiation therapy (RT) impacts white matter integrity, likely affecting those cognitive processes supported by distributed neural networks. This study examined working memory and attention in children during the early delayed stages of recovery following surgical resection and RT. The participants included 27 children diagnosed with pediatric brain tumor, treated with (n = 12) or without (n = 15) RT, who completed experimental and standardized measures of working memory and attention (n-back and digit span tasks). Children treated with radiation performed less well than those who did not receive radiation on the n-back measure, though performance at the 0-back level was considerably poorer than would be expected for both groups, perhaps suggesting difficulties with more basic processes such as vigilance. Along these lines, marginal differences were noted on digit span forward. The findings are discussed with respect to models of attention and working memory, and the interplay between the two.

  5. RAD18 mediates resistance to ionizing radiation in human glioma cells

    Energy Technology Data Exchange (ETDEWEB)

    Xie, Chen; Wang, Hongwei; Cheng, Hongbin; Li, Jianhua; Wang, Zhi, E-mail: drzwang@gmail.com; Yue, Wu, E-mail: drwuyue@gmail.com

    2014-02-28

    Highlights: • RAD18 is an important mediator of the IR-induced resistance in glioma cell lines. • RAD18 overexpression confers resistance to IR-mediated apoptosis. • The elevated expression of RAD18 is associated with recurrent GBM who underwent IR therapy. - Abstract: Radioresistance remains a major challenge in the treatment of glioblastoma multiforme (GBM). RAD18 a central regulator of translesion DNA synthesis (TLS), has been shown to play an important role in regulating genomic stability and DNA damage response. In the present study, we investigate the relationship between RAD18 and resistance to ionizing radiation (IR) and examined the expression levels of RAD18 in primary and recurrent GBM specimens. Our results showed that RAD18 is an important mediator of the IR-induced resistance in GBM. The expression level of RAD18 in glioma cells correlates with their resistance to IR. Ectopic expression of RAD18 in RAD18-low A172 glioma cells confers significant resistance to IR treatment. Conversely, depletion of endogenous RAD18 in RAD18-high glioma cells sensitized these cells to IR treatment. Moreover, RAD18 overexpression confers resistance to IR-mediated apoptosis in RAD18-low A172 glioma cells, whereas cells deficient in RAD18 exhibit increased apoptosis induced by IR. Furthermore, knockdown of RAD18 in RAD18-high glioma cells disrupts HR-mediated repair, resulting in increased accumulation of DSB. In addition, clinical data indicated that RAD18 was significantly higher in recurrent GBM samples that were exposed to IR compared with the corresponding primary GBM samples. Collectively, our findings reveal that RAD18 may serve as a key mediator of the IR response and may function as a potential target for circumventing IR resistance in human GBM.

  6. A preliminary study on the radiation-resistance mechanism in ovarian cancer

    Directory of Open Access Journals (Sweden)

    Qi Liao

    2013-01-01

    Full Text Available Aim: The present study was designed to explore the radiation-resistance mechanism by interfering in checkpoints kinase 1 (CHK1 and DNA-activated protein kinase (DNA-PK genes with short hairpin RNA (shRNA transfection into Skov3 cells derived from ovarian cancer and HeLa cells derived from cervical cancer. Materials and Methods: The cultured Skov3 and HeLa cells were transfected with plasmid vectors containing CHK1 shRNA and DNA-PK shRNA, respectively, through Lipofectimine™ 2000 mediation, and cultured for 20 hours before exposure to 2 Gy X-radiation. The cells were harvested 4 and 28 after X-irradiation respectively then washed 3 times with PBS. These cells were stained with Annexin V/PI and applied by flow cytometer to analyze alteration of apoptosis with software CellQuest. Results: The apoptotic response in Skov3 cells to X-radiation was significantly lower than that in HeLa cells at 4 hour (t = 15.22, P < 0.001 and 28 hours (t = 15.78, P < 0.001 of post-irradiation. The shRNA might not affect the apoptosis of Skov3 and HeLa cells, while shRNA-transfection significantly enhanced the apoptotic response in Skov3 cells to X-radiation as compared with that in HeLa cells. Conclusions: The present work suggests that the CHK1 and DNA-PK genes are very likely to play a role in developing a radiation resistance in ovarian cancer.

  7. Evaluation of lung tumor motion management in radiation therapy with dynamic MRI

    Science.gov (United States)

    Park, Seyoun; Farah, Rana; Shea, Steven M.; Tryggestad, Erik; Hales, Russell; Lee, Junghoon

    2017-03-01

    Surrogate-based tumor motion estimation and tracing methods are commonly used in radiotherapy despite the lack of continuous real time 3D tumor and surrogate data. In this study, we propose a method to simultaneously track the tumor and external surrogates with dynamic MRI, which allows us to evaluate their reproducible correlation. Four MRIcompatible fiducials are placed on the patient's chest and upper abdomen, and multi-slice 2D cine MRIs are acquired to capture the lung and whole tumor, followed by two-slice 2D cine MRIs to simultaneously track the tumor and fiducials, all in sagittal orientation. A phase-binned 4D-MRI is first reconstructed from multi-slice MR images using body area as a respiratory surrogate and group-wise registration. The 4D-MRI provides 3D template volumes for different breathing phases. 3D tumor position is calculated by 3D-2D template matching in which 3D tumor templates in 4D-MRI reconstruction and the 2D cine MRIs from the two-slice tracking dataset are registered. 3D trajectories of the external surrogates are derived via matching a 3D geometrical model to the fiducial segmentations on the 2D cine MRIs. We tested our method on five lung cancer patients. Internal target volume from 4D-CT showed average sensitivity of 86.5% compared to the actual tumor motion for 5 min. 3D tumor motion correlated with the external surrogate signal, but showed a noticeable phase mismatch. The 3D tumor trajectory showed significant cycle-to-cycle variation, while the external surrogate was not sensitive enough to capture such variations. Additionally, there was significant phase mismatch between surrogate signals obtained from fiducials at different locations.

  8. Graphene damage effects on radiation-resistance and configuration of copper?graphene nanocomposite under irradiation: A molecular dynamics study

    OpenAIRE

    Huang, Hai; Tang, Xiaobin; Chen, Feida; Liu, Jian; Li, Huan; Chen, Da

    2016-01-01

    Metal?graphene nanocomposite is a kind of potential radiation tolerant material. Graphene damage of the composite is inevitable within radiation environments. In this paper, two kinds of copper?graphene nanocomposite (CGNC) systems containing perfect graphene and prefabricated damage graphene, respectively, were adopted to expound the influences of graphene damage on the properties (radiation-resistance and configuration) of CGNC under irradiation by atomistic simulations. In the CGNC contain...

  9. Novel receptor tyrosine kinase targeted combination therapies for imatinib-resistant gastrointestinal stromal tumors (GIST).

    Science.gov (United States)

    Mahadevan, Daruka; Theiss, Noah; Morales, Carla; Stejskal, Amy E; Cooke, Laurence S; Zhu, Min; Kurtzman, Drew; Swart, Rachel; Ong, Evan; Qi, Wenqing

    2015-02-10

    c-Kit/α-PDGFR targeted therapies are effective for gastrointestinal stromal tumors (GIST), but, >50% develop drug resistance. RTK expression (c-Kit, c-Met, AXL, HER-1, HER-2, IGF-1R) in pre-/post-imatinib (IM) GIST patient samples (n=16) and 4 GIST cell lines were examined for RTK inhibitor activity. GIST-882 cells were cultured in IM every other day, cells collected (1 week to 6 months) and analyzed by qRT-PCR and Western blotting. Immunohistochemistry pre-/post-IM demonstrated continued expression of c-Kit and HER1, while a subset expressed IGF-1R, c-Met and AXL. In GIST cells (GIST-882, GIST430/654, GIST48) c-Kit, HER1 and c-Met are co-expressed. Acute IM over-express c-Kit while chronic IM, lose c-Kit and HER-1 in GIST882 cells. GIST882 and GIST430/654 cells have an IC50 0.077 and 0.59 µM to IM respectively. GIST48 have an IC50 0.66 µM to IM, 0.91 µM to amuvatinib [AMU] and 0.67 µM to erlotinib (Erl). Synergistic combinations: GIST882, AMU + Erl (CI 0.20); IM + AMU (CI 0.50), GIST430/654, IM + afatinib (CI 0.39); IM + AMU (CI 0.42), GIST48, IM + afatinib (CI 0.03); IM + AMU (CI 0.04); AMU + afatinib (CI 0.36); IM + Erl (CI 0.63). Targeting c-Kit plus HER1 or AXL/c-Met abrogates IM resistance in GIST.

  10. Hypoxia as a Biomarker and for Personalized Radiation Oncology

    DEFF Research Database (Denmark)

    Vordermark, Dirk; Horsman, Michael R

    2016-01-01

    Tumor hypoxia is a clinically relevant cause of radiation resistance. Direct measurements of tumor oxygenation have been performed predominantly with the Eppendorf histograph and these have defined the reduced prognosis after radiotherapy in poorly oxygenated tumors, especially head-and-neck canc...

  11. TH-A-BRF-02: BEST IN PHYSICS (JOINT IMAGING-THERAPY) - Modeling Tumor Evolution for Adaptive Radiation Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Y; Lee, CG [University of Toronto, Toronto, ON (Canada); Chan, TCY [University of Toronto, Toronto, ON (Canada); Techna Institute for the Advancement of Technology for Health, Toronto, ON (Canada); Cho, YB; Islam, MK [University of Toronto, Toronto, ON (Canada); Princess Margaret Hospital, Toronto, ON (Canada); Ontario Consortium for Adaptive Interventions in Radiation Oncology (OCAIRO) (Canada)

    2014-06-15

    Purpose: To develop mathematical models of tumor geometry changes under radiotherapy that may support future adaptive paradigms. Methods: A total of 29 cervical patients were scanned using MRI, once for planning and weekly thereafter for treatment monitoring. Using the tumor volumes contoured by a radiologist, three mathematical models were investigated based on the assumption of a stochastic process of tumor evolution. The “weekly MRI” model predicts tumor geometry for the following week from the last two consecutive MRI scans, based on the voxel transition probability. The other two models use only the first pair of consecutive MRI scans, and the transition probabilities were estimated via tumor type classified from the entire data set. The classification is based on either measuring the tumor volume (the “weekly volume” model), or implementing an auxiliary “Markov chain” model. These models were compared to a constant volume approach that represents the current clinical practice, using various model parameters; e.g., the threshold probability β converts the probability map into a tumor shape (larger threshold implies smaller tumor). Model performance was measured using volume conformity index (VCI), i.e., the union of the actual target and modeled target volume squared divided by product of these two volumes. Results: The “weekly MRI” model outperforms the constant volume model by 26% on average, and by 103% for the worst 10% of cases in terms of VCI under a wide range of β. The “weekly volume” and “Markov chain” models outperform the constant volume model by 20% and 16% on average, respectively. They also perform better than the “weekly MRI” model when β is large. Conclusion: It has been demonstrated that mathematical models can be developed to predict tumor geometry changes for cervical cancer undergoing radiotherapy. The models can potentially support adaptive radiotherapy paradigm by reducing normal tissue dose. This research

  12. Massive parallel sequencing and digital gene expression analysis reveals potential mechanisms to overcome therapy resistance in pulmonary neuroendocrine tumors.

    Science.gov (United States)

    Walter, Robert Fred Henry; Vollbrecht, Claudia; Christoph, Daniel; Werner, Robert; Schmeller, Jan; Flom, Elena; Trakada, Georgia; Rapti, Aggeliki; Adamidis, Vasilis; Hohenforst-Schmidt, Wolfgang; Kollmeier, Jens; Mairinger, Thomas; Wohlschlaeger, Jeremias; Zarogoulidis, Paul; Porpodis, Konstantinos; Schmidt, Kurt Werner; Mairinger, Fabian Dominik

    2016-01-01

    Background : Lung cancer is the leading cause of cancer-related deaths worldwide. 25% show neuroendocrine differentiation (typical/atypical carcinoids, large-/small-cell neuroendocrine carcinomas). Carcinoids present with long survival rates, but metastatic carcinoids correlate with decreased survival and are commonly insensitive to standard chemotherapy or radiation. Therefore, novel therapeutic strategies are urgently needed. Material and methods : 70 representative tumor specimens were used for next-generation sequencing analysis of 14 genes related to therapy response. Additionally, mRNA-expression profiles of 60 matching samples were determined for 13 selected drug targets by using the NanoString nCounter technology. Results : A number of features known to sensitize tumors for different targeted therapies could be identified, which hopefully improve the clinical management of this subgroup of lung neoplasias. In particular, EGFR expression was observed in the investigated tumors in a noteworthy manner. Additionally, MDM2 was strongly expressed in the majority of all samples whereas the expression of its physiological inhibitor, CDKN2A , was nearly absent in all low-grade tumors. TP53 showed a high frequency of variants in high-grade tumors but mutations were rare in carcinoids. Conclusion : Based on our results, therapeutic approaches with MDM2-inhibitors and monoclonal anti-EGFR antibodies may be promising in pulmonary carcinoid tumors.

  13. Enhancement of ovarian cancer chemotherapy by delivery of multidrug-resistance gene small interfering RNA using tumor targeting Salmonella.

    Science.gov (United States)

    Deng, Jiaqi; Guo, Yi; Jiang, Zhongmin; Yang, Min; Li, Huaifang; Wang, Jianjun

    2015-04-01

    The aim of this study was to observe the effect of attenuated Salmonella typhi as a tumor-targeting delivery vector for multidrug-resistance gene (MDR1) small interfering RNA (siRNA). The cisplatin (DDP)-resistant ovarian cancer cell line SKOV-3/DDP was established by treatment with gradually increasing concentrations of cisplatin. MDR1 siRNA expression plasmid containing short hairpin RNA (shRNA) of MDR1 gene was constructed and transformed into attenuated Salmonella typhi strain  SL7207. SKOV-3/DDP cells were incubated with recombinant Salmonella and then subjected to analysis of MDR1 expression by real-time polymerase chain reaction and Western blot. SKOV-3/DDP tumor-bearing mice were established by subcutaneously injecting BALB/c nude mice with SKOV-3/DDP cells, and were orally inoculated with Salmonella carrying MDR1 siRNA plasmid and simultaneously injected intraperitoneally with cisplatin. Tumor growth and mouse survival were observed. Compared with parental cell line, the DDP-resistant SKOV-3/DDP cells expressed a much higher level of MDR1. The expression of MDR1 in SKOV-3/DDP cells infected with the Salmonella strain bearing MDR1 siRNA plasmid in vitro was detected to be downregulated and DDP tolerance of these cells was reversed. Tumor-bearing nude mice that were orally receiving recombinant Salmonella experienced a slow tumor growth and became more sensitive to DDP. Attenuated Salmonella typhi may represent a promising vector for in vivo administration of RNA interference therapy against malignant tumors. © 2014 The Authors. Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology.

  14. Study of surface properties of ATLAS12 strip sensors and their radiation resistance

    Energy Technology Data Exchange (ETDEWEB)

    Mikestikova, M., E-mail: mikestik@fzu.cz [Academy of Sciences of the Czech Republic, Institute of Physics, Na Slovance 2, 18221 Prague 8 (Czech Republic); Allport, P.P.; Baca, M.; Broughton, J.; Chisholm, A.; Nikolopoulos, K.; Pyatt, S.; Thomas, J.P.; Wilson, J.A. [School of Physics and Astronomy, University of Birmingham, Birmingham B15 2TT (United Kingdom); Kierstead, J.; Kuczewski, P.; Lynn, D. [Brookhaven National Laboratory, Physics Department and Instrumentation Division, Upton, NY 11973-5000 (United States); Hommels, L.B.A. [Cavendish Laboratory, University of Cambridge, JJ Thomson Avenue, Cambridge CB3 0HE (United Kingdom); Ullan, M. [Centro Nacional de Microelectronica (IMB-CNM, CSIC), Campus UAB-Bellaterra, 08193 Barcelona (Spain); Bloch, I.; Gregor, I.M.; Tackmann, K. [DESY, Notkestrasse 85, 22607 Hamburg (Germany); Hauser, M.; Jakobs, K.; Kuehn, S. [Physikalisches Institut, Universität Freiburg, Hermann-Herder-Str. 3, D-79104 Freiburg (Germany); and others

    2016-09-21

    A radiation hard n{sup +}-in-p micro-strip sensor for the use in the Upgrade of the strip tracker of the ATLAS experiment at the High Luminosity Large Hadron Collider (HL-LHC) has been developed by the “ATLAS ITk Strip Sensor collaboration” and produced by Hamamatsu Photonics. Surface properties of different types of end-cap and barrel miniature sensors of the latest sensor design ATLAS12 have been studied before and after irradiation. The tested barrel sensors vary in “punch-through protection” (PTP) structure, and the end-cap sensors, whose stereo-strips differ in fan geometry, in strip pitch and in edge strip ganging options. Sensors have been irradiated with proton fluences of up to 1×10{sup 16} n{sub eq}/cm{sup 2}, by reactor neutron fluence of 1×10{sup 15} n{sub eq}/cm{sup 2} and by gamma rays from {sup 60}Co up to dose of 1 MGy. The main goal of the present study is to characterize the leakage current for micro-discharge breakdown voltage estimation, the inter-strip resistance and capacitance, the bias resistance and the effectiveness of PTP structures as a function of bias voltage and fluence. It has been verified that the ATLAS12 sensors have high breakdown voltage well above the operational voltage which implies that different geometries of sensors do not influence their stability. The inter-strip isolation is a strong function of irradiation fluence, however the sensor performance is acceptable in the expected range for HL-LHC. New gated PTP structure exhibits low PTP onset voltage and sharp cut-off of effective resistance even at the highest tested radiation fluence. The inter-strip capacitance complies with the technical specification required before irradiation and no radiation-induced degradation was observed. A summary of ATLAS12 sensors tests is presented including a comparison of results from different irradiation sites. The measured characteristics are compared with the previous prototype of the sensor design, ATLAS07. - Highlights:

  15. Sorafenib Increases Tumor Hypoxia in Cervical Cancer Patients Treated With Radiation Therapy: Results of a Phase 1 Clinical Study

    Energy Technology Data Exchange (ETDEWEB)

    Milosevic, Michael F., E-mail: mike.milosevic@rmp.uhn.ca [Radiation Medicine Program, Princess Margaret Cancer Center, University Health Network, Toronto (Canada); Department of Radiation Oncology, University of Toronto, Toronto (Canada); Townsley, Carol A. [Department of Medical Oncology, Princess Margaret Cancer Center, University Health Network, Toronto (Canada); Chaudary, Naz [Department of Advanced Molecular Oncology, Princess Margaret Cancer Center, University Health Network, Toronto (Canada); Clarke, Blaise [Department of Pathology, Princess Margaret Cancer Center, University Health Network, Toronto (Canada); Department of Laboratory Medicine and Pathology, University of Toronto, Toronto (Canada); Pintilie, Melania [Department of Clinical Study Coordination and Biostatistics, Princess Margaret Cancer Center, University Health Network, Toronto (Canada); Fan, Stacy; Glicksman, Rachel [Radiation Medicine Program, Princess Margaret Cancer Center, University Health Network, Toronto (Canada); Haider, Masoom [Department of Medical Imaging, Sunnybrook Health Sciences Centre, Toronto (Canada); Department of Medical Imaging, University of Toronto, Toronto (Canada); Kim, Sunmo [Radiation Medicine Program, Princess Margaret Cancer Center, University Health Network, Toronto (Canada); MacKay, Helen [Department of Medical Oncology, Princess Margaret Cancer Center, University Health Network, Toronto (Canada); Department of Medicine, University of Toronto, Toronto (Canada); Yeung, Ivan [Radiation Medicine Program, Princess Margaret Cancer Center, University Health Network, Toronto (Canada); Department of Radiation Oncology, University of Toronto, Toronto (Canada); Hill, Richard P. [Department of Radiation Oncology, University of Toronto, Toronto (Canada); Department of Advanced Molecular Oncology, Princess Margaret Cancer Center, University Health Network, Toronto (Canada); Department of Medical Biophysics, University of Toronto, Toronto (Canada); and others

    2016-01-01

    Purpose: Preclinical studies have shown that angiogenesis inhibition can improve response to radiation therapy (RT). The purpose of this phase 1 study was to examine the angiogenesis inhibitor sorafenib in patients with cervical cancer receiving radical RT and concurrent cisplatin (RTCT). Methods and Materials: Thirteen patients with stage IB to IIIB cervical cancer participated. Sorafenib was administered daily for 7 days before the start of standard RTCT in patients with early-stage, low-risk disease and also during RTCT in patients with high-risk disease. Biomarkers of tumor vascularity, perfusion, and hypoxia were measured at baseline and again after 7 days of sorafenib alone before the start of RTCT. The median follow-up time was 4.5 years. Results: Initial complete response was seen in 12 patients. One patient died without achieving disease control, and 4 experienced recurrent disease. One patient with an extensive, infiltrative tumor experienced pelvic fistulas during treatment. The 4-year actuarial survival was 85%. Late grade 3 gastrointestinal toxicity developed in 4 patients. Sorafenib alone produced a reduction in tumor perfusion/permeability and an increase in hypoxia, which resulted in early closure of the study. Conclusions: Sorafenib increased tumor hypoxia, raising concern that it might impair rather than improve disease control when added to RTCT.

  16. Transfer of innate resistance and susceptibility to Leishmania donovani infection in mouse radiation bone marrow chimaeras

    Energy Technology Data Exchange (ETDEWEB)

    Crocker, P.R.; Blackwell, J.M.; Bradley, D.J. (London School of Hygiene and Tropical Medicine (UK))

    1984-07-01

    Reciprocal radiation bone marrow chimaeras were made between H-2-compatible strains of mice innately resistant or susceptible to visceral leishmaniasis. In initial experiments, susceptibility but not resistance to Leishmania donovani could be transferred with donor bone marrow into irradiated recipients. In subsequent experiments it was possible to transfer both resistance and susceptibility. This was achieved either by selecting more radiosensitive mouse strains as susceptible recipients, or alternatively by increasing the irradiation dose for the susceptible recipients used in the initial experiments. Using the higher irradiation dose, successful transfer of resistance and susceptibility between congenic mice carrying the Lshsup(r) and Lshsup(s) alleles on the more radioresistant B10 genetic background provided firm evidence that the results obtained in this study were specifically related to expression of the Lsh gene. It is concluded that Lsh gene-controlled resistance and susceptibility to L. donovani is determined by bone marrow-derived cells. The cell type(s) involved is likely to be of the macrophage lineage.

  17. AB225. The tumor suppressive role of CAMK2N1 in castration-resistant prostate cancer

    OpenAIRE

    Wang, T.; Liu, Z.; Guo, S.; Wu, L.; Li, M.; Yang, J; Chen, R.; Xu, H; Cai, S.; Chen, H.; Li, W.; Hu, Z; Q. Zhuang; Xu, S; Wang, L.

    2014-01-01

    Prostate cancer at advanced stages including metastatic and castration-resistant cancer remains incurable due to the lack of effective therapies. The CAMK2N1 gene, cloned and characterized as an inhibitor of CaMKII (calcium/calmodulin-dependent protein kinase II), has been shown to affect tumor genesis and tumor growth. However, it is still unknown whether CAMK2N1 plays a role in prostate cancer development. We first examined the protein and mRNA levels of CAMK2N1 and observed a significant d...

  18. Resistivity, ESR, and Radiation Shielding Properties of the Volcanic Rock Materials

    Directory of Open Access Journals (Sweden)

    Çiğdem Nuhoğlu

    2014-01-01

    Full Text Available Pumices have been used in cement, concrete, brick, and ceramic industries as an additive and aggregate material. It will be important to study pumice types by using a different tool as EPR which is a new technique for related material to be used for industrial aims. Electron spin resonance (ESR spectra of the pumice types were taken by EMX-type spectrometer. Also, the current-voltage (I-V and surface resistivity probe stand of the thin films was studied using a four-point probe measurements. The relationship between radiation shielding properties of the pumice samples and their surface resistivity, chemical, and electrokinetic properties was evaluated using simple regression analysis. Simple regression analysis indicated a strong correlation between surface resistivity and density and SiO2, Fe2O3, CaO, MgO, and TiO2 content of pumice samples in this study. It is found that a correlation between determined g-factor by EPR spectroscopy and radiation shielding is established for pumice samples.

  19. Monitoring of Breast Tumor Response to Local Chemotherapeutic Agent Delivered by Biodegradable Fibers

    Science.gov (United States)

    2006-05-01

    induced damage and death of nondividing eucaryotic cells ”, Radiat. Res., 84, 122-132, (1980). [13] Stark, G. “The effect of ionizing radiation on...long been known that hypoxic tumor cells are more resistant to radiation therapy than well-oxygenated tumor cells [1]. Breathing elevated oxygen (100...therapy efficacy. Primary targets of radiation therapy and chemotherapy are vascular endothelial cells and smooth muscle cells [4]. Endothelial

  20. Unraveling Fungal Radiation Resistance Regulatory Networks through the Genome-Wide Transcriptome and Genetic Analyses of Cryptococcus neoformans

    Directory of Open Access Journals (Sweden)

    Kwang-Woo Jung

    2016-11-01

    Full Text Available The basidiomycetous fungus Cryptococcus neoformans has been known to be highly radiation resistant and has been found in fatal radioactive environments such as the damaged nuclear reactor at Chernobyl. To elucidate the mechanisms underlying the radiation resistance phenotype of C. neoformans, we identified genes affected by gamma radiation through genome-wide transcriptome analysis and characterized their functions. We found that genes involved in DNA damage repair systems were upregulated in response to gamma radiation. Particularly, deletion of recombinase RAD51 and two DNA-dependent ATPase genes, RAD54 and RDH54, increased cellular susceptibility to both gamma radiation and DNA-damaging agents. A variety of oxidative stress response genes were also upregulated. Among them, sulfiredoxin contributed to gamma radiation resistance in a peroxiredoxin/thioredoxin-independent manner. Furthermore, we found that genes involved in molecular chaperone expression, ubiquitination systems, and autophagy were induced, whereas genes involved in the biosynthesis of proteins and fatty acids/sterols were downregulated. Most importantly, we discovered a number of novel C. neoformans genes, the expression of which was modulated by gamma radiation exposure, and their deletion rendered cells susceptible to gamma radiation exposure, as well as DNA damage insults. Among these genes, we found that a unique transcription factor containing the basic leucine zipper domain, named Bdr1, served as a regulator of the gamma radiation resistance of C. neoformans by controlling expression of DNA repair genes, and its expression was regulated by the evolutionarily conserved DNA damage response protein kinase Rad53. Taken together, the current transcriptome and functional analyses contribute to the understanding of the unique molecular mechanism of the radiation-resistant fungus C. neoformans.

  1. Combination of Gold Nanoparticle-Conjugated Tumor Necrosis Factor-α and Radiation Therapy Results in a Synergistic Antitumor Response in Murine Carcinoma Models

    Energy Technology Data Exchange (ETDEWEB)

    Koonce, Nathan A. [Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas (United States); Quick, Charles M. [Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas (United States); Hardee, Matthew E.; Jamshidi-Parsian, Azemat; Dent, Judith A. [Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas (United States); Paciotti, Giulio F. [CytImmune Sciences, Rockville, Maryland (United States); Nedosekin, Dmitry [Department of Otolaryngology, University of Arkansas for Medical Sciences, Little Rock, Arkansas (United States); Dings, Ruud P.M. [Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas (United States); Griffin, Robert J., E-mail: RJGriffin@uams.edu [Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas (United States)

    2015-11-01

    Purpose: Although remarkable preclinical antitumor effects have been shown for tumor necrosis factor-α (TNF) alone and combined with radiation, its clinical use has been hindered by systemic dose-limiting toxicities. We investigated the physiological and antitumor effects of radiation therapy combined with the novel nanomedicine CYT-6091, a 27-nm average-diameter polyethylene glycol-TNF-coated gold nanoparticle, which recently passed through phase 1 trials. Methods and Materials: The physiologic and antitumor effects of single and fractionated radiation combined with CYT-6091 were studied in the murine 4T1 breast carcinoma and SCCVII head and neck tumor squamous cell carcinoma models. Results: In the 4T1 murine breast tumor model, we observed a significant reduction in the tumor interstitial fluid pressure (IFP) 24 hours after CYT-6091 alone and combined with a radiation dose of 12 Gy (P<.05 vs control). In contrast, radiation alone (12 Gy) had a negligible effect on the IFP. In the SCCVII head and neck tumor model, the baseline IFP was not markedly elevated, and little additional change occurred in the IFP after single-dose radiation or combined therapy (P>.05 vs control) despite extensive vascular damage observed. The IFP reduction in the 4T1 model was also associated with marked vascular damage and extravasation of red blood cells into the tumor interstitium. A sustained reduction in tumor cell density was observed in the combined therapy group compared with all other groups (P<.05). Finally, we observed a more than twofold delay in tumor growth when CYT-6091 was combined with a single 20-Gy radiation dose—notably, irrespective of the treatment sequence. Moreover, when hypofractionated radiation (12 Gy × 3) was applied with CYT-6091 treatment, a more than five-fold growth delay was observed in the combined treatment group of both tumor models and determined to be synergistic. Conclusions: Our results have demonstrated that TNF-labeled gold

  2. Hypo-Fractionated Conformal Radiation Therapy to the Tumor Bed After Segmental Mastectomy

    National Research Council Canada - National Science Library

    Formenti, Silvia C

    2005-01-01

    ... (5 fractions in 2 weeks) directed to the original tumor bed with margins in a selected subset of post-menopausal women with breast cancer with a very low risk for local recurrence elsewhere in the breast...

  3. Promising markers for the detection of premature senescence tumor cells induced by ionizing radiation: Cathepsin D and eukaryotic translation elongation factor 1

    Energy Technology Data Exchange (ETDEWEB)

    Byun, Hae-Ok; Han, Na-Kyung; Lee, Jae-Seon [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

    2008-05-15

    Recently, it has been proved that induction of senescence could be a promising way of tumor treatment. Senescence was originally described in normal human cells undergoing a finite number of divisions before permanent growth arrest. It has now become regarded more broadly as a general biological program of terminal growth arrest. A variety of stresses such as ionizing radiation (IR), oxidative stress, oncogenic transformation, DNA damaging agents triggers stress-induced premature senescence, i.e. rapid and permanent cell growth arrest. Therefore, premature senescence is bona fide barrier to tumorigenesis and hallmark of premalignant tumors. However, there is lack of obvious markers for senescent tumor cells. To identify useful premature senescence markers for tumor cells, we monitored the changes of protein expression profile in IR-induced premature senescence MCF7 human breast cancer cells. We identified biomarkers which evidently changed their expression levels in ionizing radiation-induced senescenct tumor cells.

  4. 3D printer generated thorax phantom with mobile tumor for radiation dosimetry.

    Science.gov (United States)

    Mayer, Rulon; Liacouras, Peter; Thomas, Andrew; Kang, Minglei; Lin, Liyong; Simone, Charles B

    2015-07-01

    This article describes the design, construction, and properties of an anthropomorphic thorax phantom with a moving surrogate tumor. This novel phantom permits detection of dose both inside and outside a moving tumor and within the substitute lung tissue material. A 3D printer generated the thorax shell composed of a chest wall, spinal column, and posterior regions of the phantom. Images of a computed tomography scan of the thorax from a patient with lung cancer provided the template for the 3D printing. The plastic phantom is segmented into two materials representing the muscle and bones, and its geometry closely matches a patient. A surrogate spherical plastic tumor controlled by a 3D linear stage simulates a lung tumor's trajectory during normal breathing. Sawdust emulates the lung tissue in terms of average and distribution in Hounsfield numbers. The sawdust also provides a forgiving medium that permits tumor motion and sandwiching of radiochromic film inside the mobile surrogate plastic tumor for dosimetry. A custom cork casing shields the film and tumor and eliminates film bending during extended scans. The phantom, lung tissue surrogate, and radiochromic film are exposed to a seven field plan based on an ECLIPSE plan for 6 MV photons from a Trilogy machine delivering 230 cGy to the isocenter. The dose collected in a sagittal plane is compared to the calculated plan. Gamma analysis finds 8.8% and 5.5% gamma failure rates for measurements of large amplitude trajectory and static measurements relative to the large amplitude plan, respectively. These particular gamma analysis results were achieved using parameters of 3% dose and 3 mm, for regions receiving doses >150 cGy. The plan assumes a stationary detection grid unlike the moving radiochromic film and tissues. This difference was experimentally observed and motivated calculated dose distributions that incorporated the phase of the tumor periodic motion. These calculations modestly improve agreement between

  5. Radiation survival of two nalidixic acid resistant strains of Salmonella typhimurium in various media

    Science.gov (United States)

    Shamsuzzaman, Kazi; Goodwin, Marlene; George, Ian; Singh, Harwant

    Radiation doses required for 90% inactivation, the D10 values, have been determined for two nalidixic acid-resistant strains of Salmonella typhimurium, Nal R ATCC 13311 and K1-2B, in different media. The D10 values were 0.20, 0.57 and 0.53 kGy for the ATCC 13311 strain, and were 0.21, 0.4 and 0.32 kGy for the K1-2B strain, in phosphate buffer, in nutrient broth and on chicken drumsticks, respectively. Since these two strains have radiation sensitivity similar to several Salmonella serotypes reported in the literature, they are good indicator organisms for use in studies on the effect of irradiation on Salmonella in foods that might frequently be contaminated with such organisms.

  6. Molecular exploration of the highly radiation resistant cyanobacterium Arthrospira sp. PCC 8005

    Science.gov (United States)

    Badri, Hanène; Leys, Natalie; Wattiez, Ruddy

    Arthrospira (Spirulina) is a photosynthetic cyanobacterium able to use sunlight to release oxygen from water and remove carbon dioxide and nitrate from water. In addition, it is suited for human consumption (edible). For these traits, the cyanobacterium Arthrospira sp. PCC 8005 was selected by the European Space Agency (ESA) as part of the life support system MELiSSA for recycling oxygen, water, and food during future long-haul space missions. However, during such extended missions, Arthrospira sp. PCC 8005 will be exposed to continuous artificial illumination and harmful cosmic radiation. The aim of this study was to investigate how Arthrospira will react and behave when exposed to such stress environment. The cyanobacterium Arthrospira sp. PCC 8005 was exposed to high gamma rays doses in order to unravel in details the response of this bacterium following such stress. Test results showed that after acute exposure to high doses of 60Co gamma radiation upto 3200 Gy, Arthrospira filaments were still able to restart photosynthesis and proliferate normally. Doses above 3200 Gy, did have a detrimental effect on the cells, and delayed post-irradiation proliferation. The photosystem activity, measured as the PSII quantum yield immediately after irradiation, decreased significantly at radiation doses above 3200 Gy. Likewise through pigment content analysis a significant decrease in phycocyanin was observed following exposure to 3200 Gy. The high tolerance of this bacterium to 60Co gamma rays (i.e. ca. 1000x more resistant than human cells for example) raised our interest to investigate in details the cellular and molecular mechanisms behind this amazing resistance. Optimised DNA, RNA and protein extraction methods and a new microarray chip specific for Arthrospira sp. PCC 8005 were developed to identify the global cellular and molecular response following exposure to 3200 Gy and 5000 Gy A total of 15,29 % and 30,18 % genes were found differentially expressed in RNA

  7. Heat enhancement of radiation resistivity of evaporated CsI, KI and KBr photocathodes

    CERN Document Server

    Tremsin, A S

    2000-01-01

    The photoemissive stability of as-deposited and heat-treated CsI, KI and KBr evaporated thin films under UV radiation is examined in this paper. After the deposition, some photocathodes were annealed for several hours at 90 deg. C in vacuum and their performance was then compared to the performance of non-heated samples. We observed that the post-evaporation thermal treatment not only increases the photoyield of CsI and KI photocathodes in the spectral range of 115-190 nm, but also reduces CsI, KI and KBr photocurrent degradation that occurs after UV irradiation. KBr evaporated layers appeared to be more radiation-resistant than CsI and KI layers. Post-deposition heat treatment did not result in any significant variation of KBr UV sensitivity.

  8. Proton Radiation Therapy for Pediatric Medulloblastoma and Supratentorial Primitive Neuroectodermal Tumors: Outcomes for Very Young Children Treated With Upfront Chemotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Jimenez, Rachel B., E-mail: rbjimenez@partners.org [Harvard Radiation Oncology Program, Boston, Massachusetts (United States); Sethi, Roshan [Harvard Medical School, Boston, Massachusetts (United States); Depauw, Nicolas [Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); Pulsifer, Margaret B. [Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts (United States); Adams, Judith [Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); McBride, Sean M. [Harvard Radiation Oncology Program, Boston, Massachusetts (United States); Ebb, David [Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts (United States); Fullerton, Barbara C.; Tarbell, Nancy J.; Yock, Torunn I.; MacDonald, Shannon M. [Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States)

    2013-09-01

    Purpose: To report the early outcomes for very young children with medulloblastoma or supratentorial primitive neuroectodermal tumor (SPNET) treated with upfront chemotherapy followed by 3-dimensional proton radiation therapy (3D-CPT). Methods and Materials: All patients aged <60 months with medulloblastoma or SPNET treated with chemotherapy before 3D-CPT from 2002 to 2010 at our institution were included. All patients underwent maximal surgical resection, chemotherapy, and adjuvant 3D-CPT with either craniospinal irradiation followed by involved-field radiation therapy or involved-field radiation therapy alone. Results: Fifteen patients (median age at diagnosis, 35 months) were treated with high-dose chemotherapy and 3D-CPT. Twelve of 15 patients had medulloblastoma; 3 of 15 patients had SPNET. Median time from surgery to initiation of radiation was 219 days. Median craniospinal irradiation dose was 21.6 Gy (relative biologic effectiveness); median boost dose was 54.0 Gy (relative biologic effectiveness). At a median of 39 months from completion of radiation, 1 of 15 was deceased after a local failure, 1 of 15 had died from a non-disease-related cause, and the remaining 13 of 15 patients were alive without evidence of disease recurrence. Ototoxicity and endocrinopathies were the most common long-term toxicities, with 2 of 15 children requiring hearing aids and 3 of 15 requiring exogenous hormones. Conclusions: Proton radiation after chemotherapy resulted in good disease outcomes for a small cohort of very young patients with medulloblastoma and SPNET. Longer follow-up and larger numbers of patients are needed to assess long-term outcomes and late toxicity.

  9. Proton radiation therapy for pediatric medulloblastoma and supratentorial primitive neuroectodermal tumors: outcomes for very young children treated with upfront chemotherapy.

    Science.gov (United States)

    Jimenez, Rachel B; Sethi, Roshan; Depauw, Nicolas; Pulsifer, Margaret B; Adams, Judith; McBride, Sean M; Ebb, David; Fullerton, Barbara C; Tarbell, Nancy J; Yock, Torunn I; Macdonald, Shannon M

    2013-09-01

    To report the early outcomes for very young children with medulloblastoma or supratentorial primitive neuroectodermal tumor (SPNET) treated with upfront chemotherapy followed by 3-dimensional proton radiation therapy (3D-CPT). All patients aged chemotherapy before 3D-CPT from 2002 to 2010 at our institution were included. All patients underwent maximal surgical resection, chemotherapy, and adjuvant 3D-CPT with either craniospinal irradiation followed by involved-field radiation therapy or involved-field radiation therapy alone. Fifteen patients (median age at diagnosis, 35 months) were treated with high-dose chemotherapy and 3D-CPT. Twelve of 15 patients had medulloblastoma; 3 of 15 patients had SPNET. Median time from surgery to initiation of radiation was 219 days. Median craniospinal irradiation dose was 21.6 Gy (relative biologic effectiveness); median boost dose was 54.0 Gy (relative biologic effectiveness). At a median of 39 months from completion of radiation, 1 of 15 was deceased after a local failure, 1 of 15 had died from a non-disease-related cause, and the remaining 13 of 15 patients were alive without evidence of disease recurrence. Ototoxicity and endocrinopathies were the most common long-term toxicities, with 2 of 15 children requiring hearing aids and 3 of 15 requiring exogenous hormones. Proton radiation after chemotherapy resulted in good disease outcomes for a small cohort of very young patients with medulloblastoma and SPNET. Longer follow-up and larger numbers of patients are needed to assess long-term outcomes and late toxicity. Copyright © 2013 Elsevier Inc. All rights reserved.

  10. Determination of gamma radiation lethal dose (LD{sub 50}) and resveratrol cytotoxicity level in tumor cells line

    Energy Technology Data Exchange (ETDEWEB)

    Magalhaes, Vanessa D.; Rogero, Sizue O.; Rogero, Jose R. [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil); Cruz, Aurea S. [Instituto Adolfo Lutz (IAL-SP) Secao de Culturas Celulares, SP (Brazil)

    2011-07-01

    Cancer is a disease with high incidence and it is considered a worldwide public health problem. Resveratrol is a polyphenol occurring naturally in a wide variety of plants according to response of ultraviolet radiation (UV) exposition or according to mechanical stress resulting of pathogens or chemical and physical agents. This polyphenol possesses a pharmacological activity of carcinogenesis inhibition in multiple levels. It also protects cells by scavenging the free radicals which are considered toxic products. These free radicals are formed of natural process of cell aging and also by incidence of ionizing radiation in the organism. Thus, resveratrol is considered as a cell radioprotector. On the other hand, in some elevated concentrations resveratrol may be considered as a radiosensitizing. The aim of this work was the determination of radiation lethal dose (LD{sub 50}) and also verifies the cytotoxicity level of resveratrol in tumor cells line: muco epidermoid pulmonary carcinoma cells (NCI-H292) and rhabdomyosarcoma cells (RD). The cytotoxicity test was performed by neutral red uptake assay. The results of resveratrol IC{sub 50%} in NCI-H292 cells was 192{mu}M and in RD cells was 128{mu}M; and RD cells gamma radiation LD{sub 50} was 435Gy. (author)

  11. Successful treatment of a T4 lung tumor with vertebral body invasion using fiducial markers in the thoracic spine for image-guided radiation therapy: A case report

    Directory of Open Access Journals (Sweden)

    Solin Lawrence J

    2011-09-01

    Full Text Available Abstract Introduction Paravertebral and paraspinal tumors pose a significant challenge in radiation therapy because of the radiation sensitivity of the spinal cord and the need for maximum treatment accuracy. Implantation of fiducial markers into vertebral bodies has been described as a method of increasing the accuracy of radiation treatment for single-dose stereotactic radiosurgery for spinal and paraspinal primary tumors and metastases. However, utilization of this technique has not been described for conventionally fractionated radiation therapy. This report is the first of its kind in the literature and describes successful treatment of a T4 primary lung tumor with vertebral body invasion with conventionally fractionated, image-guided radiotherapy using fiducial markers implanted in the thoracic spine. Case presentation Our patient was a 47-year-old African-American man who presented to our hospital with a history of several months of increasing left arm pain, chest pain, dyspnea on exertion, occasional dry cough, and weight loss. He was found to have stage IIIA T4, N0, M0 lung cancer with vertebral body invasion. He had fiducial markers placed in the thoracic spine for image-guided radiation treatment set-up. The patient received 74 Gy radiation therapy with concurrent chemotherapy, and daily matching of the fiducial markers on the treatment machine allowed for treatment of the tumor while sparing the dose to the adjacent spinal cord. With one year of clinical follow-up, the patient has had regression of the tumor with only asymmetric soft-tissue thickening seen on a computed tomographic scan and grade 1 dyspnea on exertion as the only side effects of the treatment. Conclusion Fiducial marker placement is a safe and effective technique for maximizing the accuracy and reproducibility for radiation treatment of lesions near the spinal cord. This technique may be used in conventionally fractionated radiation treatment regimens, such as those

  12. CD47 Receptor Globally Regulates Metabolic Pathways That Control Resistance to Ionizing Radiation.

    Science.gov (United States)

    Miller, Thomas W; Soto-Pantoja, David R; Schwartz, Anthony L; Sipes, John M; DeGraff, William G; Ridnour, Lisa A; Wink, David A; Roberts, David D

    2015-10-09

    Modulating tissue responses to stress is an important therapeutic objective. Oxidative and genotoxic stresses caused by ionizing radiation are detrimental to healthy tissues but beneficial for treatment of cancer. CD47 is a signaling receptor for thrombospondin-1 and an attractive therapeutic target because blocking CD47 signaling protects normal tissues while sensitizing tumors to ionizing radiation. Here we utilized a metabolomic approach to define molecular mechanisms underlying this radioprotective activity. CD47-deficient cells and cd47-null mice exhibited global advantages in preserving metabolite levels after irradiation. Metabolic pathways required for controlling oxidative stress and mediating DNA repair were enhanced. Some cellular energetics pathways differed basally in CD47-deficient cells, and the global declines in the glycolytic and tricarboxylic acid cycle metabolites characteristic of normal cell and tissue responses to irradiation were prevented in the absence of CD47. Thus, CD47 mediates signaling from the extracellular matrix that coordinately regulates basal metabolism and cytoprotective responses to radiation injury. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  13. Correlating planned radiation dose to the cochlea with primary site and tumor stage in patients with head and neck cancer treated with intensity-modulated radiation therapy

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Jeanette; Qureshi, Muhammad M.; Kovalchuk, Nataliya; Truong, Minh Tam, E-mail: mitruong@bu.edu

    2014-04-01

    The aim of the study was to determine tumor characteristics that predict higher planned radiation (RT) dose to the cochlea in patients with head and neck cancer (HNC) treated with intensity-modulated radiotherapy (IMRT). From 2004 to 2012, 99 patients with HNC underwent definitive IMRT to a median dose of 69.96 Gy in 33 fractions, with the right and left cochlea-vestibular apparatus contoured for IMRT optimization as avoidance structures. If disease involvement was adjacent to the cochlea, preference was given to tumor coverage by prescription dose. Descriptive statistics were calculated for dose-volume histogram planning data, and mean planning dose to the cochlea (from left or right cochlea, receiving the greater amount of RT dose) was correlated to primary site and tumor stage. Mean (standard deviation) cochlear volume was 1.0 (0.60) cm{sup 3} with maximum and mean planned doses of 31.9 (17.5) Gy and 22.1 (13.7) Gy, respectively. Mean planned dose (Gy) to cochlea by tumor site was as follows: oral cavity (18.6, 14.4), oropharynx (21.7, 9.1), nasopharynx (36.3, 10.4), hypopharynx (14.9, 7.1), larynx (2.1, 0.62), others including the parotid gland, temporal bone, and paranasal sinus (33.6, 24.0), and unknown primary (25.6, 6.7). Average mean planned dose (Gy) to the cochlea in T0-T2 and T3-T4 disease was 22.0 and 29.2 Gy, respectively (p = 0.019). By site, a significant difference was noted for nasopharynx and others (31.6 and 50.7, p = 0.012) but not for oropharynx, oral cavity, and hypopharynx. Advanced T category predicted for higher mean cochlear dose, particularly for nasopharyngeal, parotid gland, temporal bone, and paranasal sinus HNC sites.

  14. Characteristics of radiation-resistant real-time neutron monitor for accelerator-based BNCT

    Energy Technology Data Exchange (ETDEWEB)

    Nakamura, Takemi; Sakasai, Kaoru; Nakashima, Hiroshi [Japan Atomic Energy Agency, Ibaraki-ken (Japan); Takaiya, Koichi [Kyoto University, Osaka (Japan); Kumada, Hiroaki [University of Tsukuba, Ibaraki-ken (Japan)

    2016-06-15

    For an accelerator-based BNCT, we have fabricated a new detector consisting of quartz optical fibers that have excellent radiation-resistant characteristics. The developed detectors were irradiated at Kyoto University Research Reactor. The experimental results showed that the new detector had good output linearity for the neutron intensity, and the response of the new detector did not decrease during the irradiation. The new detector consisting of quartz optical fibers can be applied to measurement of neutron field of an accelerator-based BNCT.

  15. High-LET radiation-induce malignant and benign tumors in rat skin

    Energy Technology Data Exchange (ETDEWEB)

    Burns, F.J. [Institute of Environmental Medicine, New York University Medical Center, New York, NY (United States); Zhao, P.; Hiz, Z.; Chen, S.; Roy, N.

    1999-03-01

    In the multistage theory of carcinogenesis, cells progress to cancer through a series of mutations in cancer-relevant genes, and sometimes the intermediate stages become benign neoplastic lesions. Although cancer induction by low LET radiation is subject to repair or recovery in the sense that multiple exposures produce fewer cancers than the same single dose, this recovery is not seen following exposure to high LET radiation. Data are presented on squamous and basal cell carcinoma and fibroma induction in rat skin exposed to: 1. an electron beam (LET=0.34 kV/{mu}), 2. a neon ion beam (LET=30 kV/{mu} ) and 3. an argon ion beam (LET=125 kV/{mu}). Cancer yields were fitted by a LET-dependent quadratic equation, and equation parameters were estimated by regression analysis for each type of radiation. The results are consistent with the interpretation that carcinoma induction can be explained by a pathway involving 2 radiation-induced events, 1 radiation-induced mutation and 1 spontaneous mutation, while benign fibromas can be explained by a pathway involving 1 radiation-induced event and 1 radiation-induced mutation. (author)

  16. Anti-estrogen Resistance in Human Breast Tumors Is Driven by JAG1-NOTCH4-Dependent Cancer Stem Cell Activity

    Directory of Open Access Journals (Sweden)

    Bruno M. Simões

    2015-09-01

    Full Text Available Breast cancers (BCs typically express estrogen receptors (ERs but frequently exhibit de novo or acquired resistance to hormonal therapies. Here, we show that short-term treatment with the anti-estrogens tamoxifen or fulvestrant decrease cell proliferation but increase BC stem cell (BCSC activity through JAG1-NOTCH4 receptor activation both in patient-derived samples and xenograft (PDX tumors. In support of this mechanism, we demonstrate that high ALDH1 predicts resistance in women treated with tamoxifen and that a NOTCH4/HES/HEY gene signature predicts for a poor response/prognosis in 2 ER+ patient cohorts. Targeting of NOTCH4 reverses the increase in Notch and BCSC activity induced by anti-estrogens. Importantly, in PDX tumors with acquired tamoxifen resistance, NOTCH4 inhibition reduced BCSC activity. Thus, we establish that BCSC and NOTCH4 activities predict both de novo and acquired tamoxifen resistance and that combining endocrine therapy with targeting JAG1-NOTCH4 overcomes resistance in human breast cancers.

  17. Circular RNA alterations are involved in resistance to avian leukosis virus subgroup-J-induced tumor formation in chickens.

    Science.gov (United States)

    Zhang, Xinheng; Yan, Yiming; Lei, Xiaoya; Li, Aijun; Zhang, Huanmin; Dai, Zhenkai; Li, Xinjian; Chen, Weiguo; Lin, Wencheng; Chen, Feng; Ma, Jingyun; Xie, Qingmei

    2017-05-23

    Avian leukosis virus subgroup (ALV-J) is an oncogenic neoplasm-inducing retrovirus that causes significant economic losses in the poultry industry. Recent studies have demonstrated circular RNAs (circRNAs) are implicated in pathogenic processes; however, no research has indicated circRNAs are involved in resistance to disease. In this study, over 1800 circRNAs were detected by circRNA sequencing of liver tissues from ALV-J-resistant (n = 3) and ALV-J-susceptible chickens (n = 3). 32 differentially expressed circRNAs were selected for analyzing including 12 upregulated in ALV-J-resistant chickens and 20 upregulated in ALV-J-susceptible chickens, besides, the top five microRNAs (miRNAs) for 12 upregulated circRNAs in ALV-J-resistant chickens were analyzed. Gene ontology and KEGG pathway analyses were performed for miRNA target genes, the predicted genes were mainly involved in immune pathways. This study provides the first evidence that circRNA alterations are involved in resistance to ALV-J-induced tumor formation. We propose circRNAs may help to mediate tumor induction and development in chickens.

  18. The performance of RPCs with bakelite electrodes of resistivity under high radiation fluxes

    CERN Document Server

    Cwiok, M; Górski, M; Królikowski, J

    2000-01-01

    Three medium-size Resistive Plate Chambers (RPCs) with bakelite electrodes having resistivity of 5*10/sup 8/, 5*10/sup 9/ and 3*10 /sup 10/ Omega cm were tested in the Gamma Irradiation Facility at CERN in 1997, 1998 and 1999. The 2 mm gap modules working in an Inverted Double Gap configuration filled with gas mixtures containing freon C/sub 2/H/sub 2/F/sub 4/ and operated in avalanche mode exhibit wide efficiency plateau, good time resolution and small time walk due to rate variation even at intensities as high as 1 kHz/cm/sup 2//gap of a continuous radiation flux. (8 refs).

  19. 3D printer generated thorax phantom with mobile tumor for radiation dosimetry

    Energy Technology Data Exchange (ETDEWEB)

    Mayer, Rulon [Henry Jackson Foundation, Bethesda, Maryland 20817 (United States); Liacouras, Peter [Walter Reed National Military Medical Center, Bethesda, Maryland 20899 (United States); Thomas, Andrew [ATC Healthcare, Washington, District of Columbia 20006 (United States); Kang, Minglei; Lin, Liyong; Simone, Charles B. [Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania 19104 (United States)

    2015-07-15

    This article describes the design, construction, and properties of an anthropomorphic thorax phantom with a moving surrogate tumor. This novel phantom permits detection of dose both inside and outside a moving tumor and within the substitute lung tissue material. A 3D printer generated the thorax shell composed of a chest wall, spinal column, and posterior regions of the phantom. Images of a computed tomography scan of the thorax from a patient with lung cancer provided the template for the 3D printing. The plastic phantom is segmented into two materials representing the muscle and bones, and its geometry closely matches a patient. A surrogate spherical plastic tumor controlled by a 3D linear stage simulates a lung tumor’s trajectory during normal breathing. Sawdust emulates the lung tissue in terms of average and distribution in Hounsfield numbers. The sawdust also provides a forgiving medium that permits tumor motion and sandwiching of radiochromic film inside the mobile surrogate plastic tumor for dosimetry. A custom cork casing shields the film and tumor and eliminates film bending during extended scans. The phantom, lung tissue surrogate, and radiochromic film are exposed to a seven field plan based on an ECLIPSE plan for 6 MV photons from a Trilogy machine delivering 230 cGy to the isocenter. The dose collected in a sagittal plane is compared to the calculated plan. Gamma analysis finds 8.8% and 5.5% gamma failure rates for measurements of large amplitude trajectory and static measurements relative to the large amplitude plan, respectively. These particular gamma analysis results were achieved using parameters of 3% dose and 3 mm, for regions receiving doses >150 cGy. The plan assumes a stationary detection grid unlike the moving radiochromic film and tissues. This difference was experimentally observed and motivated calculated dose distributions that incorporated the phase of the tumor periodic motion. These calculations modestly improve agreement between

  20. At the Crossroads of Cancer Stem Cells, Radiation Biology, and Radiation Oncology.

    Science.gov (United States)

    Gerweck, Leo E; Wakimoto, Hiroaki

    2016-03-01

    Reports that a small subset of tumor cells initiate and sustain tumor growth, are resistant to radiation and drugs, and bear specific markers have led to an explosion of cancer stem cell research. These reports imply that the evaluation of therapeutic response by changes in tumor volume is misleading, as volume changes reflect the response of the sensitive rather than the resistant tumorigenic cell population. The reports further suggest that the marker-based selection of the tumor cell population will facilitate the development of radiation treatment schedules, sensitizers, and drugs that specifically target the resistant tumorigenic cells that give rise to treatment failure. This review presents evidence that contests the observations that cancer stem cell markers reliably identify the subset of tumor cells that sustain tumor growth and that the marker-identified population is radioresistant relative to the marker-negative cells. Experimental studies show that cells and tumors that survive large radiation doses are not more radioresistant than unirradiated cells and tumors, and also show that the intrinsic radiosensitivity of unsorted colony-forming tumor cells, in combination with the fraction of unsorted tumor cells that are tumor initiating, predicts tumor radiocurability. ©2016 American Association for Cancer Research.

  1. SU-C-204-05: Magnetic Resonance-Induced Adaptive Response to Orthovoltage Radiation Therapy in FSa and SA-NH Mouse Tumor Cell Lines

    Energy Technology Data Exchange (ETDEWEB)

    Mendel, K; Miller, R; Murley, J; Sadinski, M; Grdina, D [University of Chicago, Chicago, IL (United States)

    2016-06-15

    Purpose: To assess the effect of pre-treatment Magnetic Resonance Imaging (MRI) on cell survival following orthovoltage radiation therapy. Methods: This in vitro study examined the survival of FSa cells (extracted from methylcholanthrene-induced fibrosarcoma in the flank of a C3H female mouse) and SA-NH cells (derived from a spontaneously arising murine sarcoma tumor) having undergone an MRI scan prior to radiation exposure. Cell cultures were kept at 37 C, in a humidified environment with 5% CO2, and were grown to confluence prior to the start of the experiment. Each cell culture underwent two, 25 minute MRIs spaced 24 hours apart using a standard brain imaging protocol. The cultures were exposed to a 2 Gy dose of radiation beginning 15 minutes after the end of each MRI scan. Irradiations were performed by a Philips RT250 X-ray generator at 250 kVp and 15 mA. All MR imaging was performed on a 1.5 T Philips Achieva scanner using a head and neck vasculature coil. Results: Cells given an MRI scan prior to radiation exhibited an increase in mean surviving fraction of 10.8% and 9.6% in FSa and SA-NH cells, respectively. The difference was found to be statistically significant in both cell types by a student two-tailed t test with P = 0.011 and P < 0.001 for FSa and SA-NH, respectively. Conclusion: MRI may cause an increase in radio-resistance in FSa and SA-NH cells. If this biological effect is found to be consistent across other cell types and voltage ranges, these results could help inform treatment planning by improving our understanding of the joint effects of MRI and ionizing radiation. This work was supported in part under NIH grant numbers T32 EB002103, NCI R01-CA 132998, DOE Low Dose Program/Project Grant DE-413 SC0001271. DJ Grdina is a paid consultant to Pinnacle Biologics. DJ Grdina and JS Murley are minority equity partners in Pinnacle Oncology LLC.

  2. Massive Intra-Abdominal Imatinib-Resistant Gastrointestinal Stromal Tumor in a 21-Year-Old Male

    OpenAIRE

    Ann Falor; Arrington, Amanda K; Carrie Luu; Schoellhammer, Hans F; Michelle Ko; Warren Chow; Massimo D'Apuzzo; Jinha Park; Joseph Kim

    2013-01-01

    Gastrointestinal stromal tumors (GISTs) in adolescence are far less common than adult GISTs and have varied GIST genotypes that present diagnostic and therapeutic challenges. Here, we discuss a 21-year-old male with diagnosis of unresectable, imatinib-resistant GIST. At initial evaluation, a neoadjuvant treatment approach was recommended. As such, the patient received imatinib over the course of one year. Unfortunately, the GIST increased in size, and a subsequent attempt at surgical resectio...

  3. Effect of variations in atelectasis on tumor displacement during radiation therapy for locally advanced lung cancer

    Directory of Open Access Journals (Sweden)

    Nathan Tennyson, MD

    2017-01-01

    Conclusions: Changes in AT and PT volumes during radiation treatment were significantly associated with PT displacements that often exceeded standard setup margins. Repeated 3-dimensional imaging is recommended in patients with AT to evaluate for PT displacements during treatment.

  4. HDAC1 Upregulation by NANOG Promotes Multidrug Resistance and a Stem-like Phenotype in Immune Edited Tumor Cells.

    Science.gov (United States)

    Song, Kwon-Ho; Choi, Chel Hun; Lee, Hyo-Jung; Oh, Se Jin; Woo, Seon Rang; Hong, Soon-Oh; Noh, Kyung Hee; Cho, Hanbyoul; Chung, Eun Joo; Kim, Jae-Hoon; Chung, Joon-Yong; Hewitt, Stephen M; Baek, Seungki; Lee, Kyung-Mi; Yee, Cassian; Son, Minjoo; Mao, Chih-Ping; Wu, T C; Kim, Tae Woo

    2017-09-15

    Cancer immunoediting drives the adaptation of tumor cells to host immune surveillance. Immunoediting driven by antigen (Ag)-specific T cells enriches NANOG expression in tumor cells, resulting in a stem-like phenotype and immune resistance. Here, we identify HDAC1 as a key mediator of the NANOG-associated phenotype. NANOG upregulated HDAC1 through promoter occupancy, thereby decreasing histone H3 acetylation on K14 and K27. NANOG-dependent, HDAC1-driven epigenetic silencing of cell-cycle inhibitors CDKN2D and CDKN1B induced stem-like features. Silencing of TRIM17 and NOXA induced immune and drug resistance in tumor cells by increasing antiapoptotic MCL1. Importantly, HDAC inhibition synergized with Ag-specific adoptive T-cell therapy to control immune refractory cancers. Our results reveal that NANOG influences the epigenetic state of tumor cells via HDAC1, and they encourage a rational application of epigenetic modulators and immunotherapy in treatment of NANOG+ refractory cancer types. Cancer Res; 77(18); 5039-53. ©2017 AACR. ©2017 American Association for Cancer Research.

  5. [Ozone therapy for radiation reactions and skin lesions after neutron therapy in patients with malignant tumors].

    Science.gov (United States)

    Velikaya, V V; Gribova, O V; Musabaeva, L I; Startseva, Zh A; Simonov, K A; Aleinik, A N; Lisin, V A

    2015-01-01

    The article discusses the problem of radiation complications from normal tissues in patients after therapy with fast neutrons of 6.3 MeV. The methods of treatment using ozone technologies in patients with radiation reactions and skin lesions on the areas of irradiation after neutron and neutron-photon therapy have been worked out. Ozone therapy showed its harmlessness and increased efficiency of complex treatment of these patients.

  6. A Versatile Link for High-Speed, Radiation Resistant Optical Transmission in LHC Upgrades

    Science.gov (United States)

    Xiang, A.; Gong, D.; Hou, S.; Huffman, T.; Kwan, S.; Liu, K.; Liu, T.; Prosser, A.; Soos, C.; Su, D.; Teng, P.; Troska, J.; Vasey, F.; Weidberg, T.; Ye, J.

    The Versatile Link project is developing a general purpose physical layer optical link with high bandwidth, radiation resistance and magnetic-field tolerance that meets the requirements of LHC upgrade experiments. This paper presents recent work on system specifications, front-end transceiver prototypes, passive components studies and commercial back-end transceiver evaluations. System optical power budgets are specified for single mode (1310nm) and multi-mode (850nm) links, with a target data rate of 4.8 Gbps and a transmission length of 150 meters. Noise and interference penalties are simulated using the 10GbE link model and verified by bit error ratio measurement on reference links. The power margin is particularly constrained by radiation degradation of the front-end receivers. We report the power budgets for all link variants where at least 1.8 dB safety margins are maintained. The Versatile Transceiver (VTRx) - the front-end module to be installed on-detector - is based on a commercial small form pluggable (SFP+) package, modified to optimize size and mass, assembled to host a qualified laser, PIN photodiode, custom-designed radiation tolerant laser driver and receiving amplifier. A set of VTRxs with validated components have been prototyped and compliance tested. We also present the radiation test results on front-end components and passive components. The total fluence tests for lasers and PINs have been carried out with pions and neutrons up to 4 x 1015/cm2. SEU tests have been performed on PIN photodiodes and the full receiver optical subassembly. Radiation induced absorption in a number of single mode and multi-mode fibers, at -25¡C and up to 500 kGy, have been measured and high performance candidates identified. Commercial off-of-the-shelf parts have been examined for use as back-end transceivers. Compliance tests on SFP+, 4+4 parallel optical engines and SNAP 12 transmitter/receivers have been completed.

  7. Correlation of pretreatment polarographically measured oxygen pressures with quantified contrast-enhanced power doppler ultrasonography in spontaneous canine tumors and their impact on outcome after radiation therapy

    Energy Technology Data Exchange (ETDEWEB)

    Rohrer Bley, Carla; Laluhova, Dagmar [Section of Radiooncology, Vetsuisse Faculty, Univ. of Zurich (Switzerland); Roos, Malgorzata [Inst. for Social and Preventive Medicine, Medical Faculty, Univ. of Zurich (Switzerland); Kaser-Hotz, Barbara [Section of Radiooncology, Vetsuisse Faculty, Univ. of Zurich (Switzerland); Section Imaging Diagnostics, Vetsuisse Faculty, Univ. of Zurich (Switzerland); Ohlerth, Stefanie [Section Imaging Diagnostics, Vetsuisse Faculty, Univ. of Zurich (Switzerland)

    2009-11-15

    Purpose: to evaluate the use of noninvasive quantified contrast-enhanced power Doppler ultrasonography as a surrogate in the estimation of tumor hypoxia measured by invasive pO{sub 2} histography in canine tumors. Material and methods: data of pretreatment tumor oxygenation status, tumor vascularity and blood volume, and tumor response after radiation therapy was collected in 48 spontaneous malignant oral tumors (Table 1). Tumor oxygenation status was correlated to vascularity and blood volume, and influences on outcome after treatment were analyzed. Results: although vascularity and blood volume correlated moderately with median pO{sub 2} (r = 0.51 and 0.61; p = 0.001 and < 0.0001) and percentage of pO{sub 2} readings {<=} 2.5, 5, and 10 mmHg (r = -0.37 to -0.42; p < 0.01-0.03) for all tumors, they did not correlate within the different histology groups (p = 0.06-0.9). For all tumors, pretreatment oxygenation status, vascularity and blood volume were not found to be of prognostic value. Conclusion: these analyses show that quantified contrast-enhanced power Doppler ultrasonography does not represent a non-invasive indirect method to assess tumor hypoxia measured by invasive pO{sub 2} histography. Both technologies were nonprognostic indicators in spontaneous malignant canine oral tumors. (orig.)

  8. Occupational exposure to radio frequency/microwave radiation and the risk of brain tumors

    DEFF Research Database (Denmark)

    Berg, Gabriele; Spallek, Jacob; Schüz, Joachim

    2006-01-01

    It is still under debate whether occupational exposure to radio frequency/microwave electromagnetic fields (RF/MW-EMF) contributes to the development of brain tumors. This analysis examined the role of occupational RF/MW-EMF exposure in the risk of glioma and meningioma. A population-based, case....... No significant association between occupational exposure to RF/MW-EMF and brain tumors was found. For glioma, the adjusted odds ratio for highly exposed persons compared with persons not highly exposed was 1.21 (95% confidence interval: 0.69, 2.13); for meningioma, it was 1.34 (95% confidence interval: 0.64, 2...

  9. Lipophilic triphenylphosphonium derivatives enhance radiation-induced cell killing via inhibition of mitochondrial energy metabolism in tumor cells.

    Science.gov (United States)

    Yasui, Hironobu; Yamamoto, Kumiko; Suzuki, Motofumi; Sakai, Yuri; Bo, Tomoki; Nagane, Masaki; Nishimura, Eri; Yamamori, Tohru; Yamasaki, Toshihide; Yamada, Ken-Ichi; Inanami, Osamu

    2017-04-01

    It has recently been reported that radiation enhances mitochondrial energy metabolism in various tumor cell lines. To examine how this radiation-induced alteration in mitochondrial function influences tumor cell viability, various lipophilic triphenylphosphonium (TPP(+)) cation derivatives and related compounds such as 4-hydroxy-2,2,6,6-tetramethyl-1-oxy-piperidin (Tempol) with TPP(+) (named "Mito-") were designed to inhibit the mitochondrial electron transport chain. Mito-(CH2)10-Tempol (M10T) and its derivatives, Mito-(CH2)5-Tempol (M5T), Mito-(CH2)10-Tempol-Methyl (M10T-Me), Mito-C10H21 (M10), and C10H21-Tempol (10T), were prepared. In HeLa human cervical adenocarcinoma cells and A549 human lung carcinoma cells, the fractional uptake of the compound into mitochondria was highest among the TTP(+) analogs conjugated with Tempol (M10T, M5T, and 10T). M10T, M10T-Me, and M10 exhibited strong cytotoxicity and enhanced X-irradiation-induced reproductive cell death, while 10T and M5T did not. Furthermore, M10T, M10T-Me, and M10 decreased basal mitochondrial membrane potential and intracellular ATP. M10T treatment inhibited X-ray-induced increases in ATP production. These results indicate that the TPP cation and a long hydrocarbon linker are essential for radiosensitization of tumor cells. The reduction in intracellular ATP by lipophilic TPP(+) is partly responsible for the observed radiosensitization. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Effect of solar radiation on multidrug resistant E. coli strains and antibiotic mixture photodegradation in wastewater polluted stream

    Energy Technology Data Exchange (ETDEWEB)

    Rizzo, L., E-mail: l.rizzo@unisa.it [Department of Civil Engineering, University of Salerno, via Ponte don Melillo, 1-84084 Fisciano (Italy); Fiorentino, A. [Department of Civil Engineering, University of Salerno, via Ponte don Melillo, 1-84084 Fisciano (Italy); Anselmo, A. [Pluriacque, via Alento, 84060 Prignano Cilento (Italy)

    2012-06-15

    The effect of solar radiation on the inactivation of multidrug resistant Escherichia coli (MDR) strains selected from an urban wastewater treatment plant (UWWTP) effluent and the change of their resistance to a mixture of three antibiotics (evaluated in terms of minimum inhibit concentration (MIC)) in wastewater polluted stream were investigated. The solar photodegradation of the mixture of the three target antibiotics (amoxicillin (AMX), ciprofloxacin (CPX), and sulfamethoxazole (SMZ)) was also evaluated. Additionally, since UWWTP effluents are possible sources of antibiotics and antibiotic resistant bacteria, the disinfection by conventional chlorination process of the UWWTP effluent inoculated with MDR strains was investigated too. Solar radiation poorly affected the inactivation of the two selected antibiotic resistant E. coli strains (40 and 60% after 180 min irradiation). Moreover, solar radiation did not affect strain resistance to AMX (MIC > 256 {mu}g/mL) and SMZ (MIC > 1024 {mu}g/mL), but affected resistance of the lower resistance strain to CPX (MIC decreased by 33% but only after 180 min of irradiation). Chlorination of wastewater sample strongly decreased the number of the two selected antibiotic resistant E. coli strains (99.667 and 99.999%), after 60 min of contact time at 2.0 mg/L initial chlorine concentration, but the resistance of survived colonies to antibiotics was unchanged. Finally, the solar photodegradation rate of the antibiotic mixture (1 mg/L initial concentration respectively) resulted in the following order (half-life time): CPX (t{sub 1/2} = 24 min) < AMX (t{sub 1/2} = 99 min) < SMZ (t{sub 1/2} = 577 min). Accordingly, the risk of the development of resistance to SMZ in surface water is significantly higher compared to CPX and AMX. - Highlights: Black-Right-Pointing-Pointer Solar radiation did not affect E. coli strain resistance to AMX and SMZ. Black-Right-Pointing-Pointer Solar radiation affected the resistance of one E. coli strain

  11. Development of Bioactive PEGylated Nanostructured Platforms for Sequential Delivery of Doxorubicin and Imatinib to Overcome Drug Resistance in Metastatic Tumors.

    Science.gov (United States)

    Gupta, Biki; Ramasamy, Thiruganesh; Poudel, Bijay Kumar; Pathak, Shiva; Regmi, Shobha; Choi, Ju Yeon; Son, Youlim; Thapa, Raj Kumar; Jeong, Jee-Heon; Kim, Jae Ryong; Choi, Han-Gon; Yong, Chul Soon; Kim, Jong Oh

    2017-03-22

    Metastasis of cancers accounts for almost all cancer-related deaths. In this study, we report a PEGylated nanostructured platform for coadministration of doxorubicin (DOX) and imatinib (IMT) intended to effectively inhibit metastatic tumors. The DOX and IMT coloaded nanostructured system (DOX/IMT-N) is characterized by an excellent encapsulation potential for both drugs and shows sequential and sustained drug release in vitro. DOX/IMT-N significantly inhibited the in vitro proliferation of MDA-MB-231 and SK-MEL-28 cells. The inhibitory effect on in vitro proliferation of the cells was significantly greater than the effect of free DOX, DOX/IMT cocktail, or the nanostructured system housing DOX only (DOX-N). DOX/IMT-N remarkably enhanced cellular drug uptake, resulting in enhanced apoptosis, caused by significant increases in the expression levels of apoptotic marker proteins. Intravenous administration of DOX/IMT-N to MBA-MB-231 xenograft tumor-bearing mice resulted in significantly improved inhibition of tumor progression compared to that with DOX, DOX/IMT, or DOX-N. Therefore, the nanostructured DOX/IMT-N system could potentially aid in overcoming drug resistance in metastatic tumors and improve the effectiveness of metastatic tumor therapeutics.

  12. INPP4B-mediated tumor resistance is associated with modulation of glucose metabolism via hexokinase 2 regulation in laryngeal cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Min, Joong Won [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Kim, Kwang Il [Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Kim, Hyun-Ah; Kim, Eun-Kyu; Noh, Woo Chul [Department of Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Jeon, Hong Bae [Biomedical Research Institute, MEDIPOST Co., Ltd., Seoul (Korea, Republic of); Cho, Dong-Hyung [Graduate School of East-West Medical Science, Kyung Hee University, Gyeonggi-do (Korea, Republic of); Oh, Jeong Su [Department of Genetic Engineering, Sungkyunkwan University, Suwon (Korea, Republic of); Park, In-Chul; Hwang, Sang-Gu [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Kim, Jae-Sung, E-mail: jaesung@kirams.re.kr [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

    2013-10-11

    Highlights: •HIF-1α-regulated INPP4B enhances glycolysis. •INPP4B regulates aerobic glycolysis by inducing HK2 via Akt-mTOR pathway. •Blockage of INPP4B and HK2 sensitizes radioresistant laryngeal cancer cells to radiation and anticancer drug. •INPP4B is associated with HK2 in human laryngeal cancer tissues. -- Abstract: Inositol polyphosphate 4-phosphatase type II (INPP4B) was recently identified as a tumor resistance factor in laryngeal cancer cells. Herein, we show that INPP4B-mediated resistance is associated with increased glycolytic phenotype. INPP4B expression was induced by hypoxia and irradiation. Intriguingly, overexpression of INPP4B enhanced aerobic glycolysis. Of the glycolysis-regulatory genes, hexokinase 2 (HK2) was mainly regulated by INPP4B and this regulation was mediated through the Akt-mTOR pathway. Notably, codepletion of INPP4B and HK2 markedly sensitized radioresistant laryngeal cancer cells to irradiation or anticancer drug. Moreover, INPP4B was significantly associated with HK2 in human laryngeal cancer tissues. Therefore, these results suggest that INPP4B modulates aerobic glycolysis via HK2 regulation in radioresistant laryngeal cancer cells.

  13. Radiation-induced homotypic cell fusions of innately resistant glioblastoma cells mediate their sustained survival and recurrence.

    Science.gov (United States)

    Kaur, Ekjot; Rajendra, Jacinth; Jadhav, Shailesh; Shridhar, Epari; Goda, Jayant Sastri; Moiyadi, Aliasgar; Dutt, Shilpee

    2015-06-01

    Understanding of molecular events underlying resistance and relapse in glioblastoma (GBM) is hampered due to lack of accessibility to resistant cells from patients undergone therapy. Therefore, we mimicked clinical scenario in an in vitro cellular model developed from five GBM grade IV primary patient samples and two cell lines. We show that upon exposure to lethal dose of radiation, a subpopulation of GBM cells, innately resistant to radiation, survive and transiently arrest in G2/M phase via inhibitory pCdk1(Y15). Although arrested, these cells show multinucleated and giant cell phenotype (MNGC). Significantly, we demonstrate that these MNGCs are not pre-existing giant cells from parent population but formed via radiation-induced homotypic cell fusions among resistant cells. Furthermore, cell fusions induce senescence, high expression of senescence-associated secretory proteins (SASPs) and activation of pro-survival signals (pAKT, BIRC3 and Bcl-xL) in MNGCs. Importantly, following transient non-proliferation, MNGCs escape senescence and despite having multiple spindle poles during mitosis, they overcome mitotic catastrophe to undergo normal cytokinesis forming mononucleated relapse population. This is the first report showing radiation-induced homotypic cell fusions as novel non-genetic mechanism in radiation-resistant cells to sustain survival. These data also underscore the importance of non-proliferative phase in resistant glioma cells. Accordingly, we show that pushing resistant cells into premature mitosis by Wee1 kinase inhibitor prevents pCdk1(Y15)-mediated cell cycle arrest and relapse. Taken together, our data provide novel molecular insights into a multistep process of radiation survival and relapse in GBM that can be exploited for therapeutic interventions. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  14. The Survival and Resistance of Halobacterium salinarum NRC-1, Halococcus hamelinensis, and Halococcus morrhuae to Simulated Outer Space Solar Radiation.

    Science.gov (United States)

    Leuko, S; Domingos, C; Parpart, A; Reitz, G; Rettberg, P

    2015-11-01

    Solar radiation is among the most prominent stress factors organisms face during space travel and possibly on other planets. Our analysis of three different halophilic archaea, namely Halobacterium salinarum NRC-1, Halococcus morrhuae, and Halococcus hamelinensis, which were exposed to simulated solar radiation in either dried or liquid state, showed tremendous differences in tolerance and survivability. We found that Hcc. hamelinensis is not able to withstand high fluences of simulated solar radiation compared to the other tested organisms. These results can be correlated to significant differences in genomic integrity following exposure, as visualized by random amplified polymorphic DNA (RAPD)-PCR. In contrast to the other two tested strains, Hcc. hamelinensis accumulates compatible solutes such as trehalose for osmoprotection. The addition of 100 mM trehalose to the growth medium of Hcc. hamelinensis improved its survivability following exposure. Exposure of cells in liquid at different temperatures suggests that Hbt. salinarum NRC-1 is actively repairing cellular and DNA damage during exposure, whereas Hcc. morrhuae exhibits no difference in survival. For Hcc. morrhuae, the high resistance against simulated solar radiation may be explained with the formation of cell clusters. Our experiments showed that these clusters shield cells on the inside against simulated solar radiation, which results in better survival rates at higher fluences when compared to Hbt. salinarum NRC-1 and Hcc. hamelinensis. Overall, this study shows that some halophilic archaea are highly resistant to simulated solar radiation and that they are of high astrobiological significance. Halophiles-Solar radiation-Stress resistance-Survival.

  15. Hypo-Fractionated Conformal Radiation Therapy to the Tumor Bed after Segmental Mastectomy

    National Research Council Canada - National Science Library

    Formenti, Silvia C

    2007-01-01

    ... (5 fractions in 2 weeks)directed to the original tumor bed with margins in a selected subset of post-menopausal women with breast cancer with a very low risk for local risk for local recurrence elsewhere in the breast...

  16. Dual Agent Loaded PLGA Nanoparticles Enhanced Antitumor Activity in a Multidrug-Resistant Breast Tumor Eenograft Model

    Directory of Open Access Journals (Sweden)

    Yan Chen

    2014-02-01

    Full Text Available Multidrug-resistant breast cancers have limited and ineffective clinical treatment options. This study aimed to develop PLGA nanoparticles containing a synergistic combination of vincristine and verapamil to achieve less toxicity and enhanced efficacy on multidrug-resistant breast cancers. The 1:250 molar ratio of VCR/VRP showed strong synergism with the reversal index of approximately 130 in the multidrug-resistant MCF-7/ADR cells compared to drug-sensitive MCF-7 cells. The lyophilized nanoparticles could get dispersed quickly with the similar size distribution, zeta potential and encapsulation efficiency to the pre-lyophilized nanoparticles suspension, and maintain the synergistic in vitro release ratio of drugs. The co-encapsulated nanoparticle formulation had lower toxicity than free vincristine/verapamil combinations according to the acute-toxicity test. Furthermore, the most effective tumor growth inhibition in the MCF-7/ADR human breast tumor xenograft was observed in the co-delivery nanoparticle formulation group in comparison with saline control, free vincristine, free vincristine/verapamil combinations and single-drug nanoparticle combinations. All the data demonstrated that PLGANPs simultaneously loaded with chemotherapeutic drug and chemosensitizer might be one of the most potential formulations in the treatment of multidrug-resistant breast cancer in clinic.

  17. Relationships between Regional Radiation Doses and Cognitive Decline in Children Treated with Cranio-Spinal Irradiation for Posterior Fossa Tumors

    Directory of Open Access Journals (Sweden)

    Elodie Doger de Speville

    2017-08-01

    Full Text Available Pediatric posterior fossa tumor (PFT survivors who have been treated with cranial radiation therapy often suffer from cognitive impairments that might relate to IQ decline. Radiotherapy (RT distinctly affects brain regions involved in different cognitive functions. However, the relative contribution of regional irradiation to the different cognitive impairments still remains unclear. We investigated the relationships between the changes in different cognitive scores and radiation dose distribution in 30 children treated for a PFT. Our exploratory analysis was based on a principal component analysis (PCA and an ordinary least square regression approach. The use of a PCA was an innovative way to cluster correlated irradiated regions due to similar radiation therapy protocols across patients. Our results suggest an association between working memory decline and a high dose (equivalent uniform dose, EUD delivered to the orbitofrontal regions, whereas the decline of processing speed seemed more related to EUD in the temporal lobes and posterior fossa. To identify regional effects of RT on cognitive functions may help to propose a rehabilitation program adapted to the risk of cognitive impairment.

  18. Intravascular placement of metallic coils as lung tumor markers for CyberKnife stereotactic radiation therapy

    Energy Technology Data Exchange (ETDEWEB)

    Karaman, Kutlay; Dokdok, A. Murat; Karadeniz, Okatay; Ceylan, Cemile; Engin, Kayihan [Anadolu Medical Center, Kocaeli (Turkey)

    2015-06-15

    To present our experience with placing endovascular coils in pulmonary arteries used as a fiducial marker for CyberKnife therapy and to describe the technical details and complications of the procedure. Between June 2005 and September 2013, 163 patients with primary or secondary lung malignancies, referred for fiducial placement for stereotactic radiosurgery, were retrospectively reviewed. Fourteen patients (9 men, 5 women; mean age, 70 years) with a history of pneumonectomy (n = 3), lobectomy (n = 3) or with severe cardiopulmonary co-morbidity (n = 8) underwent coil (fiducial marker) placement. Pushable or detachable platinum micro coils (n = 49) 2-3 mm in size were inserted through coaxial microcatheters into a small distal pulmonary artery in the vicinity of the tumor under biplane angiography/fluoroscopy guidance. Forty nine coils with a median number of 3 coils per tumor were placed with a mean tumor-coil distance of 2.7 cm. Forty three (87.7%) of 49 coils were successfully used as fiducial markers. Two coils could not be used due to a larger tumor-coil distance (> 50 mm). Four coils were in an acceptable position but their non-coiling shape precluded tumor tracking for CyberKnife treatment. No major complications needing further medication other than nominal therapy, hospitalization more than one night or permanent adverse sequale were observed. Endovascular placement of coil as a fiducial marker is safe and feasible during CyberKnife therapy, and might be an option for the patients in which percutaneous transthoracic fiducial placement might be risky.

  19. Cell proliferation kinetics and radiation response in 9L tumor spheroids

    Energy Technology Data Exchange (ETDEWEB)

    Sweigert, S.E.

    1984-05-01

    Cell kinetic parameters, including population doubling-time, cell cycle time, and growth fraction, were measured in 9L gliosarcoma spheroids. These parameters were studied as the spheroids grew from 50 ..mu..m to over 900 ..mu..m in diameter. Experiments relating the cell kinetic parameters to the radiation response of 9L spheroids were also carried out. The major findings were that the average cell cycle time (T/sub c/), is considerably longer in large spheroids than in exponentially-growing monolayers, the radiosensitivity of noncycling (but still viable) cells in spheroids is not significantly different from that of cycling spheroid cells, and the radiation-induced division delay is approximately twice as long in spheroid cells as in monolayer cells given equal radiation doses. The cell loss factor for spheroids of various sizes was calculated, by using the measured kinetic parameters in the basic equations for growth of a cell population. 157 references, 6 figures, 3 tables.

  20. Dosimetric comparison of intensity modulated radiation, Proton beam therapy and proton arc therapy for para-aortic lymph node tumor

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Jung Hoon [Dept. of Radiation Oncology, Konyang University Hospital. Daejeon (Korea, Republic of)

    2014-12-15

    To test feasibility of proton arc therapy (PAT) in the treatment of para-aortic lymph node tumor and compare its dosimetric properties with advanced radiotherapy techniques such as intensity modulated radiation therapy (IMRT) and conventional 3D conformal proton beam therapy (PBT). The treatment plans for para-aortic lymph node tumor were planned for 9 patients treated at our institution using IMRT, PBT, and PAT. Feasibility test and dosimetric evaluation were based on comparisons of dose volume histograms (DVHs) which reveal mean dose, D{sub 30%}, D{sub 60%}, D{sub 90%}, V{sub 30%}, V{sub 60%}, V{sub 90}%, organ equivalent doses (OEDs), normal tissue complication probability (NTCP), homogeneity index (HI) and conformity index (CI). The average doses delivered by PAT to the liver, kidney, small bowel, duodenum, stomach were 7.6%, 3%, 17.3%, 26.7%, and 14.4%, of the prescription dose (PD), respectively, which is higher than the doses delivered by IMRT (0.4%, 7.2%, 14.2%, 15.9%, and 12.8%, respectively) and PBT (4.9%, 0.5%, 14.12%, 16.1% 9.9%, respectively). The average homogeneity index and conformity index of tumor using PAT were 12.1 and 1.21, respectively which were much better than IMRT (21.5 and 1.47, respectively) and comparable to PBT (13.1 and 1.23, respectively). The result shows that both NTCP and OED of PAT are generally lower than IMRT and PBT. This study demonstrates that PAT is better in target conformity and homogeneity than IMRT and PBT but worse than IMRT and PBT for most of dosimetric factor which indicate that PAT is not recommended for the treatment of para-aortic lymph node tumor.

  1. Predictive factors of symptomatic radiation pneumonitis in primary and metastatic lung tumors treated with stereotactic ablative body radiotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Kang Pyo; Lee, Jeong Shim; Cho, Yeona; Chung, Seung Yeun; Lee, Jason Joon Bock; Lee, Chang Geol; Cho, Jae Ho [Dept. of Radiation Oncology, Yonsei University College of Medicine, Seoul (Korea, Republic of)

    2017-06-15

    Although stereotactic ablative body radiotherapy (SABR) is widely used therapeutic technique, predictive factors of radiation pneumonitis (RP) after SABR remain undefined. We aimed to investigate the predictive factors affecting RP in patients with primary or metastatic lung tumors who received SABR. From 2012 to 2015, we reviewed 59 patients with 72 primary or metastatic lung tumors treated with SABR, and performed analyses of clinical and dosimetric variables related to symptomatic RP. SABR was delivered as 45–60 Gy in 3–4 fractions, which were over 100 Gy in BED when the α/β value was assumed to be 10. Tumor volume and other various dose volume factors were analyzed using median value as a cutoff value. RP was graded per the Common Terminology Criteria for Adverse Events v4.03. At the median follow-up period of 11 months, symptomatic RP was observed in 13 lesions (12 patients, 18.1%), including grade 2 RP in 11 lesions and grade 3 in 2 lesions. Patients with planning target volume (PTV) of ≤14.35 mL had significantly lower rates of symptomatic RP when compared to others (8.6% vs. 27%; p = 0.048). Rates of symptomatic RP in patients with internal gross tumor volume (iGTV) >4.21 mL were higher than with ≤4.21 mL (29.7% vs. 6.1%; p = 0.017). The incidence of symptomatic RP following treatment with SABR was acceptable with grade 2 RP being observed in most patients. iGTV over 4.21 mL and PTV of over 14.35 mL were significant predictive factors related to symptomatic RP.

  2. Hypoxia-induced tumor cell resistance is overcome by synergistic GAPDH-siRNA and chemotherapy co-delivered by long-circulating and cationic-interior liposomes

    NARCIS (Netherlands)

    Guan, J.; Sun, J.; Sun, F.|info:eu-repo/dai/nl/370549775; Lou, B.|info:eu-repo/dai/nl/37052537X; Zhang, D.; Mashayekhi, V.|info:eu-repo/dai/nl/413278360; Sadeghi, N.; Storm, G.|info:eu-repo/dai/nl/073356328; Mastrobattista, E.|info:eu-repo/dai/nl/228061105; He, Z.

    2017-01-01

    Chemotherapeutic drug resistance of tumor cells under hypoxic conditions is caused by the inhibition of apoptosis by autophagy and drug efflux via adenosine triphosphate (ATP)-dependent transporter activation, among other factors. Here, we demonstrate that disrupting glyceraldehyde-3-phosphate

  3. Enhancement of viability of radiosensitive (PBMC and resistant (MDA-MB-231 clones in low-dose-rate cobalt-60 radiation therapy

    Directory of Open Access Journals (Sweden)

    Patrícia Lima Falcão

    2015-06-01

    Full Text Available Abstract Objective: In the present study, the authors investigated the in vitro behavior of radio-resistant breast adenocarcinoma (MDA-MB-231 cells line and radiosensitive peripheral blood mononuclear cells (PBMC, as a function of different radiation doses, dose rates and postirradiation time kinetics, with a view to the interest of clinical radiotherapy. Materials and Methods: The cells were irradiated with Co-60, at 2 and 10 Gy and two different exposure rates, 339.56 cGy.min–1 and the other corresponding to one fourth of the standard dose rates, present over a 10-year period of cobalt therapy. Post-irradiation sampling was performed at pre-established kinetics of 24, 48 and 72 hours. The optical density response in viability assay was evaluated and a morphological analysis was performed. Results: Radiosensitive PBMC showed decrease in viability at 2 Gy, and a more significant decrease at 10 Gy for both dose rates. MDAMB- 231 cells presented viability decrease only at higher dose and dose rate. The results showed MDA-MB-231 clone expansion at low dose rate after 48–72 hours post-radiation. Conclusion: Low dose rate shows a possible potential clinical impact involving decrease in management of radio-resistant and radiosensitive tumor cell lines in cobalt therapy for breast cancer.

  4. Enhancement of viability of radiosensitive (PBMC) and resistant (MDA-MB-231) clones in low-dose-rate cobalt-60 radiation therapy

    Energy Technology Data Exchange (ETDEWEB)

    Falcao, Patricia Lima, E-mail: patricialfalcao@gmail.com [Universidade Federal do Amazonas (UFAM), Manaus, AM (Brazil); Motta, Barbara Miranda; Lima, Fernanda Castro de; Lima, Celso Vieira; Campos, Tarcisio Passos Ribeiro [Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG (Brazil)

    2015-05-15

    Objective: in the present study, the authors investigated the in vitro behavior of radio-resistant breast adenocarcinoma (MDA-MB-231) cells line and radiosensitive peripheral blood mononuclear cells (PBMC), as a function of different radiation doses, dose rates and postirradiation time kinetics, with a view to the interest of clinical radiotherapy. Materials and methods: the cells were irradiated with Co-60, at 2 and 10 Gy and two different exposure rates, 339.56 cGy.min{sup -1} and the other corresponding to one fourth of the standard dose rates, present over a 10-year period of cobalt therapy. Post-irradiation sampling was performed at pre-established kinetics of 24, 48 and 72 hours. The optical density response in viability assay was evaluated and a morphological analysis was performed. Results: radiosensitive PBMC showed decrease in viability at 2 Gy, and a more significant decrease at 10 Gy for both dose rates. MDAMB-231 cells presented viability decrease only at higher dose and dose rate. The results showed MDA-MB-231 clone expansion at low dose rate after 48-72 hours post-radiation. Conclusion: low dose rate shows a possible potential clinical impact involving decrease in management of radio-resistant and radiosensitive tumor cell lines in cobalt therapy for breast cancer. (author)

  5. Drug-Resistant Brain Metastases: A Role for Pharmacology, Tumor Evolution, and Too-Late Therapy.

    Science.gov (United States)

    Stricker, Thomas; Arteaga, Carlos L

    2015-11-01

    Two recent studies report deep molecular profiling of matched brain metastases and primary tumors. In both studies, somatic alterations in the brain metastases were frequently discordant with those in the primary tumor, suggesting divergent evolution at metastatic sites and raising questions about the use of biomarkers in patients in clinical trials with targeted therapies. ©2015 American Association for Cancer Research.

  6. Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4

    NARCIS (Netherlands)

    Todaro, Matilde; Alea, Mileidys Perez; Di Stefano, Anna B.; Cammareri, Patrizia; Vermeulen, Louis; Iovino, Flora; Tripodo, Claudio; Russo, Antonio; Gulotta, Gaspare; Medema, Jan Paul; Stassi, Giorgio

    2007-01-01

    A novel paradigm in tumor biology suggests that cancer growth is driven by stem-like cells within a tumor. Here, we describe the identification and characterization of such cells from colon carcinomas using the stem cell marker CD133 that accounts around 2% of the cells in human colon cancer. The

  7. SU-E-T-300: Dosimetric Comparision of 4D Radiation Therapy and 3D Radiation Therapy for the Liver Tumor Based On 4D Medical Image

    Energy Technology Data Exchange (ETDEWEB)

    Ma, C; Yin, Y [Shandong Tumor Hospital, Jinan, Shandong Provice (China)

    2015-06-15

    Purpose: The purpose of this work was to determine the dosimetric benefit to normal tissues by tracking liver tumor dose in four dimensional radiation therapy (4DRT) on ten phases of four dimensional computer tomagraphy(4DCT) images. Methods: Target tracking each phase with the beam aperture for ten liver cancer patients were converted to cumulative plan and compared to the 3D plan with a merged target volume based on 4DCT image in radiation treatment planning system (TPS). The change in normal tissue dose was evaluated in the plan by using the parameters V5, V10, V15, V20,V25, V30, V35 and V40 (volumes receiving 5, 10, 15, 20, 25, 30, 35 and 40Gy, respectively) in the dose-volume histogram for the liver; mean dose for the following structures: liver, left kidney and right kidney; and maximum dose for the following structures: bowel, duodenum, esophagus, stomach and heart. Results: There was significant difference between 4D PTV(average 115.71cm3 )and ITV(169.86 cm3). When the planning objective is 95% volume of PTV covered by the prescription dose, the mean dose for the liver, left kidney and right kidney have an average decrease 23.13%, 49.51%, and 54.38%, respectively. The maximum dose for bowel, duodenum,esophagus, stomach and heart have an average decrease 16.77%, 28.07%, 24.28%, 4.89%, and 4.45%, respectively. Compared to 3D RT, radiation volume for the liver V5, V10, V15, V20, V25, V30, V35 and V40 by using the 4D plans have a significant decrease(P≤0.05). Conclusion: The 4D plan method creates plans that permit better sparing of the normal structures than the commonly used ITV method, which delivers the same dosimetric effects to the target.

  8. Mathematics in medicine: tumor detection, radiation dosimetry, and simulation in psychotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Bellman, R.; Kashef, B.; Smith, C.P.; Ueno, S.; Vasudevan, R.

    1975-05-01

    Work done in the application of mathematics to medicine over the last 20 years is briefly reviewed. Scan-rescan processes, radiation dosimetry, and medical interviewing are discussed. The first uses dynamic programming, the second invariant imbedding, and the third simulation. (ACR)

  9. Elemental mapping by synchrotron radiation X-Ray microfluorescence in cellular spheroid of prostate tumor cells

    Energy Technology Data Exchange (ETDEWEB)

    Leitao, R.G.; Anjos, M.J.; Lopes, R.T., E-mail: roberta@lin.ufrj.br [Universidade Federal do Rio de Janeiro (UFRJ), RJ (Brazil). Lab. de Instrumentacao Nuclear; Santos, C.A.N. [Instituto Nacional de Metrologia, Qualidade e Tecnologia (INMETRO), Duque de Caxias, RJ (Brazil). Lab. de Biotecnologia; Palumbo Junior, A.; Souza, P.A.V.R.; Nasciutti, L.E. [Universidade Federal do Rio de Janeiro (UFRJ), RJ (Brazil). Instituto de Ciencias Biomedicas; Pereira, G.R. [Universidade Federal do Rio de Janeiro (UFRJ), RJ (Brazil). Lab. de Ensaios Nao Destrutivos, Corrosao e Soldagem

    2013-08-15

    Prostate cancer is the sixth most common type of cancer and the third most common in males in Western industrialized countries. Cellular spheroid serves as excellent physiologic tumor models as they mimic avascular tumors and micrometastases. Trace elements play a significant role in biological processes. They are capable of affecting human health by competing with essential elements for available binding sites and by the activation or inhibition of reactions between metabolic enzymes. It is well known that zinc levels in the peripheral zone of dorsal and lateral lobes of the prostate are almost 10 times higher than in other soft tissues. Prostate tumor cells were isolated of the prostate tissue samples that were collected from patients submitted to surgery. The measurements were performed in XRF beam line at the Synchrotron Light National Laboratory (LNLS) in Campinas, Brazil. The results showed that all elements were heterogeneously distributed in different areas of the spheroids analyzed. P, S and Cl showed similar elemental distribution in all the samples analyzed while K, Ca, Fe, and Cu showed different elemental distribution. In all spheroids analyzed, Zn presented more intense distributions in the central region of the spheroid. The relationship between the function of Zn in the secretory epithelial cells and the carcinogenic process suggests that more studies on elemental mapping in spheroids are necessary. (author)

  10. Reports of a Possible Causal Link between Brain, Head, and Neck Tumors and Radiation Exposure during Coronary Interventional Procedures: A Sobering Look at the Data

    Directory of Open Access Journals (Sweden)

    Ryan R. Reeves, MD

    2016-05-01

    Full Text Available Radiation exposure is a hazard for patients and physicians during fluoroscopically-guided procedures. Invasive cardiologists are exposed to high levels of scatter radiation and both increasing procedural complexity and higher operator volumes contribute to exposure above recommended thresholds. Standard shielding does not offer sufficient protection to the head and neck region and the potential for negative biological, subclinical, and clinical effects exists. Large population studies suggest that cranial exposure to low dose radiation increases the risks of tumor development. In addition, modest doses of therapeutic cranial radiation have been linked with the development of brain cancer. Although a causal association between scatter radiation in the cath lab and brain cancer does not currently exist, given the known detrimental effects of radiation exposure to the head and neck region support a focus on potential methods of protection for both the patient and the operator.

  11. Development of new mouse lung tumor models expressing EGFR T790M mutants associated with clinical resistance to kinase inhibitors.

    Directory of Open Access Journals (Sweden)

    Lucia Regales

    2007-08-01

    Full Text Available The EGFR T790M mutation confers acquired resistance to kinase inhibitors in human EGFR mutant lung adenocarcinoma, is occasionally detected before treatment, and may confer genetic susceptibility to lung cancer.To study further its role in lung tumorigenesis, we developed mice with inducible expression in type II pneumocytes of EGFR(T790M alone or together with a drug-sensitive L858R mutation. Both transgenic lines develop lung adenocarcinomas that require mutant EGFR for tumor maintenance but are resistant to an EGFR kinase inhibitor. EGFR(L858R+T790M-driven tumors are transiently targeted by hsp90 inhibition. Notably, EGFR(T790M-expressing animals develop tumors with longer latency than EGFR(L858R+T790M-bearing mice and in the absence of additional kinase domain mutations.These new mouse models of mutant EGFR-dependent lung adenocarcinomas provide insight into clinical observations. The models should also be useful for developing improved therapies for patients with lung cancers harboring EGFR(T790M alone or in conjunction with drug-sensitive EGFR kinase domain mutations.

  12. Setting the sterilization dose for a cotton-based product family using a knowledge of the distribution of radiation resistances

    Science.gov (United States)

    Yan, Aoshuang; Wang, Ailian; Zhai, Ying; Chen, Ben; Lim, Boon

    2002-03-01

    In setting a sterilization dose for a cotton-based product family that has failed the verification experiment of Method 1 given in ISO 11137, a study has been carried out to gain a knowledge of the distribution of radiation resistances of contaminating microorganisms. Overall, 155 organisms were isolated from a total of 11,000 organisms present on 100 g of products. D10 values of the isolates fall within 0.8-3.8 kGy. The derived distribution of radiation resistances can be considered as an evidence to support the use of sterilization doses given in Table B1 of ISO 11137 for different bioburden levels.

  13. Thymidylate synthase expression in circulating tumor cells: a new tool to predict 5-fluorouracil resistance in metastatic colorectal cancer patients.

    Science.gov (United States)

    Abdallah, Emne Ali; Fanelli, Marcello Ferretti; Buim, Marcilei Eliza Cavicchioli; Machado Netto, Marcelo Calil; Gasparini Junior, José Luiz; Souza E Silva, Virgílio; Dettino, Aldo Lourenço Abbade; Mingues, Natalia Breve; Romero, Juliana Valim; Ocea, Luciana Menezes Mendonça; Rocha, Bruna Maria Malagoli; Alves, Vanessa Silva; Araújo, Daniel Vilarim; Chinen, Ludmilla Thomé Domingos

    2015-09-15

    Thymidylate synthase (TYMS) is an important enzyme for 5-fluorouracil (5-FU) metabolism in metastatic colorectal cancer (mCRC) patients. The search for this enzyme in circulating tumor cells (CTCs) can be a powerful tool to follow-up cancer patients. mCRC patients were enrolled before the beginning of 5-FU-based chemotherapy. The blood was filtered on Isolation by Size of Epithelial Tumor Cells (ISET), and the analysis of TYMS expression in CTCs was made by immunocytochemistry. Additionally, we verified TYMS staining in primary tumors and metastases from the same patients. There were included 54 mCRC patients and 47 of them received 5-FU-based chemotherapy. The median CTCs number was 2 per mL. We were not able to analyze immunocytochemistry in 13 samples (9 patients with absence of CTCs and 4 samples due to technical reasons). Therefore, TYMS expression on CTCs was analyzed in 34 samples and was found positive in 9 (26.5%). Six of these patients had tumor progression after treatment with 5-FU. We found an association between CTC TYMS staining and disease progression (DP), although without statistical significance (P = 0.07). TYMS staining in primary tumors and metastases tissues did not have any correlation with disease progression (P = 0.67 and P = 0.42 respectively). Patients who had CTC count above the median (2 CTCs/mL) showed more TYMS expression (P = 0.02) correlating with worse prognosis. Our results searching for TYMS staining in CTCs, primary tumors and metastases suggest that the analysis of TYMS can be useful tool as a 5-FU resistance predictor biomarker if analyzed in CTCs from mCRC patients. © 2015 The Authors. Published by Wiley Periodicals, Inc. on behalf of UICC.

  14. Mesenchymal Stem Cell-Derived Extracellular Vesicles: Roles in Tumor Growth, Progression, and Drug Resistance

    Directory of Open Access Journals (Sweden)

    Xiaoyan Zhang

    2017-01-01

    Full Text Available Mesenchymal stem cells (MSCs are ubiquitously present in many tissues. Due to their unique advantages, MSCs have been widely employed in clinical studies. Emerging evidences indicate that MSCs can also migrate to the tumor surrounding stroma and exert complex effects on tumor growth and progression. However, the effect of MSCs on tumor growth is still a matter of debate. Several studies have shown that MSCs could favor tumor growth. On the contrary, other groups have demonstrated that MSCs suppressed tumor progression. Extracellular vesicles have emerged as a new mechanism of cell-to-cell communication in the development of tumor diseases. MSCs-derived extracellular vesicles (MSC-EVs could mimic the effects of the mesenchymal stem cells from which they originate. Different studies have reported that MSC-EVs may exert various effects on the growth, metastasis, and drug response of different tumor cells by transferring proteins, messenger RNA, and microRNA to recipient cells. In the present review, we summarize the components of MSC-EVs and discuss the roles of MSC-EVs in different malignant diseases, including the related mechanisms that may account for their therapeutic potential. MSC-EVs open up a promising opportunity in the treatment of cancer with increased efficacy.

  15. Total Ionizing Dose (TID) Effects of γ Ray Radiation on Ag/AlOx/Pt Resistive Switching Memory

    Science.gov (United States)

    Yuan, Fang; Zhang, Zhigang; Shen, Shanshan; Pan, Liyang; Xu, Jun; Memory Research Team

    2014-03-01

    The TID effects of γ rays generated from a 60Co source on the Ag/AlOx/Pt resistive switching (RS) memory is studied. Memory performances, including initial resistance state (IRS), low/high resistance state (LRS/HRS), forming voltage (Vf) , switching voltage (Vset/Vreset) and retention reliability are examined on the memory devices before and after exposure to 1M rad (Si) radiation. The LRS is robust to the radiation whereas a little degeneration of uniformity is found in IRS and HRS, which is caused by the radiation induced defects (mainly holes), trapped in the oxide. For the same reason, Vf increases several multiples after radiation. However surprisingly, both Vset and Vreset decrease during the RS and the retention performance is greatly improved. Based on these TID effects, it is proposed that the RS mechanism in Ag/AlOx/Pt, Ag conducting filament based switching, may be reinforced through γ radiation, which assists in stabilizing the growth/rupture of Ag filaments. The high radiation tolerance of AlOx-based RS memory devices suggests a potential for aerospace and nuclear applications. Supported by the National Natural Science Foundation of China (20111300789).

  16. Development of the radiation-resistant strain of Moraxella osloensis and effect of penicillin G on its growth

    Energy Technology Data Exchange (ETDEWEB)

    Lim, Sangyong; Yun, Hyejeong; Joe, Minho [Radiation Research Division for Biotechnology, Korea Atomic Energy Research Institute, Jeongeup 580-185 (Korea, Republic of); Kim, Dongho [Radiation Research Division for Biotechnology, Korea Atomic Energy Research Institute, Jeongeup 580-185 (Korea, Republic of)], E-mail: fungikim@kaeri.re.kr

    2009-07-15

    A series of repeated exposures to {gamma}-radiation with intervening outgrowth of survivors was used to develop radioresistant cultures of Moraxella osloensis that have been recognized as potential pathogenic microorganism. The D{sub 10} value of the radiation-resistant strain, 5.903{+-}0.006 kGy, was increased by four-fold compared to the parent wild-type strain, 1.637{+-}0.004 kGy. Since most strains of M. osloensis are sensitive to penicillin, we have surveyed the sensitivity of radiation-resistant strain to this antibiotic. When the optical density was monitored after the addition of penicillin G, the radioresistant strain appeared to be more resistant to only a low concentration of penicillin G (0.5 U/ml) than the parent strain. Interestingly, however, there was no apparent difference in the number of viable cells between both strains. Scanning electron microscope data showed that the resistance cells were generally larger than the parent cells, suggesting that this increase in size may cause a higher optical density of radioresistant cells. In conclusion, radiation mutation does not affect the penicillin resistance of M. osloensis.

  17. Development of the radiation-resistant strain of Moraxella osloensis and effect of penicillin G on its growth

    Science.gov (United States)

    Lim, Sangyong; Yun, Hyejeong; Joe, Minho; Kim, Dongho

    2009-07-01

    A series of repeated exposures to γ-radiation with intervening outgrowth of survivors was used to develop radioresistant cultures of Moraxella osloensis that have been recognized as potential pathogenic microorganism. The D10 value of the radiation-resistant strain, 5.903±0.006 kGy, was increased by four-fold compared to the parent wild-type strain, 1.637±0.004 kGy. Since most strains of M. osloensis are sensitive to penicillin, we have surveyed the sensitivity of radiation-resistant strain to this antibiotic. When the optical density was monitored after the addition of penicillin G, the radioresistant strain appeared to be more resistant to only a low concentration of penicillin G (0.5 U/ml) than the parent strain. Interestingly, however, there was no apparent difference in the number of viable cells between both strains. Scanning electron microscope data showed that the resistance cells were generally larger than the parent cells, suggesting that this increase in size may cause a higher optical density of radioresistant cells. In conclusion, radiation mutation does not affect the penicillin resistance of M. osloensis.

  18. Acquired Immune Resistance Follows Complete Tumor Regression without Loss of Target Antigens or IFN gamma Signaling

    DEFF Research Database (Denmark)

    Donia, Marco; Harbst, Katja; van Buuren, Marit

    2017-01-01

    Cancer immunotherapy can result in durable tumor regressions in some patients. However, patients who initially respond often experience tumor progression. Here, we report mechanistic evidence of tumoral immune escape in an exemplary clinical case: a patient with metastatic melanoma who developed...... disease recurrence following an initial, unequivocal radiologic complete regression after T-cell-based immunotherapy. Functional cytotoxic T-cell responses, including responses to one mutant neoantigen, were amplified effectively with therapy and generated durable immunologic memory. However, these immune...... radiologic regression. Personalized studies to uncover mechanisms leading to disease recurrence within each individual patient are warranted....

  19. Parallel selection of chemotherapy-resistant cell lines to illuminate mechanisms of drug resistance in human tumors

    DEFF Research Database (Denmark)

    Krzystanek, Marcin; Eklund, Aron Charles; Birkbak, Nicolai Juul

    2011-01-01

    -cancer drugs: doxorubicin and paclitaxel. By monitoring changes at two different levels (DNA and RNA) of the genome and developing multiple cell lines developing resistance against the same drug under identical conditions, we were able to separate relevant changes from spurious ones and thus reducing the noise...... the identification of reliable predictive biomarkers for each drug. Currently, we are developing a framework for systematic biomarker discovery by using a combination of gene expression and CGH arrays to keep track of consistent changes that take place during resistance acquisition in cell lines towards two anti....... Our findings are validated on already existing gene expression profiles of patient cohorts treated with the drugs in question, and the most promising ones will be chosen for functional validation by RNAi knock down. Successful validation will improve understanding of drug resistance mechanisms...

  20. Microcapsular imaging of malignant tumors and radiation induced release of liquid-core microcapsules for their treatment

    Energy Technology Data Exchange (ETDEWEB)

    Harada, S.; Ehara, S. [Department of Radiology, School of Medicine, Iwate Medical University, Iwate (Japan); Ishii, K. [Department of Quantum Science and Energy Engineering, School of Engineering, Tohoku University, Miyagi (Japan); Sato, T.; Enatsu, M.; Kamiya, T. [Takasaki Advanced Radiation Research Institute, Japan Atomic Energy Agency, Gunma (Japan); Sera, K. [Cyclotron Center, Iwate Medical University, Iwate (Japan); Goto, S. [Nishina Memorial Cyclotron Center (NMCC), Japan Radioisotope Association, Iwate (Japan)

    2013-07-01

    Full text: Purpose: Basing on the study of PIXE and Micro PIXE camera, microcapsules of 2 types were designed: (1) CT detectable anti-αvβ3 (E[c(RGDfK)]{sub 2}, microcapsules containing P-selectin and P-selectin glycoprotein ligand-1 (PSGL-1) to observe malignant tumors via αvβ3-antigen-antibody accumulation, and (2) malignant tumors-treating microcapsules that release anticancer drug on irradiation and have a high affinity to P-selectin. To test the ability of these microcapsules for imaging malignant tumors and for treating them, we subject C3He/N mice with MM48 tumor to 2 radiotherapy sessions. Methods and Materials: For the first session, microcapsules were prepared by spraying a mixture of 4.0% alginate, 3.0% hyaluronic acid, and 1 μg E[c(RGDfK)]{sub 2}, (αvβ3 antibody) into 0.5 mmol FeCI{sub 2}, supplemented with 1 μg P-selectin. Microcapsules for the second session were produced by spraying the above-mentioned mixture with 5mg carboplatin into 0.5 mol/L FeCI{sub 2}, containing 0.1 μmol/L of PSGL-1 and the FcSv antibody against P-selectin [1]. In the first session, the microcapsules were intravenously injected, and 6 h later, the incipient metastatic foci were observed using CT. Subsequently, a 10- or 20-Gy {sup 60}Co γ-radiation dose was administered. In the second session, 1 x 10{sup 10} microcapsules were intravenously injected 1 h before P-selectin expression peaked; the microcapsules were allowed to interact with P-selectin for 1-6 h after irradiation in order to deliver sufficient microcapsules. The second session was conducted in a similar manner to the first. The releasing of P-selectin or carboplatin were imaged using micro PIXE camera. The amount of carboplatin (Pt containing anticancer drug) were quantified, using PIXE. Results. The capsule and liquid core sizes (φ) were 2.3 ± 0.92 m and 1.6 ± 0.6 m, respectively. The injected anti-αvβ3 E[c(RGDfK)]{sub 2}, microcapsules accumulated in the vascular endothelium of the incipient

  1. Hypo-Fractionated Conformal Radiation Therapy to the Tumor Bed after Segmental Mastectomy

    Science.gov (United States)

    2007-07-01

    include area code) tandard Form 298 (Rev. 8-98) •rescribed by ANSI SW. Z39.18 "able of Contents ntroduction tody Cev Research Accomplishments...protocols. Int J Radiat Oncol Biol Phys. 2005 July :62(3):943-944. Formenti SC. Wernicke AG, DeWyngaert JK. External beam partial-breast radiotherapy...friendly regimen than the nandard 5-7 weeks of Dostoperative radiotherapy (RT) has ecenilv become an area of intense research, because in :enain

  2. Hypo-Fractionated Conformal Radiation Therapy to the Tumor Bed After Segmental Mastectomy

    Science.gov (United States)

    2005-07-01

    invasive breast cancer. Menopause was defined as at least 2 years without menstrual periods. In patients who had undergone prior hysterectomy, follicle... Recovery kinetics deduced from continuous low 73. Vicini FA, Kestin L, Chen P, et al. Limited-field radiation dose-rate experiments. Radiother Oncol...xx: © 2005 Elsevier Inc. All rights reserved. "A A though most studies treating patientswith partial-breast will require the procedure to be aborted , as

  3. High-Speed Live-Cell Interferometry: A New Method for Quantifying Tumor Drug Resistance and Heterogeneity.

    Science.gov (United States)

    Huang, Dian; Leslie, Kevin A; Guest, Daniel; Yeshcheulova, Olga; Roy, Irena J; Piva, Marco; Moriceau, Gatien; Zangle, Thomas A; Lo, Roger S; Teitell, Michael A; Reed, Jason

    2018-02-13

    We report the development of high-speed live-cell interferometry (HSLCI), a new multisample, multidrug testing platform for directly measuring tumor therapy response via real-time optical cell biomass measurements. As a proof of concept, we show that HSLCI rapidly profiles changes in biomass in BRAF inhibitor (BRAFi)-sensitive parental melanoma cell lines and in their isogenic BRAFi-resistant sublines. We show reproducible results from two different HSLCI platforms at two institutions that generate biomass kinetic signatures capable of discriminating between BRAFi-sensitive and -resistant melanoma cells within 24 h. Like other quantitative phase imaging (QPI) modalities, HSLCI is well-suited to noninvasive measurements of single cells and cell clusters, requiring no fluorescence or dye labeling. HSLCI is substantially faster and more sensitive than field-standard growth inhibition assays, and in terms of the number of cells measured simultaneously, the number of drugs tested in parallel, and temporal measurement range, it exceeds the state of the art by more than 10-fold. The accuracy and speed of HSLCI in profiling tumor cell heterogeneity and therapy resistance are promising features of potential tools to guide patient therapeutic selections.

  4. Reduced Toxicity With Intensity Modulated Radiation Therapy (IMRT) for Desmoplastic Small Round Cell Tumor (DSRCT): An Update on the Whole Abdominopelvic Radiation Therapy (WAP-RT) Experience

    Energy Technology Data Exchange (ETDEWEB)

    Desai, Neil B. [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Stein, Nicholas F. [Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); LaQuaglia, Michael P. [Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Alektiar, Kaled M. [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Kushner, Brian H.; Modak, Shakeel; Magnan, Heather M. [Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Goodman, Karyn [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Wolden, Suzanne L., E-mail: woldens@mskcc.org [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States)

    2013-01-01

    Purpose: Desmoplastic small round cell tumor (DSRCT) is a rare malignancy typically involving the peritoneum in young men. Whole abdominopelvic radiation therapy (WAP-RT) using conventional 2-dimensional (2D) radiation therapy (RT) is used to address local recurrence but has been limited by toxicity. Our objectives were to assess the benefit of intensity modulated radiation therapy (IMRT) on toxicity and to update the largest series on radiation for DSRCT. Methods and Materials: The records of 31 patients with DSRCT treated with WAP-RT (22 with 2D-RT and 9 with IMRT) between 1992 and 2011 were retrospectively reviewed. All received multi-agent chemotherapy and maximal surgical debulking followed by 30 Gy of WAP-RT. A further focal boost of 12 to 24 Gy was used in 12 cases. Boost RT and autologous stem cell transplantation were nearly exclusive to patients treated with 2D-RT. Toxicities were assessed with the Common Terminology Criteria for Adverse Events. Dosimetric analysis compared IMRT and simulated 2D-RT dose distributions. Results: Of 31 patients, 30 completed WAP-RT, with a median follow-up after RT of 19 months. Acute toxicity was reduced with IMRT versus 2D-RT: P=.04 for gastrointestinal toxicity of grade 2 or higher (33% vs 77%); P=.02 for grade 4 hematologic toxicity (33% vs 86%); P=.01 for rates of granulocyte colony-stimulating factor; and P=.04 for rates of platelet transfusion. Post treatment red blood cell and platelet transfusion rates were also reduced (P=.01). IMRT improved target homogeneity ([D05-D95]/D05 of 21% vs 46%) and resulted in a 21% mean bone dose reduction. Small bowel obstruction was the most common late toxicity (23% overall). Updated 3-year overall survival and progression-free survival rates were 50% and 24%, respectively. Overall survival was associated with distant metastasis at diagnosis on multivariate analysis. Most failures remained intraperitoneal (88%). Conclusions: IMRT for consolidative WAP-RT in DSRCT improves

  5. Manganese binding to antioxidant peptides involved in extreme radiation resistance in Deinococcus radiodurans.

    Science.gov (United States)

    Peana, Massimiliano; Medici, Serenella; Pangburn, Heather A; Lamkin, Thomas J; Ostrowska, Malgorzata; Gumienna-Kontecka, Elzbieta; Zoroddu, Maria Antonietta

    2016-11-01

    A decapeptide, DEHGTAVMLK (DP1), and its random scrambled version, THMVLAKGED (DP2), have been studied for their interactions with manganese. The amino acid composition of the peptides was selected to include the majority of the most prevalent amino acids present in a Deinococcus radiodurans bacterium cell-free extract that contains components capable of conferring extreme resistance to ionizing radiation. The extract appears to be rich in Mn(II) complexes which seem to be responsible for protecting proteins from Reactive Oxygen Species damage. We focused our attention on the interaction of the decapeptides with Mn(II) ion with the aim of obtaining information on the possible complexes formed, by using NMR, EPR, and ESI-MS techniques. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Cyanobacteria: photosynthetic factories combining biodiversity, radiation resistance, and genetics to facilitate drug discovery.

    Science.gov (United States)

    Cassier-Chauvat, Corinne; Dive, Vincent; Chauvat, Franck

    2017-02-01

    Cyanobacteria are ancient, abundant, and widely diverse photosynthetic prokaryotes, which are viewed as promising cell factories for the ecologically responsible production of chemicals. Natural cyanobacteria synthesize a vast array of biologically active (secondary) metabolites with great potential for human health, while a few genetic models can be engineered for the (low level) production of biofuels. Recently, genome sequencing and mining has revealed that natural cyanobacteria have the capacity to produce many more secondary metabolites than have been characterized. The corresponding panoply of enzymes (polyketide synthases and non-ribosomal peptide synthases) of interest for synthetic biology can still be increased through gene manipulations with the tools available for the few genetically manipulable strains. In this review, we propose to exploit the metabolic diversity and radiation resistance of cyanobacteria, and when required the genetics of model strains, for the production and radioactive ((14)C) labeling of bioactive products, in order to facilitate the screening for new drugs.

  7. Radiation-resistant composite scintillators based on GSO and GPS grains

    Energy Technology Data Exchange (ETDEWEB)

    Boyarintsev, A.Yu. [Institute for Scintillation Materials, National Academy of Sciences of Ukraine, 60 Nauki Avenue, 61001 Kharkiv (Ukraine); Galunov, N.Z. [Institute for Scintillation Materials, National Academy of Sciences of Ukraine, 60 Nauki Avenue, 61001 Kharkiv (Ukraine); V.N. Karasin Kharkov National University, 4 Svobody Sq., 61022 Kharkiv (Ukraine); Gerasymov, Ia.V.; Karavaeva, N.L. [Institute for Scintillation Materials, National Academy of Sciences of Ukraine, 60 Nauki Avenue, 61001 Kharkiv (Ukraine); Krech, A.V., E-mail: AntonKrech@gmail.com [Institute for Scintillation Materials, National Academy of Sciences of Ukraine, 60 Nauki Avenue, 61001 Kharkiv (Ukraine); Levchuk, L.G.; Popov, V.F. [National Science Center, Kharkov Institute of Physics and Technology, 1 Akademicheskaya Str., 61108 Kharkiv (Ukraine); Sidletskiy, O.Ts. [Institute for Scintillation Materials, National Academy of Sciences of Ukraine, 60 Nauki Avenue, 61001 Kharkiv (Ukraine); Sorokin, P.V. [National Science Center, Kharkov Institute of Physics and Technology, 1 Akademicheskaya Str., 61108 Kharkiv (Ukraine); Tarasenko, O.A. [Institute for Scintillation Materials, National Academy of Sciences of Ukraine, 60 Nauki Avenue, 61001 Kharkiv (Ukraine)

    2017-01-01

    The effect of irradiation on the scintillation light output, optical transmittance, and luminescent spectra of composite scintillators based on grains of single crystals Gd{sub 2}SiO{sub 5}:Ce (GSO) and Gd{sub 2}Si{sub 2}O{sub 7}:Ce (GPS) is studied. The dielectric gel Sylgard-184 is the base and the binder for the grains inside the composite scintillator. The paper presents and analyzes the results obtained for the scintillators exposed by 10 MeV electrons from the linear electron accelerator at room temperature. The exposure doses D≤250 Mrad. The dose rate is 0.2 or 1500 Mrad/h. The study has shown that the composite scintillators based on the grains of GSO and GPS are radiation-resistant over the range of the irradiation.

  8. Targeting c-Met receptor overcomes TRAIL-resistance in brain tumors

    National Research Council Canada - National Science Library

    Du, Wanlu; Uslar, Liubov; Sevala, Sindhura; Shah, Khalid

    2014-01-01

    .... We show that the knock down c-Met protein, but not inhibition, sensitized brain tumor cells to TRAIL-mediated apoptosis by interrupting the interaction between c-Met and TRAIL cognate death receptor (DR) 5...