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Sample records for stimulation increases radiosensitivity

  1. Insulin-like growth factor stimulation increases radiosensitivity of a pancreatic cancer cell line through endoplasmic reticulum stress under hypoxic conditions

    International Nuclear Information System (INIS)

    Isohashi, Fumiaki; Endo, Hiroko; Mukai, Mutsuko; Inoue, Masahiro; Inoue, Takehiro

    2008-01-01

    Tumor hypoxia is an obstacle to radiotherapy. Radiosensitivity under hypoxic conditions is determined by molecular oxygen levels, as well as by various biological cellular responses. The insulin-like growth factor (IGF) signaling pathway is a widely recognized survival signal that confers radioresistance. However, under hypoxic conditions the role of IGF signaling in radiosensitivity is still poorly understood. Here, we demonstrate that IGF-II stimulation decreases clonogenic survival under hypoxic conditions in the pancreatic cancer cell lines AsPC-1 and Panc-1, and in the human breast cancer cell line MCF-7. IGF treatment under hypoxic conditions suppressed increased radiation sensitivity in these cell lines by pharmacologically inhibiting the phosphoinositide 3-kinase-mammalian target of rapamycin pathway, a major IGF signal-transduction pathway. Meanwhile, IGF-II induced the endoplasmic reticulum stress response under hypoxia, including increased protein levels of CHOP and ATF4, mRNA levels of CHOP, GADD34, and BiP as well as splicing levels of XBP-1. The response was suppressed by inhibiting phosphoinositide 3-kinase and mammalian target of rapamycin activity. Overexpression of CHOP in AsPC-1 cells increased radiation sensitivity by IGF-II simulation under hypoxic conditions, whereas suppression of CHOP expression levels with small hairpin RNA or a dominant negative form of a proline-rich extensin-like receptor protein kinase in hypoxia decreased IGF-induced radiosensitivity. IGF-induced endoplasmic reticulum stress contributed to radiosensitization independent of cell cycle status. Taken together, IGF stimulation increased radiosensitivity through the endoplasmic reticulum stress response under hypoxic conditions. (author)

  2. Increased chromosome radiosensitivity during pregnancy

    International Nuclear Information System (INIS)

    Ricoul, Michelle; Sabatier, Laure; Dutrillaux, Bernard

    1997-01-01

    It was necessary to consider the risks of exposure of pregnant women, not only in relation to the child, but also in relation to their own hypersensitivity. We have demonstrated that pregnancy increases radiosensitivity of chromosome in the mouse at the end of gestation. This is of importance since it may have implications on radioprotection of pregnant women and give experimental guidelines to the problems of hypersensitivity to drugs and cancer aggravation during pregnancy. Blood obtained from women at various times of pregnancy was exposed to ionizing radiations. By comparison to non-pregnant women, an increase in chromosome breakage was observed in metaphases from lymphocytes, after short-term culture in the presence of the serum of the same donor. Immediately after delivery, this increase in radiosensitivity disappeared. In a prospective study, serial analyses showed a very strong correlation between the amount of pregnancy hormones, progesterone in particular, and the increase in radiosensitivity. Pregnant women may have an increased sensitivity to ionizing radiation during the second half of their pregnancy. This study provides the first evidence in human that radiosensitivity may vary in relation to physiological conditions

  3. Cell kinetic and radiosensitivity of PHA stimulated goat lymphocytes

    International Nuclear Information System (INIS)

    Debuyst, B.; Rosenthal, M.; Leonard, A.

    1982-01-01

    The harlequin-staining method has been used to study the cell kinetic of goat peripheral blood lymphocytes stimulated by phytohemagglutinin and to assess their radiosensitivity. At 48 h, the standardized culture time employed for human lymphocytes, 71% of the goat lymphocytes are in first mitosis, 23% are in second mitosis and 5% in third. Irradiation with 200 rads X-rays induces an average of 24,5 dicentric chromosomes per hundred cells in first mitosis [fr

  4. Cisplatin-mediated radiosensitization of non-small cell lung cancer cells is stimulated by ATM inhibition

    International Nuclear Information System (INIS)

    Toulany, Mahmoud; Mihatsch, Julia; Holler, Marina; Chaachouay, Hassan; Rodemann, H. Peter

    2014-01-01

    Background and purpose: Cisplatin activates ataxia-telangiectasia-mutated (ATM), a protein with roles in DNA repair, cell cycle progression and autophagy. We investigated the radiosensitizing effect of cisplatin with respect to its effect on ATM pathway activation. Material and methods: Non-small cell lung cancer cells (NSCLC) cell lines (A549, H460) and human fibroblast (ATM-deficient AT5, ATM-proficient 1BR3) cells were used. The effects of cisplatin combined with irradiation on ATM pathway activity, clonogenicity, DNA double-strand break (DNA-DSB) repair and cell cycle progression were analyzed with Western blotting, colony formation and γ-H2AX foci assays as well as FACS analysis, respectively. Results: Cisplatin radiosensitized H460 cells, but not A549 cells. Radiosensitization of H460 cells was not due to impaired DNA-DSB repair, increased apoptosis or cell cycle dysregulation. The lack of radiosensitization demonstrated for A549 cells was associated with cisplatin-mediated stimulation of ATM (S1981) and AMPKα (T172) phosphorylation and autophagy. However, in both cell lines inhibition of ATM and autophagy by KU-55933 and chloroquine diphosphate (CQ) respectively resulted in a significant radiosensitization. Combined treatment with the AMPK inhibitor compound-C led to radiosensitization of A549 but not of H460 cells. As compared to the treatment with KU-55933 alone, radiosensitivity of A549 cells was markedly stimulated by the combination of KU-55933 and cisplatin. However, the combination of CQ and cisplatin did not modulate the pattern of radiation sensitivity of A549 or H460 cells. In accordance with the results that cisplatin via stimulation of ATM activity can abrogate its radiosensitizing effect, ATM deficient cells were significantly sensitized to ionizing radiation by cisplatin. Conclusion: The results obtained indicate that ATM targeting can potentiate cisplatin-induced radiosensitization

  5. Autophagy involved in resveratrol increased radiosensitivity in glioma stem cells

    International Nuclear Information System (INIS)

    Long Linmei; Zhang Qingqing; Yang Neng; Ji Wenjun; Song Yunzhen; Zhao Jianghu; Liang Zhongqin

    2012-01-01

    Objective: To investigate the effect of Resveratrol combined with X-ray on radiosensitivity in glioma stem cells. Methods: The proliferation inhibition of glioma stem cells induced by X-rays and Resveratrol was assessed with MTT assay. The activation of proapoptotic effect was characterized by Hoechst 33258 stain. MDC stain and Western blot analysis were used to analyze the autophagy mechanism in X-rays-induced death of glioma stem cells. Results: MTT assay indicated that X-rays and Resveratrol decreased the viability of glioma stem cells (P<0.05); we found the proliferative inhibition of glioma stem cells was declined when we used 3-MA to inhibit autophagy(P<0.05). When the cells were treated by the Resveratrol and x-rays, their spherical shape were changed. Apoptosis was induced in glioma stem cells by combined X-rays and Resveratrol as detected by Hoechst 33258 staining. In addition, autophagy was induced in glioma stem cells in the combined treatment group as detected by MDC staining. Western blotting showed that Bcl-2 expression was decreased. in the combined treatment group (P<0.01), and the LC3-Ⅱ expression was increased in the combined treatment group (P<0.01). Conclusion: Resveratrol can increased the radiation sensitivity of glioma stem cells, the apoptosis and autophagy was induced in the glioma stem cells in the combined treatment X-rays and Resveratrol. Our results suggest that autophagy plays an essential role in the regulation of radiosensitization of glioma stem cells. (authors)

  6. Neoplasms radiosensitivity: how to increase the efficiency of radiotherapy

    International Nuclear Information System (INIS)

    Calais, G.

    1991-01-01

    The hypoxia in the neoplasms is a radioresistance factor. This article is about the methods able to reduce the hypoxia in tumors: use of hyperbaric oxygen, radiosensitizers (as metronidazole), hyperthermia and modification of oxygen release in the tissues in modifying the blood flow and in reducing the hemoglobin affinity for oxygen [fr

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

    International Nuclear Information System (INIS)

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

    1980-01-01

    In vitro radiation-survival of peripheral blood T-lymphocytes was studied in fifteen clinically normal adults and four patients with Fanconi's anemia (FA). Lymphocyte blastogenesis and cloning were measured following phytohemagglutinin (PHA) or Concanavalin-A (Con-A) stimulation. PHA-responsive lymphocytes from FA patients were significantly more radiosensitive than lymphocytes from normal individuals

  8. Expression of p210 BCR/ABl increases hematopoietic progenitor cell radiosensitivity

    International Nuclear Information System (INIS)

    Santucci, M.A.; Anklesaria, P.; Das, I.J.; Sakakeeny, M.A.; FitzGerald, T.J.; Greenberger, J.S.; Laneuville, P.

    1993-01-01

    The cytogenetic finding of the Ph1+ chromosome and its molecular biologic marker bcr/abl gene rearrangement in cells from patients with chronic myeloid leukemia are associated with a proliferative advantage of the Ph1+ clone in vivo. Although the transition to the acute terminal phase or blastic crisis is often associated with additional cytogenetic abnormalities, the molecular events which correlate the initial cytogenetic lesion with the terminal phase are poorly understood. Defective cellular DNA repair capacity is often associated with chromosomal instability, increased mutation frequency, and biologic alterations. The authors tested whether the protein product of the bcr/abl translocation (p210) could alter DNA repair after gamma-irradiation of murine cell lines expressing the bcr/abl cDNA. The 32D cl 3 parent, 32D cl 3 pYN (containing the control vector plasmid) and each of two sources of 32D cl 3 cells expressing p210 cDNA (32D-PC1 cell line and 32D-LG7 subclone) showed a D 0 of 1.62, 1.57, 1.16, and 1.27 Gy, respectively. Thus, expression of the p210 product induced a significant increase in radiosensitivity at the clinically relevant radiation therapy dose-rate. The increased radiosensitivity of p210-expressing cells persisted if cells were held before plating in a density-inhibited state for 8 hr after gamma-irradiation, indicating little effect on the repair of potentially lethal gamma-irradiation damage. The IL-3 dependent parent 32D cl 3 cells demonstrated programmed cell death in the absence of growth factor or following gamma-irradiation to 200 cGy. Expression of p210 cDNA in the 32D-PC1 and 32D-LG7 subclones abrogated IL-3 requirement of these cell lines and inhibited gamma-irradiation induced programmed cell death. These data suggest a role for p210 in amplifying gamma-irradiation DNA damage or broadly inhibiting DNA repair, conditions that may stimulate further cytogenetic alterations in hematopoietic cells. 43 refs., 3 figs., 1 tab

  9. Procedures for increasing the radiosensitivity of malignant tumors with special regard to synchronized radiotherapy

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    Guenther, W

    1975-01-01

    Two principal ways to increase the radiosensitivity of malignant tumours are described: to begin with, both the use of highly ionizing corpuscular radiation - e.g. in neutron therapy - and the simultaneous application of photons and high-pressure oxygen heighten radiosensitivity by increasing the number of secondary hit events. The second principal direction - in which the radiation intervals are timed in dependence of lifetime and division rhythm of the tumour cells - is described and illustrated by results of 5-fluorouracil and /sup 60/Co irradiation of 71 patients. The results show a particularly good response of carcinomas of the ENT region and the breast. Questions of the radiosensitive stage, the time of infusion, the influence of the generation cycle and the influence of oxygen-starved cells on the results are major points for future studies on synchronized radiotherapy. Mathematical calculations are carried out concerning the time of infusion and the influence of the generation cycle. Some consequences are mentioned which had not been dealt with so far in synchronized radiotherapy: high single doses and short intervals between sessions for tumours with short generation and duplication times, and low doses and long intervals for small tumours with slow growth rates. There is no principal difference between oxygen-starved and oxygen-rich cells as far as the dependence of radiosensitivity on the generation cycle - i.e. the starting point of synchronized radiotherapy - is concerned.

  10. Radiosensitization In Vivo by Histone Deacetylase Inhibition with No Increase in Early Normal Tissue Radiation Toxicity.

    Science.gov (United States)

    Groselj, Blaz; Ruan, Jia-Ling; Scott, Helen; Gorrill, Jessica; Nicholson, Judith; Kelly, Jacqueline; Anbalagan, Selvakumar; Thompson, James; Stratford, Michael R L; Jevons, Sarah J; Hammond, Ester M; Scudamore, Cheryl L; Kerr, Martin; Kiltie, Anne E

    2018-02-01

    As the population ages, more elderly patients require radiotherapy-based treatment for their pelvic malignancies, including muscle-invasive bladder cancer, as they are unfit for major surgery. Therefore, there is an urgent need to find radiosensitizing agents minimally toxic to normal tissues, including bowel and bladder, for such patients. We developed methods to determine normal tissue toxicity severity in intestine and bladder in vivo , using novel radiotherapy techniques on a small animal radiation research platform (SARRP). The effects of panobinostat on in vivo tumor growth delay were evaluated using subcutaneous xenografts in athymic nude mice. Panobinostat concentration levels in xenografts, plasma, and normal tissues were measured in CD1-nude mice. CD1-nude mice were treated with drug/irradiation combinations to assess acute normal tissue effects in small intestine using the intestinal crypt assay, and later effects in small and large intestine at 11 weeks by stool assessment and at 12 weeks by histologic examination. In vitro effects of panobinostat were assessed by qPCR and of panobinostat, TMP195, and mocetinostat by clonogenic assay, and Western blot analysis. Panobinostat resulted in growth delay in RT112 bladder cancer xenografts but did not significantly increase acute (3.75 days) or 12 weeks' normal tissue radiation toxicity. Radiosensitization by panobinostat was effective in hypoxic bladder cancer cells and associated with class I HDAC inhibition, and protein downregulation of HDAC2 and MRE11. Pan-HDAC inhibition is a promising strategy for radiosensitization, but more selective agents may be more useful radiosensitizers clinically, resulting in fewer systemic side effects. Mol Cancer Ther; 17(2); 381-92. ©2017 AACR See all articles in this MCT Focus section, "Developmental Therapeutics in Radiation Oncology." ©2017 American Association for Cancer Research.

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

    International Nuclear Information System (INIS)

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

    1981-01-01

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

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

    International Nuclear Information System (INIS)

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

    1981-01-01

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

  13. EGFR inhibitor C225 increases the radiosensitivity of human lung squamous cancer cells

    Directory of Open Access Journals (Sweden)

    Yang Ruijie

    2010-10-01

    Full Text Available Abstract Background The purpose of the present study is to investigate the direct biological effects of the epidermal growth factor receptor (EGFR inhibitor C225 on the radiosensitivity of human lung squamous cancer cell-H520. H520 cells were treated with different dosage of 60Co γ ray irradiation (1.953 Gy/min in the presence or absence of C225. The cellular proliferation, colony forming capacity, apoptosis, the cell cycle distribution as well as caspase-3 were analyzed in vitro. Results We found that C225 treatment significantly increased radiosensitivity of H-520 cells to irradiation, and led to cell cycle arrest in G1 phase, whereas 60Co γ ray irradiation mainly caused G2 phase arrest. H-520 cells thus displayed both the G1 and G2 phase arrest upon treatment with C225 in combination with 60Co γ ray irradiation. Moreover, C225 treatment significantly increased the apoptosis percentage of H-520 cells (13.91% ± 1.88% compared with the control group (5.75% ± 0.64%, P Conclusion In this regard, C225 treatment may make H-520 cells more sensitive to irradiation through the enhancement of caspase-3 mediated tumor cell apoptosis and cell cycle arrest.

  14. Increasing the radiosensitivity of tumours in an hypoxic environment using inhibitors of the pentose phosphate pathway

    International Nuclear Information System (INIS)

    Sahasrabudhe, M.B.; Bhonsle, S.R.; Krishnamurti, K.; Tilak, B.D.

    1977-01-01

    Rapidly growing tumours contain few blood vessels in the tumour mass. Cells in such tumours obtain nutrients and oxygen from the periphery by diffusion, resulting in a diminishing oxygen and nutrient gradient from the periphery to centre of the tumour mass. In normal tissues, oxygen is utilized via a tricarboxylic acid (TCA) cycle; in tumour cells oxygen is utilized via a hexose monophosphate (HMP) pathway and through the TCA cycle at a 30% reduced level. Interference with the HMP pathway selectively inhibits the utilization of oxygen by tumour cells, thus increasing the availability of oxygen to hypoxic cells situated deeper in the tumour mass. This effect has been exploited for increasing the radiosensitivity of tumour cells situated in an hypoxic environment. The influence of sixteen potential antimetabolites on the HMP pathway has been studied. Of these, six compounds, namely, (1) 2-carboxy 5-hydroxymethyl thiophene, (2) the sodium salt of 2:5 dicarbethoxy 3:4 dihydroxy thiophene, (3) the dihydrazide of 2:5 dicarboxy thiophene, (4) the dihydrazide of 3:4 dimethoxy 2:5 dicarboxy thiophene, (5) trithiocyanuric acid, and (6) cyanuric trithioglycollic acid showed an inhibiting effect on the HMP pathway without any influence on the TCA cycle. Influence of administration of compounds (1), (2) and (4) prior to radiation on the growth of transplanted fibrosarcomas in mice has been studied and is reported here. These three compounds showed marked potentiation of radiosensitivity of tumours. (author)

  15. Increased catalase activity by all-trans retinoic acid and its effect on radiosensitivity in rat glioma cells

    International Nuclear Information System (INIS)

    Jin, Hua; Jeon, Ha Yeun; Park, Woo Yoon; Kim, Won Dong; Ahn, Hee Yul; Yu, Jae Ran

    2005-01-01

    It has been reported that all-trans retinoic acid (ATRA) can inhibit glioma growing in vitro. However, clinical trials with ATRA alone in gliomas revealed modest results. ATRA has been shown to increase radiosensitivity in other tumor types, so combining radiation and ATRA would be one of alternatives to increase therapeutic efficacy in malignant gliomas. Thus, we intended to know the role of catalase, which is induced by ATRA, for radiosensitivity. If radiation-reduced reactive oxygen species (ROS) is removed by catalase, the effect of radiation will be reduced. A rat glioma cell line (36B10) was used for this study. The change of catalase activity and radiosensitivity by ATRA, with or without 3-amino-1, 2, 4-triazole (ATZ), a chemical inhibitor of catalase were measured. Catalase activity was measured by the decomposition of H 2 O 2 spectrophotometrically. Radiosensitivity was measured with clonogenic assay. Also ROS was measured using a 2, 7-dichlorofluores-cein diacetate spectrophotometrically. When 36B10 cells were exposed to 10, 25 and 50 μ M of ATRA for 48 h, the expression of catalase activity were increased with increasing concentration and incubation time of ATRA. Catalase activity was decreased with increasing the concentration of AT (1, 10 mM) dose-dependently. ROS was increased with ATRA and it was augmented with the combination of ATRA and radiation. ATZ decreased ROS production and increased cell survival in combination of ATRA and radiation despite the reduction of catalase. The increase of ROS is one of the reasons for the increased radiosensitivity in combination with ATRA. The catalase that is induced by ATRA doesn't decrease ROS production and radiosensitivity

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

    International Nuclear Information System (INIS)

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

    2010-01-01

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

  17. Increased betulinic acid induced cytotoxicity and radiosensitivity in glioma cells under hypoxic conditions

    International Nuclear Information System (INIS)

    Bache, Matthias; Taubert, Helge; Vordermark, Dirk; Zschornak, Martin P; Passin, Sarina; Keßler, Jacqueline; Wichmann, Henri; Kappler, Matthias; Paschke, Reinhard; Kaluđerović, Goran N; Kommera, Harish

    2011-01-01

    Betulinic acid (BA) is a novel antineoplastic agent under evaluation for tumor therapy. Because of the selective cytotoxic effects of BA in tumor cells (including gliomas), the combination of this agent with conservative therapies (such as radiotherapy and chemotherapy) may be useful. Previously, the combination of BA with irradiation under hypoxic conditions had never been studied. In this study, the effects of 3 to 30 μM BA on cytotoxicity, migration, the protein expression of PARP, survivin and HIF-1α, as well as radiosensitivity under normoxic and hypoxic conditions were analyzed in the human malignant glioma cell lines U251MG and U343MG. Cytotoxicity and radiosensitivity were analyzed with clonogenic survival assays, migration was analyzed with Boyden chamber assays (or scratch assays) and protein expression was examined with Western blot analyses. Under normoxic conditions, a half maximal inhibitory concentration (IC 50 ) of 23 μM was observed in U251MG cells and 24 μM was observed in U343MG cells. Under hypoxic conditions, 10 μM or 15 μM of BA showed a significantly increased cytotoxicity in U251MG cells (p = 0.004 and p = 0.01, respectively) and U343MG cells (p < 0.05 and p = 0.01, respectively). The combination of BA with radiotherapy resulted in an additive effect in the U343MG cell line under normoxic and hypoxic conditions. Weak radiation enhancement was observed in U251MG cell line after treatment with BA under normoxic conditions. Furthermore, under hypoxic conditions, the incubation with BA resulted in increased radiation enhancement. The enhancement factor, at an irradiation dose of 15 Gy after treatment with 10 or 15 μM BA, was 2.20 (p = 0.02) and 4.50 (p = 0.03), respectively. Incubation with BA led to decreased cell migration, cleavage of PARP and decreased expression levels of survivin in both cell lines. Additionally, BA treatment resulted in a reduction of HIF-1α protein under hypoxic conditions. Our results suggest that BA is capable

  18. Increased radiosensitivity and radiation-induced apoptosis in SRC-3 knockout mice

    International Nuclear Information System (INIS)

    Jin Jie; Wang Yu; Xu Yang; Chen Shilei; Wang Junping; Ran Xinze; Su Yongping; Wang Jin

    2014-01-01

    Steroid receptor coactivator-3 (SRC-3), a multifunctional transcriptional coactivator, plays an important role in regulation of cell apoptosis in chemoresistant cancer cells. However, its role in radiation-induced apoptosis in hematopoietic cells is still unclear. In this study, we used SRC-3 knockout (SRC-3 -/- ) mice to assess the role of SRC-3 in radiation-induced hematopoietic injury in vivo. After a range of doses of irradiation, SRC-3 -/- mice exhibited lower counts of peripheral blood cells and bone marrow (BM) mononuclear cells and excessive BM depression, which resulted in a significantly higher mortality compared with wildtype mice. Moreover, BM mononuclear cells obtained from SRC-3 -/- mice showed a remarkable increase in radiation-induced apoptosis. Collectively, our data demonstrate that SRC-3 plays a role in radiation-induced apoptosis of BM hematopoietic cells. Regulation of SRC-3 might influence the radiosensitivity of hematopoietic cells, which highlights a potential therapeutic target for radiation-induced hematopoietic injury. (author)

  19. Radiosensitivity is increased by knockdown of FTS in uterine cervical cancer cells

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    Park, Wo Yoon; Anandharaj, Arunkumar; Cinghu, Senthikumar; Kim, Won Dong [Dept. of Radiation Oncology, Chungbuk National University College of Medicine, Cheongju (Korea, Republic of); Yu, Jae Ran [Dept. of Environmental and Tropical Medicine, Konkuk University College of Medicine, Seoul (Korea, Republic of)

    2012-04-15

    Uterine cervical cancer is still the second largest cancer in women worldwide, despite of effective screening methods. Radiotherapy is used to treat all the stages of cervical cancer and more than 60% of cervical cancer patients receive radiotherapy. New therapeutic targets or approaches are needed to further increase the results of radiotherapy. In the present study, we demonstrated the radiation induced overexpression and nuclear export of FTS in cervical cancer cells. Furthermore, we showed that silencing of FTS expression with FTS shRNA enhanced radiosensitivity of cervical cancer cells, induced cell cycle arrest and apoptosis FTS is involved in radioresistance of cervical cancer. Targeted inhibition of FTS can shutdown the key elemental characteristics of cervical cancer and could lead to an effective therapeutic strategy.

  20. Radiosensitivity is increased by knockdown of FTS in uterine cervical cancer cells

    International Nuclear Information System (INIS)

    Park, Wo Yoon; Anandharaj, Arunkumar; Cinghu, Senthikumar; Kim, Won Dong; Yu, Jae Ran

    2012-01-01

    Uterine cervical cancer is still the second largest cancer in women worldwide, despite of effective screening methods. Radiotherapy is used to treat all the stages of cervical cancer and more than 60% of cervical cancer patients receive radiotherapy. New therapeutic targets or approaches are needed to further increase the results of radiotherapy. In the present study, we demonstrated the radiation induced overexpression and nuclear export of FTS in cervical cancer cells. Furthermore, we showed that silencing of FTS expression with FTS shRNA enhanced radiosensitivity of cervical cancer cells, induced cell cycle arrest and apoptosis FTS is involved in radioresistance of cervical cancer. Targeted inhibition of FTS can shutdown the key elemental characteristics of cervical cancer and could lead to an effective therapeutic strategy

  1. The HER2-binding affibody molecule (Z(HER2∶342₂ increases radiosensitivity in SKBR-3 cells.

    Directory of Open Access Journals (Sweden)

    Lina Ekerljung

    Full Text Available We have previously shown that the HER2-specific affibody molecule (Z(HER2∶342₂ inhibits proliferation of SKBR-3 cells. Here, we continue to investigate its biological effects in vitro by studying receptor dimerization and clonogenic survival following irradiation. We found that (Z(HER2∶342₂ sensitizes the HER2-overexpressing cell line SKBR-3 to ionizing radiation. The survival after exposure to (Z(HER2∶342₂ and 8 Gy (S(8Gy 0.006 was decreased by a factor four compared to the untreated (S(8Gy 0.023. The low HER2-expressing cell line MCF-7 was more radiosensitive than SKBR-3 but did not respond to (Z(HER2∶342₂. Treatment by (Z(HER2∶342₂ strongly increased the levels of dimerized and phosphorylated HER2 even after 5 minutes of stimulation. The monomeric Z(HER2∶342 does not seem to be able to induce receptor phosphorylation and dimerization or sensitize cells to irradiation.

  2. Enterolactone: A novel radiosensitizer for human breast cancer cell lines through impaired DNA repair and increased apoptosis

    International Nuclear Information System (INIS)

    Bigdeli, Bahareh; Goliaei, Bahram; Masoudi-Khoram, Nastaran; Jooyan, Najmeh; Nikoofar, Alireza; Rouhani, Maryam; Haghparast, Abbas; Mamashli, Fatemeh

    2016-01-01

    Introduction: Radiotherapy is a potent treatment against breast cancer, which is the most commonly diagnosed cancer among women. However, the emergence of radioresistance due to increased DNA repair leads to radiotherapeutic failure. Applying polyphenols combined with radiation is a more promising method leading to better survival. Enterolactone, a phytoestrogenic polyphenol, has been reported to inhibit an important radioresistance signaling pathway, therefore we conjectured that enterolactone could enhance radiosensitivity in breast cancer. To assess this hypothesis, radiation response of enterolactone treated MDA-MB-231 and T47D cell lines and corresponding cellular mechanisms were investigated. Methods: Cytotoxicity of enterolactone was measured via MTT assay. Cells were treated with enterolactone before X-irradiation, and clonogenic assay was used to evaluate radiosensitivity. Cell cycle distribution and apoptosis were measured by flow cytometric analysis. In addition, DNA damages and corresponding repair, chromosomal damages, and aberrations were assessed by comet, micronucleus, and cytogenetic assays, respectively. Results: Enterolactone decreased the viability of cells in a concentration- and time dependent manner. Enterolactone significantly enhanced radiosensitivity of cells by abrogating G2/M arrest, impairing DNA repair, and increasing radiation-induced apoptosis. Furthermore, increased chromosomal damages and aberrations were detected in cells treated with enterolactone combined with X-rays than X-ray alone. These effects were more prominent in T47D than MDA-MB-231 cells. Discussion: To our knowledge, this is the first report that enterolactone is a novel radiosensitizer for breast cancer irrespective of estrogen receptor status. Authors propose enterolactone as a candidate for combined therapy to decrease the radiation dose delivered to patients and subsequent side effects. - Highlights: • Enterolactone is proposed to be a novel radiosensitizer for

  3. Enterolactone: A novel radiosensitizer for human breast cancer cell lines through impaired DNA repair and increased apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Bigdeli, Bahareh, E-mail: bhr.bigdeli@ut.ac.ir [Department of Biophysics, Institute of Biochemistry and Biophysics, University of Tehran, 16th Azar St., Enghelab Sq., Tehran (Iran, Islamic Republic of); Goliaei, Bahram, E-mail: goliaei@ut.ac.ir [Department of Biophysics, Institute of Biochemistry and Biophysics, University of Tehran, 16th Azar St., Enghelab Sq., Tehran (Iran, Islamic Republic of); Masoudi-Khoram, Nastaran, E-mail: n.masoudi@alumni.ut.ac.ir [Department of Biophysics, Institute of Biochemistry and Biophysics, University of Tehran, 16th Azar St., Enghelab Sq., Tehran (Iran, Islamic Republic of); Jooyan, Najmeh, E-mail: n.jooyan@ut.ac.ir [Department of Biophysics, Institute of Biochemistry and Biophysics, University of Tehran, 16th Azar St., Enghelab Sq., Tehran (Iran, Islamic Republic of); Nikoofar, Alireza, E-mail: nikoofar@iums.ac.ir [Department of Radiotherapy, Iran University of Medical Sciences (IUMS), Shahid Hemmat Highway, Tehran (Iran, Islamic Republic of); Rouhani, Maryam, E-mail: rouhani@iasbs.ac.ir [Department of Biological Sciences, Institute for Advanced Studies in Basic Sciences (IASBS), Prof. Yousef Sobouti Blvd., Gava Zang, Zanjan (Iran, Islamic Republic of); Haghparast, Abbas, E-mail: Haghparast@sbmu.ac.ir [Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Daneshjo St., Evin, Tehran (Iran, Islamic Republic of); Mamashli, Fatemeh, E-mail: mamashli@ut.ac.ir [Department of Biophysics, Institute of Biochemistry and Biophysics, University of Tehran, 16th Azar St., Enghelab Sq., Tehran (Iran, Islamic Republic of)

    2016-12-15

    Introduction: Radiotherapy is a potent treatment against breast cancer, which is the most commonly diagnosed cancer among women. However, the emergence of radioresistance due to increased DNA repair leads to radiotherapeutic failure. Applying polyphenols combined with radiation is a more promising method leading to better survival. Enterolactone, a phytoestrogenic polyphenol, has been reported to inhibit an important radioresistance signaling pathway, therefore we conjectured that enterolactone could enhance radiosensitivity in breast cancer. To assess this hypothesis, radiation response of enterolactone treated MDA-MB-231 and T47D cell lines and corresponding cellular mechanisms were investigated. Methods: Cytotoxicity of enterolactone was measured via MTT assay. Cells were treated with enterolactone before X-irradiation, and clonogenic assay was used to evaluate radiosensitivity. Cell cycle distribution and apoptosis were measured by flow cytometric analysis. In addition, DNA damages and corresponding repair, chromosomal damages, and aberrations were assessed by comet, micronucleus, and cytogenetic assays, respectively. Results: Enterolactone decreased the viability of cells in a concentration- and time dependent manner. Enterolactone significantly enhanced radiosensitivity of cells by abrogating G2/M arrest, impairing DNA repair, and increasing radiation-induced apoptosis. Furthermore, increased chromosomal damages and aberrations were detected in cells treated with enterolactone combined with X-rays than X-ray alone. These effects were more prominent in T47D than MDA-MB-231 cells. Discussion: To our knowledge, this is the first report that enterolactone is a novel radiosensitizer for breast cancer irrespective of estrogen receptor status. Authors propose enterolactone as a candidate for combined therapy to decrease the radiation dose delivered to patients and subsequent side effects. - Highlights: • Enterolactone is proposed to be a novel radiosensitizer for

  4. N-acetylphytosphingosine enhances the radiosensitivity of tumor cells by increasing apoptosis

    International Nuclear Information System (INIS)

    Han, Y.; Kim, Y.; Yun, Y.; Jeon, S.; Kim, K.; Song, J.; Hong, S.H.; Park, C.

    2005-01-01

    Ceramides are well-known second messengers which mediate apoptosis, proliferation, differentiation in mammalian cells, but the physiological roles of phytosphingosines are poorly understood. We hypothesized that one of the phytosphingosine derivatives, N-acetylphytosphingosine (NAPS) can induce apoptosis in human leukemia Jurkat cell line and increase apoptosis in irradiated MDA-MB-231 cells. We first examined the effect of NAPS on apoptosis of Jurkat cells. NAPS had a more rapid and stronger apoptotic effect than C 2 -ceramide in Jurkat cells and significant increase of apoptosis was observed at 3 h after treatment. In contrast, the apoptosis induced by C2-ceramide was observed only after 16 h of treatment. NAPS induced apoptosis was mediated by caspase 3 and 8 activation and inhibited by z-VAD-fmk. Ceramide plays a pivotal role in radiation induced apoptosis. We postulated that exogenous treatment of NAPS sensitizes tumor cells to ionizing radiation, since NAPS might be used as a more effective alternative to C2-ceramide. As expected, NAPS decreased clonogenic survival of irradiated MDA-MB-231 cells dose dependently, and apoptosis of irradiated cells in the presence of NAPS was increased through the caspase activation. Taken together, NAPS is an effective apoptosis-inducing agent, which can be readily synthesized from yeast sources, and is a potent alternative to ceramide for the further study of ceramide associated signaling and the development of radiosensitizing agent. (orig.)

  5. antiEGFR conjugated gold nanoparticles for increasing radiosensitivity in lung cancer cells

    International Nuclear Information System (INIS)

    Pujari, Geetanjali; Sarma, Asitikantha; Avasthi, Devesh K.

    2014-01-01

    One of the set back that lies in lung cancer treatment is the over expression of Epidermal Growth Factor Receptor (EGFR). EGFR is a transmembrane receptor that is highly expressed in lung cancer that leads to cell survival, proliferation and spread of the disease. Over the years, EGFR inhibitors, monoclonal antibodies, are being used in combination with radiotherapy in lung cancer patients so as to achieve better results. In the recent time, application of Au nanoparticles (AuNPs) in diagnosis and treatment of cancer has been extensively used in biomedical research. Among various applications, there is considerable use of AuNPs seen on the dose enhancement effect (radiosensitization) in radiation therapy of cancer. The conjugation of AuNP with monoclonal antibody antiEGFR (antiEGFR-AuNP) may provide excellent agent to sensitize the cells to heavy ion radiation. We synthesized AuNPs by citrate reduction method. Most of AuNPs were in the size range of 6-8 nm as studies by Transmission Electron Microscope (TEM). These AuNPs were found to be non toxic in A549 cells and thus biocompatible. Further, we conjugated AuNPs with antiEGFR (antiEGFR-AuNP). The conjugation was confirmed by UV-Vis spectroscopy. A549 cells were treated with antiEGFR-AuNP. TEM was carried out of ultrathin cross sections of antiEGFR-AuNP treated A549 cells to check the attachment internalization of AuNPs. We observed that the AuNPs are attached on the cell membrane as well as internalized in cytoplasm. Upon exposure of antiEGFR-AuNP treated cells to heavy ion 12 C beam, showed increase in radiosensitization as studied by survival assay and MTT assay. We will also explain the EGFR expression and cell cycle proliferation in A549 cells upon heavy ion beam irradiation of these. The study aims to overcome the current limitations of cancer-targeted therapies and improve the treatment modality of lung cancer. (author)

  6. [Electrical acupoint stimulation increases athletes' rapid strength].

    Science.gov (United States)

    Yang, Hua-yuan; Liu, Tang-yi; Kuai, Le; Gao, Ming

    2006-05-01

    To search for a stimulation method for increasing athletes' performance. One hundred and fifty athletes were randomly divided into a trial group and a control group, 75 athletes in each group. Acupoints were stimulated with audio frequency pulse modulated wave and multi-blind method were used to investigate effects of the electric stimulation of acupoints on 30-meter running, standing long jumping and Cybex isokinetic testing index. The acupoint electric stimulation method could significantly increase athlete's performance (P < 0.05), and the biomechanical indexes, maximal peak moment of force (P < 0.05), force moment accelerating energy (P < 0.05) and average power (P < 0.05). Electrical acupoint stimulation can enhance athlete's rapid strength.

  7. Is Increased Low-dose somatic Radiosensitivity Associated with Increased Transgenerational Germline Mutation

    International Nuclear Information System (INIS)

    Brenner, David J.

    2008-01-01

    Using single-molecule polymerase chain reaction, the frequency of spontaneous and radiation-induced mutation at an expanded simple tandem repeat (ESTR) locus was studied in DNA samples extracted from sperm and bone marrow of Atm knockout (Atm+/-) heterozygous male mice. The frequency of spontaneous mutation in sperm and bone marrow in Atm+/- males did not significantly differ from that in wild-type BALB/c mice. Acute gamma-ray exposure did not affect ESTR mutation frequency in bone marrow and resulted in similar increases in sperm samples taken from Atm+/- and BALB/c males. Taken together, these results suggest that the Atm haploinsufficiency analyzed in our study does not affect spontaneous and radiation-induced ESTR mutation frequency in mice

  8. The comparison of radiosensitivity of human lymphocytes stimulated with PHA Con A and PWM

    International Nuclear Information System (INIS)

    Geng Yongzhi; Su Liaoyuan

    1989-11-01

    The transformation, DNA strand breaks and its repair ability in human peripheral blood lymphocytes stimulated with PHA, Con A and PWM were respectively assessed following exposure to 60 Co gamma rays by 3 H-thymidine uptake and hydroxylapatite chromatography. It was showed the transformation of lymphocytes stimulated with PHA, Con A and PWM were suppressed by gamma rays and the dose-effect curves were biphase within the range of 0∼8 Gy. The lymphocytes stimulated with PWM was the most resistant to gamma rays. The extent of DNA strand breaks in lymphocytes induced by gamma rays was linearly related to the dose within the range of 0∼30 Gy and was identical in three kinds of lymphocytes. After post-irradiation incubation of 37 deg C, the DNA strand breaks could be repaired incompletely and after maxium repair the strand breaks were observed again. The repair ratio of strand breaks in the lymphocytes stimulated with PWM was the highest in the cells with three mitogens. The results showed that the difference of radiation effect on the transformation is probably related to the repair ability of DNA strand breaks

  9. Knockdown of AMPKα decreases ATM expression and increases radiosensitivity under hypoxia and nutrient starvation in an SV40-transformed human fibroblast cell line, LM217.

    Science.gov (United States)

    Murata, Yasuhiko; Hashimoto, Takuma; Urushihara, Yusuke; Shiga, Soichiro; Takeda, Kazuya; Jingu, Keiichi; Hosoi, Yoshio

    2018-01-22

    Presence of unperfused regions containing cells under hypoxia and nutrient starvation contributes to radioresistance in solid human tumors. It is well known that hypoxia causes cellular radioresistance, but little is known about the effects of nutrient starvation on radiosensitivity. We have reported that nutrient starvation induced decrease of mTORC1 activity and decrease of radiosensitivity in an SV40-transformed human fibroblast cell line, LM217, and that nutrient starvation induced increase of mTORC1 activity and increase of radiosensitivity in human liver cancer cell lines, HepG2 and HuH6 (Murata et al., BBRC 2015). Knockdown of mTOR using small interfering RNA (siRNA) for mTOR suppressed radiosensitivity under nutrient starvation alone in HepG2 cells, which suggests that mTORC1 pathway regulates radiosensitivity under nutrient starvation alone. In the present study, effects of hypoxia and nutrient starvation on radiosensitivity were investigated using the same cell lines. LM217 and HepG2 cells were used to examine the effects of hypoxia and nutrient starvation on cellular radiosensitivity, mTORC1 pathway including AMPK, ATM, and HIF-1α, which are known as regulators of mTORC1 activity, and glycogen storage, which is induced by HIF-1 and HIF-2 under hypoxia and promotes cell survival. Under hypoxia and nutrient starvation, AMPK activity and ATM expression were increased in LM217 cells and decreased in HepG2 cells compared with AMPK activity under nutrient starvation alone or ATM expression under hypoxia alone. Under hypoxia and nutrient starvation, radiosensitivity was decreased in LM217 cells and increased in HepG2 cells compared with radiosensitivity under hypoxia alone. Under hypoxia and nutrient starvation, knockdown of AMPK decreased ATM activity and increased radiation sensitivity in LM217 cells. In both cell lines, mTORC1 activity was decreased under hypoxia and nutrient starvation. Under hypoxia alone, knockdown of mTOR slightly increased ATM

  10. Treatment of HeLa cells with Giloe (Tinospora cordifolia meirs) increases the radiosensitivity by increasing DNA damage

    International Nuclear Information System (INIS)

    Varma, Hari Krishna; Jagetia, Ganesh Chandra; Nayak, Vijayashree

    2014-01-01

    Radiotherapy is an important treatment modality and screening of phytoceuticals may enhance the clinical outcome of radiotherapy, therefore radiosensitizing activity of various guduchi (Tinospora cordifolia) extracts was studied in HeLa cells. Chromosomal aberrations were scored in HeLa cells treated with 10 μg/ml of aqueous, methanol, or methylene chloride guduchi extracts or doxorubicin before exposure to 0, 0.5, 1, 2 or 3 Gy of γ-radiation at 12, 24, 36 or 48 h post-irradiation. Irradiation of HeLa cells caused a dose dependent rise in the chromatid breaks, chromosome breaks, dicentric, centric rings, acentric fragments and total aberrations at all post-irradiation times and the dose response was linear quadratic for all types of aberrations scored. Chromatid breaks increased up to 12 h post-irradiation and declined steadily up to 48 h post-irradiation, whereas chromosome breaks, dicentric, acentric fragments and total aberrations elevated up to 24 h post-irradiation and declined thereafter. However, centric rings continued to rise steadily up to 48 h post-irradiation. Treatment of HeLa cells with aqueous, methanol or methylene chloride guduchi extract or doxorubicin before irradiation significantly enhanced various types of chromosomal aberrations and a maximum rise in the chromosome aberrations was observed in the HeLa cells treated with methylene chloride extract before irradiation when compared to other groups. Various guduchi extracts enhanced the effect of radiation in HeLa cells by increasing the molecular damage to cellular genome and their effect was similar to or even greater than doxorubicin (positive control) pretreatment, depending on the type of guduchi extract used. (author)

  11. Radioresponsiveness at low doses. Hyper-radiosensitivity and increased radioresistance in mammalian cells

    International Nuclear Information System (INIS)

    Skov, K.A.

    1999-01-01

    The rationale for and importance of research on effects after radiation at 'low doses' are outlined. Such basic radiobiological studies on induction of repair enzymes, protective mechanisms, priming, and hypersensitivity are certainly all relevant to treatment of cancer (see Section 1, Studies at low doses - relevance to cancer treatment). Included are examples from many groups, using various endpoints to address the possibility of an induced resistance, which has been compared to the adaptive response [M.C. Joiner, P. Lambin, E.P. Malaise, T. Robson, J.E. Arrand, K.A. Skov, B. Marples, Hypersensitivity to very low single radiation doses: its relationship to the adaptive response and induced radioresistance, Mutat. Res. 358 (1996) 171-183.]. This is not intended to be an exhaustive review - rather a re-introduction of concepts such as priming and a short survey of molecular approaches to understanding induced resistance. New data on the response of HT29 cells after treatment (priming) with co-cultured activated neutrophils are included, with protection against X-rays (S1). Analysis of previously published results in various cells lines in terms of increased radioresistance (IRR)/intrinsic sensitivity are presented which complement a study on human tumour lines [P. Lambin, E.P. Malaise, M.C. Joiner, Might intrinsic radioresistance of human tumour cells be induced by radiation?, Int. Radiat. Biol. 69 (1996) 279-290]. It is not feasible to extrapolate to low doses from studies at high doses. The biological responses probably vary with dose, LET, and have variable time frames. The above approaches may lead to new types of treatment, or additional means to assess radioresponsiveness of tumours. Studies in many areas of biology would benefit from considerations of different dose regions, as the biological responses vary with dose. There may also be some implications in the fields of radiation protection and carcinogenesis, and the extensions of concepts of hyper-radiosensitivity

  12. BMI-1 suppression increases the radiosensitivity of oesophageal carcinoma via the PI3K/Akt signaling pathway.

    Science.gov (United States)

    Yang, Xing-Xiao; Ma, Ming; Sang, Mei-Xiang; Zhang, Xue-Yuan; Liu, Zhi-Kun; Song, Heng; Zhu, Shu-Chai

    2018-02-01

    B-cell‑specific Moloney murine leukaemia virus integration site-1 (BMI-1) contributes to the growth of tumour cells post-irradiation (IR). The aim of the present study was to characterize the effects of BMI-1 on cell viability, radiosensitivity and its mechanisms of action in oesophageal squamous cell cancer (ESCC). Western blotting and immunohistochemistry were employed to evaluate the protein expression of BMI-1 in ESCC cells and specimens, respectively. Additionally, the protein expression levels of BMI-1, H2AK119ub and γH2AX in ESCC cells were detected following different doses of IR and at different times after IR. The protein expression levels of MDC1 and 53BP1 were also measured. Flow cytometry and MTT assays were used to determine cell cycle progression, apoptosis and cell viability. The phosphatidylinositol 3-kinase inhibitor LY294002 and the agonist IGF-1 were employed to suppress or induce the phosphorylation of Akt to determine whether BMI-1 induces radioresistance in ESCC cells via activation of the PI3K/Akt pathway. The expression of BMI-1 was higher in ESCC tissues and cells compared with that in normal oesophageal tissues and cells. In addition, BMI-1 was positively related to tumour size and lymph node metastases and negatively to the overall survival of ESCC patients. IR induced the expression of BMI-1, H2AK119ub and γH2AX in a dose- and time-dependent manner. BMI-1 knockdown lowered the expression of γH2AX, MDC1 and 53BP1, suppressed cell viability and increased radiosensitivity. G2/M phase arrest was eliminated; this was followed by an increased proportion of cells entering the G0/G1 phase after IR and BMI-1 knockdown via the upregulation of P16 and downregulation of cyclin D2 and cyclin-dependent kinase-4. Moreover, BMI-1 knockdown increased cell apoptosis, downregulated MCL-1 and p-Akt and upregulated Bax. Additionally, the inhibitory effect of the downregulation of p-Akt by LY294002 on tumour cell viability was identical to that of

  13. Increased radiosensitivity of cerebral capillaries in neonatal Gunn rats as compared to Sprague-Dawley rats

    International Nuclear Information System (INIS)

    Landolt, R.; Arn, D.

    1979-01-01

    The extent of petechial haemorrhages of the cerebral cortex examined between 14 hours and 4 days after X-irradiation to the head was compared in Sprague-Dawley and homozygous Gunn rats with congenital hyperbilirubinaemia. Animals 1 to 2 days old received single doses of either 250, 500 or 750 rad. By means of a special scoring scale the degree of the damage to the micro vasculature was semi-quantitatively estimated. In both strains a significant difference in effect was obtained between 250 and 500 rad, but not between 500 and 750 rad. The shape of the dose-effect curve in Gunn rats was similar to that of Sprague-Dawley rats, but displaced upwards. In Gunn rats the effect of 250 rad was greater that that of 750 rad in Sprague-Dawley rats. Possible radiosensitizing mechanisms are discussed with reference to the literature and these results. (author)

  14. The Effect of VPA on Increasing Radiosensitivity in Osteosarcoma Cells and Primary-Culture Cells from Chemical Carcinogen-Induced Breast Cancer in Rats.

    Science.gov (United States)

    Liu, Guochao; Wang, Hui; Zhang, Fengmei; Tian, Youjia; Tian, Zhujun; Cai, Zuchao; Lim, David; Feng, Zhihui

    2017-05-10

    This study explored whether valproic acid (VPA, a histone deacetylase inhibitor) could radiosensitize osteosarcoma and primary-culture tumor cells, and determined the mechanism of VPA-induced radiosensitization. The working system included osteosarcoma cells (U2OS) and primary-culture cells from chemical carcinogen (DMBA)-induced breast cancer in rats; and clonogenic survival, immunofluorescence, fluorescent in situ hybridization (FISH) for chromosome aberrations, and comet assays were used in this study. It was found that VPA at the safe or critical safe concentration of 0.5 or 1.0 mM VPA could result in the accumulation of more ionizing radiation (IR)-induced DNA double strand breaks, and increase the cell radiosensitivity. VPA-induced radiosensitivity was associated with the inhibition of DNA repair activity in the working systems. In addition, the chromosome aberrations including chromosome breaks, chromatid breaks, and radial structures significantly increased after the combination treatment of VPA and IR. Importantly, the results obtained by primary-culture cells from the tissue of chemical carcinogen-induced breast cancer in rats further confirmed our findings. The data in this study demonstrated that VPA at a safe dose was a radiosensitizer for osteosarcoma and primary-culture tumor cells through suppressing DNA-double strand breaks repair function.

  15. Inhibition of UBE2D3 expression attenuates radiosensitivity of MCF-7 human breast cancer cells by increasing hTERT expression and activity.

    Directory of Open Access Journals (Sweden)

    Wenbo Wang

    Full Text Available The known functions of telomerase in tumor cells include replenishing telomeric DNA and maintaining cell immortality. We have previously shown the existence of a negative correlation between human telomerase reverse transcriptase (hTERT and radiosensitivity in tumor cells. Here we set out to elucidate the molecular mechanisms underlying regulation by telomerase of radiosensitivity in MCF-7 cells. Toward this aim, yeast two-hybrid (Y2H screening of a human laryngeal squamous cell carcinoma radioresistant (Hep2R cDNA library was first performed to search for potential hTERT interacting proteins. We identified ubiquitin-conjugating enzyme E2D3 (UBE2D3 as a principle hTERT-interacting protein and validated this association biochemically. ShRNA-mediated inhibition of UBE2D3 expression attenuated MCF-7 radiosensitivity, and induced the accumulation of hTERT and cyclin D1 in these cells. Moreover, down-regulation of UBE2D3 increased hTERT activity and cell proliferation, accelerating G1 to S phase transition in MCF-7 cells. Collectively these findings suggest that UBE2D3 participates in the process of hTERT-mediated radiosensitivity in human breast cancer MCF-7 cells by regulating hTERT and cyclin D1.

  16. S-phase checkpoint elements of the E2F-1 family increase radiosensitivity in fibrosarcoma cells lacking p53

    International Nuclear Information System (INIS)

    Bodis, Stephan; Pruschy, Martin; Wirbelauer, Christiane; Glanzmann, Christoph; Krek, Wilhelm

    1997-01-01

    'null' fibrosarcoma cells with E2F-1 wild-type revealed a synergistic effect at 2 and 5 Gy. The cytotoxic effect of E2F-1 mutants lacking the cyclin-A binding domain in these p53 'null' tumor cells combined with ionizing RT was at least additive. Ionizing RT alone induces massive apoptosis only in the radiosensitive p53 wild-type tumor cells in vitro and in vivo after transplantation into nude mice. The cell death mechanisms of E2F-1 wt and the E2F-1 mt alone and in combination with RT in p53 'null' tumor cells is currently investigated. Conclusion: -S-phase checkpoints elements can increase radiosensitivity in presence and absence of p53. - The cytotoxic effect of a specific E2F-1 mutant lacking the cyclin-A-binding domain is much higher and less p53 dependent compared to the cytotoxic effect of E2F-1 wild-type

  17. Lethal outcome after pelvic salvage radiotherapy in a patient with prostate cancer due to increased radiosensitivity. Case report and literature review

    International Nuclear Information System (INIS)

    Fahrig, Antje; Koch, T.; Lenhart, M.; Rieckmann, P.; Fietkau, R.; Distel, Luitpold; Schuster, B.

    2018-01-01

    In general, late side effects after salvage radiotherapy (RT) for prostate cancer are below 10%. Patients with impaired DNA repair ability and genetic instability can have significantly increased reactions after RT. We present a patient who experienced severe side effects after additive RT for prostate cancer and died from the complications 25 months after RT. Imaging (MR) is shown as well as three-color fluorescence in situ hybridization. The blood sample testing revealed that radiosensitivity was increased by 35-55%. We undertook a review of the literature to give an overview over the tests established that are currently considered useful. This case highlights that the identification of patients with increased radiosensitivity is an important task in radiation protection. Groups of patients who should be screened have to be found and corresponding research facilities have to be set up. (orig.) [de

  18. The occurrence of recruitment supported from the finding of an increase in radiosensitivity of quiescent cells in solid tumors after fractionated irradiation with X-rays

    International Nuclear Information System (INIS)

    Masunaga, Shinichiro; Ono, Koji; Kinashi, Yuko; Suzuki, Minoru; Akaboshi, Mitsuhiko

    1998-01-01

    We examined the behavior of quiescent cells in solid tumors irradiated twice at various intervals with X-rays, using our recently developed method for selectively detecting the response of quiescent cells in solid tumors. To determine the labeling indices of tumors at the second irradiation, each mouse group included mice that were continuously administered BrdU until just before the second irradiation using mini-osmotic pumps which had been implanted before the first irradiation. Radiosensitivity of total tumor cells at the second irradiation decreased in proportion to the increase in interval time. However, radiosensitivity of quiescent cells was raised with increase in the interval time. In addition, the labeling index at the second irradiation was higher than that at the first irradiation. These findings supported the occurrence of recruitment from quiescent to proliferating state during fractionated irradiation. (author)

  19. A preliminary investigation into the extent of increased radioresistance or hyper-radiosensitivity in cells of hamster cell lines known to be deficient in DNA repair

    International Nuclear Information System (INIS)

    Skov, K.; Marples, B.; Matthews, J.B.; Zhou, H.; Joiner, M.C.

    1994-01-01

    The response to low doses of X rays was assessed in cells of three hamster cell lines which are defective in DNA repair and was compared with their parental lines. Cells of the V79-derived double-strand break repair-deficient line XR-V15B showed no radioresistance in the 0.5-Gy range compared with the V79B wild type, but instead showed an exponential response. Cells of the single-strand break repair-deficient line EM9 showed hyper-radiosensitivity and exhibited increased radioresistance. Most interestingly, cells of the UV-20 cell line appeared to respond exponentially, as a continuation of the hyper-radiosensitive portion of the curve, with no evidence of increased radioresistance. This line is defective in an incision step of excision repair and is sensitive to crosslinking agents. Further studies are warranted to address the possible role of single- and double-strand break repair and excision repair in hyper-radiosensitivity and increased radioresistance. 24 refs., 4 figs

  20. Identification and Characterization of a Small Inhibitory Peptide That Can Target DNA-PKcs Autophosphorylation and Increase Tumor Radiosensitivity

    Energy Technology Data Exchange (ETDEWEB)

    Sun Xiaonan [Department of Radiation Oncology, Sir Run Run Shaw Hospital, Sir Run Run Shaw Institute of Clinical Medicine of Zhejiang University, Hangzhou (China); Yang Chunying [Department of Radiation Oncology, Methodist Hospital Research Institute, Weill Cornell Medical College, Houston, TX (United States); Liu Hai; Wang Qi [Department of Radiation Oncology, Sir Run Run Shaw Hospital, Sir Run Run Shaw Institute of Clinical Medicine of Zhejiang University, Hangzhou (China); Wu Shixiu [Department of Radiation Oncology, The First Affiliated Hospital of Wenzhou Medical College, Wenzhou (China); Li Xia; Xie Tian [Research Center of Biomedicine and Health, Hangzhou Normal University, Hangzhou (China); Brinkman, Kathryn L.; Teh, Bin S.; Butler, E. Brian [Department of Radiation Oncology, Methodist Hospital Research Institute, Weill Cornell Medical College, Houston, TX (United States); Xu Bo, E-mail: bxu@tmhs.org [Department of Radiation Oncology, Methodist Hospital Research Institute, Weill Cornell Medical College, Houston, TX (United States); Zheng, Shu, E-mail: zhengshu@zju.edu.cn [Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou (China)

    2012-12-01

    Purpose: The DNA protein kinase catalytic subunit (DNA-PKcs) is one of the critical elements involved in the DNA damage repair process. Inhibition of DNA-PKcs results in hypersensitivity to ionizing radiation (IR); therefore, this approach has been explored to develop molecular targeted radiosensitizers. Here, we aimed to develop small inhibitory peptides that could specifically target DNA-PKcs autophosphorylation, a critical step for the enzymatic activation of the kinase in response to IR. Methods and Materials: We generated several small fusion peptides consisting of 2 functional domains, 1 an internalization domain and the other a DNA-PKcs autophosphorylation inhibitory domain. We characterized the internalization, toxicity, and radiosensitization activities of the fusion peptides. Furthermore, we studied the mechanisms of the inhibitory peptides on DNA-PKcs autophosphorylation and DNA repair. Results: We found that among several peptides, the biotin-labeled peptide 3 (BTW3) peptide, which targets DNA-PKcs threonine 2647 autophosphorylation, can abrogate IR-induced DNA-PKcs activation and cause prolonged {gamma}-H2AX focus formation. We demonstrated that BTW3 exposure led to hypersensitivity to IR in DNA-PKcs-proficient cells but not in DNA-PKcs-deficient cells. Conclusions: The small inhibitory peptide BTW3 can specifically target DNA-PKcs autophosphorylation and enhance radiosensitivity; therefore, it can be further developed as a novel class of radiosensitizer.

  1. Identification and Characterization of a Small Inhibitory Peptide That Can Target DNA-PKcs Autophosphorylation and Increase Tumor Radiosensitivity

    International Nuclear Information System (INIS)

    Sun Xiaonan; Yang Chunying; Liu Hai; Wang Qi; Wu Shixiu; Li Xia; Xie Tian; Brinkman, Kathryn L.; Teh, Bin S.; Butler, E. Brian; Xu Bo; Zheng, Shu

    2012-01-01

    Purpose: The DNA protein kinase catalytic subunit (DNA-PKcs) is one of the critical elements involved in the DNA damage repair process. Inhibition of DNA-PKcs results in hypersensitivity to ionizing radiation (IR); therefore, this approach has been explored to develop molecular targeted radiosensitizers. Here, we aimed to develop small inhibitory peptides that could specifically target DNA-PKcs autophosphorylation, a critical step for the enzymatic activation of the kinase in response to IR. Methods and Materials: We generated several small fusion peptides consisting of 2 functional domains, 1 an internalization domain and the other a DNA-PKcs autophosphorylation inhibitory domain. We characterized the internalization, toxicity, and radiosensitization activities of the fusion peptides. Furthermore, we studied the mechanisms of the inhibitory peptides on DNA-PKcs autophosphorylation and DNA repair. Results: We found that among several peptides, the biotin-labeled peptide 3 (BTW3) peptide, which targets DNA-PKcs threonine 2647 autophosphorylation, can abrogate IR-induced DNA-PKcs activation and cause prolonged γ-H2AX focus formation. We demonstrated that BTW3 exposure led to hypersensitivity to IR in DNA-PKcs-proficient cells but not in DNA-PKcs-deficient cells. Conclusions: The small inhibitory peptide BTW3 can specifically target DNA-PKcs autophosphorylation and enhance radiosensitivity; therefore, it can be further developed as a novel class of radiosensitizer.

  2. Radiation-induced increase in lifespan of insects. Implications for theories of mammalian aging and radiosensitivity

    International Nuclear Information System (INIS)

    Ducoff, H.S.

    1976-01-01

    The well-known and well-documented decline in longevity of irradiated mammals contrasts sharply with the increase of lifespan frequently observed in irradiated insects. First reported in 1919 for flour beetles of the genus Tribolium, increase of lifespan has been found following irradiation of adults of many insect taxa, particularly in the order Diptera. The effect may be more pronounced in one sex or the other, or about the same in both, depending on species, and can be observed in sexually segregated as well as in mated populations. This makes it unlikely that the phenomenon can be accounted for by radiation effects on gametogenesis or on mating behaviour. Our recent data on Tribolium castaneum and on T. confusum indicate that the degree of benefit is dose dependent; is markedly reduced as age-at-exposure increases, though still detectable in beetles irradiated six months after emergence; and is probably also induced by exposure to low doses of fast neutrons. The lowered mortality rate of irradiated populations persists for many months, but eventually may exceed that of the controls. Insects are much less dependent than mammals on cell renewal systems, and the Diptera are completely lacking in somatic cell turnover. This suggests that, in mammals as well as in insects, radiation may exert only detrimental effects in rapidly proliferative tissues but a beneficial effect in postmitotic tissues. A mechanism is proposed, based on the hypothesis that repair capacity is regulated in a fashion analogous to that of inducible enzymes. (author)

  3. Knock-down of hypoxia-induced carbonic anhydrases IX and XII radiosensitizes tumor cells by increasing intracellular acidosis

    Energy Technology Data Exchange (ETDEWEB)

    Doyen, Jérome [Institute for Research on Cancer and Aging of Nice, CNRS UMR 7284, University of Nice Sophia-Antipolis,, Nice (France); Department of Radiation Oncology, Centre Antoine-Lacassagne, Nice (France); Parks, Scott K. [Institute for Research on Cancer and Aging of Nice, CNRS UMR 7284, University of Nice Sophia-Antipolis,, Nice (France); Marcié, Serge [Department of Radiation Oncology, Centre Antoine-Lacassagne, Nice (France); Pouysségur, Jacques [Institute for Research on Cancer and Aging of Nice, CNRS UMR 7284, University of Nice Sophia-Antipolis,, Nice (France); Centre Scientifique de Monaco (Monaco); Chiche, Johanna, E-mail: chiche@unice.fr [Institute for Research on Cancer and Aging of Nice, CNRS UMR 7284, University of Nice Sophia-Antipolis,, Nice (France)

    2013-01-07

    The relationship between acidosis within the tumor microenvironment and radioresistance of hypoxic tumor cells remains unclear. Previously we reported that hypoxia-induced carbonic anhydrases (CA) IX and CAXII constitute a robust intracellular pH (pH{sub i})-regulating system that confers a survival advantage on hypoxic human colon carcinoma LS174Tr cells in acidic microenvironments. Here we investigate the role of acidosis, CAIX and CAXII knock-down in combination with ionizing radiation. Fibroblasts cells (-/+ CAIX) and LS174Tr cells (inducible knock-down for ca9/ca12) were analyzed for cell cycle phase distribution and survival after irradiation in extracellular pH{sub o} manipulations and hypoxia (1% O{sub 2}) exposure. Radiotherapy was used to target ca9/ca12-silenced LS174Tr tumors grown in nude mice. We found that diminishing the pH{sub i}-regulating capacity of fibroblasts through inhibition of Na{sup +}/H{sup +} exchanger 1 sensitize cells to radiation-induced cell death. Secondly, the pH{sub i}-regulating function of CAIX plays a key protective role in irradiated fibroblasts in an acidic environment as accompanied by a reduced number of cells in the radiosensitive phases of the cell cycle. Thirdly, we demonstrate that irradiation of LS174Tr spheroids, silenced for either ca9 or both ca9/ca12, showed a respective 50 and 75% increase in cell death as a result of a decrease in cell number in the radioresistant S phase and a disruption of CA-mediated pH{sub i} regulation. Finally, LS174Tr tumor progression was strongly decreased when ca9/ca12 silencing was combined with irradiation in vivo. These findings highlight the combinatory use of radiotherapy with targeting of the pH{sub i}-regulating CAs as an anti-cancer strategy.

  4. Increase in tumor oxygen tension and radiosensitivity after administration of pentoxifylline

    International Nuclear Information System (INIS)

    Hasegawa, Takeo; Gu, Yeun Hwa; Nagao, Takashi; Miyata, Katsuyuki; Song, Chang W.; Tanake, Yoshimasa; Hasegawa, Takashi

    1999-01-01

    The effects of pentoxifylline (PTX) on the pO2 and radioresponse in SCK tumors of A/J mice were investigated. When the mice were injected intraperitoneally with 5 mg/kg of PTX, the tumor pO2 increased slowly, peaked 20-50 min postinjection, and returned to its original level in 70-90 min. The magnitude of the changes in tumor pO2 after on ip injection of 25 or 50 mg/kg PTX was similar to that caused by 5 mg/kg PTX. When the A/J mice bearing SCK tumors in the legs were injected ip with 50 mg/kg PTX and the tumors were X ray irradiated 20 min later, the tumor growth delay was greater than that of radiation alone

  5. KCl stimulation increases norepinephrine transporter function in PC12 cells.

    Science.gov (United States)

    Mandela, Prashant; Ordway, Gregory A

    2006-09-01

    The norepinephrine transporter (NET) plays a pivotal role in terminating noradrenergic signaling and conserving norepinephrine (NE) through the process of re-uptake. Recent evidence suggests a close association between NE release and regulation of NET function. The present study evaluated the relationship between release and uptake, and the cellular mechanisms that govern these processes. KCl stimulation of PC12 cells robustly increased [3H]NE uptake via the NET and simultaneously increased [3H]NE release. KCl-stimulated increases in uptake and release were dependent on Ca2+. Treatment of cells with phorbol-12-myristate-13-acetate (PMA) or okadaic acid decreased [3H]NE uptake but did not block KCl-stimulated increases in [3H]NE uptake. In contrast, PMA increased [3H]NE release and augmented KCl-stimulated release, while okadaic acid had no effects on release. Inhibition of Ca2+-activated signaling cascades with KN93 (a Ca2+ calmodulin-dependent kinase inhibitor), or ML7 and ML9 (myosin light chain kinase inhibitors), reduced [3H]NE uptake and blocked KCl-stimulated increases in uptake. In contrast, KN93, ML7 and ML9 had no effect on KCl-stimulated [3H]NE release. KCl-stimulated increases in [3H]NE uptake were independent of transporter trafficking to the plasma membrane. While increases in both NE release and uptake mediated by KCl stimulation require Ca2+, different intracellular mechanisms mediate these two events.

  6. Mechanical stimulation increases proliferation, differentiation and protein expression in culture

    DEFF Research Database (Denmark)

    Grossi, Alberto; Yadav, Kavita; Lawson, Moira Ann

    2007-01-01

    Myogenesis is a complex sequence of events, including the irreversible transition from the proliferation-competent myoblast stage into fused, multinucleated myotubes. Myogenic differentiation is regulated by positive and negative signals from surrounding tissues. Stimulation due to stretch- or load...... to elucidate also the signaling pathway by which this mechanical stimulation can causes an increase in protein expression. When mechanically stimulated via laminin receptors on cell surface, C(2)C(12) cells showed an increase in cell proliferation and differentiation. Populations undergoing mechanical...... stimulation through laminin receptors show an increase in expression of Myo-D, myogenin and an increase in ERK1/2 phosphorylation. Cells stimulated via fibronectin receptors show no significant increases in fusion competence. We conclude that load induced signalling through integrin containing laminin...

  7. In vivo charge injection limits increased after 'unsafe' stimulation

    DEFF Research Database (Denmark)

    Meijs, Suzan; Sørensen, Søren; Rechendorff, Kristian

    2015-01-01

    was not observed with any of the stimulation protocols and no tissue damage was observed for the 20 mA – 200 Hz stimulation group. This indicates that the ‘safe potential window’ may not be applicable in vivo, as no damage was done stimulating with 20 mA at 200 Hz, while damage was done using the same current......The effect of unsafe stimulation on charge injection limits (Qinj) and pulsing capacitance (Cpulse) was investigated. Four stimulation protocols were applied: 20 mA – 200 and 400 Hz, 50 mA – 200 and 400 Hz. Increasing Qinj and Cpulse were observed for all stimulation protocols. Corrosion...

  8. Histone deacetylase inhibitor, 2-propylpentanoic acid, increases the chemosensitivity and radiosensitivity of human glioma cell lines in vitro

    Institute of Scientific and Technical Information of China (English)

    SHAO Cui-jie; WU Ming-wei; CHEN Fu-rong; LI Cong; XIA Yun-fei; CHEN Zhong-ping

    2012-01-01

    Background Treatment for malignant glioma generally consists of cytoreductive surgery followed by radiotherapy and chemotherapy.In this study,we intended to investigate the effects of 2-propylpentanoic acid (VPA),a histone deacetylase inhibitor,on chemosensitivity and radiosensitivity in human glioma cell lines.Methods Human glioma cell lines,T98-G,and SF295,were treated with temozolomide (TMZ) or irradiation (IR),with or without VPA (1.0 mmol/L).Then,cytotoxicity and clonogenic survival assay was performed.Cell cycle stage,apoptosis,and autophagy were also detected using flow cytometry and dansyl monocadaverin (MDC) incorporation assay.One-way analysis of variance (ANOVA) and t-test were used to analyze the differences among variant groups.Results Mild cytotoxicity of VPA was revealed in both cell lines,T98-G and SF295,with the 50% inhibiting concentration (IC50) value of (3.85±0.58) mmol/L and (2.15±0.38) mmol/L,respectively; while the IC50 value of TMZ was (0.20±0.09) mmol/L for T98-G and (0.08±0.02) mmol/L for SF295.Moreover,if combined with VPA (1.0 mmol/L) for 96hours,the sensitivity of glioma cells to TMZ was significant increased (P <0.05).The surviving fractions at 2 Gy (SF2) of T98-G and SF295 cells exposed to IR alone were 0.52 and 0.58.However,when VPA was combined with IR,the SF2 of T98-G and SF295 dropped to 0.39 (P=0.047) and 0.49 (P=-0.049),respectively.Treatment with VPA plus TMZ or IR also resulted in a significant decrease in the proportion of cells in the G2 phase and increased apoptotic rates as well as autophagy in T98-G and SF295 cell lines (P <0.01).Conclusion VPA may enhance the activities of TMZ and IR on glioma cells possibly through cell cycle block and promote autophagy,and thus could be a potential sensitizer of glioma treatment.

  9. Resveratrol-Induced Apoptosis and Increased Radiosensitivity in CD133-Positive Cells Derived From Atypical Teratoid/Rhabdoid Tumor

    International Nuclear Information System (INIS)

    Kao, C.-L.; Huang, P.-I; Tsai, P.-H.; Tsai, M.-L.; Lo, J.-F.; Lee, Y.-Y.; Chen, Y.-J.; Chen, Y.-W.; Chiou, S.-H.

    2009-01-01

    Purpose: CD133 has recently been proposed as a marker for cancer stem-like cells (CSC) in brain tumors. The aim of the present study was to investigate the possible role of resveratrol (RV) in radiosensitivity of CD133-positive/-negative cells derived from atypical teratoid/rhabdoid tumors (AT/RT-CD133 +/- ). Materials and Methods: AT/RT-CD133 +/- were isolated and characterized by flow cytometry and quantitative real-time reverse transcription-polymerase chain reaction, and then treated with RV at different doses. Migratory ability, colony formation, apoptotic activity, and xenotransplantation were assessed for RV alone, ionizing radiation (IR) alone, and IR with RV conditions. Results: AT/RT-CD133 + displayed enhanced self-renewal and highly coexpressed 'stem cell' genes and drug-resistant genes, in addition to showing significant resistance to chemotherapeutic agents and radiotherapy as compared with CD133 - cells. After treatment with 200 μM RV, the in vitro proliferation rates and in vivo tumor restoration abilities of ATRT-CD133 + were dramatically inhibited. Importantly, treatment with 150 μM RV can effectively inhibit the expression of drug-resistant genes in AT/RT-CD133 + , and further facilitate to the differentiation of CD133 + into CD133 - . In addition, treatment with 150 μM RV could significantly enhance the radiosensitivity and IR-mediated apoptosis in RV-treated ATRT-CD133 +/- . Kaplan-Meier survival analysis indicated that the mean survival rate of mice with ATRT-CD133 + that were treated with IR could be significantly improved when IR was combined with 150 μM RV treatment. Conclusions: AT/RT-CD133 + exhibit CSC properties and are refractory to IR treatment. Our results suggest that RV treatment plays crucial roles in antiproliferative, proapoptotic, and radiosensitizing effects on treated-CD133 +/- ; RV may therefore improve the clinical treatment of AT/RT.

  10. Radiosensitivity of hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Hennequin, C.; Quero, L.; Rivera, S.

    2011-01-01

    The frequency of hepatocellular carcinoma (HCC) is increasing in the western world and the role of radiotherapy is more and more discussed. Classically, hepatocellular carcinoma was considered as a radioresistant tumour: in fact, modern radio-biologic studies, performed on cell lines directly established from patients, showed that hepatocellular carcinoma has the same radiosensitivity than the other epithelial tumours. From clinical studies, its α/β ratio has been estimated to be around 15 Gy. Radiosensitivity of normal hepatic parenchyma is now well evaluated and some accurate NTCP models are available to guide hepatic irradiation. The biology of hepatocellular carcinoma is also better described: the combination of radiotherapy and targeted therapies will be a promising approach in the near future. (authors)

  11. Increased intestinal mucosal turnover and radiosensitivity to supralethal whole-body irradiation resulting from cholic acid-induced alterations of the intestinal microecology of germfree CFW mice

    International Nuclear Information System (INIS)

    Mastromarino, A.J.; Wilson, R.

    1976-01-01

    The prolonged mean survival time of germfree mice, compared to conventional mice, after exposure to 1000-10,000 rad whole-body irradiation has been postulated to be a function of an increased turnover time of the intestinal mucosal cells caused by the absence of free bile acids. To test this hypothesis, the diet of germ-free CFW mice was supplemented with 0.15 percent cholic acid for 2 weeks. The turnover of thymidine-labeled intestinal mucosal cells and the radiosensitivity to supralethal whole-body irradiation were significantly increased compared to germfree controls. There was a positive correlation between increased survivial time after supralethal whole-body irradiation and slower intestinal mucosal turnover time. Germfree mice supplemented with cholic acid had intestinal mucosal turnover times comparable to those of conventionalized controls. Although cholic acid reduces the mean survival time of germfree mice after suppralethal whole-body irradiation, the mean survival value is significantly greater than the conventionalized controls. Supplementing the diet of conventionalized CFW mice with cholic acid did not significantly decrease the intestinal mucosal turnover time nor did it significantly alter their radiosensitivity to supralethal whole-body irradiation. The data suggest that cholic acid is one of the microecological factors responsible for controlling the mucosal renewal rate and the mean survival time after whole-body irradiation

  12. Targeted radiosensitization of cells expressing truncated DNA polymerase {beta}.

    NARCIS (Netherlands)

    Neijenhuis, S.; Verwijs-Janssen, M.; Broek, Bart van den; Begg, A.C.; Vens, C.

    2010-01-01

    Ionizing radiation (IR) is an effective anticancer treatment, although failures still occur. To improve radiotherapy, tumor-targeted strategies are needed to increase radiosensitivity of tumor cells, without influencing normal tissue radiosensitivity. Base excision repair (BER) and single-strand

  13. Increased radiosensitivity of HPV-positive head and neck cancer cell lines due to cell cycle dysregulation and induction of apoptosis

    International Nuclear Information System (INIS)

    Arenz, Andrea; Ziemann, Frank; Wittig, Andrea; Preising, Stefanie; Engenhart-Cabillic, Rita; Mayer, Christina; Wagner, Steffen; Klussmann, Jens-Peter; Wittekindt, Claus; Dreffke, Kirstin

    2014-01-01

    Human Papillomavirus (HPV)-related head and neck squamous cell carcinoma (HNSCC) respond favourably to radiotherapy as compared to HPV-unrelated HNSCC. We investigated DNA damage response in HPV-positive and HPV-negative HNSCC cell lines aiming to identify mechanisms, which illustrate reasons for the increased sensitivity of HPV-positive cancers of the oropharynx. Radiation response including clonogenic survival, apoptosis, DNA double-strand break (DSB) repair, and cell cycle redistribution in four HPV-positive (UM-SCC-47, UM-SCC-104, 93-VU-147T, UPCI:SCC152) and four HPV-negative (UD-SCC-1, UM-SCC-6, UM-SCC-11b, UT-SCC-33) cell lines was evaluated. HPV-positive cells were more radiosensitive (mean SF2: 0.198 range: 0.22-0.18) than HPV-negative cells (mean SF2: 0.34, range: 0.45-0.27; p = 0.010). Irradiated HPV-positive cell lines progressed faster through S-phase showing a more distinct accumulation in G2/M. The abnormal cell cycle checkpoint activation was accompanied by a more pronounced increase of cell death after x-irradiation and a higher number of residual and unreleased DSBs. The enhanced responsiveness of HPV-related HNSCC to radiotherapy might be caused by a higher cellular radiosensitivity due to cell cycle dysregulation and impaired DNA DSB repair. (orig.) [de

  14. Radiosensitivity and genes

    Energy Technology Data Exchange (ETDEWEB)

    Qiyue, Hu; Mingyue, Lun [Suzhou Medical Coll., JS (China)

    1995-07-01

    Reported effects of some oncogenes, tumour suppressor genes and DNA repair genes on sensitivity of cells to ionizing radiation are reviewed. The role of oncogenes in cellular response to irradiation is discussed, especially the extensively studied oncogenes such as the ras gene family. For tumour suppressor genes, mainly the p53, which is increasingly implicated as a gene affecting radiosensitivity, is reviewed. It is considered that there is a cell cycle checkpoint determinant which is postulated to be able to arrest the irradiated cells in G{sub 1} phase to allow them to repair damage before they undergo DNA synthesis. So far there are six DNA repair genes which have been cloned in mammalian cells, but only one, XRCC1, appears to be involved in repair of human X-ray damage. XRCC1 can correct high sisterchromatid exchange levels when transferred into EM{sub 9} cells, but its expression seems to have no correlation with radiosensitivity of human neck and head tumour cells. Radiosensitivity is an intricate issue which may involve many factors. A scheme of cellular reactions after exposure to irradiation is proposed to indicate a possible sequence of events initiated by ionizing radiation.

  15. Radiosensitivity and genes

    International Nuclear Information System (INIS)

    Hu Qiyue; Lun Mingyue

    1995-07-01

    Reported effects of some oncogenes, tumour suppressor genes and DNA repair genes on sensitivity of cells to ionizing radiation are reviewed. The role of oncogenes in cellular response to irradiation is discussed, especially the extensively studied oncogenes such as the ras gene family. For tumour suppressor genes, mainly the p53, which is increasingly implicated as a gene affecting radiosensitivity, is reviewed. It is considered that there is a cell cycle checkpoint determinant which is postulated to be able to arrest the irradiated cells in G 1 phase to allow them to repair damage before they undergo DNA synthesis. So far there are six DNA repair genes which have been cloned in mammalian cells, but only one, XRCC1, appears to be involved in repair of human X-ray damage. XRCC1 can correct high sisterchromatid exchange levels when transferred into EM 9 cells, but its expression seems to have no correlation with radiosensitivity of human neck and head tumour cells. Radiosensitivity is an intricate issue which may involve many factors. A scheme of cellular reactions after exposure to irradiation is proposed to indicate a possible sequence of events initiated by ionizing radiation

  16. Hormonal status can modify radiosensitivity

    International Nuclear Information System (INIS)

    Ricoul, M.; Sabatier, L.; Dutrillaux, B.

    1997-01-01

    In preliminary experiments, we have demonstrated that pregnancy increases chromosome radiosensitivity in the mouse at the end of gestation. Blood obtained from women at various times of pregnancy was then exposed to ionizing radiations in vitro. By comparison to non pregnant women, an increase in chromosome breakages was observed in metaphases from lymphocytes. Immediately after delivery, this increase of radiosensitivity disappeared. In a prospective study, serial analyses showed a very strong correlation between the amount of pregnancy hormones, progesterone in particular, and the increase of radiosensitivity. Thus, pregnant women may have an increased sensitivity to ionizing radiation during the second half of their pregnancy and the risks of radiation exposure of pregnant women have to be considered not only n relation to the child, but also to their own hypersensitivity. (authors)

  17. Deregulation of cap-dependent mRNA translation increases tumour radiosensitivity through reduction of the hypoxic fraction

    International Nuclear Information System (INIS)

    Rouschop, Kasper M.A.; Dubois, Ludwig; Schaaf, Marco B.E.; Beucken, Twan van den; Lieuwes, Natasja; Keulers, Tom G.H.; Savelkouls, Kim G.M.; Bussink, Johan; Kogel, Albert J. van der; Koritzinsky, Marianne; Wouters, Bradly G.

    2011-01-01

    Background and purpose: Tumour hypoxia is an important limiting factor in the successful treatment of cancer. Adaptation to hypoxia includes inhibition of mTOR, causing scavenging of eukaryotic initiation factor 4E (eIF4E), the rate-limiting factor for cap-dependent translation. The aim of this study was to determine the effect of preventing mTOR-dependent translation inhibition on hypoxic cell survival and tumour sensitivity towards irradiation. Material and methods: The effect of eIF4E-overexpression on cell proliferation, hypoxia-tolerance, and radiation sensitivity was assessed using isogenic, inducible U373 and HCT116 cells. Results: We found that eIF4E-overexpression significantly enhanced proliferation of cells under normal conditions, but not during hypoxia, caused by increased cell death during hypoxia. Furthermore, eIF4E-overexpression stimulated overall rates of tumour growth, but resulted in selective loss of hypoxic cells in established tumours and increased levels of necrosis. This markedly increased overall tumour sensitivity to irradiation. Conclusions: Our results demonstrate that hypoxia induced inhibition of translational control through regulation of eIF4E is an important mediator of hypoxia tolerance and radioresistance of tumours. These data also demonstrate that deregulation of metabolic pathways such as mTOR can influence the proliferation and survival of tumour cells experiencing metabolic stress in opposite ways of nutrient replete cells.

  18. Hereditary syndromes with enhanced radiosensitivity

    International Nuclear Information System (INIS)

    Lohmann, D.

    2000-01-01

    Sensitivity to ionizing radiation is modified by heritable genetic factors. This is exemplified by heritable disorders that are characterized by predisposition to the development of neoplasms. Cells derived from patients with ataxia telangiectasia, Nijmegen breakage syndrome and ataxia telangiektasia-like disorder show a markedly changed reaction to exposure to ionizing radiation. Correspondingly, at least in patients with ataxia telangiectasia, an enhanced radiosensitivity that is of clinical importance has been observed. In addition to these recessive disorders, some autosomal dominant cancer predisposition syndromes are associated with increased radiosensitivity. As cells from these patients still have a normal allele (that is dominant over the mutant allele), the cellular phenotype is most often normal. Specifically, there is no overtly altered reaction in response to ionizing radiation. Nevertheless, two dominant cancer predisposition syndromes, namely hereditary retinoblastoma and naevoid basal cell carcinoma syndrome, are associated with a enhanced radiosensitivity as indicated by increased development of tumors following radiation therapy. (orig.) [de

  19. Tactile thermal oral stimulation increases the cortical representation of swallowing

    Directory of Open Access Journals (Sweden)

    Suntrup Sonja

    2009-06-01

    Full Text Available Abstract Background Dysphagia is a leading complication in stroke patients causing aspiration pneumonia, malnutrition and increased mortality. Current strategies of swallowing therapy involve on the one hand modification of eating behaviour or swallowing technique and on the other hand facilitation of swallowing with the use of pharyngeal sensory stimulation. Thermal tactile oral stimulation (TTOS is an established method to treat patients with neurogenic dysphagia especially if caused by sensory deficits. Little is known about the possible mechanisms by which this interventional therapy may work. We employed whole-head MEG to study changes in cortical activation during self-paced volitional swallowing in fifteen healthy subjects with and without TTOS. Data were analyzed by means of synthetic aperture magnetometry (SAM and the group analysis of individual SAM data was performed using a permutation test. Results Compared to the normal swallowing task a significantly increased bilateral cortical activation was seen after oropharyngeal stimulation. Analysis of the chronological changes during swallowing suggests facilitation of both the oral and the pharyngeal phase of deglutition. Conclusion In the present study functional cortical changes elicited by oral sensory stimulation could be demonstrated. We suggest that these results reflect short-term cortical plasticity of sensory swallowing areas. These findings facilitate our understanding of the role of cortical reorganization in dysphagia treatment and recovery.

  20. Lethal outcome after pelvic salvage radiotherapy in a patient with prostate cancer due to increased radiosensitivity. Case report and literature review

    Energy Technology Data Exchange (ETDEWEB)

    Fahrig, Antje; Koch, T. [Klinikum Bamberg, Sozialstiftung Bamberg, Klinik und Praxis fuer Radioonkologie und Strahlentherapie, Bamberg (Germany); Lenhart, M. [Klinikum Bamberg, Sozialstiftung Bamberg, Klinik fuer Diagnostische Radiologie, Interventionelle Radiologie und Neuroradiologie, Bamberg (Germany); Rieckmann, P. [Klinikum Bamberg, Sozialstiftung Bamberg, Neurologische Klinik, Bamberg (Germany); Fietkau, R.; Distel, Luitpold; Schuster, B. [Universitaetsklinikum Erlangen, Strahlenklinik, Erlangen (Germany)

    2018-01-15

    In general, late side effects after salvage radiotherapy (RT) for prostate cancer are below 10%. Patients with impaired DNA repair ability and genetic instability can have significantly increased reactions after RT. We present a patient who experienced severe side effects after additive RT for prostate cancer and died from the complications 25 months after RT. Imaging (MR) is shown as well as three-color fluorescence in situ hybridization. The blood sample testing revealed that radiosensitivity was increased by 35-55%. We undertook a review of the literature to give an overview over the tests established that are currently considered useful. This case highlights that the identification of patients with increased radiosensitivity is an important task in radiation protection. Groups of patients who should be screened have to be found and corresponding research facilities have to be set up. (orig.) [German] Generell sind spaete Nebenwirkungen nach additiver Radiotherapie (RT) beim Prostatakarzinom mit deutlich unter 10 % selten. Allerdings haben Patienten mit eingeschraenkter DNA-Reparatur-Kapazitaet und genetischer Instabilitaet ein signifikant erhoehtes Nebenwirkungsrisiko. In diesem Fallbeispiel stellen wir einen Patienten vor, der nach additiver RT wegen Prostatakarzinom massive Nebenwirkungen erlitt und 25 Monate nach der RT daran verstarb. Wir zeigen die Ergebnisse der konsekutiven MR-Untersuchungen und 3-Farben-Fluoreszenz-in-situ-Hybridisierung. Die Blutuntersuchung ergab eine um 35-55 % erhoehte Strahlenempfindlichkeit. Eine aktuelle Literaturrecherche ergab, dass mittlerweile verschiedene Testverfahren zur Untersuchung der Strahlenempfindlichkeit etabliert sind. Das Fallbeispiel zeigt, dass die Identifikation besonders strahlenempfindlicher Patienten ein wichtiges Arbeitsziel im Strahlenschutz ist. Patientenparameter fuer eine erforderliche Testung ueber die bekannten Syndrome hinaus sollten identifizierbar werden. Entsprechende Forschungseinrichtungen sind

  1. Radiosensitivity of higher plants

    International Nuclear Information System (INIS)

    Feng Zhijie

    1992-11-01

    The general views on radiosensitivity of higher plants have been introduced from published references. The radiosensitivity varies with species, varieties and organs or tissues. The main factors of determining the radiosensitivity in different species are nucleus volume, chromosome volume, DNA content and endogenous compounds. The self-repair ability of DNA damage and chemical group of biological molecules, such as -SH thiohydroxy of proteins, are main factors to determine the radiosensitivity in different varieties. The moisture, oxygen, temperature radiosensitizer and protector are important external factors for radiosensitivity. Both the multiple target model and Chadwick-Leenhouts model are ideal mathematical models for describing the radiosensitivity of higher plants and the latter has more clear significance in biology

  2. Higher Levels of c-Met Expression and Phosphorylation Identify Cell Lines With Increased Sensitivity to AMG-458, a Novel Selective c-Met Inhibitor With Radiosensitizing Effects

    International Nuclear Information System (INIS)

    Li Bo; Torossian, Artour; Sun, Yunguang; Du, Ruihong; Dicker, Adam P.; Lu Bo

    2012-01-01

    Purpose: c-Met is overexpressed in some non-small cell lung cancer (NSCLC) cell lines and tissues. Cell lines with higher levels of c-Met expression and phosphorylation depend on this receptor for survival. We studied the effects of AMG-458 on 2 NSCLC cell lines. Methods and Materials: 3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl) -2H-tetrazolium assays assessed the sensitivities of the cells to AMG-458. Clonogenic survival assays illustrated the radiosensitizing effects of AMG-458. Western blot for cleaved caspase 3 measured apoptosis. Immunoblotting for c-Met, phospho-Met (p-Met), Akt/p-Akt, and Erk/p-Erk was performed to observe downstream signaling. Results: AMG-458 enhanced radiosensitivity in H441 but not in A549. H441 showed constitutive phosphorylation of c-Met. A549 expressed low levels of c-Met, which were phosphorylated only in the presence of exogenous hepatocyte growth factor. The combination of radiation therapy and AMG-458 treatment was found to synergistically increase apoptosis in the H441 cell line but not in A549. Radiation therapy, AMG-458, and combination treatment were found to reduce p-Akt and p-Erk levels in H441 but not in A549. H441 became less sensitive to AMG-458 after small interfering RNA knockdown of c-Met; there was no change in A549. After overexpression of c-Met, A549 became more sensitive, while H441 became less sensitive to AMG-458. Conclusions: AMG-458 was more effective in cells that expressed higher levels of c-Met/p-Met, suggesting that higher levels of c-Met and p-Met in NSCLC tissue may classify a subset of tumors that are more sensitive to molecular therapies against this receptor.

  3. Stimulation of Suicidal Erythrocyte Death by Increased Extracellular Phosphate Concentrations

    Directory of Open Access Journals (Sweden)

    Jakob Voelkl

    2014-02-01

    Full Text Available Background/Aim: Anemia in renal insufficiency results in part from impaired erythrocyte formation due to erythropoietin and iron deficiency. Beyond that, renal insufficiency enhances eryptosis, the suicidal erythrocyte death characterized by phosphatidylserine-exposure at the erythrocyte surface. Eryptosis may be stimulated by increase of cytosolic Ca2+-activity ([Ca2+]i. Several uremic toxins have previously been shown to stimulate eryptosis. Renal insufficiency is further paralleled by increase of plasma phosphate concentration. The present study thus explored the effect of phosphate on erythrocyte death. Methods: Cell volume was estimated from forward scatter, phosphatidylserine-exposure from annexin V binding, and [Ca2+]i from Fluo3-fluorescence. Results: Following a 48 hours incubation, the percentage of phosphatidylserine exposing erythrocytes markedly increased as a function of extracellular phosphate concentration (from 0-5 mM. The exposure to 2 mM or 5 mM phosphate was followed by slight but significant hemolysis. [Ca2+]i did not change significantly up to 2 mM phosphate but significantly decreased at 5 mM phosphate. The effect of 2 mM phosphate on phosphatidylserine exposure was significantly augmented by increase of extracellular Ca2+ to 1.7 mM, and significantly blunted by nominal absence of extracellular Ca2+, by additional presence of pyrophosphate as well as by presence of p38 inhibitor SB203580. Conclusion: Increasing phosphate concentration stimulates erythrocyte membrane scrambling, an effect depending on extracellular but not intracellular Ca2+ concentration. It is hypothesized that suicidal erythrocyte death is triggered by complexed CaHPO4.

  4. Chromosomes, cancer and radiosensitivity

    International Nuclear Information System (INIS)

    Samouhos, E.

    1983-01-01

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

  5. Oscillatory frontal theta responses are increased upon bisensory stimulation.

    Science.gov (United States)

    Sakowitz, O W; Schürmann, M; Başar, E

    2000-05-01

    To investigate the functional correlation of oscillatory EEG components with the interaction of sensory modalities following simultaneous audio-visual stimulation. In an experimental study (15 subjects) we compared auditory evoked potentials (AEPs) and visual evoked potentials (VEPs) to bimodal evoked potentials (BEPs; simultaneous auditory and visual stimulation). BEPs were assumed to be brain responses to complex stimuli as a marker for intermodal associative functioning. Frequency domain analysis of these EPs showed marked theta-range components in response to bimodal stimulation. These theta components could not be explained by linear addition of the unimodal responses in the time domain. Considering topography the increased theta-response showed a remarkable frontality in proximity to multimodal association cortices. Referring to methodology we try to demonstrate that, even if various behavioral correlates of brain oscillations exist, common patterns can be extracted by means of a systems-theoretical approach. Serving as an example of functionally relevant brain oscillations, theta responses could be interpreted as an indicator of associative information processing.

  6. Radiosensitivities of sensitized lymphocytes

    International Nuclear Information System (INIS)

    Taniguchi, Kazuto

    1979-01-01

    Immunization of mice with cell antigens such as allogeneic tumor cells or xenogeneic erythrocytes raises a variety of immune reactions mediated by T lymphocytes: i.e. delayed type hypersensitivity (DTH), cytotoxicity, and antibody production. The radiosensitivities of these reactions were examined in mice exposed to 600 R x-irradiation a few hours before or after immunization. 1) DTH to xenogeneic erythrocytes, as demonstrated by footpad reaction, was not suppressed by irradiation 3 h before or after immunization. DTH to allogeneic tumor cells, as demonstrated by a migration inhibition test, hardly developed in mice that had been irradiated before or after immunization. It may have belonged to distinct types of delayed reactions which were mediated by distinct subpopulations of T lymphocytes. 2) Cytotoxicity against allogeneic cells and xenogeneic erythrocytes showed almost the same radiosensitivity. It was scarcely detected in mice that had been irradiated before immunization. However, a low but definite degree of cytotoxicity was detected in mice that had been irradiated only a few hours after immunization. Solubilized allogeneic cells instead of native cells were used as immunizing antigens. It was also possible for precursor cells with cytotoxicity to acquire a radioresistant nature by immunization of solubilized antigens, but native cells were required as stimulation for radioresistant precursor cells to differentiated into nature cytotoxic effector cells. 3) Antibody production against xenogeneic erythrocytes or allogeneic cells was almost completely depleted in mice that had been irradiated before or after immunization. It is possible that antibody production essentially requires cell division and clonal expansion of B lymphocytes. (Bell, E.)

  7. Increased radiosensitivity and radiothermosensitivity of human pancreatic MIA PaCa-2 and U251 glioblastoma cell lines treated with the novel Hsp90 inhibitor NVP-HSP990

    International Nuclear Information System (INIS)

    Milanović, Dušan; Firat, Elke; Grosu, Anca Ligia; Niedermann, Gabriele

    2013-01-01

    Heat shock Protein 90 (Hsp90) is a molecular chaperone that folds, stabilizes, and functionally regulates many cellular proteins involved in oncogenic signaling and in the regulation of radiosensitivity. It is upregulated in response to stress such a heat. Hyperthermia is a potent radiosensitizer, but induction of Hsp90 may potentially limit its efficacy. Our aim was to investigate whether the new Hsp90 inhibitor NVP-HSP990 increases radiosensitivity, thermosensitivity and radiothermosensitivity of human tumor cell lines. U251 glioblastoma and MIA PaCa-2 pancreatic carcinoma cells were used. To determine clonogenic survival, colony forming assays were performed. Cell viability and proliferation were assesed by Trypan blue staining. Cell cycle and apoptosis analyses were performed by flow cytometry. DAPI staining was used to detect mitotic catastrophe. NVP-HSP990 increased the thermosensitivity, radiosensitivity and radio-thermosensitivity of both cell lines in clonogenic assays. 72 hours after irradiation with 4 Gy, a significant reduction in cell number associated with considerable G2/M acumulation and mitotic catastrophe as well as cell death by apoptosis/necrosis was observed. Treatment with NVP-HSP990 strongly sensitized U251 and MIA PaCa-2 cells to hyperthermia and ionizing radiation or combination thereof through augmentation of G2/M arrest, mitotic catastrophe and associated apoptosis

  8. Thyroid stimulating hormone increases hepatic gluconeogenesis via CRTC2.

    Science.gov (United States)

    Li, Yujie; Wang, Laicheng; Zhou, Lingyan; Song, Yongfeng; Ma, Shizhan; Yu, Chunxiao; Zhao, Jiajun; Xu, Chao; Gao, Ling

    2017-05-05

    Epidemiological evidence indicates that thyroid stimulating hormone (TSH) is positively correlated with abnormal glucose levels. We previously reported that TSH has direct effects on gluconeogenesis. However, the underlying molecular mechanism remains unclear. In this study, we observed increased fasting blood glucose and glucose production in a mouse model of subclinical hypothyroidism (only elevated TSH levels). TSH acts via the classical cAMP/PKA pathway and CRTC2 regulates glucose homeostasis. Thus, we explore whether CRTC2 is involved in the process of TSH-induced gluconeogenesis. We show that TSH increases CRTC2 expression via the TSHR/cAMP/PKA pathway, which in turn upregulates hepatic gluconeogenic genes. Furthermore, TSH stimulates CRTC2 dephosphorylation and upregulates p-CREB (Ser133) in HepG2 cells. Silencing CRTC2 and CREB decreases the effect of TSH on PEPCK-luciferase, the rate-limiting enzyme of gluconeogenesis. Finally, the deletion of TSHR reduces the levels of the CRTC2:CREB complex in mouse livers. This study demonstrates that TSH activates CRTC2 via the TSHR/cAMP/PKA pathway, leading to the formation of a CRTC2:CREB complex and increases hepatic gluconeogenesis. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Radiosensitization by hematocrit manipulation

    International Nuclear Information System (INIS)

    Hirst, D.G.; Hazlehurst, J.L.; Brown, J.M.

    1985-01-01

    The authors show that tumors in mice adapt to anemia in a rather complex manner. Radiosensitivity may be lower, higher or equal to normal depending on when the anemia is induced prior to irradiation. The authors study these changes in radiosensitivity which occur during a period of anemia followed by the restoration of the hematocrit. When mice were made anemic immediately before irradiation, their tumors were very resistant, but the resistance was lost over the following 24 hrs even though the anemia was maintained. If mice which had been anemic for 24 hrs were retransfused to normal levels with red blood cells immediately before irradiation, their tumors were considerably more sensitive than normal. As the interval between retransfusion and irradiation was increased, sensitization was rapidly lost so that by 24 hrs sensitivity was the same as that of control tumors. They attribute this loss of sensitization to rapid tumor growth in response to a restored oxygen supply so that new hypoxic cells are created. The implications of this for the treatment of the anemic patient are discussed

  10. High-Frequency Neuromuscular Electrical Stimulation Increases Anabolic Signaling.

    Science.gov (United States)

    Mettler, Joni A; Magee, Dillon M; Doucet, Barbara M

    2018-03-16

    Neuromuscular electrical stimulation (NMES) is commonly used in rehabilitation settings to increase muscle mass and strength. However, the effects of NMES on muscle growth are not clear and no human studies have compared anabolic signaling between low-frequency (LF-) and high-frequency (HF-) NMES. The purpose of this study was to determine the skeletal muscle anabolic signaling response to an acute bout of LF- and HF-NMES. Eleven young healthy volunteers (6 men; 5 women) received an acute bout of LF- (20 Hz) and HF- (60 Hz) NMES. Muscle biopsies were obtained from the vastus lateralis muscle prior to the first NMES treatment and 30-mins following each NMES treatment. Phosphorylation of the following key anabolic signaling proteins was measured by Western blot and proteins are expressed as a ratio of phosphorylated to total: mammalian target of rapamycin (mTOR), p70-S6 kinase 1 (S6K1), and eukaryotic initiation factor 4E binding protein 1 (4E-BP1). Compared to Pre-NMES, phosphorylation of mTOR was upregulated 40.2% for LF-NMES (P = 0.018) and 68.4% for HF-NMES (P 0.05). There were no differences between treatment conditions for 4E-BP1 phosphorylation (P > 0.05). An acute bout of LF- and HF-NMES upregulated anabolic signaling with HF-NMES producing a greater anabolic response compared to LF-NMES, suggesting that HF-stimulation may provide a stronger stimulus for processes that initiate muscle hypertrophy. Additionally, the stimulation frequency parameter should be considered by clinicians in the design of optimal NMES treatment protocols.

  11. Bisensory stimulation increases gamma-responses over multiple cortical regions.

    Science.gov (United States)

    Sakowitz, O W; Quiroga, R Q; Schürmann, M; Başar, E

    2001-04-01

    In the framework of the discussion about gamma (approx. 40 Hz) oscillations as information carriers in the brain, we investigated the relationship between gamma responses in the EEG and intersensory association. Auditory evoked potentials (AEPs) and visual evoked potentials (VEPs) were compared with bisensory evoked potentials (BEPs; simultaneous auditory and visual stimulation) in 15 subjects. Gamma responses in AEPs, VEPs and BEPs were assessed by means of wavelet decomposition. Overall maximum gamma-components post-stimulus were highest in BEPs (P < 0.01). Bisensory evoked gamma-responses also showed significant central, parietal and occipital amplitude-increases (P < 0.001, P < 0.01, P < 0.05, respectively; prestimulus interval as baseline). These were of greater magnitude when compared with the unisensory responses. As a correlate of the marked gamma responses to bimodal stimulation we suggest a process of 'intersensory association', i.e. one of the steps between sensory transmission and perception. Our data may be interpreted as a further example of function-related gamma responses in the EEG.

  12. Inhibition of DNA-PKcs enhances radiosensitivity and increases the levels of ATM and ATR in NSCLC cells exposed to carbon ion irradiation.

    Science.gov (United States)

    Yang, Lina; Liu, Yuanyuan; Sun, Chao; Yang, Xinrui; Yang, Zhen; Ran, Juntao; Zhang, Qiuning; Zhang, Hong; Wang, Xinyu; Wang, Xiaohu

    2015-11-01

    Non-small cell lung cancer (NSCLC) exhibits radioresistance to conventional rays, due to its DNA damage repair systems. NSCLC may potentially be sensitized to radiation treatment by reducing those factors that continuously enhance the repair of damaged DNA. In the present study, normal lung fibroblast MRC-5 and lung cancer A549 cells were treated with NU7026 and CGK733, which are inhibitors of the DNA-dependent protein kinase catalytic subunit (PKcs) and ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR), respectively, followed by exposure to X-rays and carbon ion irradiation. The cytotoxic activity, cell survival rate, DNA damage repair ability, cell cycle arrest and apoptosis rate of the treated cells were analyzed with MTT assay, colony formation assay, immunofluorescence and flow cytometry, respectively. The transcription and translation levels of the ATM, ATR and DNA-PKcs genes were detected by reverse transcription-quantitative polymerase chain reaction and western blotting, respectively. The results indicated that the radiosensitivity and DNA repair ability of A549 cells were reduced, and the percentages of apoptotic cells and those arrested at the G 2 /M phase of the cell cycle were significantly increased, following ionizing radiation with inhibitor-pretreatment. The expression levels of ATM, ATR, DNA-PKcs and phosphorylated histone H2AX, a biomarker for DNA double-strand breaks, were all upregulated at the transcriptional or translational level in A549 cells treated with carbon ion irradiation, compared with the control and X-rays-treated cells. In addition, the treatment with 5-50 µM NU7026 or CGK733 did not produce any obvious cytotoxicity in MRC-5 cells, and the effect of the DNA-PKcs-inhibitor on enhancing the radiosensitivity of A549 cells was stronger than that observed for the ATM and ATR-inhibitor. These findings demonstrated a minor role for ATM and ATR in radiation-induced cell death, since the upregulation of

  13. Transition in Survival From Low-Dose Hyper-Radiosensitivity to Increased Radioresistance Is Independent of Activation of ATM SER1981 Activity

    International Nuclear Information System (INIS)

    Krueger, Sarah A.; Collis, Spencer J.; Joiner, Michael C.; Wilson, George D.; Marples, Brian

    2007-01-01

    Purpose: The molecular basis of low-dose hyper-radiosensitivity (HRS) is only partially understood. The aim of this study was to define the roles of ataxia telangiectasia mutated (ATM) activity and the downstream ATM-dependent G 2 -phase cell cycle checkpoint in overcoming HRS and triggering radiation resistance. Methods and Materials: Survival was measured using a high-resolution clonogenic assay. ATM Ser1981 activation was measured by Western blotting. The role of ATM was determined in survival experiments after molecular (siRNA) and chemical (0.4 mM caffeine) inhibition and chemical (20 μg/mL chloroquine, 15 μM genistein) activation 4-6 h before irradiation. Checkpoint responsiveness was assessed in eight cell lines of differing HRS status using flow cytometry to quantify the progression of irradiated (0-2 Gy) G 2 -phase cells entering mitosis, using histone H3 phosphorylation analysis. Results: The dose-response pattern of ATM activation was concordant with the transition from HRS to radioresistance. However, ATM activation did not play a primary role in initiating increased radioresistance. Rather, a relationship was discovered between the function of the downstream ATM-dependent early G 2 -phase checkpoint and the prevalence and overcoming of HRS. Four cell lines that exhibited HRS failed to show low-dose ( 2 -phase checkpoint. These data suggest that clinical exploitation of HRS could be achieved by combining radiotherapy with chemotherapeutic agents that modulate this cell cycle checkpoint

  14. Radiosensitivity of primary cultured fish cells with different ploidy

    International Nuclear Information System (INIS)

    Mitani, Hiroshi; Egami, Nobuo; Kobayashi, Hiromu.

    1986-01-01

    The radiosensitivity of primary cultured goldfish cells (Carassius auratus) was investigated by colony formation assay. The radiosensitivity of cells from two varieties of goldfish, which show different sensitivity to lethal effect of ionizing radiation in vivo, was almost identical. Primary cultured cells from diploid, triploid and tetraploid fish retained their DNA content as measured by microfluorometry, and the nuclear size increases as ploidy increases. However, radiosensitivity was not related to ploidy. (author)

  15. Radiosensitizers and protectors

    International Nuclear Information System (INIS)

    Nori, D.; Kim, J.H.; Hilaris, B.; Chu, F.C.

    1987-01-01

    Over the past decades, various physical, biological, and clinical strategies have been investigated to improve the therapeutic effectiveness of radiation. One of these efforts has been to develop chemical radiosensitizers and protectors. In the broadest sense, a radiation sensitizer is any agent that enhances the cytolethal effects of radiation. Drugs that selectively protect tissues from radiation injury are under active study. This chapter briefly reviews the present status of chemical radiosensitizers and protectors. The discussion of sensitizers will be limited to the oxic cell and hypoxic cell radiosensitizers and their clinical applications

  16. Extracting the normal lung dose–response curve from clinical DVH data: a possible role for low dose hyper-radiosensitivity, increased radioresistance

    International Nuclear Information System (INIS)

    Gordon, J J; Snyder, K; Zhong, H; Barton, K; Sun, Z; Chetty, I J; Matuszak, M; Ten Haken, R K

    2015-01-01

    In conventionally fractionated radiation therapy for lung cancer, radiation pneumonitis’ (RP) dependence on the normal lung dose-volume histogram (DVH) is not well understood. Complication models alternatively make RP a function of a summary statistic, such as mean lung dose (MLD). This work searches over damage profiles, which quantify sub-volume damage as a function of dose. Profiles that achieve best RP predictive accuracy on a clinical dataset are hypothesized to approximate DVH dependence.Step function damage rate profiles R(D) are generated, having discrete steps at several dose points. A range of profiles is sampled by varying the step heights and dose point locations. Normal lung damage is the integral of R(D) with the cumulative DVH. Each profile is used in conjunction with a damage cutoff to predict grade 2 plus (G2+) RP for DVHs from a University of Michigan clinical trial dataset consisting of 89 CFRT patients, of which 17 were diagnosed with G2+ RP.Optimal profiles achieve a modest increase in predictive accuracy—erroneous RP predictions are reduced from 11 (using MLD) to 8. A novel result is that optimal profiles have a similar distinctive shape: enhanced damage contribution from low doses (<20 Gy), a flat contribution from doses in the range ∼20–40 Gy, then a further enhanced contribution from doses above 40 Gy. These features resemble the hyper-radiosensitivity / increased radioresistance (HRS/IRR) observed in some cell survival curves, which can be modeled using Joiner’s induced repair model.A novel search strategy is employed, which has the potential to estimate RP dependence on the normal lung DVH. When applied to a clinical dataset, identified profiles share a characteristic shape, which resembles HRS/IRR. This suggests that normal lung may have enhanced sensitivity to low doses, and that this sensitivity can affect RP risk. (paper)

  17. Radiosensitivity of garlic air bulbs

    International Nuclear Information System (INIS)

    Zhila, Eh.D.

    1975-01-01

    The paper presents data on the radiosensitivity of various sorts of garlic. It is shown that the frequency of chromosomal aberrations in the irradiated aerial bulbs of stemmed varieties of garlic is directly dependent upon the gmma-ray dose. With increasing dose the germination capacity and the viability of the plants diminishes. A dose of 750 r was found to be critical for the bulbs of the garlic varieties studied

  18. Increased radiosensitivity of HPV-positive head and neck cancer cell lines due to cell cycle dysregulation and induction of apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Arenz, Andrea; Ziemann, Frank; Wittig, Andrea; Preising, Stefanie; Engenhart-Cabillic, Rita [Philipps-University, Department of Radiotherapy and Radiooncology, BMFZ - Biomedical Research Center, Marburg (Germany); Mayer, Christina; Wagner, Steffen; Klussmann, Jens-Peter; Wittekindt, Claus [Justus Liebig University, Department of Otorhinolaryngology and Head and Neck Surgery, Giessen (Germany); Dreffke, Kirstin [Philipps-University, Institute for Radiobiology and Molecular Radiooncology, Marburg (Germany)

    2014-09-15

    Human Papillomavirus (HPV)-related head and neck squamous cell carcinoma (HNSCC) respond favourably to radiotherapy as compared to HPV-unrelated HNSCC. We investigated DNA damage response in HPV-positive and HPV-negative HNSCC cell lines aiming to identify mechanisms, which illustrate reasons for the increased sensitivity of HPV-positive cancers of the oropharynx. Radiation response including clonogenic survival, apoptosis, DNA double-strand break (DSB) repair, and cell cycle redistribution in four HPV-positive (UM-SCC-47, UM-SCC-104, 93-VU-147T, UPCI:SCC152) and four HPV-negative (UD-SCC-1, UM-SCC-6, UM-SCC-11b, UT-SCC-33) cell lines was evaluated. HPV-positive cells were more radiosensitive (mean SF2: 0.198 range: 0.22-0.18) than HPV-negative cells (mean SF2: 0.34, range: 0.45-0.27; p = 0.010). Irradiated HPV-positive cell lines progressed faster through S-phase showing a more distinct accumulation in G2/M. The abnormal cell cycle checkpoint activation was accompanied by a more pronounced increase of cell death after x-irradiation and a higher number of residual and unreleased DSBs. The enhanced responsiveness of HPV-related HNSCC to radiotherapy might be caused by a higher cellular radiosensitivity due to cell cycle dysregulation and impaired DNA DSB repair. (orig.) [German] Fuer Patienten mit HPV-assoziierten Kopf-Hals-Tumoren (HNSCC) ist im Vergleich zu Patienten mit nicht-HPV-assoziierten Tumoren ein besseres Ueberleben nach Radiotherapie gesichert. Ziel der Untersuchung war die Identifizierung von Unterschieden in der zellulaeren DNA-Schadensantwort von HPV-positiven und HPV-negativen Zelllinien, wodurch die bereits in Erprobung stehende Deeskalation einer Radiotherapie bei Patienten mit HPV-assoziierten HNSCC durch experimentelle Daten abgesichert werden koennte. Klonogenes Ueberleben, Induktion von Apoptose, DNA-Doppelstrang-Reparatur und Zellzyklusverhalten wurden in vier HPV-positiven (UM-SCC-47, UM-SCC-104, 93-VU-147T, UPCI:SCC152) und vier HPV

  19. Decreasing size of radiosensitive capsules from micro to nano, and its increased antitumor effect and decreasing adverse effect

    International Nuclear Information System (INIS)

    Harada, S.; Ehara, S.; Ishii, K.; Yamazaki, H.; Matsuyama, S.; Sato, Takahiro; Kamiya, Tomihiro; Sera, K.; Saito, Y.

    2012-01-01

    We have been developing microcapsules that release anticancer drug with response to radiation. We attempted to decrease the diameter of capsules. Then, two categories were tested in VIVO in C3He mice: (1) the antitumor effect in combination with radiation and subcutaneously injected nanocapsules, (2) the kidnetics of nanocapsules when they were injected intravenously. Microcapsules were produced by spraying a mixture of 3.0 % hyaluronic acid, 2.0 % alginate, 3.0 % H 2 O 2 , and 0.3 mmol carboplatin (Pt containing anticancer drug) onto a mixture of vibrated 0.3 mol FeCl 2 and 0.15 mol CaCl 2 . The antitumor effect was measured by measuring tumor diameter every day. The kinetics of microcapsules were expressed as the numbers of capsules in 5 views (25 x 25 μm) of micro PIXE camera and Pt concentration of quantiative PIXE. The generated microcapsules 752 ± 64 nm, which were significantly downsized relative to previous capsules. The accumulations of capsules in lungs, liver, and kidneys were decreased by downsizing, whereas those of tumors were increased. By adjusting Pt concentration in tumor, there were no significant differences in antitumor effect between not downsized and downsized microcapsules with combination with radiation. Decreased trapping of downsized microcapsules to lungs, liver, and kidneys, also increased trapping in tumors will lead to new targeted chemoradiotherapy via intravenous injection of microcapsules. (author)

  20. Dual PI3K/mTOR inhibitors, GSK2126458 and PKI-587, suppress tumor progression and increase radiosensitivity in nasopharyngeal carcinoma.

    Science.gov (United States)

    Liu, Tongxin; Sun, Quanquan; Li, Qi; Yang, Hua; Zhang, Yuqin; Wang, Rong; Lin, Xiaoshan; Xiao, Dong; Yuan, Yawei; Chen, Longhua; Wang, Wei

    2015-02-01

    Although combined chemoradiotherapy has provided considerable improvements for nasopharyngeal carcinoma (NPC), recurrence and metastasis are still frequent. The PI3K/Akt/mTOR pathway plays a critical role in tumor formation and tumor cell survival after radiation-induced DNA damage. In the present study, we evaluated whether inhibition of PI3K/mTOR by two novel dual inhibitors, GSK2126458 and PKI-587, could suppress tumor progression and sensitize NPC cells to radiation. Four NPC cell lines (CNE-1, CNE-2, 5-8F, and 6-10B) were used to analyze the effects of GSK216458 and PKI-587 on cell proliferation, migration, invasion, clonogenic survival, amount of residual γ-H2AX foci, cell cycle, and apoptosis after radiation. A 5-8F xenograft model was used to evaluate the in vivo effects of the two compounds in combination with ionizing radiation (IR). Both GSK216458 and PKI-587 effectively inhibited cell proliferation and motility in NPC cells and suppressed phosphorylation of Akt, mTOR, S6, and 4EBP1 proteins in a concentration- and time-dependent manner. Moreover, both compounds sensitized NPC cells to IR by increasing DNA damage, enhancing G2-M cell-cycle delay, and inducing apoptosis. In vivo, the combination of IR with GSK2126458 or PKI-587 significantly inhibited tumor growth. Antitumor effect was correlated with induction of apoptosis and suppression of the phosphorylation of mTOR, Akt, and 4EBP1. These new findings suggest the usefulness of PI3K/mTOR dual inhibition for antitumor and radiosensitizing. The combination of IR with a dual PI3K/mTOR inhibitor, GSK2126458 or PKI-587, might be a promising therapeutic strategy for NPC. ©2014 American Association for Cancer Research.

  1. Radiosensitivity of fingermillet genotypes

    Energy Technology Data Exchange (ETDEWEB)

    Raveendran, T S; Nagarajan, C; Appadurai, R; Prasad, M N; Sundaresan, N [Tamil Nadu Agricultural Univ., Coimbatore (India)

    1984-07-01

    Varietal differences in radiosensitivity were observed in a study involving 4 genotypes of fingermillet (Eleusine coracana (Linn.) Gaertn.) subjected to gamma-irradiation. Harder seeds were found to tolerate a higher dose of the mutagen.

  2. Sacral nerve stimulation increases activation of the primary somatosensory cortex by anal canal stimulation in an experimental model.

    LENUS (Irish Health Repository)

    Griffin, K M

    2011-08-01

    Sacral and posterior tibial nerve stimulation may be used to treat faecal incontinence; however, the mechanism of action is unknown. The aim of this study was to establish whether sensory activation of the cerebral cortex by anal canal stimulation was increased by peripheral neuromodulation.

  3. Mild electrical stimulation with heat stimulation increase heat shock protein 70 in articular chondrocyte.

    Science.gov (United States)

    Hiraoka, Nobuyuki; Arai, Yuji; Takahashi, Kenji A; Mazda, Osam; Kishida, Tsunao; Honjo, Kuniaki; Tsuchida, Shinji; Inoue, Hiroaki; Morino, Saori; Suico, Mary Ann; Kai, Hirofumi; Kubo, Toshikazu

    2013-06-01

    The objective of this study is to investigate the effects of mild electrical stimulation (MES) and heat stress (HS) on heat shock protein 70 (HSP70), that protects chondrocytes and enhances cartilage matrix metabolism, in chondrocyte and articular cartilage. Rabbit articular chondrocytes were treated with MES and/or HS. The safeness was assessed by LDH assay and morphology. HSP70 protein, ubiquitinated proteins and HSP70 mRNA were examined by Western blotting and real-time PCR. Rat knee joints were treated with MES and/or HS. HSP70 protein, ubiquitinated proteins, HSP70 mRNA and proteoglycan core protein (PG) mRNA in articular cartilage were investigated. In vitro, HS increased HSP70 mRNA and HSP70 protein. MES augmented ubiquitinated protein and HSP70 protein, but not HSP70 mRNA. MES + HS raised HSP70 mRNA and ubiquitinated protein, and significantly increased HSP70 protein. In vivo, HS and MES + HS treatment augmented HSP70 mRNA. HS modestly augmented HSP70 protein. MES + HS significantly increased HSP70 protein and ubiquitinated proteins. PG mRNA was markedly raised by MES + HS. This study demonstrated that MES, in combination with HS, increases HSP70 protein in chondrocytes and articular cartilage, and promotes cartilage matrix metabolism in articular cartilage. MES in combination with HS can be a novel physical therapy for osteoarthritis by inducing HSP70 in articular cartilage. Copyright © 2013 Orthopaedic Research Society.

  4. Catecholamines of the body tissues and radiosensitivity of rodents

    Energy Technology Data Exchange (ETDEWEB)

    Grayevskaya, V M; Zolotariova, N N [AN SSSR, Moscow. Inst. Morfologii Zhivotnykh

    1975-01-01

    Various species of rodents are distinguished by their radiosensitivity (increasing): bank vole < Wistar rat < wild mouse < CC/sub 57/Br mouse < golden hamster < BALB mouse < guinea pig. There is a positive correlation between radiosensitivity of these species and catecholamines content in the adrenals, urea and blood; and negative correlation between radiosensitivity and adrenaline and noradrenaline concentrations in liver and spleen cells. Presumable causes of this correlation, and the possibility of application of the index under study for predicting the organism radiosensitivity and forecasting the outcome of radiation damage are discussed.

  5. Catecholamines of the body tissues and radiosensitivity of rodents

    International Nuclear Information System (INIS)

    Grayevskaya, V.M.; Zolotariova, N.N.

    1975-01-01

    Various species of rodents are distinguished by their radiosensitivity (increasing): bank vole 57 Br mouse < golden hamster < BALB mouse < guinea pig. There is a positive correlation between radiosensitivity of these species and catecholamines content in the adrenals, urea and blood; and negative correlation between radiosensitivity and adrenaline and noradrenaline concentrations in liver and spleen cells. Presumable causes of this correlation, and the possibility of application of the index under study for predicting the organism radiosensitivity and forecasting the outcome of radiation damage are discussed

  6. Follicle-Stimulating Hormone Increases the Risk of Postmenopausal Osteoporosis by Stimulating Osteoclast Differentiation.

    Directory of Open Access Journals (Sweden)

    Jie Wang

    Full Text Available The objectives of this study were to observe the changes in follicle-stimulating hormone (FSH and bone mineral density (BMD in postmenopausal women, to research the relationship between FSH and postmenopausal osteoporosis, and to observe the effects of FSH on osteoclast differentiation in RAW264.7 cells.We analyzed 248 postmenopausal women with normal bone metabolism. A radioimmunoassay (RIA was used to detect serum FSH, luteinizing hormone (LH, and estradiol (E2. Dual-energy X-ray absorptiometry was used to measure forearm BMD. Then, we analyzed the age-related changes in serum FSH, LH and E2. Additionally, FSH serum concentrations were compared between a group of postmenopausal women with osteoporosis and a control group. Osteoclasts were induced from RAW264.7 cells in vitro by receptor activator of nuclear factor kappa B ligand (RANKL, and these cells were treated with 0, 5, 10, and 20 ng/ml FSH. After the osteoclasts matured, tartrate-resistant acid phosphatase (TRAP staining was used to identify osteoclasts, and the mRNA expression levels of genes involved in osteoclastic phenotypes and function, such as receptor activator of NF-κB (Rank, Trap, matrix metalloproteinase-9 (Mmp-9 and Cathepsin K, were detected in different groups using real-time PCR (polymerase chain reaction.1. FSH serum concentrations in postmenopausal women with osteoporosis increased notably compared with the control group. 2. RANKL induced RAW264.7 cell differentiation into mature osteoclasts in vitro. 3. FSH increased mRNA expression of genes involved in osteoclastic phenotypes and function, such as Rank, Trap, Mmp-9 and Cathepsin K, in a dose-dependent manner.The circulating concentration of FSH may play an important role in the acceleration of bone loss in postmenopausal women. FSH increases osteoclastogenesis in vitro.

  7. Radiosensitivity in ataxia-telangiectasia

    International Nuclear Information System (INIS)

    Lavin, M.F.; Khanna, K.K.; Watters, D.

    1998-01-01

    Full text: Radiosensitivity is a major hallmark of the human genetic disorder ataxia-telangiectasia. This hypersensitivity to ionizing radiation has been demonstrated in vitro after exposure of patients to therapeutic thought to be the major factor contculture. Clearly an understanding of the nature of the molecular defect in ataxia-telangiectasia will be of considerable assistance in delineating additional pathways that determine cellular radiosensitivity/radioresistance. Furthermore, since patients with this syndrome are also predisposed to developing a number of leukaemias and lymphomas the possible connection between radiosensitivity and cancer predisposition is of interest. Now that the gene (ATM) responsible for this genetic disease has been cloned and identified, progress is being made in determining the role of the ATM protein in mediating the effects of cellular exposure to ionizing radiation and other forms of redox stress. Proteins such as the product of the tumour suppressor gene p53 and the proto-oncogene c-Abl (a protein tyrosine kinase) have been shown to interact with ATM. Since several intermediate steps in both the p53 and c-Abl pathways, activated by ionizing radiation, are known it will be possible to map the position of ATM in these pathways and describe its mechanism of action. What are the clinical implications of understanding the molecular basis of the defect in ataxia-telangiectasia? As outlined above since radiosensitivity is a universal characteristic of A-T understanding the mechanism of action of ATM will provide additional information or radiation signalling in human cells. With this information it may be possible to sensitize tumour cells to radiation and thus increase the therapeutic benefit of radiotherapy. This might involve the use of small molecules that would interfere with the normal ATM controlled pathways and thus sensitize cells to radiation or alternatively it might involve the efficient introduction of ATM anti-sense c

  8. Radiosensitivity in ataxia-telangiectasia

    Energy Technology Data Exchange (ETDEWEB)

    Lavin, M.F. [Royal Brisbane Hospital, QLD (Australia). Queensland Institute of Medical Research and The Department of Surgery; Khanna, K.K.; Watters, D. [Royal Brisbane Hospital, QLD (Australia). Queensland Institute of Medical Research

    1998-12-31

    Full text: Radiosensitivity is a major hallmark of the human genetic disorder ataxia-telangiectasia. This hypersensitivity to ionizing radiation has been demonstrated in vitro after exposure of patients to therapeutic thought to be the major factor contculture. Clearly an understanding of the nature of the molecular defect in ataxia-telangiectasia will be of considerable assistance in delineating additional pathways that determine cellular radiosensitivity/radioresistance. Furthermore, since patients with this syndrome are also predisposed to developing a number of leukaemias and lymphomas the possible connection between radiosensitivity and cancer predisposition is of interest. Now that the gene (ATM) responsible for this genetic disease has been cloned and identified, progress is being made in determining the role of the ATM protein in mediating the effects of cellular exposure to ionizing radiation and other forms of redox stress. Proteins such as the product of the tumour suppressor gene p53 and the proto-oncogene c-Abl (a protein tyrosine kinase) have been shown to interact with ATM. Since several intermediate steps in both the p53 and c-Abl pathways, activated by ionizing radiation, are known it will be possible to map the position of ATM in these pathways and describe its mechanism of action. What are the clinical implications of understanding the molecular basis of the defect in ataxia-telangiectasia? As outlined above since radiosensitivity is a universal characteristic of A-T understanding the mechanism of action of ATM will provide additional information or radiation signalling in human cells. With this information it may be possible to sensitize tumour cells to radiation and thus increase the therapeutic benefit of radiotherapy. This might involve the use of small molecules that would interfere with the normal ATM controlled pathways and thus sensitize cells to radiation or alternatively it might involve the efficient introduction of ATM anti-sense c

  9. Radiosensitizers: rationale and potential

    International Nuclear Information System (INIS)

    Brown, J.M.

    1981-01-01

    This paper briefly reviews agents that are capable of sensitizing hypoxic cells to radiation and chemotherapeutic agents. The first part is a synopsis of the development of hypoxic radiosensitizers, which concludes that misonidazole can be effective against human tumors. Unfortunately, neurotoxicity limits its effectiveness in humans because the dose that can be given in conjunction with daily fractionated radiation is five to ten times lower than is required for full radiosensitization of the hypoxic cells. The second part covers our recent efforts to develop a drug that does not produce such limiting neurotoxicity. The primary rationale of our program was to synthesize a drug with a short plasma half-life that was too hydrophilic to cross the blood-brain barrier but was able to penetrate tumors and radiosensitize hypoxic cells. From this program, a new drug, SR-2508, has been found that is as efficient as misonidazole in its radiosensitizing ability, but is four to ten times less toxic. Finally, the potential of radiosensitizers not only as agents that can sensitize tumor cells to radiation, but also as agents that can specifically sensitize tumors to chemotherapeutic agents, is discussed. In addition, these drugs may be potential cytotoxic agents that produce toxicity only in solid tumors

  10. ADPRT inhibitors and hyperthermia as radiosensitizers

    International Nuclear Information System (INIS)

    Jonsson, G.G.

    1985-01-01

    Hyperthermia given in combination with gamma radiation has given considerable improvement in the therapeutic results for treatment of malignant tumors. The mechanism behind the hyperthermia effect is probably operative at the tissue level as well as at the molecular level. The metabolism of NAD + in relation to the activity of the chromosomal enzyme ADP-ribosyl transferase (ADPRT) has been studied as a possible molecular mechanism for this effect. The ADPRT activity was measured after radiosensitization with both hyperthermia and nicotinamide, which is a potent inhibitor of ADPRT. The results indicate that hyperthermia can improve the effect of radiotherapy by reducing the supply of NAD + , which is a co-substrate for ADPRT, while nicotinamide functions as a radiosensitizing agent by direct inhibition of the enzyme. The hypothesis is discussed in the thesis where inhibition of ADPRT might increase the radiosensitivity because the radiation-induced DNA damage can not be repaired with normal efficiency. The function of nicotinamide as a radiosensitizer was verified by studies on C3H mice with transplanted spontaneous mammary tumors. Because nicotinamide is not toxic, it seems quite attractive to test this vitamin as a radiosensitizing agent against human tumors. (251 refs.) (author)

  11. Age-dependent radiosensitivity of mouse oocytes

    International Nuclear Information System (INIS)

    Koehler, C.

    1976-01-01

    It has been shown that there are three distinct phases of radiosensitivity in oocytes of prepubertal mice: a period of rapidly increasing sensitivity between 0 and 4 days of age; a period of consistent, high sensitivity between 5 and 18 days of age; and a period of decreasing sensitivity from 19 to at least 21 days of age. Two distinct phases have been demonstrated for the rate of population decline of the oocytes of primary follicles: an initial period of rapid loss from 0 to 4 days of age; and a period of much slower loss from 5 through 23 days of age. Correlations have been drawn between the first two phases of radiosensitivity and morphological changes in the oocyte, and between the third phase of radiosensitivity and endocrinological changes in the maturing animal. The reaction of oocytes to radiation has been separated into two categories: immediate death (within 24 hours); and delayed death (over the entire lifespan of the animal)

  12. Radiosensitivity in plants

    International Nuclear Information System (INIS)

    Nauman, A.F.

    1979-01-01

    The report presents a compilation of available data on the sensitivity of plants to ionizing radiation, and provides basic information on methods of determining such sensitivities, or of estimating radiosensitivities by calcuation of the nuclear factors upon which they depend. The scope of the data presented here is necessarily limited to the most generally useful radiobiological end points and to the most commonly-used types of radiation. Many of the factors which influence radiosensitivity, particularly nuclear factors, will be discussed. Emphasis will be upon whole-plant studies done at Brookhaven National Laboratory by A.H. Sparrow and his associates, since these studies are the source of most of the available radiosensitivity data and of all the sensitivity predictions listed here. Data presented here include summaries of experimentally-determined radiosensitivities at various end points for both herbaceous and woody higher plants, and for a few species of ferns and lower plants. The algae and fungi have not been considered here due to space limitations

  13. Radiosensitivity in plants

    Energy Technology Data Exchange (ETDEWEB)

    Nauman, A F

    1979-01-01

    The report presents a compilation of available data on the sensitivity of plants to ionizing radiation, and provides basic information on methods of determining such sensitivities, or of estimating radiosensitivities by calcuation of the nuclear factors upon which they depend. The scope of the data presented here is necessarily limited to the most generally useful radiobiological end points and to the most commonly-used types of radiation. Many of the factors which influence radiosensitivity, particularly nuclear factors, will be discussed. Emphasis will be upon whole-plant studies done at Brookhaven National Laboratory by A.H. Sparrow and his associates, since these studies are the source of most of the available radiosensitivity data and of all the sensitivity predictions listed here. Data presented here include summaries of experimentally-determined radiosensitivities at various end points for both herbaceous and woody higher plants, and for a few species of ferns and lower plants. The algae and fungi have not been considered here due to space limitations.

  14. Mutations in the FHA-domain of ectopically expressed NBS1 lead to radiosensitization and to no increase in somatic mutation rates via a partial suppression of homologous recombination

    International Nuclear Information System (INIS)

    Ohara, Maki; Funyu, Yumi; Ebara, Shunsuke

    2014-01-01

    Ionizing radiation induces DNA double-strand breaks (DSBs). Mammalian cells repair DSBs through multiple pathways, and the repair pathway that is utilized may affect cellular radiation sensitivity. In this study, we examined effects on cellular radiosensitivity resulting from functional alterations in homologous recombination (HR). HR was inhibited by overexpression of the forkhead-associated (FHA) domain-mutated NBS1 (G27D/R28D: FHA-2D) protein in HeLa cells or in hamster cells carrying a human X-chromosome. Cells expressing FHA-2D presented partially (but significantly) HR-deficient phenotypes, which were assayed by the reduction of gene conversion frequencies measured with a reporter assay, a decrease in radiation-induced Mre11 foci formation, and hypersensitivity to camptothecin treatments. Interestingly, ectopic expression of FHA-2D did not increase the frequency of radiation-induced somatic mutations at the HPRT locus, suggesting that a partial reduction of HR efficiency has only a slight effect on genomic stability. The expression of FHA-2D rendered the exponentially growing cell population slightly (but significantly) more sensitive to ionizing radiation. This radiosensitization effect due to the expression of FHA-2D was enhanced when the cells were irradiated with split doses delivered at 24-h intervals. Furthermore, enhancement of radiation sensitivity by split dose irradiation was not seen in contact-inhibited G0/G1 populations, even though the cells expressed FHA-2D. These results suggest that the FHA domain of NBS1 might be an effective molecular target that can be used to induce radiosensitization using low molecular weight chemicals, and that partial inhibition of HR might improve the effectiveness of cancer radiotherapy. (author)

  15. Effect of laser radiation on rat radiosensitivity

    Energy Technology Data Exchange (ETDEWEB)

    Laprun, I.B.

    1979-03-01

    Quite a few experimental data have been obtained to date indicating that radioresistance of the organism is enhanced under the influence of electromagnetic emissions in the radiofrequency and optical ranges. But no studies were made of the possible radioprotective properties of coherent laser radiation. At the same time, it was demonstrated that the low-energy emission of optical quantum generators (lasers) in the red band stimulates the protective forces of the organism and accelerates regenerative processes; i.e., it induces effects that are the opposite of that of ionizing radiation. Moreover, it was recently demonstrated that there is activation of catalase, a radiosensitive enzyme that plays an important role in the metabolism of peroxide compounds, under the influence of lasers. For this reason, the effect of pre-exposure to laser beams on radiosensitivity of rats was tested.

  16. Stimulation of the sensory pudendal nerve increases bladder capacity in the rat.

    Science.gov (United States)

    Hokanson, James A; Langdale, Christopher L; Sridhar, Arun; Grill, Warren M

    2018-04-01

    Pudendal nerve stimulation is a promising treatment approach for lower urinary tract dysfunction, including symptoms of overactive bladder. Despite some promising clinical studies, there remain many unknowns as to how best to stimulate the pudendal nerve to maximize therapeutic efficacy. We quantified changes in bladder capacity and voiding efficiency during single-fill cystometry in response to electrical stimulation of the sensory branch of the pudendal nerve in urethane-anesthetized female Wistar rats. Increases in bladder capacity were dependent on both stimulation amplitude and rate. Stimulation that produced increases in bladder capacity also led to reductions in voiding efficiency. Also, there was a stimulation carryover effect, and increases in bladder capacity persisted during several nonstimulated trials following stimulated trials. Intravesically administered PGE 2 reduced bladder capacity, producing a model of overactive bladder (OAB), and sensory pudendal nerve stimulation again increased bladder capacity but also reduced voiding efficiency. This study serves as a basis for future studies that seek to maximize the therapeutic efficacy of sensory pudendal nerve stimulation for the symptoms of OAB.

  17. Pressure pain thresholds increase after preconditioning 1 Hz repetitive transcranial magnetic stimulation with transcranial direct current stimulation.

    Science.gov (United States)

    Moloney, Tonya M; Witney, Alice G

    2014-01-01

    The primary motor cortex (M1) is an effective target of non-invasive cortical stimulation (NICS) for pain threshold modulation. It has been suggested that the initial level of cortical excitability of M1 plays a key role in the plastic effects of NICS. Here we investigate whether transcranial direct current stimulation (tDCS) primed 1 Hz repetitive transcranial magnetic stimulation (rTMS) modulates experimental pressure pain thresholds and if this is related to observed alterations in cortical excitability. 15 healthy, male participants received 10 min 1 mA anodal, cathodal and sham tDCS to the left M1 before 15 min 1 Hz rTMS in separate sessions over a period of 3 weeks. Motor cortical excitability was recorded at baseline, post-tDCS priming and post-rTMS through recording motor evoked potentials (MEPs) from right FDI muscle. Pressure pain thresholds were determined by quantitative sensory testing (QST) through a computerized algometer, on the palmar thenar of the right hand pre- and post-stimulation. Cathodal tDCS-primed 1 Hz-rTMS was found to reverse the expected suppressive effect of 1 Hz rTMS on cortical excitability; leading to an overall increase in activity (ppain thresholds (ppain. This study demonstrates that priming the M1 before stimulation of 1 Hz-rTMS modulates experimental pressure pain thresholds in a safe and controlled manner, producing a form of analgesia.

  18. Radiosensitivity of antibody responses and radioresistant secondary tetanus antitoxin responses

    International Nuclear Information System (INIS)

    Stoner, R.; Terres, G.; Cottier, H.; Hess, M.

    1976-01-01

    Primary tetanus antitoxin responses were increasingly repressed in mice when gamma radiation doses of 100 to 400 rads were delivered by whole-body exposure prior to immunization with fluid tetanus toxoid (FTT). Nearly normal secondary antitoxin responses were obtained in mice exposed to 600 rads of gamma radiation 4 days after secondary antigenic stimulation with FTT. A rapid transition from radiosensitivity of the antibody-forming system on days 1 to 3 was followed by relative radioresistance on day 4 after the booster injection of toxoid. Studies on lymphoid cellular kinetics in popliteal lymph nodes after injection of 3 H--thymidine ( 3 H--TdR) and incorporation of 3 H--L-histidine into circulating antitoxin were carried out. Analysis of tritium radioactivity in antigen--antibody precipitates of serums 2 hr after injection of the labeled amino acid revealed maximum incorporation into antibody around day 7 after the booster in nonirradiated controls and about day 12, i.e., 8 days after irradiation, in experimental mice. The shift from radiosensitivity to relative radioresistance was attributed to a marked peak of plasma-cell proliferation in the medulla of lymph nodes on day 3. Many medullary plasma cells survived and continued to proliferate after exposure to radiation. Germinal centers were destroyed by radiation within 1 day. Since antibody formation continued after exposure to radiation and after the loss of germinal centers, this supports the view that germinal-center cells were involved more in the generation of memory cells than in antibody synthesis

  19. Radiosensitivity of cells

    Energy Technology Data Exchange (ETDEWEB)

    Alexander, P [Radiation Biology Section, Chester Beatty Research Institute, Royal Cancer Hospital, London (United Kingdom)

    1960-07-15

    The mechanism by which radiation kills cells must be investigated with the goal to make possible to devise means to alter the radiosensitivity of cells. The object of our investigation, supported by IAEA, is to try and find the reasons for the variation in sensitivity between different cells. Once we know the reason for the differences in radiosensitivity of different micro-organisms we can begin to look rationally for ways of enhancing the radiation response of the more sensitive organisms. An investigation of this type has implications far beyond food sterilization, as it cannot fail to provide fundamental facts about radiation injury to cells in general. Cancer researchers have looked for many years for means of sensitizing cancer cells to radiation

  20. Radiosensitivity of cells

    International Nuclear Information System (INIS)

    Alexander, P.

    1960-01-01

    The mechanism by which radiation kills cells must be investigated with the goal to make possible to devise means to alter the radiosensitivity of cells. The object of our investigation, supported by IAEA, is to try and find the reasons for the variation in sensitivity between different cells. Once we know the reason for the differences in radiosensitivity of different micro-organisms we can begin to look rationally for ways of enhancing the radiation response of the more sensitive organisms. An investigation of this type has implications far beyond food sterilization, as it cannot fail to provide fundamental facts about radiation injury to cells in general. Cancer researchers have looked for many years for means of sensitizing cancer cells to radiation

  1. Chromosomal radiosensitivity of prostate cancer patients

    International Nuclear Information System (INIS)

    McRobbie, M.L.; Riches, A.; Baxby, K.

    2003-01-01

    Full text: Radiosensitivity of peripheral blood lymphocytes from prostate cancer patients is being investigated using the G2 assay and the Cytokinesis Block Micronucleus(CBMN)assay. The G2 assay evaluates chromosomal damage caused by irradiating cells in the G2 phase of the cell cycle. The CBMN assay quantifies the post mitotic micronuclei, which are the expression of damage incurred during G0. An association between hypersensitivity to the chromosome damaging effects of ionising radiation and cancer predispostion has been demonstrated in a number of heritable conditions by using the aforementioned techniques. Recently, increased chromosomal radiosensitivity has been demonstrated in a significant proportion of patients with no obvious family history of malignancy. The aim of this study is to establish whether a group of prostatic carcinoma patients exists and if so whether there are any correlations between their G2 and G0 sensitivities. The study has shown there is no correlation between G2 and G0 sensitivity, confirming the general trend that individuals exhibiting chromosomal radiosensitivity are defective in only one mechanism and G2 and G0 sensitivity are largely independent. Current data indicates that there is an identifiable group of men within the prostate cancer population with increased chromosomal radiosensitivity. Using the G2 assay and the 90th percentile of the controls as a cut off point for sensitivity, no significant difference between the controls and the patient population has been found. However, using the CBMN assay and again the 90th percentile, approximately 11% of the control group are sensitive compared with approximately 40% of the carcinoma cases. The implications of this increased radiosensitivity are as yet unclear, but it is indicative of increased chromosomal fragility and therefore, possibly associated with malignant transformation. Hence, it may prove a useful tool in identifying individuals at increased risk of developing

  2. Radiosensitivity of amphibia

    Energy Technology Data Exchange (ETDEWEB)

    Muramatsu, S [National Inst. of Radiological Sciences, Chiba (Japan)

    1975-04-01

    Radiosensitivity (semi-lethal dose) and the damages of radiation in the amphibia were studied by /sup 3/H-TdR from the standpoint of cellular kinetics. The cell mitosis cycle of the amphibia required a long time. The functional cell regeneration and the physiological function of the cell were slower than in mice. The reason for the low radiosensitivity of the amphibia was discussed relative to the environmental factor of temperature. Because the amphibia change body temperature according to environmental temperature, the danger of radiation damage, the actual lethal dose and the period of survival were influenced by the environmental temperature. Acute radiation danger to amphibia was essentially the same as the danger to mammalia, both young and old. LD/sub 50/ irradiation effects varied among the species. The cell regeneration, turn over, and the mitosis in the amphibia, were affected by environmental temperature, however, the courses proceeded slower than those of the mammalia. Therefore, the question remains, whether the comparison of the radiosensitivities of amphibia with other classes of animal by LDsub(50/30) irradiation was appropriate.

  3. Pressure pain thresholds increase after preconditioning 1 Hz repetitive transcranial magnetic stimulation with transcranial direct current stimulation.

    Directory of Open Access Journals (Sweden)

    Tonya M Moloney

    Full Text Available BACKGROUND: The primary motor cortex (M1 is an effective target of non-invasive cortical stimulation (NICS for pain threshold modulation. It has been suggested that the initial level of cortical excitability of M1 plays a key role in the plastic effects of NICS. OBJECTIVE: Here we investigate whether transcranial direct current stimulation (tDCS primed 1 Hz repetitive transcranial magnetic stimulation (rTMS modulates experimental pressure pain thresholds and if this is related to observed alterations in cortical excitability. METHOD: 15 healthy, male participants received 10 min 1 mA anodal, cathodal and sham tDCS to the left M1 before 15 min 1 Hz rTMS in separate sessions over a period of 3 weeks. Motor cortical excitability was recorded at baseline, post-tDCS priming and post-rTMS through recording motor evoked potentials (MEPs from right FDI muscle. Pressure pain thresholds were determined by quantitative sensory testing (QST through a computerized algometer, on the palmar thenar of the right hand pre- and post-stimulation. RESULTS: Cathodal tDCS-primed 1 Hz-rTMS was found to reverse the expected suppressive effect of 1 Hz rTMS on cortical excitability; leading to an overall increase in activity (p<0.001 with a parallel increase in pressure pain thresholds (p<0.01. In contrast, anodal tDCS-primed 1 Hz-rTMS resulted in a corresponding decrease in cortical excitability (p<0.05, with no significant effect on pressure pain. CONCLUSION: This study demonstrates that priming the M1 before stimulation of 1 Hz-rTMS modulates experimental pressure pain thresholds in a safe and controlled manner, producing a form of analgesia.

  4. Tumour-specific radiosensitizers for radiation therapy

    International Nuclear Information System (INIS)

    Denekamp, J.

    1977-01-01

    Recently Adams and coworkers at the Gray Laboratory have developed a new class of radiosensitizers which act specifically on hypoxic cells by abolishing the protection afforded by low oxygen concentrations. Since most experimental tumours contain a high proportion of oxygen-deprived cells, and most normal tissues are well oxygenated, these drugs are tumour specific radiosensitizers. Based on the hypothesis that sensitization increases with increasing electron affinity, the two nitroimidazoles, metronidazole (Flagyl) and Ro-07/0582 were identified as potent radiosensitizers with low toxicity. These drugs are effective only in the absence of oxygen, and only if the drug is present at the time of irradiation. The degree of sensitization increases with drug concentration rapidly over the range 0.1 to 1.0mg/g body weight for Ro-07-0582, and more gradually for Flagyl. Tumour studies have been performed on at least 12 different experimental tumours, using a variety of end points. Significant sensitization has been observed in every tumour studied, often corresponding to a dose reduction factor of 2.0 for high but non-toxic drug doses. Fractionated studies have also been performed on a few tumour lines. In most cases a useful therapeutic advantage was observed, although the sensitization was smaller. Ro-07-0582 used with X-rays gives a therapeutic gain comparable with that from cyclotron-produced fast neutrons. Neutrons used together with Ro-07-0582 are even more effective. In addition to the radiosensitization there is a specific cytotoxicity to hypoxic cells after prolonged exposure to Ro-07-0582. This cytotoxicity can be greatly enhanced in vitro by moderate hyperthermia. Flagyl and Ro-07-0582 have been used clinically as radiosensitizers, with promising early results. The clinical application is limited to certain dose fractionation patterns because of neurotoxicity. (author)

  5. Development of Radiosensitizer using farnesyltransferase inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Lim, Jong Seok; Choe, Yong Kyung; Han, Mi Young; Kim, Kwang Dong [Korea Research Institute of Bioscience and Biotechnology, Taejon (Korea)

    1999-03-01

    We selected some compounds that were reported to have an activity of farneyltransferase inhibitor and tested the hypothesis that they might be used to radiosensitize cells transformed by ras oncogenes. The inhibition of ras processing using some, but not all, inhibitors resulted in higher levels of cell death after {gamma}-irradiation and increased radiosensitivity in H-ras-transformed NIH3T3 cells and MCF-10A human tumor cells. They did not induce additional cell death in control cells that doe not have ras mutation. Furthermore, the treatment of inhibitors alone induced a weak G0/G1 block, whereas inhibitors in combination with {gamma}-irradiation induced an additional enrichment in the G2/M phase of the cell cycle that typically represents irradiation-induced growth arrest. At present, the underling mechanism by which the farnesylltransferase inhibitors exert radiosensitizing effect is not known. In summary, our results suggest and lead to the possibility that some of farnesylation inhibitors may prove clinically useful not only as antitumor agents, but also radiosensitizers of tumors whose growth is dependent on ras function. (author). 15 refs., 10 figs., 4 tabs.

  6. Photosensitizers and radiosensitizers in dermatology and oncology

    International Nuclear Information System (INIS)

    Bruckner, V.

    1979-01-01

    Two therapeutic modalities are currently of great interest, namely photo- and radiosensitization. Whereas photosensitizers only function in combination with ultraviolet (UV) light, radiosensitizers act only in combination with ionizing radiation. Because of the small UV penetration, up to a maximum of 0,5 mm, photosensitization can take place only at the surface of the body, i.e. the skin. Photosensitizers are applied in dermatology in order to optimize and improve the UV therapy of certain diseases (mainly psoriasis, mycosis fungoides and vitiligo). Radiosensitizers lead to an increase in sensitivity of the hypoxic and therefore radioresistant parts of tumours against X- and gamma-radiation. With sufficient concentration within the tumour, they can act where the radiation can reach, even in the deeper parts of the body. They represent a modern and useful aid to radiation oncology. Because of neurotoxic effects, however, their practical use is limited. A short review of the history, mechanisms of action, application and side-effects of these photo- and radiosensitizers is presented

  7. Photosensitizers and radiosensitizers in dermatology and oncology

    Energy Technology Data Exchange (ETDEWEB)

    Bruckner, V [Stellenbosch University, Parowvallei (South Africa). Departments of Medical Physics and Radiology

    1979-09-22

    Two therapeutic modalities are currently of great interest, namely photo- and radiosensitization. Whereas photosensitizers only function in combination with ultraviolet (UV) light, radiosensitizers act only in combination with ionizing radiation. Because of the small UV penetration, up to a maximum of 0,5 mm, photosensitization can take place only at the surface of the body, i.e. the skin. Photosensitizers are applied in dermatology in order to optimize and improve the UV therapy of certain diseases (mainly psoriasis, mycosis fungoides and vitiligo). Radiosensitizers lead to an increase in sensitivity of the hypoxic and therefore radioresistant parts of tumours against X- and gamma-radiation. With sufficient concentration within the tumour, they can act where the radiation can reach, even in the deeper parts of the body. They represent a modern and useful aid to radiation oncology. Because of neurotoxic effects, however, their practical use is limited. A short review of the history, mechanisms of action, application and side-effects of these photo- and radiosensitizers is presented.

  8. Increased Androgen Response to Follicle-Stimulating Hormone Administration in Women with Polycystic Ovary Syndrome

    OpenAIRE

    Wachs, Deborah S.; Coffler, Mickey S.; Malcom, Pamela J.; Shimasaki, Shunichi; Chang, R. Jeffrey

    2008-01-01

    Context: In women with polycystic ovary syndrome (PCOS), excess ovarian androgen production is driven by increased LH secretion. Studies conducted in animals suggest that the granulosa cell may influence LH-stimulated theca cell androgen production.

  9. Radiosensitization of NSCLC cells by EGFR inhibition is the result of an enhanced p53-dependent G1 arrest

    International Nuclear Information System (INIS)

    Kriegs, Malte; Gurtner, Kristin; Can, Yildiz; Brammer, Ingo; Rieckmann, Thorsten; Oertel, Reinhard; Wysocki, Marek; Dorniok, Franziska; Gal, Andreas; Grob, Tobias J.; Laban, Simon; Kasten-Pisula, Ulla; Petersen, Cordula; Baumann, Michael; Krause, Mechthild; Dikomey, Ekkehard

    2015-01-01

    Purpose: How EGF receptor (EGFR) inhibition induces cellular radiosensitization and with that increase in tumor control is still a matter of discussion. Since EGFR predominantly regulates cell cycle and proliferation, we studied whether a G1-arrest caused by EGFR inhibition may contribute to these effects. Materials and methods: We analyzed human non-small cell lung cancer (NSCLC) cell lines either wild type (wt) or mutated in p53 (A549, H460, vs. H1299, H3122) and HCT116 cells (p21 wt and negative). EGFR was inhibited by BIBX1382BS, erlotinib or cetuximab; p21 was knocked down by siRNA. Functional endpoints analyzed were cell signaling, proliferation, G1-arrest, cell survival as well as tumor control using an A549 tumor model. Results: When combined with IR, EGFR inhibition enhances the radiation-induced permanent G1 arrest, though solely in cells with intact p53/p21 signaling. This increase in G1-arrest was always associated with enhanced cellular radiosensitivity. Strikingly, this effect was abrogated when cells were re-stimulated, suggesting the initiation of dormancy. In line with this, only a small non-significant increase in tumor control was observed for A549 tumors treated with fractionated RT and EGFR inhibition. Conclusion: For NSCLC cells increase in radiosensitivity by EGFR inhibition results from enhanced G1-arrest. However, this effect does not lead to improved tumor control because cells can be released from this arrest by re-stimulation

  10. Epinephrine-stimulated glycogen breakdown activates glycogen synthase and increases insulin-stimulated glucose uptake in epitrochlearis muscles

    DEFF Research Database (Denmark)

    Kolnes, Anders J; Birk, Jesper Bratz; Eilertsen, Einar

    2015-01-01

    Adrenaline increases glycogen synthase (GS) phosphorylation and decreases GS activity but also stimulates glycogen breakdown and low glycogen content normally activates GS. To test the hypothesis that glycogen content directly regulates GS phosphorylation, glycogen breakdown was stimulated...... in condition with decreased GS activation. Saline or adrenaline (0.02mg/100g rat) was injected subcutaneously in Wistar rats (~130 g) with low (24 h fasted), normal (normal diet) and high glycogen content (fasted-refed) and epitrochlearis muscles were removed after 3 h and incubated ex vivo eliminating...... adrenaline action. Adrenaline injection reduced glycogen content in epitrochlearis muscles with high (120.7±17.8 vs 204.6±14.5 mmol•kg(-1); pglycogen (89.5±7.6 vs 152.6±8.1 mmol•kg(-1); pglycogen (90.0±5.0 vs 102.8±7.8 mmol•kg(-1); p=0...

  11. Pulsed Light Stimulation Increases Boundary Preference and Periodicity of Episodic Motor Activity in Drosophila melanogaster.

    Directory of Open Access Journals (Sweden)

    Shuang Qiu

    Full Text Available There is considerable interest in the therapeutic benefits of long-term sensory stimulation for improving cognitive abilities and motor performance of stroke patients. The rationale is that such stimulation would activate mechanisms of neural plasticity to promote enhanced coordination and associated circuit functions. Experimental approaches to characterize such mechanisms are needed. Drosophila melanogaster is one of the most attractive model organisms to investigate neural mechanisms responsible for stimulation-induced behaviors with its powerful accessibility to genetic analysis. In this study, the effect of chronic sensory stimulation (pulsed light stimulation on motor activity in w1118 flies was investigated. Flies were exposed to a chronic pulsed light stimulation protocol prior to testing their performance in a standard locomotion assay. Flies responded to pulsed light stimulation with increased boundary preference and travel distance in a circular arena. In addition, pulsed light stimulation increased the power of extracellular electrical activity, leading to the enhancement of periodic electrical activity which was associated with a centrally-generated motor pattern (struggling behavior. In contrast, such periodic events were largely missing in w1118 flies without pulsed light treatment. These data suggest that the sensory stimulation induced a response in motor activity associated with the modifications of electrical activity in the central nervous system (CNS. Finally, without pulsed light treatment, the wild-type genetic background was associated with the occurrence of the periodic activity in wild-type Canton S (CS flies, and w+ modulated the consistency of periodicity. We conclude that pulsed light stimulation modifies behavioral and electrophysiological activities in w1118 flies. These data provide a foundation for future research on the genetic mechanisms of neural plasticity underlying such behavioral modification.

  12. Increased follicle-stimulating hormone is associated with higher assisted reproduction use after vasectomy reversal.

    Science.gov (United States)

    Hsiao, Wayland; Sultan, Raymond; Lee, Richard; Goldstein, Marc

    2011-06-01

    Of men with vasectomy 6% elect to have more children. When considering vasectomy reversal vs in vitro fertilization/intracytoplasmic sperm injection, an elucidation of preoperative factors that predict surgical success would help determine appropriate management. We tested the hypothesis that preoperative follicle-stimulating hormone 10 U/l or greater predict a lower paternity rate after vasectomy reversal. Using preoperative follicle-stimulating hormone levels we retrospectively reviewed the records of patients who underwent vasectomy reversal. Follicle-stimulating hormone was measured in cases suspicious for impaired spermatogenesis. The final analysis included 206 men, who were divided by follicle-stimulating hormone less than 10 U/l (normal in 155) and 10 U/l or greater (high in 51). Nominal logistic regression was performed to evaluate assisted reproduction predictors. Mean ± SD follicle-stimulating hormone in the normal and high groups was 5.1 ± 2.2 and 16.2 ± 6.2 U/l, respectively. Postoperative semen parameters were similar. However, in the high hormone group there was greater use of any type of assisted reproduction (78.4% vs 54.8%, p = 0.0028). On multivariate analysis follicle-stimulating hormone 10 U/l or greater (OR 3.02, 95% CI 1.34-6.83) and vasoepididymostomy that was bilateral or to a solitary testis (OR 3.26, 95% CI 1.09-9.69) was associated with greater assisted reproduction use. We evaluated preoperative follicle-stimulating hormone as a predictor of reproductive outcome in men with suspected subfertility who underwent vasectomy reversal. Increased follicle-stimulating hormone was associated with a higher rate of assisted reproduction even after controlling for confounding covariates. Thus, men with increased follicle-stimulating hormone should be counseled on the increased likelihood of needing assisted reproduction to achieve pregnancy after vasectomy reversal. Copyright © 2011 American Urological Association Education and Research, Inc

  13. Do prescription stimulants increase the risk of adverse cardiovascular events?: A systematic review

    Directory of Open Access Journals (Sweden)

    Westover Arthur N

    2012-06-01

    Full Text Available Abstract Background There is increasing concern that prescription stimulants may be associated with adverse cardiovascular events such as stroke, myocardial infarction, and sudden death. Public health concerns are amplified by increasing use of prescription stimulants among adults. Methods The objective of this study was to conduct a systematic review of the evidence of an association between prescription stimulant use and adverse cardiovascular outcomes. PUBMED, MEDLINE, EMBASE and Google Scholar searches were conducted using key words related to these topics (MESH: ADHD; Adults; Amphetamine; Amphetamines; Arrhythmias, Cardiac; Cardiovascular Diseases; Cardiovascular System; Central Nervous Stimulants; Cerebrovascular; Cohort Studies; Case–control Studies; Death; Death, Sudden, Cardiac; Dextroamphetamine; Drug Toxicity; Methamphetamine; Methylphenidate; Myocardial Infarction; Stimulant; Stroke; Safety. Eligible studies were population-based studies of children, adolescents, or adults using prescription stimulant use as the independent variable and a hard cardiovascular outcome as the dependent variable. Results Ten population-based observational studies which evaluated prescription stimulant use with cardiovascular outcomes were reviewed. Six out of seven studies in children and adolescents did not show an association between stimulant use and adverse cardiovascular outcomes. In contrast, two out of three studies in adults found an association. Conclusions Findings of an association between prescription stimulant use and adverse cardiovascular outcomes are mixed. Studies of children and adolescents suggest that statistical power is limited in available study populations, and the absolute risk of an event is low. More suggestive of a safety signal, studies of adults found an increased risk for transient ischemic attack and sudden death/ventricular arrhythmia. Interpretation was limited due to differences in population, cardiovascular outcome

  14. X-ray induced degradation of DNA in radiosensitive mutants of Anacystis nidulans

    Energy Technology Data Exchange (ETDEWEB)

    Zhukas, K I; Vorontsova, G V; Groshev, V V; Shestakov, S V [Moskovskij Gosudarstvennyj Univ. (USSR). Biologo-Pochvennyj Fakul' tet

    1975-01-01

    In irradiated Cyanophyceae (Anacystis nidulans) cells there occurs a process of DNA degeneration to acid-soluble products which is linked with protein synthesis and stimulated by caffeine and acriflavine. The degree of DNA degeneration increases with x-ray dose, is not very dependent on the composition of the incubation medium and is weakly linked with photosynthesis. In the cells of a radiation-resistant mutant the degree of DNA degeneration is slighter, and in the cells of radiosensitive mutants larger, than in ordinary cells. The role of DNA degradation in the radiation detruction of cells is discussed.

  15. X-ray induced degradation of DNA in radiosensitive mutants of Anacystis nidulans x-rays

    International Nuclear Information System (INIS)

    Zhukas, K.I.; Vorontsova, G.V.; Groshev, V.V.; Shestakov, S.V.

    1975-01-01

    In irradiated Cyanophyceae (Anacystis nidulans) cells there occurs a process of DNA degeneration to acid-soluble products which is linked with protein synthesis and stimulated by caffeine and acriflavine. The degree of DNA degeneration increases with X-ray dose, is not very dependent on the composition of the incubation medium and is weakly linked with photosynthesis. In the cells of a radiation-resistant mutant the degree of DNA degeneration is slighter, and in the cells of radiosensitive mutants larger, than in ordinary cells. The role of DNA degradation in the radiation detruction of cells is discussed. (author)

  16. Radiosensitizers action on Iodine 131 therapeutical effect

    International Nuclear Information System (INIS)

    Agote, Marcos; Kreimann, Erica L.; Bocanera, Laura V.; Dagrosa, Maria A.; Juvenal, Guillermo J.; Pisarev, Mario A.

    1999-01-01

    Present studies were aimed to research the possible application of a radiosensitizer, nicotinamide, to increase the therapeutical effect of radioiodine. There were used goitrous and normal rats with growing dose of Iodine 131, with and without simultaneous treatment with nicotinamide. The obtained results show that the nicotinamide treatment importantly increases the thyroid radio destructive effect induced by radioiodine. Under these experimental conditions, nicotinamide induces to a significant increase of thyroid vascularisation, without changes in the proteins ADP-ribosylation activity. These results show, for the first time, the radiosensitizer effect of nicotinamide in front of Iodine 131 and give the possibility of using it in the treatment of hyperthyroid or thyroid difference cancer patients. (author)

  17. Brainstem stimulation increases functional connectivity of basal forebrain-paralimbic network in isoflurane-anesthetized rats.

    Science.gov (United States)

    Pillay, Siveshigan; Liu, Xiping; Baracskay, Péter; Hudetz, Anthony G

    2014-09-01

    Brain states and cognitive-behavioral functions are precisely controlled by subcortical neuromodulatory networks. Manipulating key components of the ascending arousal system (AAS), via deep-brain stimulation, may help facilitate global arousal in anesthetized animals. Here we test the hypothesis that electrical stimulation of the oral part of the pontine reticular nucleus (PnO) under light isoflurane anesthesia, associated with loss of consciousness, leads to cortical desynchronization and specific changes in blood-oxygenation-level-dependent (BOLD) functional connectivity (FC) of the brain. BOLD signals were acquired simultaneously with frontal epidural electroencephalogram before and after PnO stimulation. Whole-brain FC was mapped using correlation analysis with seeds in major centers of the AAS. PnO stimulation produced cortical desynchronization, a decrease in δ- and θ-band power, and an increase in approximate entropy. Significant increases in FC after PnO stimulation occurred between the left nucleus Basalis of Meynert (NBM) as seed and numerous regions of the paralimbic network. Smaller increases in FC were present between the central medial thalamic nucleus and retrosplenium seeds and the left caudate putamen and NBM. The results suggest that, during light anesthesia, PnO stimulation preferentially modulates basal forebrain-paralimbic networks. We speculate that this may be a reflection of disconnected awareness.

  18. Stimulation of GPR30 increases release of EMMPRIN-containing microvesicles in human uterine epithelial cells.

    Science.gov (United States)

    Burnett, Lindsey A; Light, Mallory M; Mehrotra, Pavni; Nowak, Romana A

    2012-12-01

    Uterine remodeling is highly dependent on the glycosylated transmembrane protein extracellular matrix metalloproteinase (MMP) inducer (EMMPRIN). Previous studies indicate estradiol can increase EMMPRIN expression in uterine cells and promote subsequent induction of MMP production. The aim of this study was to investigate the role of G protein-coupled receptor 30 (GPR30) stimulation on EMMPRIN microvesicle release in the human uterine epithelial cell line hTERT-EEC (EECs). We examined EMMPRIN release by human EECs in response to GPR30 stimulation by microvesicle isolation, Western blot, and immunocytochemistry. We employed a pharmacological approach using the GPR30-selective agonist G1 and the antagonist G15 to determine the receptor specificity of this response. We demonstrated GPR30 expression in EECs and release of EMMPRIN in microvesicles in response to stimulation of GPR30. G1, estradiol, and cholera toxin stimulated EMMPRIN release in microvesicles as detected by Western blot and immunocytochemistry, indicating that stimulation of GPR30 can induce EMMPRIN microvesicle release. These data indicate that EMMPRIN release in microvesicles can be mediated by stimulation of GPR30 in human EECs, suggesting that inappropriate stimulation or expression of this receptor may be significant in uterine pathology.

  19. Radiosensitization of mouse skin by oxygen and depletion of glutathione

    International Nuclear Information System (INIS)

    Stevens, Graham; Joiner, Michael; Joiner, Barbara; Johns, Helen; Denekamp, Juliana

    1995-01-01

    Purpose: To determine the oxygen enhancement ratio (OER) and shape of the oxygen sensitization curve of mouse foot skin, the extent to which glutathione (GSH) depletion radiosensitized skin, and the dependence of such sensitization on the ambient oxygen tension. Methods and Materials: The feet of WHT mice were irradiated with single doses of 240 kVp x-rays while mice were exposed to carbogen or gases with oxygen/nitrogen mixtures containing 8-100% O 2 . The anoxic response was obtained by occluding the blood supply to the leg of anesthetized mice with a tourniquet, surrounding the foot with nitrogen, and allowing the mice to breathe 10% O 2 . Further experiments were performed to assess the efficacy of this method to obtain an anoxic response. Radiosensitivity of skin was assessed using the acute skin-reaction assay. Glutathione levels were modified using two schedules of dl-buthionine sulphoximine (BSO) and diethylmaleate (DEM), which were considered to produce extensive and intermediate levels of GSH depletion in the skin of the foot during irradiation. Results: Carbogen caused the greatest radiosensitization of skin, with a reproducible enhancement of 2.2 relative to the anoxic response. The OER of 2.2 is lower than other reports for mouse skin. This may indicate that the extremes of oxygenation were not produced, although there was no direct evidence for this. When skin radiosensitivity was plotted against the logarithm of the oxygen tension in the ambient gas, a sigmoid curve with a K value of 17-21% O 2 in the ambient gas was obtained. Depletion of GSH caused minimal radiosensitization when skin was irradiated under anoxic or well-oxygenated conditions. Radiosensitization by GSH depletion was maximal at intermediate oxygen tensions of 10-21% O 2 in the ambient gas. Increasing the extent of GSH depletion led to increasing radiosensitization, with sensitization enhancement ratios of 1.2 and 1.1, respectively, for extensive and intermediate levels of GSH

  20. DNA repair , cell repair and radiosensitivity

    International Nuclear Information System (INIS)

    Zhestyanikov, V.D.

    1983-01-01

    Data obtained in laboratory of radiation cytology and literature data testifying to a considerable role of DNA repair in cell sensitivity to radiation and chemical DNA-tropic agents have been considered. Data pointing to the probability of contribution of inducible repair of DNA into plant cells sensitivity to X-rays are obtained. Certain violations of DNA repair do not result in the increase of radiosensitivity. It is assumed that in the cases unknown mechanisms of DNA repair operate

  1. Radiosensitivity of neuroblastoma

    International Nuclear Information System (INIS)

    Deacon, J.M.; Wilson, P.; Steel, G.G.

    1985-01-01

    Neuroblastoma is known to be clinically radioresponsive: it is possible to obtain local tumour control with relatively small doses of radiation. The main therapeutic problem, however, is one of metastatic disease, where in spite of modern combination chemotherapy, the prognosis remains poor. Systemic therapy with either drugs or radiation is dose-limited by toxicity to bone marrow stem cells. However, the advent of new technology which enables tumour cells to be removed from infiltrated marrow prior to autologous bone marrow ''rescue'' allows dose escalation, and makes the use of systemic irradiation in the treatment of stage IV disease feasible. The objective of this study was to investigate the radiobiology of neuroblastoma in detail, including intrinsic cellular radiosensitivity, repair capacity, and extrinsic dose-modifying factors which may affect tumour response in vivo. Cells at three levels of organisation were used: single cell suspensions multicellular tumour spheroids; and xenografts grown in immune-suppressed mice

  2. The molecular basis of radiosensitivity

    International Nuclear Information System (INIS)

    McMillan, T.J.

    1989-01-01

    This paper considers how DNA damage induced by ionising radiation is processed within the cell. The current view of radiobiology is discussed. The author explains the molecular processes that underlie the differences in radiosensitivity

  3. Predictive radiosensitivity tests in human lymphocytes

    International Nuclear Information System (INIS)

    Di Giorgio, Marina; Vallerga, Maria B.; Taja, Maria R.; Sardi, M.; Busto, E.; Mairal, L.; Roth, B.; Menendez, P.; Bonomi, M.

    2004-01-01

    Individual radiosensitivity is an inherent characteristic, associated with an abnormally increased reaction to ionising radiation of both the whole body and cells derived from body tissues. Human population is not uniform in its radiation sensitivity. Radiosensitive sub-groups exist, which would suffer an increased incidence of both deterministic and stochastic effects. Clinical studies have suggested that a large part of the spectrum of normal tissue reaction may be due to differences in individual radiosensitivity. The identification of such sub-groups should be relevant for radiation therapy and radiation protection purposes. It is suggested that DNA repair mechanisms are involved. Consequently, the characterization of DNA repair in lymphocytes through cytokinesis blocked micronucleus (MN) and alkaline single-cell microgel electrophoresis (comet) assays could be a suitable approache to evaluate individual radiosensitivity in vitro. The aims of this study were: 1) To assess the in vitro radiosensitivity of peripheral blood lymphocytes from two groups of cancer patients (prospectively and retrospectively studied), using MN and comet assays, in comparison with the clinical radiation reaction and 2) To test the predictive potential of both techniques for the identification of radiosensitivity sub-groups. 38 cancer patients receiving radiation therapy were enrolled in this study. 19 patients were evaluated prior, mid-way and on completion of treatment (prospective group) and 19 patients were evaluated about 6-18 month after radiotherapy (retrospective group). Cytogenetic data from the prospective group were analysed using a mathematical model to evaluate the attenuation of the cytogenetic effect as a function of the time between a single exposure and blood sampling, estimating a cytogenetic recovery factor k. In the retrospective group, blood samples were irradiated in vitro with 0 (control) or 2 Gy and evaluated using MN test. Cytogenetic data were analysed

  4. PERCEPTION STIMULATION GROUP ACTIVITY THERAPY INCREASES E CHILDREN SELF ESTEEM AT PRISON

    Directory of Open Access Journals (Sweden)

    Ah. Yusuf

    2017-07-01

    Full Text Available Introduction: Prison is societal implementer unit which accommodate care and develop the delinquent children. It was recorded that 57% of children at Blitar Child Prison undergo some self concept problems such as low self esteem. This was caused by some factors such as society’s stigmatization toward criminals, development pattern and education, and less support from family. If the self esteem problem is not being overcome soon, the children may  fell useless, disable to control their self and recrime when they are back to society. The objective of this study was to analyze the influence of  GAT (Group Activity Therapy perception stimulation in increasing the children  self esteem at prison. Method:  A quasy experimental pre post control design was used in this study. Samples were recruited by using total sampling and there were 22 samples as on inclusion criteria. The independent variable was GAT perception stimulation and the dependent variable was increasing self esteem of these childen. Data were collected by using questionnare and analyzed by using Wilcoxon Signed Ranks Test and Mann Whitney U Test with the significance level α≤0.05.Result:  The result showed that controlled group has significance level was p=0.654, it is mean there was no self esteem change before and after GAT perception stimulation was given. Whereas treatment group has significance level was p=0.001, it revealed that  there was self esteem change before and after GAT perception stimulation was given. The result of Mann Whitney U Test showed p=0.000 which means was accepted. Discussion: It can be concluded that perception stimulation can increase the children self esteem at prison. Further studies are recommended to study the effect of GAT perception stimulation modified by skill therapy in increasing children self esteem in prison.

  5. Studies on Drosophila radiosensitive strains

    International Nuclear Information System (INIS)

    Varentsova, E.P.; Zakharov, I.A.

    1976-01-01

    45 of radiosensitive strains of Drosophila melanogaster were isolated by Curly/Lobe technique after EMS treatment of Livadia population males. The lethality of non-Curly late larvae after gamma-irradiation (4000r) characterized radiosensitivity strains. Most of them exhibited higher frequency of the spontaneous dominant lethals (up to 69%). The males of 6 strains were semi-sterile. 5 of these strains exhibited higher frequency of X-chromosome non-disjunction

  6. Enhanced Radiosensitivity of Tumor Cells Treated with Vanadate in Vitro

    International Nuclear Information System (INIS)

    Lee, Myung Za; Lee, Won Young

    1994-01-01

    Intracellular ions which have a major role in cellular function have been reported to affect repair of radiation damage. Recently it has been reported that ouabain sensitizes A549 tumor cells hut not CCL-120 normal cells to radiation. Ouabain inhibits the Na+-K+-pump rapidly thus it increases intracellular Na concentration. Vanadate which is distributed extensively in almost all living organisms in known to be a Na+-K+-ATPase inhibitors. This study was performed to see any change in radiosensitivity of tumor cell by vanadate and any role of Na+-K+-ATPase in radiosensitization. Experiments have been carried out by pretreatment with vanadate in human cell line(A549, JMG) and mouse cell line(L1210, spleen). For the cell survival MTT assay was performed for A549 and JMG cell and trypan blue dye exclusion test for L120, and spleen cells. Measurements of Na+-K+-ATPase activity in control, vanadate treated cell, radiation treated cell (9 Gy for A549 and JMG, 2 Gy for L1201, spleen), and combined 10-6 M vanadate and radiation treated cells were done. The results were summarized as follows. 1. L1210 cell was most radiosensitive, and spleen cell and JMG cell were intermediate, and A549 cell was least radiosensitive. 2. Minimum or cytotoxicity was seen with vanadate below concentration of 10-6 M. 3. In A549 cells there was a little change in radiosensitivity with treatment of vanadate. However radiation sensitization was shown in low dose level of radiation i. E. 2-Gy. In JMG cells no change in radiosensitivity was noted. Both L1210 and spleen cell had radiosensitization but change was greater in tumor cell. 4. Na+-K+-ATPase activity was inhibited significantly in tumor cell by treatment of vanadate. 5. Radiation itself inhibited Na+-K+-ATPase activity of tumor cell with high Na+- K+-ATPase concention. Increase in radiosensitivity by vanadate was closely associated with original Na+-K+-ATPase contents. From the above results vanadate had little cytotoxicity and it sensitized

  7. Radiation stimulation of yeast crops for increasing output of alcohol and baker yeasts

    International Nuclear Information System (INIS)

    Vlad, E.; Marsheu, P.

    1974-01-01

    The purpose of this study was to stimulate by gamma radiation the existing commercial types of yeast so as to obtain yeasts that would better reflect the substrate and have improved reproductive capacity. The experiments were conducted under ordinary conditions using commercial yeasts received from one factory producing alcohol and bakery yeasts and isolated as pure cultures. Irradiating yeast cultures with small doses (up to 10 krad) was found to stimulate the reproduction and fermenting activity of yeast cells as manifested in increased accumulation of yeast biomass and greater yield of ethyl alcohol. (E.T.)

  8. Non-invasive brain stimulation targeting the right fusiform gyrus selectively increases working memory for faces.

    Science.gov (United States)

    Brunyé, Tad T; Moran, Joseph M; Holmes, Amanda; Mahoney, Caroline R; Taylor, Holly A

    2017-04-01

    The human extrastriate cortex contains a region critically involved in face detection and memory, the right fusiform gyrus. The present study evaluated whether transcranial direct current stimulation (tDCS) targeting this anatomical region would selectively influence memory for faces versus non-face objects (houses). Anodal tDCS targeted the right fusiform gyrus (Brodmann's Area 37), with the anode at electrode site PO10, and cathode at FP2. Two stimulation conditions were compared in a repeated-measures design: 0.5mA versus 1.5mA intensity; a separate control group received no stimulation. Participants completed a working memory task for face and house stimuli, varying in memory load from 1 to 4 items. Individual differences measures assessed trait-based differences in facial recognition skills. Results showed 1.5mA intensity stimulation (versus 0.5mA and control) increased performance at high memory loads, but only with faces. Lower overall working memory capacity predicted a positive impact of tDCS. Results provide support for the notion of functional specialization of the right fusiform regions for maintaining face (but not non-face object) stimuli in working memory, and further suggest that low intensity electrical stimulation of this region may enhance demanding face working memory performance particularly in those with relatively poor baseline working memory skills. Published by Elsevier Inc.

  9. ANODAL TRANSCRANIAL DIRECT CURRENT STIMULATION (TDCS) INCREASES ISOMETRIC STRENGTH OF SHOULDER ROTATORS MUSCLES IN HANDBALL PLAYERS.

    Science.gov (United States)

    Hazime, Fuad Ahmad; da Cunha, Ronaldo Alves; Soliaman, Renato Rozenblit; Romancini, Ana Clara Bezerra; Pochini, Alberto de Castro; Ejnisman, Benno; Baptista, Abrahão Fontes

    2017-06-01

    Weakness of the rotator cuff muscles can lead to imbalances in the strength of shoulder external and internal rotators, change the biomechanics of the glenohumeral joint and predispose an athlete to injury. Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that has demonstrated promising results in a variety of health conditions. However few studies addressed its potential approach in the realm of athletics. The purpose of this study was to investigate if transcranial direct current stimulation (tDCS) technique increases the isometric muscle strength of shoulder external and internal rotators in handball athletes. Randomized, double-blind, placebo-controlled, crossover study. Eight female handball players aged between 17 and 21 years (Mean=19.65; SD=2.55) with 7.1 ± 4.8 years of experience in training, participating in regional and national competitions were recruited. Maximal voluntary isometric contraction (MVIC) of shoulder external and internal rotator muscles was evaluated during and after 30 and 60 minutes post one session of anodal and sham current (2mA; 0.057mA/cm 2 ) with a one-week interval between stimulations. Compared to baseline, MVIC of shoulder external and internal rotators significantly increased after real but not sham tDCS. Between-group differences were observed for external and internal rotator muscles. Maximal voluntary isometric contraction of external rotation increased significantly during tDCS, and 30 and 60 minutes post-tDCS for real tDCS compared to that for sham tDCS. For internal rotation MVIC increased significantly during and 60 minutes post-tDCS. The results indicate that transcranial direct current stimulation temporarily increases maximal isometric contractions of the internal and external rotators of the shoulder in handball players. 2.

  10. Increased rate of repair of ultraviolet-induced DNA strand breaks in mitogen stimulated lymphocytes

    Energy Technology Data Exchange (ETDEWEB)

    Hamlet, S.M.; Lavin, M.F.; Jennings, P.A. (Queensland Univ., St. Lucia (Australia). Dept. of Biochemistry; Queensland Univ., St. Lucia (Australia). Dept. of Veterinary Pathology; Queensland Univ. St. Lucia (Australia). Dept. of Public Health)

    1982-05-01

    Previous results have shown that phytohaemagglutinin-stimulated bovine lymphocytes exhibit a peak of ultraviolet-induced DNA repair synthesis 3 to 4 days after addition of mitogen. The level of repair synthesis was approximately tenfold higher than that in unstimulated lymphocytes. These studies have been extended to examine the rate of repair of strand breaks in U.V.-irradiated bovine lymphocytes. The extent of breakage of DNA was shown to be the same in mitogen-stimulated and unstimulated lymphocytes from two breeds of cattle, when determined by sedimentation of nucleoids on sucrose gradients. However, in mitogen-stimulated cells the time taken to repair DNA strand breaks was 6 hours compared with 12 hours in stationary phase lymphocytes after a U.V. dose of 5 J/m/sup 2/. These results suggest that the increased rate of repair of strand breaks is due to the induction of enzymes involved at the post-incision stage of DNA repair. Thus the increased level of repair synthesis observed in earlier work correlates with an increased rate of repair of DNA strand breaks in phytohaemagglutinin-stimulated bovine lymphocytes.

  11. Increased rate of repair of ultraviolet-induced DNA strand breaks in mitogen stimulated lymphocytes

    International Nuclear Information System (INIS)

    Hamlet, S.M.; Lavin, M.F.; Jennings, P.A.; Queensland Univ., St. Lucia; Queensland Univ. St. Lucia

    1982-01-01

    Previous results have shown that phytohaemagglutinin-stimulated bovine lymphocytes exhibit a peak of ultraviolet-induced DNA repair synthesis 3 to 4 days after addition of mitogen. The level of repair synthesis was approximately tenfold higher than that in unstimulated lymphocytes. These studies have been extended to examine the rate of repair of strand breaks in U.V.-irradiated bovine lymphocytes. The extent of breakage of DNA was shown to be the same in mitogen-stimulated and unstimulated lymphocytes from two breeds of cattle, when determined by sedimentation of nucleoids on sucrose gradients. However, in mitogen-stimulated cells the time taken to repair DNA strand breaks was 6 hours compared with 12 hours in stationary phase lymphocytes after a U.V. dose of 5 J/m 2 . These results suggest that the increased rate of repair of strand breaks is due to the induction of enzymes involved at the post-incision stage of DNA repair. Thus the increased level of repair synthesis observed in earlier work correlates with an increased rate of repair of DNA strand breaks in phytohaemagglutinin-stimulated bovine lymphocytes. (author)

  12. Electrical stimulation of schwann cells promotes sustained increases in neurite outgrowth.

    Science.gov (United States)

    Koppes, Abigail N; Nordberg, Andrea L; Paolillo, Gina M; Goodsell, Nicole M; Darwish, Haley A; Zhang, Linxia; Thompson, Deanna M

    2014-02-01

    Endogenous electric fields are instructive during embryogenesis by acting to direct cell migration, and postnatally, they can promote axonal growth after injury (McCaig 1991, Al-Majed 2000). However, the mechanisms for these changes are not well understood. Application of an appropriate electrical stimulus may increase the rate and success of nerve repair by directly promoting axonal growth. Previously, DC electrical stimulation at 50 mV/mm (1 mA, 8 h duration) was shown to promote neurite outgrowth and a more pronounced effect was observed if both peripheral glia (Schwann cells) and neurons were co-stimulated. If electrical stimulation is delivered to an injury site, both the neurons and all resident non-neuronal cells [e.g., Schwann cells, endothelial cells, fibroblasts] will be treated and this biophysical stimuli can influence axonal growth directly or indirectly via changes to the resident, non-neuronal cells. In this work, non-neuronal cells were electrically stimulated, and changes in morphology and neuro-supportive cells were evaluated. Schwann cell response (morphology and orientation) was examined after an 8 h stimulation over a range of DC fields (0-200 mV/mm, DC 1 mA), and changes in orientation were observed. Electrically prestimulating Schwann cells (50 mV/mm) promoted 30% more neurite outgrowth relative to co-stimulating both Schwann cells with neurons, suggesting that electrical stimulation modifies Schwann cell phenotype. Conditioned medium from the electrically prestimulated Schwann cells promoted a 20% increase in total neurite outgrowth and was sustained for 72 h poststimulation. An 11-fold increase in nerve growth factor but not brain-derived neurotrophic factor or glial-derived growth factor was found in the electrically prestimulated Schwann cell-conditioned medium. No significant changes in fibroblast or endothelial morphology and neuro-supportive behavior were observed poststimulation. Electrical stimulation is widely used in

  13. Effect of hypothermia on radiosensitization

    International Nuclear Information System (INIS)

    Nias, A.H.W.; Perry, P.; Photiou, A.; Reghebi, K.

    1986-01-01

    The blood supply and oxygen tension have been measured in C3H mouse mammary tumours under hypothermia and hyperbaric oxygen, and the enhancement of radiosensitivity by hyperbaric oxygen has been estimated in mice irradiated at different temperatures with and without anaesthesia. Measurement of xenon-133 clearance showed that the blood supply of a tumour tended to increase when anaesthetized mice became hypothermic. Oxygen cathode data showed that the oxygen tension tended to be relatively higher in tumours and lower in subcutaneous tissue when mice exposed to hyperbaric oxygen became hypothermic under anaesthesia. Hyperbaric oxygen enhanced the radiation response of the tumour in terms of an increase in regrowth delay by a factor of 1.7 when the mice had been anaesthetized, whether or not they became hypothermic. A lower factor of 1.4 was obtained without anaesthesia although induced hypothermia increased the response to a small extent. The authors conclude that anaesthesia and hypothermia affect oxygen metabolism in tumours by different mechanisms. (author)

  14. Illicit stimulant use in humans is associated with a long-term increase in tremor.

    Directory of Open Access Journals (Sweden)

    Stanley C Flavel

    Full Text Available Use of illicit stimulants such as methamphetamine, cocaine, and ecstasy is a significant health problem. The United Nations Office on Drugs and Crime estimates that 14-57 million people use stimulants each year. Chronic use of illicit stimulants can cause neurotoxicity in animals and humans but the long-term functional consequences are not well understood. Stimulant users self-report problems with tremor whilst abstinent. Thus, the aim of the current study was to investigate the long-term effect of stimulant use on human tremor during rest and movement. We hypothesized that individuals with a history of stimulant use would exhibit abnormally large tremor during rest and movement. Tremor was assessed in abstinent ecstasy users (n = 9; 22 ± 3 yrs and abstinent users of amphetamine-like drugs (n = 7; 33 ± 9 yrs and in two control groups: non-drug users (n = 23; 27 ± 8 yrs and cannabis users (n = 12; 24 ± 7 yrs. Tremor was measured with an accelerometer attached to the index finger at rest (30 s and during flexion and extension of the index finger (30 s. Acceleration traces were analyzed with fast-Fourier transform. During movement, tremor amplitude was significantly greater in ecstasy users than in non-drug users (frequency range 3.9-13.3 Hz; P<0.05, but was unaffected in cannabis users or users of amphetamine-like drugs. The peak frequency of tremor did not significantly differ between groups nor did resting tremor. In conclusion, abstinent ecstasy users exhibit an abnormally large tremor during movement. Further work is required to determine if the abnormality translates to increased risk of movement disorders in this population.

  15. Indomethacin increases the formation of lipoxygenase products in calcium ionophore stimulated human neutrophils.

    Science.gov (United States)

    Docherty, J C; Wilson, T W

    1987-10-29

    Arachidonic acid metabolism in human neutrophils stimulated in vitro with the calcium ionophore A23187 was studied using combined HPLC and radioimmunoassays. Indomethacin (0.1 and 1.0 microM) caused a 300% increase in LTB4 formation in neutrophils stimulated with A23187. 5-, 12- and 15-HETE levels were also increased. In the presence of exogenous arachidonic acid 1.0 microM Indomethacin caused a 37% increase in LTB4 formation. Acetyl Salicylic Acid and Ibuprofen had no effect on the formation of lipoxygenase metabolites. The effect of indomethacin on LTB4 formation does not appear to be due to a simple redirection of substrate arachidonic acid from the cyclooxygenase to the lipoxygenase pathways.

  16. Ovarian stimulation with follicle-stimulating hormone under increasing or minimal concentration of progesterone in dairy cows.

    Science.gov (United States)

    El-Sherry, T M; Matsui, M; Kida, K; Miyamoto, A; Megahed, G A; Shehata, S H; Miyake, Y-I

    2010-03-01

    The objective of this study was to investigate the effect of the presence or absence of Corpus luteum (CL) on the follicular population during superstimulation in dairy cows (Holstein-Friesian cattle). Animals were divided into two groups as follows: (1) Growing CL group (G1): Cows (n=7) received a total dose of 28 Armour units (AU) follicle-stimulating hormone (FSH) through the first 4 d (twice daily) after spontaneous ovulation (Day 0). (2) CL Absence group (G2): Cows (n=10) received prostaglandin F(2alpha) (PGF(2alpha)) at 9 or 10 d after ovulation. After 36h, all the follicles (larger than 5mm) were aspirated (Day 0). The FSH treatment started 24h after aspiration and continued for 4 d. The number of small (3 to or = 8mm) follicles was examined on Days 1, 3, and 5 in all groups. Blood samples were collected daily for 5 d, and progesterone (P(4)), estradiol (E(2)), insulin-like growth factor-1 (IGF-1), and growth hormone (GH) in plasma were measured by enzyme immunoassays. The results showed that in G1, the P(4) level increased gradually from 0.5 ng/mL at Day 1 to 2 ng/mL at Day 5, whereas in G2, the P(4) level was completely below 0.5 ng/mL. All cows of the G2 group showed an increase of E(2) at Day 3 or Day 4 followed by an increase of IGF-1 within 24h, while GH increased concomitantly with the E(2) increase in 8 of 10 trials. On the other hand, cows of the G1 group showed neither E(2) nor IGF-1 increase. Moreover, at the end of the treatment, the number of follicles in the G2 group was significantly increased compared with that of the G1 group (22.8+/-2.0 vs. 11.6+/-2.0). In conclusion, low P(4) level during FSH treatment enhanced multiple follicular growth and E(2) secretion, which was followed by increase of IGF-1 and GH. Therefore, the absence of the CL may play a critical role in the superovulation response by controlling the number of growing follicles. Copyright 2010 Elsevier Inc. All rights reserved.

  17. Intermittent Theta Burst Stimulation Increases Reward Responsiveness in Individuals with Higher Hedonic Capacity.

    Science.gov (United States)

    Duprat, Romain; De Raedt, Rudi; Wu, Guo-Rong; Baeken, Chris

    2016-01-01

    Repetitive transcranial magnetic stimulation over the left dorsolateral prefrontal cortex (DLPFC) has been documented to influence striatal and orbitofrontal dopaminergic activity implicated in reward processing. However, the exact neuropsychological mechanisms of how DLPFC stimulation may affect the reward system and how trait hedonic capacity may interact with the effects remains to be elucidated. In this sham-controlled study in healthy individuals, we investigated the effects of a single session of neuronavigated intermittent theta burst stimulation (iTBS) on reward responsiveness, as well as the influence of trait hedonic capacity. We used a randomized crossover single session iTBS design with an interval of 1 week. We assessed reward responsiveness using a rewarded probabilistic learning task and measured individual trait hedonic capacity (the ability to experience pleasure) with the temporal experience of pleasure scale questionnaire. As expected, the participants developed a response bias toward the most rewarded stimulus (rich stimulus). Reaction time and accuracy for the rich stimulus were respectively shorter and higher as compared to the less rewarded stimulus (lean stimulus). Active or sham stimulation did not seem to influence the outcome. However, when taking into account individual trait hedonic capacity, we found an early significant increase in the response bias only after active iTBS. The higher the individual's trait hedonic capacity, the more the response bias toward the rich stimulus increased after the active stimulation. When taking into account trait hedonic capacity, one active iTBS session over the left DLPFC improved reward responsiveness in healthy male participants with higher hedonic capacity. This suggests that individual differences in hedonic capacity may influence the effects of iTBS on the reward system.

  18. Cell proliferation and radiosensitivity of cow lymphocytes in culture

    International Nuclear Information System (INIS)

    Modave, C.; Fabry, L.; Leonard, A.

    1982-01-01

    The harlequin-staining technique has been used to study, after PHA-stimulation, the cell proliferation of cow lymphocytes in culture and to assess the radiosensitivity in first mitosis cells. At the 48 h fixation time, only 34% of the cells are in first mitosis whereas 55% are already in second and 11% in third mitosis. The exposure of cow lymphocytes to 200 rad X-rays result in the production of 16% dicentric chromosomes in first mitosis cells [fr

  19. Human θ burst stimulation enhances subsequent motor learning and increases performance variability.

    Science.gov (United States)

    Teo, James T H; Swayne, Orlando B C; Cheeran, Binith; Greenwood, Richard J; Rothwell, John C

    2011-07-01

    Intermittent theta burst stimulation (iTBS) transiently increases motor cortex excitability in healthy humans by a process thought to involve synaptic long-term potentiation (LTP), and this is enhanced by nicotine. Acquisition of a ballistic motor task is likewise accompanied by increased excitability and presumed intracortical LTP. Here, we test how iTBS and nicotine influences subsequent motor learning. Ten healthy subjects participated in a double-blinded placebo-controlled trial testing the effects of iTBS and nicotine. iTBS alone increased the rate of learning but this increase was blocked by nicotine. We then investigated factors other than synaptic strengthening that may play a role. Behavioral analysis and modeling suggested that iTBS increased performance variability, which correlated with learning outcome. A control experiment confirmed the increase in motor output variability by showing that iTBS increased the dispersion of involuntary transcranial magnetic stimulation-evoked thumb movements. We suggest that in addition to the effect on synaptic plasticity, iTBS may have facilitated performance by increasing motor output variability; nicotine negated this effect on variability perhaps via increasing the signal-to-noise ratio in cerebral cortex.

  20. ATM-induced radiosensitization in vitro and in vivo

    International Nuclear Information System (INIS)

    Choi, E. K.; Ahn, S. D.; Rhee, Y. H.; Chung, H. S.; Ha, S. W; Song, C. W.; Griffin, R. J.; Park, H. J.

    2003-01-01

    It has been known that ATM plays a central role in response of cells to ionizing radiation by enhancing DNA repair. We have investigated the feasibility of increasing radiosensitivity of tumor cells with the use of ATM inhibitors such as caffeine, pentoxifylline and wortmannin. Human colorectal cancer RKO.C cells and RKO-ATM cells (RKO cells overexpressing ATM) were used in the present study. The clonogenic cell survival in vitro indicated that RKO-ATM cells were markedly radioresistant than RKO.C cells. Treatment with 3 mM of caffeine significantly increased the radiosensitivity of cells, particulary the RKO-ATM cells, so that the radiosensitivity of RKO.C cells and RKO-ATM cells were almost similar. The radiation induced G2/M arrest in RKO-ATM cells was noticeably longer than that in RKO.C cells and caffeine treatment significantly reduced the length of the radiation induced G2/M arrest in both RKO.C and RKO-ATM cells. Pentoxifylline and wortmannin were also less effective than caffeine to radiosensitize RKO.C or RKO-ATM cells. However, wortmannin was more effective than caffeine against human lung adenocarcinoma A549 cells indicating the efficacy of ATM inhibitor to increase radiosensitivity is cell line dependent. For in vivo study, RKO.C cells were injected s.c. into the hind-leg of BALB/c-nuslc nude mice, and allowed to grow to 130mm3 tumor. The mice were i.p. injected with caffeine solution or saline and the tumors irradiated with 10 Gy of X-rays. The radiation induced growth delay was markedly increased by 1-2 mg/g of caffeine. It was concluded that caffeine increases radiosensitivity of tumor cells by inhibiting ATM kinase function, thereby inhibiting DNA repair, that occurs during the G2/M arrest after radiation

  1. Parotid radiosensitivity changes: a temporal relation to glandular circadian rhythms

    International Nuclear Information System (INIS)

    El-Mofty, S.K.; Hovenga, T.L.; Russell, J.E.; Simmons, D.J.

    1982-01-01

    The radiosensitivity of the rat parotid gland to X-radiation increased considerably towards the end of the daily light span (0800-2000 hours) and to a lesser extent before the onset of that period. The major sensitivity peak occurred at 1600 hours and coincides with a diurnal nadir in the rates of protein and RNA synthesis. The minor peak occurred at 0400 hours and was temporally related to a daily period of maximal secretory activity. It is suggested that suboptimal repair and secretion-linked cellular perturbations might contribute to the pathogenesis of the circadian increases in radiosensitivity of parotid cells. (author)

  2. Synergism between two helper cell subpopulations characterized by different radiosensitivity and nylon adherence

    International Nuclear Information System (INIS)

    Agarossi, G.; Mancini, C.; Doria, G.

    1981-01-01

    The present work extends our previous results on the radiosensitivity of the helper cell function. Two helper cell subpopulations, 1 radiosensitive and the other radioresistant, have been demonstrated in the spleen of mice at different times after priming with HRBC. The radiosensitive subpopulation increases with the increasing time interval between carrier-priming and irradiation. The 2 cell subpopulations have been further characterized by different nylon adherence properties: radioresistant helper cells adhere to nylon wool, whereas radiosensitive cells pass through. The 2 cell subpopulations were separated by x-irradiation and nylon wool filtration, and their helper activity was assessed separately or after recombination. The results favor the notion that 2 functionally independent helper T cells, as characterized by different radiosensitivity and nylon adherence, participate synergistically in the helper activity of primed spleen cells

  3. Follicular fluid placental growth factor is increased in polycystic ovarian syndrome: correlation with ovarian stimulation.

    Science.gov (United States)

    Tal, Reshef; Seifer, David B; Grazi, Richard V; Malter, Henry E

    2014-08-20

    Polycystic ovarian syndrome (PCOS) is characterized by increased ovarian angiogenesis and vascularity. Accumulating evidence indicates that vascular endothelial growth factor (VEGF) is increased in PCOS and may play an important role in these vascular changes and the pathogenesis of this disease. Placental growth factor (PlGF), a VEGF family member, has not been previously characterized in PCOS women. We investigated levels and temporal expression patterns of PlGF and its soluble receptor sFlt-1 (soluble Fms-like tyrosine kinase) in serum and follicular fluid (FF) of women with PCOS during controlled ovarian stimulation. This was a prospective cohort study of 14 PCOS women (Rotterdam criteria) and 14 matched controls undergoing controlled ovarian stimulation. Serum was collected on day 3, day of hCG and day of oocyte retrieval. FF was collected on retrieval day. PlGF, sFlt-1 and anti-mullerian hormone (AMH) protein concentrations were measured using ELISA. Since sFlt-1 binds free PlGF, preventing its signal transduction, we calculated PlGF bioavailability as PlGF/sFlt-1 ratio. Serum PlGF and sFlt-1 levels were constant throughout controlled ovarian stimulation, and no significant differences were observed in either factor in PCOS women compared with non-PCOS controls at all three measured time points. However, FF PlGF levels were increased 1.5-fold in PCOS women compared with controls (p ovarian reserve marker anti-mullerian hormone (AMH) and negatively with age. In addition, FF sFlt-1 levels were decreased 1.4-fold in PCOS women compared to controls (p = 0.04). PlGF bioavailability in FF was significantly greater (2-fold) in PCOS women compared with non-PCOS controls (p ovarian stimulation and that its bioavailability is increased in women with PCOS undergoing controlled ovarian stimulation. This suggests that PlGF may play a role in PCOS pathogenesis and its angiogenic dysregulation.

  4. A study on increasing the breeding rate of chicks with low-dosage stimulation

    International Nuclear Information System (INIS)

    Wang Shuyu; Zhang Hongwei; Cui Zaijiu; Liu Dashen; Zhang Peng; Yi Jun

    1991-10-01

    During the years 1985 ∼ 1990, the semen of male fowl was irradiated by β-rays, the survival time of the spermatozoa was prolonged and fertility increased by 2% to 5%. The breeding eggs of 'Harbin White hen' were irradiated by 60 Co γ-rays to stimulate the growth of the blastoderm of fertilized eggs, the hatching rate increased by 6.86%, the healthy bird rate increased by 5.52%, and the chick weight increased by 5% to 6%. The egg production rate of the first irradiated generation hens increased by 8.03%, the first-egg age of the second irradiated generation hens shifted 6 to 7 weeks earlier and the egg production period prolonged. 72-week egg production was raised by 10.48%

  5. Development of novel radiosensitizers for cancer therapy

    CERN Document Server

    Akamatsu, K

    2002-01-01

    The novel radiosensitizers for cancer therapy, which have some atoms with large X-ray absorption cross sections, were synthesized. The chemical and radiation (X-rays, W target, 100kVp) toxicities and the radiosensitivities to LS-180 human colon adenocarcinoma cells were also evaluated. 2,3,4,5,6-pentabromobenzylalcohol (PBBA) derivatives were not radiosensitive even around the maximum concentration. On the other hand, the hydrophilic sodium 2,4,6-triiodobenzoate (STIB) indicated meaningful radiosensitivity to the cells. Moreover, the membrane-specific radiosensitizers, cetyl fluorescein isthiocyanate (cetyl FITC), cetyl eosin isothiocyanate (cetyl br-FITC), cetyl erythrosin isothiocyanate (cetyl I-FITC), which aim for the membrane damage by X-ray photoabsorption on the target atoms, were localized in the plasma membrane. As the results of the colony formation assay, it was found that both cetyl FITC are similarly radiosensitive. In this report, we demonstrate the synthetic methods of the radiosensitizers, the...

  6. Macrophage migration inhibitory factor stimulated by Helicobacter pylori increases proliferation of gastric epithelial cells

    Science.gov (United States)

    Xia, Harry Hua-Xiang; Lam, Shiu Kum; Chan, Annie O.O.; Lin, Marie Chia Mi; Kung, Hsiang Fu; Ogura, Keiji; Berg, Douglas E.; Wong, Benjamin C. Y.

    2005-01-01

    AIM: Helicobacter pylori (H pylori) is associated with increased gastric inflammatory and epithelial expression of macrophage migration inhibitory factor (MIF) and gastric epithelial cell proliferation. This study aimed at determining whether H pylori directly stimulates release of MIF in monocytes, whether the cag pathogenicity island (PAI) is involved for this function, and whether MIF stimulated by H pylori increases gastric epithelial cell proliferation in vitro. METHODS: A cytotoxic wild-type H pylori strain (TN2)and its three isogenic mutants (TN2△cag, TN2△cagA and TN2△cagE) were co-cultured with cells of a human monocyte cell line, THP-1, for 24 h at different organism/cell ratios. MIF in the supernatants was measured by an ELISA. Cells of a human gastric cancer cell line, MKN45, were then co-cultured with the supernatants, with and without monoclonal anti-MIF antibody for 24 h. The cells were further incubated for 12 h after addition of 3H-thymidine, and the levels of incorporation of 3H-thymidine were measured with a liquid scintillation counter. RESULTS: The wild-type strain and the isogenic mutants, TN2△cagA and TN2△cagE, increased MIF release at organism/cell ratios of 200/1 and 400/1, but not at the ratios of 50/1 and 100/1. However, the mutant TN2△cag did not increase the release of MIF at any of the four ratios. 3H-thymidine readings for MKN-45 cells were significantly increased with supernatants derived from the wild-type strain and the mutants TN2△cagA and TN2△cagE, but not from the mutant TN2△cag. Moreover, in the presence of monoclonal anti-MIF antibody, the stimulatory effects of the wild-type strain on cell proliferation disappeared. CONCLUSION: H pylori stimulates MIF release in monocytes, likely through its cag PAI, but not related to cagA or cagE. H pylori-stimulated monocyte culture supernatant increases gastric cell proliferation, which is blocked by anti-MIF antibody, suggesting that MIF plays an important role in H

  7. Evaluation of 2-amino-5-nitrothiazole as a hypoxic cell radiosensitizer

    International Nuclear Information System (INIS)

    Rockwell, S.; Mroczkowski, Z.; Rupp, W.D.

    1982-01-01

    The nitroheterocyclic compound 2-amino-5-nitrothiazole (ANT) was evaluated as a hypoxic radiosensitizer. Experiments with bacteria showed that this agent was similar to misonidozole in radiosensitizing activity, but was less cytotoxic and less mutagenic than misonidazole. Experiments with EMT6 tumor cells in culture showed ANT to be an effective hypoxic radiosensitizer, although slightly less active than misonidazole, and to be less cytotoxic than misonidazole. ANT was more toxic to mice than misonidazole and produced a spectrum of symptoms, including hyperactivity and agitation, different from those of misonidazole. The toxicities of ANT and misonidazole were additive. The maximum levels of ANT achieveable in the tumors after ip injection of nontoxic doses of drug were low ( -4 M) and the radiosensitization obtainable with the drug in vivo was inferior to that obtainable with misonidazole. These findings suggest that nitrothiazoles might be an interesting class of nitroheterocyclic radiosensitizers, but that molecules with increased solubility and improved pharmacokinetics would be necessary for efficacy in vivo

  8. Mechanisms of oxygen radiosensitization in CHO cells

    International Nuclear Information System (INIS)

    Whillans, D.W.

    1981-01-01

    A model is presented for repair and fixation pathways when CHO cells are irradiated in the presence of O 2 . This analysis predicts that an increase in the repair path such as has been postulated for addition of a radioprotective sulfhydryl should increase OER/sub max/ in porportion to k prime, the new repair rate constant and also increase K with k prime. Any radiosensitizer which mimics the action of O 2 simply increases k prime 2 , so that the OER/sub max/ decreases at 1/k prime 2 but K increases as k prime 2 . These predictions have been tested in mammalian CHO cells making use of a Clark-type oxygen probe with defined conditions to ensure that O 2 is not depleted by radiation or cellular consumption, and so O 2 levels are known with accuracy. In a complementary study, the technique of rapid-mixing was used to measure the rate of development of O 2 sensitization in these same cells. By a variation of this rapid-mixing approach, the rate of diffusion into these cells has also been measured independently. Neither the dependence of OER on O 2 concentration nor the development of radiosensitivity with time of incubation in O 2 gives evidence in CHO cells for two components of sensitization indicative of two sites or two mechanisms of action, as seen in some V79 sublines. 13 references, 4 figures

  9. Radiosensitivity of carcinoma of esophagus

    International Nuclear Information System (INIS)

    Furusawa, Hidenori

    1986-01-01

    With a detailed graphic reconstruction of radiation effects shown in 11 operation materials of carcinoma of esophagus with preoperative irradiation, histologic analysis of the radiosensitivity was made. Residual cancer lesions in 11 operation specimens contained adenocarcinoma elements. Carcinoma of esophagus belonged to mixed carcinoma (syn. metaplastic cancer). Radioresistant nature resulted from the remnant adenocarcinoma elements. Protruded type (3 cases) showed about 60 % of residual cancer after preoperative irradiation of 40 Gy (Lineac or 60 Co.). The residual cancer nests histologically revealed well-differentiated squamous cell carcinoma with a few signet-ring cells, compatible with mucoepidermoid carcinoma. In protruded type, the mixed carcinoma was composed of segmental, disproportioned zonal squamous metaplasia. As its histogenetic origin, a main duct of esophageal gland was suggested. In 9 autopsy cases of esophageal cancer, recurrent lesion within the field of irradiation failed to respond to radiotherapy. In recurrent residual lesions, a higher proportion of adenocarcinoma elements was noticed. Therefore, the cancer part formed by a high rate of metaplasia was markedly responsive to irradiation, whereas increased residue of adenocarcinoma elements was enhanced the radioresistant property. In a middle thoracic esophagus (Im) corresponding to the commonest site of esophageal cancer, the distribution of esohageal glands was in a high density with a constant ratio of density in each age group particularly in male. In age groups with higher incidence of carcinoma of esophagus, esophageal glands markedly increased especially in male, in contrast with the indefinite number and density ratio in female cases. A high density of esophageal glands was noticed in the upper (Iu) and lower (Im) parts of the 2nd physiologic constriction, in proportion to the commonest site of carcinoma of esophagus. (J.P.N.)

  10. Skin test of radiosensitivity. Application to Fanconi anemia

    International Nuclear Information System (INIS)

    Dutreix, J.; Gluckman, E.

    1983-01-01

    A test of skin radiosensitivity is described. It is achieved by irradiating small skin fields (15 mm in diameter) with 50 kV X-rays. The radiosensitivity is evaluated from the skin reaction observed for a single acute dose of 8 and 10 Gy; it is considered increased if the reaction for 10 Gy exceeds the desquamation threshold, and scored according to the observed reaction. The test includes an evaluation of the cellular repair, assessed on the comparison of the reactions for single dose and split irradiation. The time of the reaction peak is also reported. Abnormal reactions have been observed on 4 out of 8 patients with Fanconi Anemia

  11. Skin test of radiosensitivity. Application to Fanconi anemia

    Energy Technology Data Exchange (ETDEWEB)

    Dutreix, J. (Institut Gustave-Roussy, 94 - Villejuif (France)); Gluckman, E. (Centre Hayem, Hopital St.-Louis, 75 Paris (France))

    1983-01-01

    A test of skin radiosensitivity is described. It is achieved by irradiating small skin fields (15 mm in diameter) with 50 kV X-rays. The radiosensitivity is evaluated from the skin reaction observed for a single acute dose of 8 and 10 Gy; it is considered increased if the reaction for 10 Gy exceeds the desquamation threshold, and scored according to the observed reaction. The test includes an evaluation of the cellular repair, assessed on the comparison of the reactions for single dose and split irradiation. The time of the reaction peak is also reported. Abnormal reactions have been observed on 4 out of 8 patients with Fanconi Anemia.

  12. Predisposition to cancer and radiosensitivity

    International Nuclear Information System (INIS)

    Pichierri, P.; Franchitto, A.; Palitti, F.

    2000-01-01

    Many cancer-prone diseases have been shown to be radiosensitive. The radiosensitivity has been attributed to pitfalls in the mechanisms of repair of induced DNA lesions or to an impaired cell cycle checkpoint response. Although discrepancies exist in the results obtained by various authors on the radiosensitivity of individuals affected by the same disease, these can be attributed to the large variability observed already in the response to radiation of normal individuals. To date three test are commonly used to assess radiosensitivity in human cells: survival, micronucleus and G 2 chromosomal assay. The three tests may be performed using either fibroblasts or peripheral blood lymphocytes and all the three tests share large interindividual variability. In this regard a new approach to the G 2 chromosomal assay which takes into account the eventual differences in cell cycle progression among individuals has been developed. This new approach is based on the analysis of G 2 homogeneous cell populations. Cells irradiated are immediately challenged with medium containing bromodeoxyuridine (BrdU rd). Then cells are sampled at different post-irradiation times and BrdU rd incorporation detected on metaphases spread and the scoring is done only at time points showing similar incidence of labelled cells among the different donors. Using this approach it has been possible to reduce the interindividual variability of the G 2 chromosomal assay. (author)

  13. Increasing Goat Productivity Through the Improvement of Endogenous Secretion of Pregnant Hormones Using Follicle Stimulating Hormone

    Directory of Open Access Journals (Sweden)

    Andriyanto Andriyanto

    2011-05-01

    Full Text Available Abstract. Previous studies reported that the improvement of endogenous estrogen and progesterone secretions during gestation improved fetal prenatal growth, birth weight, mammary gland growth and development, milk production, litter size, pre- and post-weaning growths. An experiment was conducted to apply the improvement of endogenous secretion of pregnant hormones during pregnancy to increase goat productivity. Thirty-six female ettawah-cross does were divided into 2 groups. Group 1 (control: 18 does included does without improvement of endogenous secretion of pregnant hormones and Group 2 (treatment: 18 does included does with improvement of endogenous secretion of pregnant hormones using follicle stimulating hormones to stimulate super ovulation. The application of this technology increased total offspring born (control: 25 offspring; treatment: 42 offspring, average litter size (control: 1.88; treatment: 2.33, offspring birth weight (control: 2.85±0.50 kg; treatment: 3.82±0.40 kg, and does milk production (control: 1.36±0.34 L/does/day; treatment: 2.10±0.21 L/does/day. Offspring born to does with improved endogenous secretion of pregnant hormones had better weaning weight (control: 11.17±1.99 kg/offspring; treatment: 14.5±1.11 kg/offspring. At weaning period, does with improved endogenous secretion of pregnant hormones produced offspring with total weaning weight twice as heavy as control does (control: 189.9 kg; treatment: 403.6 kg. By a simple calculation of economic analysis, this technology application could increase gross revenue per does until weaning by Rp. 432.888,89. It was concluded that this technology is economically feasible to be applied in small-scale farm. Key Words: follicle stimulating hormone, pregnant hormones, endogenous secretion, super ovulation, ettawah-cross does

  14. Ebselen increases cytosolic free Ca2+ concentration, stimulates glutamate release and increases GFAP content in rat hippocampal astrocytes

    International Nuclear Information System (INIS)

    Salazar, Miguel; Pariente, Jose Antonio; Salido, Gines Maria; Gonzalez, Antonio

    2008-01-01

    We have investigated the effect of the seleno-organic compound and radical scavenger ebselen on rat hippocampal astrocytes in culture. Throughout our study we carried out determinations of [Ca 2+ ] c in fura-2-loaded cells by single cell imaging, glutamate secretion employing an enzymatic-based assay and GFAP expression, which was monitorized by immunocytochemistry and confocal microscopy. Our results show that ebselen (1-20 μM) dose dependently increases [Ca 2+ ] c , stimulates glutamate release and increases GFAP content, a hallmark of astrocyte reactivity. Ebselen did not alter significantly cell viability as assayed by determination of LDH release into the extracellular medium. Ebselen-evoked glutamate release and increase in GFAP content were Ca 2+ -dependent, because incubation of astrocytes in the absence of extracellular Ca 2+ (medium containing 0.5 mM EGTA) and in the presence of the intracellular Ca 2+ chelator BAPTA (10 μM) significantly reduced ebselen-evoked changes in these parameters. The effects of ebselen we have observed may underline various signalling pathways which are important for cell proliferation, differentiation and function. However, aberrations in astroglial physiology could significantly compromise brain function, due to their role as modulators of neuron activity. Therefore, we consider that careful attention should be paid when employing ebselen as a prophylactic agent against brain damage

  15. Regularity increases middle latency evoked and late induced beta brain response following proprioceptive stimulation

    DEFF Research Database (Denmark)

    Arnfred, Sidse M.; Hansen, Lars Kai; Parnas, Josef

    2008-01-01

    as an indication of increased readiness. This is achieved through detailed analysis of both evoked and induced responses in the time-frequency domain. Electroencephalography in a 64 channels montage was recorded in four-teen healthy subjects. Two paradigms were explored: A Regular alternation between hand......). After initial exploration of the AvVVT and Induced collapsed files of all subjects using two-way factor analyses (Non-Negative Matrix Factorization), further data decomposition was performed in restricted windows of interest (WOI). Main effects of side of stimulation, onset or offset, regularity...

  16. Electrical Stimulation of Schwann Cells Promotes Sustained Increases in Neurite Outgrowth

    OpenAIRE

    Koppes, Abigail N.; Nordberg, Andrea L.; Paolillo, Gina M.; Goodsell, Nicole M.; Darwish, Haley A.; Zhang, Linxia; Thompson, Deanna M.

    2013-01-01

    Endogenous electric fields are instructive during embryogenesis by acting to direct cell migration, and postnatally, they can promote axonal growth after injury (McCaig 1991, Al-Majed 2000). However, the mechanisms for these changes are not well understood. Application of an appropriate electrical stimulus may increase the rate and success of nerve repair by directly promoting axonal growth. Previously, DC electrical stimulation at 50 mV/mm (1 mA, 8 h duration) was shown to promote neurite ou...

  17. Psychotherapeutical effects of stimulate positive connotation in the increase of forgiveness

    Directory of Open Access Journals (Sweden)

    Andrés Fernando López Pell

    2009-10-01

    Full Text Available This work presents different aspects that have been related to the aptitude to forgive, emphasizing its importance for the psychotherapeutic practice in order to promote an increase of such capacity. Existing empirical evidence tends to relate forgiveness to emotional, physical and psychological well-being of the persons, and shows that the way of providing sense to the experiences influences the process of forgiveness. An alternative to increase the aptitude to forgive is proposed and results of an experimental study with 60 patients demonstrate the psychotherapeutic effects of stimulating positive connotation in the increase of forgiveness. The independent variable was the type of psychotherapeutic approach applied and the dependant variables were measured with the Aptitude to Forgive Scale (CAPER that evaluates the general predisposition of a subject to forgive, across four independent constructs: a Self, b Others, c Situation, and d Beliefs.

  18. Transcranial direct current stimulation transiently increases the blood-brain barrier solute permeability in vivo

    Science.gov (United States)

    Shin, Da Wi; Khadka, Niranjan; Fan, Jie; Bikson, Marom; Fu, Bingmei M.

    2016-03-01

    Transcranial Direct Current Stimulation (tDCS) is a non-invasive electrical stimulation technique investigated for a broad range of medical and performance indications. Whereas prior studies have focused exclusively on direct neuron polarization, our hypothesis is that tDCS directly modulates endothelial cells leading to transient changes in blood-brain-barrier (BBB) permeability (P) that are highly meaningful for neuronal activity. For this, we developed state-of-the-art imaging and animal models to quantify P to various sized solutes after tDCS treatment. tDCS was administered using a constant current stimulator to deliver a 1mA current to the right frontal cortex of rat (approximately 2 mm posterior to bregma and 2 mm right to sagittal suture) to obtain similar physiological outcome as that in the human tDCS application studies. Sodium fluorescein (MW=376), or FITC-dextrans (20K and 70K), in 1% BSA mammalian Ringer was injected into the rat (SD, 250-300g) cerebral circulation via the ipsilateral carotid artery by a syringe pump at a constant rate of ~3 ml/min. To determine P, multiphoton microscopy with 800-850 nm wavelength laser was applied to take the images from the region of interest (ROI) with proper microvessels, which are 100-200 micron below the pia mater. It shows that the relative increase in P is about 8-fold for small solute, sodium fluorescein, ~35-fold for both intermediate sized (Dex-20k) and large (Dex-70k) solutes, 10 min after 20 min tDCS pretreatment. All of the increased permeability returns to the control after 20 min post treatment. The results confirmed our hypothesis.

  19. Interleukin-2 stimulates osteoclastic activity: Increased acid production and radioactive calcium release

    International Nuclear Information System (INIS)

    Ries, W.L.; Seeds, M.C.; Key, L.L.

    1989-01-01

    Recombinant human interleukin-2 (IL-2) was studied to determine effects on acid production by individual osteoclasts in situ on mouse calvarial bones. This analysis was performed using a microspectrofluorimetric technique to quantify acid production in individual cells. Radioactive calcium release was determined using calvarial bones in a standard tissue culture system. This allowed us to correlate changes in acid production with a measure of bone resorption. IL-2 stimulated acid production and bone resorbing activity. Both effects were inhibited by calcitonin. No stimulation of bone resorption occurred when IL-2-containing test media was incubated with a specific anti-IL-2 antibody and ultrafiltered. Our data demonstrated a correlation between acid production and bone resorbing activity in mouse calvaria exposed to parathyroid hormone (PTH). The data obtained from cultured mouse calvaria exposed to IL-2 demonstrated similar stimulatory effects to those seen during PTH exposure. These data suggest that calvaria exposed to IL-2 in vitro have increased osteoclastic acid production corresponding with increased bone resorption. (author)

  20. Epalrestat increases glutathione, thioredoxin, and heme oxygenase-1 by stimulating Nrf2 pathway in endothelial cells

    Directory of Open Access Journals (Sweden)

    Kaori Yama

    2015-04-01

    Full Text Available Epalrestat (EPS is the only aldose reductase inhibitor that is currently available for the treatment of diabetic neuropathy. Recently, we found that EPS at near-plasma concentration increases the intracellular levels of glutathione (GSH in rat Schwann cells. GSH plays a crucial role in protecting endothelial cells from oxidative stress, thereby preventing vascular diseases. Here we show that EPS increases GSH levels in not only Schwann cells but also endothelial cells. Treatment of bovine aortic endothelial cells (BAECs, an in vitro model of the vascular endothelium, with EPS caused a dramatic increase in intracellular GSH levels. This was concomitant with the up-regulation of glutamate cysteine ligase, an enzyme catalyzing the first and rate-limiting step in de novo GSH synthesis. Moreover, EPS stimulated the expression of thioredoxin and heme oxygenase-1, which have important redox regulatory functions in endothelial cells. Nuclear factor erythroid 2-related factor 2 (Nrf2 is a key transcription factor that regulates the expression of antioxidant genes. EPS increased nuclear Nrf2 levels in BAECs. Nrf2 knockdown by siRNA suppressed the EPS-induced glutamate cysteine ligase, thioredoxin-1, and heme oxygenase-1 expression. Interestingly, LY294002, an inhibitor of phosphatidylinositol 3-kinase, abolished the EPS-stimulated GSH synthesis, suggesting that the kinase is associated with Nrf2 activation induced by EPS. Furthermore, EPS reduced the cytotoxicity induced by H2O2 and tert-butylhydroperoxide, indicating that EPS plays a role in protecting cells from oxidative stress. Taken together, the results provide evidence that EPS exerts new beneficial effects on endothelial cells by increasing GSH, thioredoxin, and heme oxygenase-1 levels through the activation of Nrf2. We suggest that EPS has the potential to prevent several vascular diseases caused by oxidative stress.

  1. Investigation of radiosensitivity and growth dynamics for callus tissues Crepis Capillaris, Haplopappus gracilis, Phasolium vulgaris exposed to gamma radiation

    International Nuclear Information System (INIS)

    Gatsek, Eh.; Glinkova, E.; Ismailova, Eh.N.

    1983-01-01

    Radiosensitivity of three kinds of callus tissues (Crepis capillaris, Haplopappus gracilis, Phasolium vulgaris) manifested in the change of fresh weight after γ-irradiation has been investigated. Irradiated callus arowth showed decrease with increasing doses. It is shown that the radiosensitivity of ''young'' callus tissues is determined by the kind of the plant. Callus of Phaseolis has been found to have the highest radioresistance, while that of Crepis has the lowest one. Radiosensitivity of ''old'' callus tissues is the same for all kinds. Potential mechanism of radiosensitivity of callus tissUes are discussed

  2. Acute Stimulant Treatment and Reinforcement Increase the Speed of Information Accumulation in Children with ADHD.

    Science.gov (United States)

    Fosco, Whitney D; White, Corey N; Hawk, Larry W

    2017-07-01

    The current studies utilized drift diffusion modeling (DDM) to examine how reinforcement and stimulant medication affect cognitive task performance in children with ADHD. In Study 1, children with (n = 25; 88 % male) and without ADHD (n = 33; 82 % male) completed a 2-choice discrimination task at baseline (100 trials) and again a week later under alternating reinforcement and no-reinforcement contingencies (400 trials total). In Study 2, participants with ADHD (n = 29; 72 % male) completed a double-blind, placebo-controlled trial of 0.3 and 0.6 mg/kg methylphenidate and completed the same task utilized in Study 1 at baseline (100 trials). Children with ADHD accumulated information at a much slower rate than controls, as evidenced by a lower drift rate. Groups were similar in nondecision time and boundary separation. Both reinforcement and stimulant medication markedly improved drift rate in children with ADHD (ds = 0.70 and 0.95 for reinforcement and methylphenidate, respectively); both treatments also reduced boundary separation (ds = 0.70 and 0.39). Reinforcement, which emphasized speeded accuracy, reduced nondecision time (d = 0.37), whereas stimulant medication increased nondecision time (d = 0.38). These studies provide initial evidence that frontline treatments for ADHD primarily impact cognitive performance in youth with ADHD by improving the speed/efficiency of information accumulation. Treatment effects on other DDM parameters may vary between treatments or interact with task parameters (number of trials, task difficulty). DDM, in conjunction with other approaches, may be helpful in clarifying the specific cognitive processes that are disrupted in ADHD, as well as the basic mechanisms that underlie the efficacy of ADHD treatments.

  3. Aging increases cell-to-cell transcriptional variability upon immune stimulation.

    Science.gov (United States)

    Martinez-Jimenez, Celia Pilar; Eling, Nils; Chen, Hung-Chang; Vallejos, Catalina A; Kolodziejczyk, Aleksandra A; Connor, Frances; Stojic, Lovorka; Rayner, Timothy F; Stubbington, Michael J T; Teichmann, Sarah A; de la Roche, Maike; Marioni, John C; Odom, Duncan T

    2017-03-31

    Aging is characterized by progressive loss of physiological and cellular functions, but the molecular basis of this decline remains unclear. We explored how aging affects transcriptional dynamics using single-cell RNA sequencing of unstimulated and stimulated naïve and effector memory CD4 + T cells from young and old mice from two divergent species. In young animals, immunological activation drives a conserved transcriptomic switch, resulting in tightly controlled gene expression characterized by a strong up-regulation of a core activation program, coupled with a decrease in cell-to-cell variability. Aging perturbed the activation of this core program and increased expression heterogeneity across populations of cells in both species. These discoveries suggest that increased cell-to-cell transcriptional variability will be a hallmark feature of aging across most, if not all, mammalian tissues. Copyright © 2017, American Association for the Advancement of Science.

  4. Increased macrophage colony-stimulating factor levels in patients with Graves' disease.

    Science.gov (United States)

    Morishita, Eriko; Sekiya, Akiko; Hayashi, Tomoe; Kadohira, Yasuko; Maekawa, Mio; Yamazaki, Masahide; Asakura, Hidesaku; Nakao, Shinji; Ohtake, Shigeki

    2008-10-01

    Previous studies have found markedly elevated serum concentrations of proinflammatory cytokines in patients with Graves' disease (GD). We investigated the role of macrophage colony-stimulating factor (M-CSF) in GD. We assayed concentrations of M-CSF in sera from 32 patients with GD (25 untreated; 7 receiving thiamazole therapy). We also studied 32 age-matched healthy subjects as controls. Relationships between serum M-CSF and both thyroid state and serum lipids were examined. Moreover, to examine the effect of thyroid hormone alone on serum M-CSF, T3 was administered orally to normal subjects. Serum concentrations of M-CSF in GD patients who were hyperthyroid were significantly increased compared with GD patients who were euthyroid (P oral T3 administered to 15 volunteers for 7 days produced significant increases in serum levels of M-CSF (P production of M-CSF in patients with GD.

  5. Increasing Sucrose Uptake Capacity of Wheat Grains Stimulates Storage Protein Synthesis1[W

    Science.gov (United States)

    Weichert, Nicola; Saalbach, Isolde; Weichert, Heiko; Kohl, Stefan; Erban, Alexander; Kopka, Joachim; Hause, Bettina; Varshney, Alok; Sreenivasulu, Nese; Strickert, Marc; Kumlehn, Jochen; Weschke, Winfriede; Weber, Hans

    2010-01-01

    Increasing grain sink strength by improving assimilate uptake capacity could be a promising approach toward getting higher yield. The barley (Hordeum vulgare) sucrose transporter HvSUT1 (SUT) was expressed under control of the endosperm-specific Hordein B1 promoter (HO). Compared with the wild type, transgenic HOSUT grains take up more sucrose (Suc) in vitro, showing that the transgene is functional. Grain Suc levels are not altered, indicating that Suc fluxes are influenced rather than steady-state levels. HOSUT grains have increased percentages of total nitrogen and prolamins, which is reflected in increased levels of phenylalanine, tyrosine, tryptophan, isoleucine, and leucine at late grain development. Transcript profiling indicates specific stimulation of prolamin gene expression at the onset of storage phase. Changes in gene expression and metabolite levels related to carbon metabolism and amino acid biosynthesis suggest deregulated carbon-nitrogen balance, which together indicate carbon sufficiency and relative depletion of nitrogen. Genes, deregulated together with prolamin genes, might represent candidates, which respond positively to assimilate supply and are related to sugar-starch metabolism, cytokinin and brassinosteroid functions, cell proliferation, and sugar/abscisic acid signaling. Genes showing inverse expression patterns represent potential negative regulators. It is concluded that HvSUT1 overexpression increases grain protein content but also deregulates the metabolic status of wheat (Triticum aestivum) grains, accompanied by up-regulated gene expression of positive and negative regulators related to sugar signaling and assimilate supply. In HOSUT grains, alternating stimulation of positive and negative regulators causes oscillatory patterns of gene expression and highlights the capacity and great flexibility to adjust wheat grain storage metabolism in response to metabolic alterations. PMID:20018590

  6. Effect of electroporation on radiosensitization with cisplatin in two cell lines with different chemo- and radiosensitivity

    International Nuclear Information System (INIS)

    Kranjc, S.; Cemazar, M.; Grosel, A.; Pipan, Z.; Sersa, G.

    2003-01-01

    Aim. Radiosensitization with cisplatin can be enhanced by electroporation of cells and tumours. The aim of this study was to extend our previous studies on two carcinoma tumour models with different chemo- and radiosensitivity in order to evaluate whether this treatment is effective also on less chemo- and radiosensitive tumour cells. Materials and methods. This in vitro study was performed on carcinoma SCK and EAT-E cells. The cytotoxicity of three-modality treatment consisting of cisplatin, electroporation and irradiation was determined by the clonogenic assay. Results. The radiosensitizing effect of cisplatin on the two cell lines was greatly enhanced by electroporation. By this combined treatment, less chemo and radiosensitive EAT-E cells were rendered as sensitive as more chemo and radiosensitive SCK cells. Conclusion. The enhancement of cisplatin-induced radiosensitization of cells by electroporation could be beneficially used in the treatment of intrinsically less chemo- and radiosensitive tumours. (author)

  7. Stimulation of marketing channels of innovations participants as the way of increasing its management efficiency

    OpenAIRE

    L.О. Syhyda

    2012-01-01

    In article participants of distribution marketing channel are defined. Variants of manufacturer stimulation carrying out are separated. Stages of stimulation process in marketing channel are offered. Methods of stimulation carrying out in marketing channels of traditional and innovative production are defined.

  8. Focal increase of blood flow in the cerebral cortex of man during vestibular stimulation

    DEFF Research Database (Denmark)

    Friberg, L; Olsen, T S; Roland, P E

    1985-01-01

    This study is an attempt to reveal projection areas for vestibular afferents to the human brain. Changes in regional cerebral blood flow (rCBF) were measured over 254 cortical regions during caloric vestibular stimulation with warm water (44 degrees C). rCBF was measured when the external auditory...... meatus was irrigated with water at body temperature as a control to vestibular stimulation. During vestibular stimulation there was only a single cortical area, located in the superior temporal region, which showed a consistent focal activation in the hemisphere contralateral to the stimulated side...... stimulation that gives rise to the associated conscious vestibular sensation of vertigo....

  9. Particulate matter in cigarette smoke increases ciliary axoneme beating through mechanical stimulation.

    Science.gov (United States)

    Navarrette, Chelsea R; Sisson, Joseph H; Nance, Elizabeth; Allen-Gipson, Diane; Hanes, Justin; Wyatt, Todd A

    2012-06-01

    The lung's ability to trap and clear foreign particles via the mucociliary elevator is an important mechanism for protecting the lung against respirable irritants and microorganisms. Although cigarette smoke (CS) exposure and particulate inhalation are known to alter mucociliary clearance, little is known about how CS and nanoparticles (NPs) modify cilia beating at the cytoskeletal infrastructure, or axonemal, level. We used a cell-free model to introduce cigarette smoke extract (CSE) and NPs with variant size and surface chemistry to isolated axonemes and measured changes in ciliary motility. We hypothesized that CSE would alter cilia beating and that alterations in ciliary beat frequency (CBF) due to particulate matter would be size- and surface chemistry-dependent. Demembranated axonemes were isolated from ciliated bovine tracheas and exposed to adenosine triphosphate (ATP) to initiate motility. CBF was measured in response to 5% CSE, CSE filtrate, and carboxyl-modified (COOH), sulphate (SO(4))-modified (sulfonated), or PEG-coated polystyrene (PS) latex NPs ranging in size from 40 nm to 500 nm. CSE concentrations as low as 5% resulted in rapid, significant stimulation of CBF (pIntroduction of sulphate-modified PS beads ~300 nm in diameter resulted in a similar increase in CBF above baseline ATP levels. Uncharged, PEG-coated beads had no effect on CBF regardless of size. Similarly, COOH-coated particles less than 200 nm in diameter did not alter ciliary motility. However, COOH-coated PS particles larger than 300 nm increased CBF significantly and increased the number of motile points. These data show that NPs, including those found in CSE, mechanically stimulate axonemes in a size- and surface chemistry-dependent manner. Alterations in ciliary motility due to physicochemical properties of NPs may be important for inhalational lung injury and efficient drug delivery of respirable particles.

  10. Membrane specific drugs as radiosensitizers

    Energy Technology Data Exchange (ETDEWEB)

    George, K.C.; Mishra, K.P.; Shenoy, M.A.; Singh, B.B.; Srinivasan, V.T.; Verma, N.C.

    1981-01-01

    Procaine, paracetamol, and chlorpromazine showed inhibition of post irradiation repair. The chlorpromazie effect could be further augmented by treatment of cells with procaine. Chlorpromazine was also found to be preferentially toxic to hypoxid bacterial cells, and the survivors showed extreme radiosensitivity to gamma rays. Chlorpromazine was found to inhibit tumour growth in swiss mice when given intraperitoneally as well as when injected directly into the tumour. When combined with single x-ray doses, significant radiosensitization was observed in two in vivo tumours sarcoma 180A and fibrosarcoma. These results indicated that chlorpromazine may prove a good drug for combined chemo-radiotherapy of solid tumours. Investigations continued studying various aspects such as effectiveness in other tumour lines, distribution in healthy and tumour bearing animals, hyperthermia and drug combination effects, and encapsulation of the drug in artificial liposomes and blood cells. (ERB)

  11. Differential radiosensitivity among B cell subpopulations

    International Nuclear Information System (INIS)

    Riggs, J.E.

    1988-01-01

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

  12. Stimulation of the ventral tegmental area increased nociceptive thresholds and decreased spinal dorsal horn neuronal activity in rat.

    Science.gov (United States)

    Li, Ai-Ling; Sibi, Jiny E; Yang, Xiaofei; Chiao, Jung-Chih; Peng, Yuan Bo

    2016-06-01

    Deep brain stimulation has been found to be effective in relieving intractable pain. The ventral tegmental area (VTA) plays a role not only in the reward process, but also in the modulation of nociception. Lesions of VTA result in increased pain thresholds and exacerbate pain in several pain models. It is hypothesized that direct activation of VTA will reduce pain experience. In this study, we investigated the effect of direct electrical stimulation of the VTA on mechanical, thermal and carrageenan-induced chemical nociceptive thresholds in Sprague-Dawley rats using our custom-designed wireless stimulator. We found that: (1) VTA stimulation itself did not show any change in mechanical or thermal threshold; and (2) the decreased mechanical and thermal thresholds induced by carrageenan injection in the hind paw contralateral to the stimulation site were significantly reversed by VTA stimulation. To further explore the underlying mechanism of VTA stimulation-induced analgesia, spinal cord dorsal horn neuronal responses to graded mechanical stimuli were recorded. VTA stimulation significantly inhibited dorsal horn neuronal activity in response to pressure and pinch from the paw, but not brush. This indicated that VTA stimulation may have exerted its analgesic effect via descending modulatory pain pathways, possibly through its connections with brain stem structures and cerebral cortex areas.

  13. ATM-mediated Snail Serine 100 phosphorylation regulates cellular radiosensitivity

    International Nuclear Information System (INIS)

    Boohaker, Rebecca J.; Cui, Xiaoli; Stackhouse, Murray; Xu, Bo

    2013-01-01

    Purpose: Activation of the DNA damage responsive protein kinase ATM is a critical step for cellular survival in response to ionizing irradiation (IR). Direct targets of ATM regulating radiosensitivity remain to be fully investigated. We have recently reported that ATM phosphorylates the transcriptional repressor Snail on Serine 100. We aimed to further study the functional significance of ATM-mediated Snail phosphorylation in response to IR. Material and methods: We transfected vector-only, wild-type, the Serine 100 to alanine (S100A) or to glutamic acid (S100E) substitution of Snail into various cell lines. We assessed colony formation, γ-H2AX focus formation and the invasion index in the cells treated with or without IR. Results: We found that over-expression of the S100A mutant Snail in HeLa cells significantly increased radiosensitivity. Meanwhile the expression of S100E, a phospho-mimicking mutation, resulted in enhanced radio-resistance. Interestingly, S100E could rescue the radiosensitive phenotype in ATM-deficient cells. We also found that expression of S100E increased γ-H2AX focus formation and compromised inhibition of invasion in response to IR independent of cell survival. Conclusion: ATM-mediated Snail Serine 100 phosphorylation in response to IR plays an important part in the regulation of radiosensitivity

  14. Studies on Drosophila radiosensitivity strains

    International Nuclear Information System (INIS)

    Varentsova, E.R.; Sharygin, V.I.; Khromykh, Yu.U.

    1985-01-01

    Fertility of radiosensitive mutant drosophila female strain rad (2) 201 61 after irradiation and frequency of dominant lethal mutations (DLM), induced by γ-radiation for 0-5 h and 5-7 days, are investigated. It is shown, that oocytes of the mutant strain are more radiosensitive as compared with cells of mongrel flies as to criterion of DLM appearance over the period of maturing. Early oocytes of stages 2-7 are the most sensitive, i.e. at the stages, corresponding to the manifestation of previously established recombination-defective properties of mutations rad (2) 201 61 . It is also sown, that doses of γ-rays, exceeding 10 Gy produce a strong sterilizing effect on mutant females due to destruction and resorption of egg chambers, irradiated at the stages of previtellogenetic growth of oocytes. In females, carrying mutation of radiosensitivity there is no direct correlation betwen sensitivity of oocytes proper to DLM induction and sensitivity of egg folleicles to resorbing effect of γ-rays. The ways of possible involvement of mutant locus studied into genetic processes in various specialized cells of drosophila

  15. Applied means to increase stimulation in the control room work at the Swedish nuclear power plants

    International Nuclear Information System (INIS)

    Blomberg, P.E.; Akerhielm, F.

    1988-01-01

    Nuclear power plants are generally designed and built with a quality which implies that the units seldom require intervention from the operating staff under normal operating conditions. This leaves the operators with the dominating task of only passively supervising the process. A number of measures have been taken to counteract the problem of under-stimulated individuals in the control rooms and to maintain active and purposeful working conditions. Basically these measures derive from the belief that augmented competence, increased responsibilities and a enhanced sense of indispensability functions as an inspiration even in a monotonous working situation. For this purpose a number of activities and tasks, parallel to the normal duties as member of the operating staff, have been implemented

  16. The inherited basis of human radiosensitivity

    International Nuclear Information System (INIS)

    Gatti, R.A.

    2001-01-01

    Certain individuals cannot tolerate 'conventional' doses of radiation therapy. This is known to be true of patients with ataxia-telangiectasia and ligase IV deficiency. Although in vitro testing may not correlate completely with clinical radiosensitivity, fibroblasts and lymphoblasts from patients with both of these disorders have been clearly shown to be radiosensitive. Using a colony survival assay (CSA) to test lymphoblastoid cells after irradiation with 1 Gy, a variety of other genetic disorders have been identified as strong candidates for clinical radiosensitivity, such as Nijmegen breakage syndrome, Mre11 deficiency, and Fanconi's anemia. These data are presented and considered as a starting-point for the inherited basis of human radiosensitivity

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

    International Nuclear Information System (INIS)

    Saelen, Marie Grøn; Ree, Anne Hansen; Kristian, Alexandr; Fleten, Karianne Giller; Furre, Torbjørn; Hektoen, Helga Helseth; Flatmark, Kjersti

    2012-01-01

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

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

    Science.gov (United States)

    Saelen, Marie Grøn; Ree, Anne Hansen; Kristian, Alexandr; Fleten, Karianne Giller; Furre, Torbjørn; Hektoen, Helga Helseth; Flatmark, Kjersti

    2012-09-27

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

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

    Directory of Open Access Journals (Sweden)

    Saelen Marie

    2012-09-01

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

  20. Lithium-stimulated recovery of granulopoiesis after sublethal irradiation is not mediated via increased levels of colony stimulating factor (CSF)

    International Nuclear Information System (INIS)

    Gallicchio, V.S.; Chen, M.G.; Watts, T.D.

    1985-01-01

    Lithium accelerates the recovery of granulopoiesis following sublethal (2 Gy) whole body x-irradiation. Studies are described that further define this Li-mediated recovery by measuring the levels of colony-stimulating factor (CSF) present in serum from mice administered 105 μg/mouse (total dose) of ultra-pure Li 2 CO 3 for 3 days following irradiation. On days 1-28 following the last lithium dose, the serum was tested for its CSF activity against both normal non-adherent derived bone marrow target cells and non-adherent marrow cells from mice administered cyclophosphamide (200 mg/kg body weight). Serum was assayed at 0.01, 0.1, 1 and 10% final concentration. No significant difference in the total number of CFU-GM was observed from normal marrow using either serum from irradiated mice or lithium-treated and irradiated mice, although the irradiation did produce a 300% rise in CFU-GM colonies compared to normal serum (days 4 and 10-15). From regenerating marrow, a significant difference (P <= 0.01) was observed in CFU-GM cultured with serum at 0.1% concentration from irradiated and lithium-treated mice compared to irradiated mice without lithium. The presence of CSF was confirmed by its reduced activity in the presence of anti-(CSF). (U.K.)

  1. EGFR and its mutant EGFRvIII as modulators of tumor cell radiosensitivity

    International Nuclear Information System (INIS)

    Lammering, G.; Hewit, T.H.; Contessa, J.N.; Hawkins, W.; Lin, P.S.; Valerie, K.; Mikkelsen, R.; Dent, P.; Schmidt-Ullrich, R.K.

    2001-01-01

    tumors for MDA-MB-231 and U-87 MG tumors, with dose enhancement ratios of 1.9. U-373 MG tumors expressing EGFR-CD533 demonstrated a 4-fold increase in the tumor doubling time after IR (3 x 3 Gy) compared with LacZ transduced tumors. EGF treatment activated EGFR, as quantified by tyrosine phosphorylation (Tyr-P) and mediated activation of its downstream target mitogen activated protein kinase (MAPK), but had no effect on EGFRvIII. In contrast, IR stimulated a 4-fold increase in Tyr-P of EGFRvIII, resulting in a maximum 9-fold activation of MAPK and a 3-fold activation of the PI3K signal transduction pathway. A specific tyrphostin inhibitor of EGFR and EGFRvIII, AG1478, reduced the radiation-induced activation of MAPK and PI3K to a maximum of 2-fold, similar to the activation profile observed in CHO cells transfected with null vectors. Colony formation and cell growth assays verified that cells expressing EGFRvIII are markedly protected against the cytotoxic effects of IR. Finally, Ad-EGFR-CD533 transduction of U-373 MG cells expressing EGFRvIII significantly reduced basal Tyr-P and IR-induced activation of EGFRvIII. Conclusion: The effects of in vivo expression of constitutively active EGFRvIII on cellular radiosensitivity have not previously been considered. We demonstrate here that expression of EGFRvIII enhances the relative radioresistance of tumor cells in vitro and in vivo. This resistance is mediated by the significantly greater radiation-induced activation of EGFRvIII relative to EGFR and as a consequence a greater stimulation of both the MAPK and PI3K cytoprotective pathways. Importantly, the genetic disruption of EGFR function by expression of EGFR-CD533 is equally effective with either EGFR or EGFRvIII

  2. Enhancement of misonidazole radiosensitization by an inhibitor of glutathione biosynthesis

    International Nuclear Information System (INIS)

    Hodgkiss, R.J.; Middleton, R.W.

    1983-01-01

    A well known inhibitor of glutathione biosynthesis, buthione sulphoximine (S-n-butyl homocysteine sulphoximine, BSO) depletes non-protein sulphydryls (NPSH) in Chinese hamster cells in vitro, resulting in a marked increase in the radiosensitization efficiency of misonidazole. V79 379A Chinese hamster cells were maintained in suspension cultures and irradiated in monolayers using 250 kVp X-rays at a dose rate of 3.93 Gy/min. Radiosensitization by misonidazole alone gave results within 0.1 sensitizer enhancement ratio (s.e.r.) of the curve reported by Watts et al. (1980). GSH (2 mmol dm - 3 ) added to the extracellular medium resulted in a marked decrease in the radiosensitization efficiency of misonidazole, eliminating the effect at 0.1 mmol dm - 3 misonidazole (s.e.r. = 1.0 relative to nitrogen control). A marked enhancement of the radiosensitization by misonidazole was observed when the cells had been incubated with BSO (0.1 mmol dm - 3 ). BSO alone at this concentration gave s.e.r. = 1.17; misonidazole alone (0.1 mmol dm - 3 ) gave s.e.r. = 1.18 and misonidazole with BSO (both 0.1. mmol dm - 3 ) gave s.e.r. = 1.9. The BSO treatment gave little effect in aerated cells. The concentration of BSO needed to produce these effects in vitro is ca. 40-fold lower than doses tolerated by mice in repeated administrations. (U.K.)

  3. Follicle stimulating hormone increases spermatogonial stem cell colonization during in vitro co-culture.

    Science.gov (United States)

    Narenji Sani, Reza; Tajik, Parviz; Yousefi, Mohammad Hassan; Movahedin, Mansoureh; Qasemi-Panahi, Babak; Shafiei, Shiva; Ahmadi Hamedani, Mahmood

    2013-01-01

    The complex process of spermatogenesis is regulated by various factors. Studies on spermatogonial stem cells (SCCs) have provided very important tool to improve herd genetic and different field. 0.2 to 0.3 percent of total cells of seminiferous tubules is consist of spermatogonial stem cells. To investigate and biomanipulation of these cells, proliferation and viability rate of cells should be increased in vitro, at first. Follicle stimulating hormone (FSH) has been suggested to play a determinant role in the survival of germ cells in addition to increasing spermatogonial proliferation. In this study, the in vitro effects of FSH on spermatogonial cell colony formation were investigated. Sertoli and spermatogonial cells were isolated from 3-5 months old calves. The identity of the Sertoli cells and spermatogonial stem cells were confirmed through immunocytochemistry and colony morphology, respectively. Co-cultured Sertoli and spermatogonial cells were treated with FSH in different dose of 10, 20 and 40 IU mL(-1) FSH, before colony assay. Results indicated that, FSH increased in vitro colonization of spermatogonial cells in comparison with control group. In conclusion, using FSH provided proper bovine spermatogonial stem cell culture medium for in vitro study of these cells.

  4. Increased androgen response to follicle-stimulating hormone administration in women with polycystic ovary syndrome.

    Science.gov (United States)

    Wachs, Deborah S; Coffler, Mickey S; Malcom, Pamela J; Shimasaki, Shunichi; Chang, R Jeffrey

    2008-05-01

    In women with polycystic ovary syndrome (PCOS), excess ovarian androgen production is driven by increased LH secretion. Studies conducted in animals suggest that the granulosa cell may influence LH-stimulated theca cell androgen production. The objective of this study was to determine whether FSH enhances androgen production in women with PCOS compared with that of normal women. A prospective study was conducted to compare androgen production in response to FSH in two groups of women. The study was conducted in a General Clinical Research Center in a tertiary academic medical center. Women with PCOS, 18-35 yr (n = 20), and normal ovulatory controls, 18-35 yr (n = 10), were recruited for study. Serial blood samples were obtained over a 24-h period after an iv injection of recombinant human FSH (150 IU). The main outcome measures were serum 17-hydroxyprogesterone (17-OHP), androstenedione (A), dehydroepiandrosterone (DHEA), testosterone (T), and inhibin B (Inh B) responses after FSH administration. Basal serum 17-OHP, A, and T levels were markedly increased in women with PCOS compared with that observed in normal women. Basal DHEA and Inh B levels were similar to those of normal controls. After FSH injection, PCOS women demonstrated enhanced production of 17-OHP, A, DHEA, and Inh B, whereas in normal women no increases were observed. T levels declined slightly in both groups. These findings provide evidence that, in PCOS women, theca cell androgen production is enhanced by FSH administration and suggest a granulosa-theca cell paracrine mechanism.

  5. Anorectal stimulation causes increased colonic motor activity in subjects with spinal cord injury.

    Science.gov (United States)

    Korsten, Mark A; Singal, Ashwani K; Monga, Amit; Chaparala, Geeta; Khan, Amir M; Palmon, Ron; Mendoza, John Reagan D; Lirio, Juan P; Rosman, Alan S; Spungen, Ann; Bauman, William A

    2007-01-01

    Difficulty with evacuation (DWE) is a major problem after spinal cord injury (SCI). Stimulation of the anal canal and lower rectum, accomplished using a gloved finger (so-called digital rectal stimulation or DRS) is often used as an adjunct to laxatives and enemas to facilitate bowel evacuation. However, the basis for the efficacy of DRS is not known. This study assessed the effect of DRS on colonic motility. Six subjects with SCI were studied several hours after a bowel care session. Colonic motility was assessed using a manometric catheter (affixed endoscopically to the splenic flexure) at baseline, during DRS, and after DRS. In addition, evacuation of barium oatmeal paste (with the consistency of stool and introduced into the rectum and descending colon) was assessed simultaneously using fluoroscopic techniques. The mean number (+/- SEM) of peristaltic waves per minute increased from 0 at baseline to 1.9 (+/- 0.5/min) during DRS and 1.5 (+/- 0.3/min) during the period immediately after cessation of DRS (P < 0.05). The mean amplitude (+/- SEM) of the peristaltic contractions was 43.4 (+/- 2.2) mmHg. The frequency of contractions, as well as amplitude of contractions, during or immediately after DRS was not significantly different. These manometric changes in response to DRS were accompanied by expulsion of barium oatmeal paste in every subject by the fifth DRS. DRS causes left-sided colonic activity in subjects with SCI. At least in part, an anorectal colonic reflex that results in enhanced contractions of the descending colon and rectum may contribute to bowel evacuation in individuals with SCI.

  6. Radiosensitizing effect of RHOB protein in melanoma cells

    International Nuclear Information System (INIS)

    Notcovich, C.; Grissi, C.; Sánchez Crespo, R.; Delgado, D.C.; Molinari, B.; Ibañez, I.L.; Durán, H.

    2015-01-01

    Melanoma cells are highly resistant to chemo or radiotherapy. DNA damage agents such as ionizing radiation induce apoptosis involving RhoB protein. In a great variety of tumors the levels of this protein decrease along tumor progression. RhoB is considered a tumor suppressor gene due to its antiproliferative and proapoptotic effect. Considering the aforementioned, the aim of this study was to characterize the radiobiological response of different human melanoma cell lines, and to evaluate the possible correlation between RhoB expression and radiosensitivity. The human melanoma cell lines A375, MELJ and SB2 were gamma-irradiated ( 137 Cs). Survival curves were obtained by clonogenic assay and fitted to the Linear-Quadratic (LQ) model. Radiosensitivity was evaluated by surviving fraction at 2 Gy (SF2). Results showed that MELJ was significantly more radioresistant (SF2=0.71) than A375 and SB2 (0.29 and 0.21 respectively. Expression levels of RhoB, evaluated by western blot, increased in all lines vs. non-irradiated control. SB2, the most radiosensitive cells, showed a greater induction (p<0.05) of RhoB. Finally, to study whether RhoB has a radiosensitizing effect, these cell lines were stably transfected with a wild type RhoB construction, a constitutively active RhoB mutant V14, or with the empty plasmid as control. For all cell lines higher expression level of this protein was found in RhoB or V14 transfected cells (p<0.05). Sensitization was evaluated by SF2. Significant radiosensitization was demonstrated in clones derived from A375 and SB2 ((p<0.05), while for MELJ cells, radio-sensitization was only found in clones overexpressing V14. In conclusion, the increase of RhoB in melanoma cell lines, either by radiation or transfection has a radiosensitizing effect. Thus, we propose RhoB modulation as a potential therapeutic tool to improve the radiation response of radioresistant melanoma. (authors)

  7. Mechanical stimulation of C2C12 cells increases m-calpain expression, focal adhesion plaque protein degradation

    DEFF Research Database (Denmark)

    Grossi, Alberto; Karlsson, Anders H; Lawson, Moira Ann

    2008-01-01

    . Stimulation due to stretch- or load-induced signaling is now beginning to be understood as a factor which affects gene sequences, protein synthesis and an increase in Ca2+ influx in myocytes. Evidence of the involvement of Ca2+ -dependent activity in myoblast fusion, cell membrane and cytoskeleton component...... reorganization due to the activity of the ubiquitous proteolytic enzymes, calpains, has been reported. Whether there is a link between stretch- or load-induced signaling and calpain expression and activation is not known. Using a magnetic bead stimulation assay and C2C12 mouse myoblasts cell population, we have...... demonstrated that mechanical stimulation via laminin receptors leads to an increase in m-calpain expression, but no increase in the expression of other calpain isoforms. Our study revealed that after a short period of stimulation, m-calpain relocates into focal adhesion complexes and is followed by a breakdown...

  8. Luteal-phase ovarian stimulation increases the number of mature oocytes in older women with severe diminished ovarian reserve.

    Science.gov (United States)

    Rashtian, Justin; Zhang, John

    2018-03-22

    In older women with severe diminished ovarian response (DOR), in vitro fertilization (IVF) treatment is much less successful due to the low number of mature oocytes collected. The objective of this study was to assess whether follicular-phase stimulation (FPS) and luteal-phase stimulation (LPS) in the same menstrual cycle (double ovarian stimulation) in older women with severe DOR will produce a higher number of oocytes compared to FPS alone. Women with DOR (n = 69; mean age = 42.4) who underwent double ovarian stimulation for IVF were included. Women underwent ovarian stimulation in FPS using clomiphene citrate, letrozole, and gonadotropins followed by oocyte retrieval. The next day following oocyte retrieval, women underwent a second ovarian stimulation (LPS) using the same medications followed by a second oocyte retrieval. T-test was performed in order to compare the clinical characteristics and outcome in the same participant between FPS and LPS. Although antral follicle count at the start of FPS tended to be higher than at the start of the LPS cycle, there was no statistically significant difference between the duration of ovarian stimulation, peak estradiol levels, number of small (FPS alone. The addition of LPS to the conventional FPS increases the number of mature oocytes retrieved in the same IVF cycle, thus potentially increasing the chances of pregnancy in older women with severe DOR. AFC: antral follicle count; BMI: body mass index; DOR: diminished ovarian reserve; E2: estradiol; FPS: follicular-phase stimulation; FSH: follicle stimulating hormone; GnRH: gonadotropin-releasing hormone; HCG: human chorionic gonadotropin; IRB: institutional review board; IVF: in vitro fertilization; LH: luteinizing hormone; LPS: luteal-phase stimulation; MII: metaphase II.

  9. Inhibiting DNA-PKCS radiosensitizes human osteosarcoma cells

    International Nuclear Information System (INIS)

    Mamo, Tewodros; Mladek, Ann C.; Shogren, Kris L.; Gustafson, Carl; Gupta, Shiv K.; Riester, Scott M.; Maran, Avudaiappan; Galindo, Mario; Wijnen, Andre J. van; Sarkaria, Jann N.; Yaszemski, Michael J.

    2017-01-01

    Osteosarcoma survival rate has not improved over the past three decades, and the debilitating side effects of the surgical treatment suggest the need for alternative local control approaches. Radiotherapy is largely ineffective in osteosarcoma, indicating a potential role for radiosensitizers. Blocking DNA repair, particularly by inhibiting the catalytic subunit of DNA-dependent protein kinase (DNA-PK CS ), is an attractive option for the radiosensitization of osteosarcoma. In this study, the expression of DNA-PK CS in osteosarcoma tissue specimens and cell lines was examined. Moreover, the small molecule DNA-PK CS inhibitor, KU60648, was investigated as a radiosensitizing strategy for osteosarcoma cells in vitro. DNA-PK CS was consistently expressed in the osteosarcoma tissue specimens and cell lines studied. Additionally, KU60648 effectively sensitized two of those osteosarcoma cell lines (143B cells by 1.5-fold and U2OS cells by 2.5-fold). KU60648 co-treatment also altered cell cycle distribution and enhanced DNA damage. Cell accumulation at the G2/M transition point increased by 55% and 45%, while the percentage of cells with >20 γH2AX foci were enhanced by 59% and 107% for 143B and U2OS cells, respectively. These results indicate that the DNA-PK CS inhibitor, KU60648, is a promising radiosensitizing agent for osteosarcoma. - Highlights: • DNA-PKcs is consistently expressed in human osteosarcoma tissue and cell lines. • The DNA-PKcs inhibitor, KU60648, effectively radiosensitizes osteosarcoma cells. • Combining KU60648 with radiation increases G2/M accumulation and DNA damage.

  10. Increasing carbon availability stimulates growth and secondary metabolites via modulation of phytohormones in winter wheat

    Science.gov (United States)

    Reichelt, Michael; Chowdhury, Somak; Hammerbacher, Almuth; Hartmann, Henrik

    2017-01-01

    Abstract Phytohormones play important roles in plant acclimation to changes in environmental conditions. However, their role in whole-plant regulation of growth and secondary metabolite production under increasing atmospheric CO2 concentrations ([CO2]) is uncertain but crucially important for understanding plant responses to abiotic stresses. We grew winter wheat (Triticum aestivum) under three [CO2] (170, 390, and 680 ppm) over 10 weeks, and measured gas exchange, relative growth rate (RGR), soluble sugars, secondary metabolites, and phytohormones including abscisic acid (ABA), auxin (IAA), jasmonic acid (JA), and salicylic acid (SA) at the whole-plant level. Our results show that, at the whole-plant level, RGR positively correlated with IAA but not ABA, and secondary metabolites positively correlated with JA and JA-Ile but not SA. Moreover, soluble sugars positively correlated with IAA and JA but not ABA and SA. We conclude that increasing carbon availability stimulates growth and production of secondary metabolites via up-regulation of auxin and jasmonate levels, probably in response to sugar-mediated signalling. Future low [CO2] studies should address the role of reactive oxygen species (ROS) in leaf ABA and SA biosynthesis, and at the transcriptional level should focus on biosynthetic and, in particular, on responsive genes involved in [CO2]-induced hormonal signalling pathways. PMID:28159987

  11. Loss of Huntingtin stimulates capture of retrograde dense-core vesicles to increase synaptic neuropeptide stores.

    Science.gov (United States)

    Bulgari, Dinara; Deitcher, David L; Levitan, Edwin S

    2017-08-01

    The Huntington's disease protein Huntingtin (Htt) regulates axonal transport of dense-core vesicles (DCVs) containing neurotrophins and neuropeptides. DCVs travel down axons to reach nerve terminals where they are either captured in synaptic boutons to support later release or reverse direction to reenter the axon as part of vesicle circulation. Currently, the impact of Htt on DCV dynamics in the terminal is unknown. Here we report that knockout of Drosophila Htt selectively reduces retrograde DCV flux at proximal boutons of motoneuron terminals. However, initiation of retrograde transport at the most distal bouton and transport velocity are unaffected suggesting that synaptic capture rate of these retrograde DCVs could be altered. In fact, tracking DCVs shows that retrograde synaptic capture efficiency is significantly elevated by Htt knockout or knockdown. Furthermore, synaptic boutons contain more neuropeptide in Htt knockout larvae even though bouton size, single DCV fluorescence intensity, neuropeptide release in response to electrical stimulation and subsequent activity-dependent capture are unaffected. Thus, loss of Htt increases synaptic capture as DCVs travel by retrograde transport through boutons resulting in reduced transport toward the axon and increased neuropeptide in the terminal. These results therefore identify native Htt as a regulator of synaptic capture and neuropeptide storage. Copyright © 2017 Elsevier GmbH. All rights reserved.

  12. ß-Adrenergic Stimulation Increases RyR2 Activity via Intracellular Ca2+ and Mg2+ Regulation

    Science.gov (United States)

    Li, Jiao; Imtiaz, Mohammad S.; Beard, Nicole A.; Dulhunty, Angela F.; Thorne, Rick; vanHelden, Dirk F.; Laver, Derek R.

    2013-01-01

    Here we investigate how ß-adrenergic stimulation of the heart alters regulation of ryanodine receptors (RyRs) by intracellular Ca2+ and Mg2+ and the role of these changes in SR Ca2+ release. RyRs were isolated from rat hearts, perfused in a Langendorff apparatus for 5 min and subject to 1 min perfusion with 1 µM isoproterenol or without (control) and snap frozen in liquid N2 to capture their phosphorylation state. Western Blots show that RyR2 phosphorylation was increased by isoproterenol, confirming that RyR2 were subject to normal ß-adrenergic signaling. Under basal conditions, S2808 and S2814 had phosphorylation levels of 69% and 15%, respectively. These levels were increased to 83% and 60%, respectively, after 60 s of ß-adrenergic stimulation consistent with other reports that ß-adrenergic stimulation of the heart can phosphorylate RyRs at specific residues including S2808 and S2814 causing an increase in RyR activity. At cytoplasmic [Ca2+] adrenergic stimulation increased luminal Ca2+ activation of single RyR channels, decreased luminal Mg2+ inhibition and decreased inhibition of RyRs by mM cytoplasmic Mg2+. At cytoplasmic [Ca2+] >1 µM, ß-adrenergic stimulation only decreased cytoplasmic Mg2+ and Ca2+ inhibition of RyRs. The Ka and maximum levels of cytoplasmic Ca2+ activation site were not affected by ß-adrenergic stimulation. Our RyR2 gating model was fitted to the single channel data. It predicted that in diastole, ß-adrenergic stimulation is mediated by 1) increasing the activating potency of Ca2+ binding to the luminal Ca2+ site and decreasing its affinity for luminal Mg2+ and 2) decreasing affinity of the low-affinity Ca2+/Mg2+ cytoplasmic inhibition site. However in systole, ß-adrenergic stimulation is mediated mainly by the latter. PMID:23533585

  13. Radiosensitivity of lymphocytes among Filipinos: final report

    International Nuclear Information System (INIS)

    Medina, F.I.S.; Gregorio, J.S.; Aguilar, C.P.; Poblete, E.E.

    1996-01-01

    This report is about the studies on the radiosensitivity of Filipino lymphocytes to radiation that can elucidate on the potential of blood chromosomes as biological dosimeters. The objective of this study is to determine the radiosensitivity of lymphocytes among Filipinos and to establish the radiation-induced chromosome anomaly standard curve in lymphocytes for radiological dosimetry. 47 refs., 9 figs., 1 tab

  14. Increased probability of repetitive spinal motoneuron activation by transcranial magnetic stimulation after muscle fatigue in healthy subjects

    DEFF Research Database (Denmark)

    Andersen, Birgit; Felding, Ulrik Ascanius; Krarup, Christian

    2012-01-01

    Triple stimulation technique (TST) has previously shown that transcranial magnetic stimulation (TMS) fails to activate a proportion of spinal motoneurons (MNs) during motor fatigue. The TST response depression without attenuation of the conventional motor evoked potential suggested increased...... probability of repetitive spinal MN activation during exercise even if some MNs failed to discharge by the brain stimulus. Here we used a modified TST (Quadruple stimulation; QuadS and Quintuple stimulation; QuintS) to examine the influence of fatiguing exercise on second and third MN discharges after......, reflecting that a greater proportion of spinal MNs were activated 2 or 3 times by the transcranial stimulus. The size of QuadS responses did not return to pre-contraction levels during 10 min observation time indicating long-lasting increase in excitatory input to spinal MNs. In addition, the post...

  15. Base excision repair of both uracil and oxidatively damaged bases contribute to thymidine deprivation-induced radiosensitization

    International Nuclear Information System (INIS)

    Allen, Bryan G.; Johnson, Monika; Marsh, Anne E.; Dornfeld, Kenneth J.

    2006-01-01

    Purpose: Increased cellular sensitivity to ionizing radiation due to thymidine depletion is the basis of radiosensitization with fluoropyrimidine and methotrexate. The mechanism responsible for cytotoxicity has not been fully elucidated but appears to involve both the introduction of uracil into, and its removal from, DNA. The role of base excision repair of uracil and oxidatively damaged bases in creating the increased radiosensitization during thymidine depletion is examined. Methods and Materials: Isogenic strains of S. cerevisiae differing only at loci involved in DNA repair functions were exposed to aminopterin and sulfanilamide to induce thymidine deprivation. Cultures were irradiated and survival determined by clonogenic survival assay. Results: Strains lacking uracil base excision repair (BER) activities demonstrated less radiosensitization than the parental strain. Mutant strains continued to show partial radiosensitization with aminopterin treatment. Mutants deficient in BER of both uracil and oxidatively damaged bases did not demonstrate radiosensitization. A recombination deficient rad52 mutant strain was markedly sensitive to radiation; addition of aminopterin increased radiosensitivity only slightly. Radiosensitization observed in rad52 mutants was also abolished by deletion of the APN1, NTG1, and NTG2 genes. Conclusion: These data suggest radiosensitization during thymidine depletion is the result of BER activities directed at both uracil and oxidatively damaged bases

  16. Omalizumab Increases the Intrinsic Sensitivity of Human Basophils to IgE-Mediated Stimulation

    Science.gov (United States)

    MacGlashan, Donald; Saini, Sarbjit S.

    2013-01-01

    Background Treatment of allergic patients with omalizumab results in a paradoxical increase in their basophil histamine release response, ex vivo, to crosslinking anti-IgE antibody. It is not known whether this change in response is associated with an increase in intrinsic cellular sensitivity, which would be a paradoxical response. Objective To determine if the increase in response to anti-IgE Ab is a reflection of an increased cellular sensitivity, expressed as molecules of antigen-specific IgE per basophil required to produce a 50% of maximal response. Methods Patients were treated with omalizumab or placebo agent for 12 weeks (NCT01003301 at ClinicalTrials.gov) and the metric of basophil sensitivity was assessed at 4 time points, baseline, 6–8 weeks, 12 weeks (after which treatment stopped) and 24 weeks (12 weeks after the end of treatment). Results As observed previously, treatment with omalizumab resulted in a marked increase in the maximal histamine release induced by crosslinking anti-IgE Ab. This change was accompanied by a marked shift in intrinsic basophil sensitivity, ranging from 2.5 to 125 fold, with an average of 6 fold at the midpoint of the treatment to 12 fold after 12 weeks. The magnitude of the increase in cellular sensitivity was inversely related to the starting sensitivity or the starting maximum histamine release. The increased cellular sensitivity also occurred when using LTC4 secretion as a metric of the basophil response. 12 weeks after the end of treatment, cellular sensitivity was found to shift towards the baseline level although the return to baseline was not yet complete at this time point. Conclusions Treatment with omalizumab results in a markedly increased sensitivity of basophils to IgE-mediated stimulation, in terms of the number of IgE molecules required to produce a given response. These results provide a better quantitative sense of the phenotypic change that occurs in basophils during omalizumab treatment which has

  17. Chromosomal fragility syndrome and family history of radiosensitivity as indicators for radiotherapy dose modification

    International Nuclear Information System (INIS)

    Alsbeih, Ghazi; Story, Michael D.; Maor, Moshe H.; Geara, Fady B.; Brock, William A.

    2003-01-01

    Beside a few known radiosensitive syndromes, a patient's reaction to radiotherapy is difficult to predict. In this report we describe the management of a pediatric cancer patient presented with a family history of radiosensitivity and cancer proneness. Laboratory investigations revealed a chromosomal fragility syndrome and an increased cellular radiosensitivity in vitro. AT gene sequencing revealed no mutations. The patient was treated with reduced radiation doses to avoid the presumed increased risks of toxicity to normal tissues. The patient tolerated well the treatment with no significant acute or late radiation sequelae. Five years later, the patient remains both disease and complications free. While an accurate laboratory test for radiosensitivity is still lacking, assessments of chromosomal fragility, cell survival and clinical medicine will continue to be useful for a small number of patients

  18. Assessment of in vitro radiosensitivity of human peripheral blood lymphocytes

    International Nuclear Information System (INIS)

    Knox, S.J.; Shifrine, M.; Rosenblatt, L.S.

    1980-01-01

    The proliferative capacity of sensitive lymphocyte progenitor cells, from thirty-one clinically normal adults, was evaluated following in vitro x-irradiation (0-400R). Radiation effects were studied using both whole blood and lymphocyte-enriched mononuclear cell fractions in the lymphocyte stimulation test and colony formation assay with 6 different mitogens and antigens. Radiation dose-response survival curves were determined for the different test groups. The sensitivity of the different assay systems is compared and normative values are presented that may be used for comparison purposes to determine the relative radiosensitivity of atypical individuals and groups of individuals

  19. Increase in short-term memory capacity induced by down-regulating individual theta frequency via transcranial alternating current stimulation.

    Science.gov (United States)

    Vosskuhl, Johannes; Huster, René J; Herrmann, Christoph S

    2015-01-01

    Working memory (WM) and short-term memory (STM) supposedly rely on the phase-amplitude coupling (PAC) of neural oscillations in the theta and gamma frequency ranges. The ratio between the individually dominant gamma and theta frequencies is believed to determine an individual's memory capacity. The aim of this study was to establish a causal relationship between the gamma/theta ratio and WM/STM capacity by means of transcranial alternating current stimulation (tACS). To achieve this, tACS was delivered at a frequency below the individual theta frequency. Thereby the individual ratio of gamma to theta frequencies was changed, resulting in an increase of STM capacity. Healthy human participants (N = 33) were allocated to two groups, one receiving verum tACS, the other underwent a sham control protocol. The electroencephalogram (EEG) was measured before stimulation and analyzed with regard to the properties of PAC between theta and gamma frequencies to determine individual stimulation frequencies. After stimulation, EEG was recorded again in order to find after-effects of tACS in the oscillatory features of the EEG. Measures of STM and WM were obtained before, during and after stimulation. Frequency spectra and behavioral data were compared between groups and different measurement phases. The tACS- but not the sham stimulated group showed an increase in STM capacity during stimulation. WM was not affected in either groups. An increase in task-related theta amplitude after stimulation was observed only for the tACS group. These augmented theta amplitudes indicated that the manipulation of individual theta frequencies was successful and caused the increase in STM capacity.

  20. Increase in short-term memory capacity induced by down-regulating individual theta frequency via transcranial alternating current stimulation

    Directory of Open Access Journals (Sweden)

    Johannes eVosskuhl

    2015-05-01

    Full Text Available Working memory (WM and short-term memory (STM supposedly rely on the phase-amplitude coupling of neural oscillations in the theta and gamma frequency ranges. The ratio between the individually dominant gamma and theta frequencies is believed to determine an individual’s memory capacity. The aim of this study was to establish a causal relationship between the gamma/theta ratio and WM/STM capacity by means of transcranial alternating current stimulation (tACS. To achieve this, tACS was delivered at a frequency below the individual theta frequency. Thereby the individual ratio of gamma to theta frequencies was changed, resulting in an increase of STM capacity. Healthy human participants (N=33 were allocated to two groups, one receiving verum tACS, the other underwent a sham control protocol. The electroencephalogram (EEG was measured before stimulation and analyzed with regard to the properties of phase-amplitude coupling between theta and gamma frequencies to determine individual stimulation frequencies. After stimulation, EEG was recorded again in order to find after-effects of tACS in the oscillatory features of the EEG. Measures of STM and WM were obtained before, during and after stimulation. Frequency spectra and behavioral data were compared between groups and different measurement phases. The tACS- but not the sham stimulated group showed an increase in STM capacity during stimulation. WM was not affected in either groups. An increase in task-related theta amplitude after stimulation was observed only for the tACS group. These augmented theta amplitudes indicated that the manipulation of individual theta frequencies was successful and caused the increase in STM capacity.

  1. Radiosensitivity of mesothelioma cell lines

    International Nuclear Information System (INIS)

    Haekkinen, A.M.; Laasonen, A.; Linnainmaa, K.; Mattson, K.; Pyrhoenen, S.

    1996-01-01

    The present study was carried out in order to examine the radiosensitivity of malignant pleural mesothelioma cell lines. Cell kinetics, radiation-induced delay of the cell cycle and DNA ploidy of the cell lines were also determined. For comparison an HeLa and a human foetal fibroblast cell line were simultaneously explored. Six previously cytogenetically and histologically characterized mesothelioma tumor cell lines were applied. A rapid tiazolyl blue microtiter (MTT) assay was used to analyze radiosensitivity and cell kinetics and DNA ploidy of the cultured cells were determined by flow cytometry. The survival fraction after a dose of 2 Gy (SF2), parameters α and β of the linear quadratic model (LQ-model) and mean inactivation dose (D MID ) were also estimated. The DNA index of four cell lines equaled 1.0 and two cell lines equaled 1.5 and 1.6. Different mesothelioma cell lines showed a great variation in radiosensitivity. Mean survival fraction after a radiation dose of 2 Gy (SF2) was 0.60 and ranged from 0.36 to 0.81 and mean α value was 0.26 (range 0.48-0.083). The SF2 of the most sensitive diploid mesothelioma cell line was 0.36: Less than that of the foetal fibroblast cell line (0.49). The survival fractions (0.81 and 0.74) of the two most resistant cell lines, which also were aneuploid, were equal to that of the HeLa cell line (0.78). The α/β ratios of the most sensitive cell lines were almost an order of magnitude greater than those of the two most resistant cell lines. Radiation-induced delay of the most resistant aneuploid cell line was similar to that of HeLa cells but in the most sensitive (diploid cells) there was practically no entry into the G1 phase following the 2 Gy radiation dose during 36 h. (orig.)

  2. THE INCREASING OF PRESCHOOL MULTIPLE INTELLIGENCES BY EDUCATIVE PLAYING INSTRUMENT STIMULATION

    Directory of Open Access Journals (Sweden)

    Yuni Sufyanti Arief

    2017-04-01

    Full Text Available Introduction: Multiple Intelligences can be incresed by playing stimulation with educative playing instrument. Educative playing is the activity that uses educate ways and instrument. Educative playing very important to increase speech development, cognitive, socialisation with the environment and also increse the streght and skill of child’s body. Method: Design used in this study was quasy experiment design. The population was preschool children 4–5 years old in working area of Mojo Public Health Centre of Surabaya. The sample was preschool children 4–5 years old that spesific in inclution criteria of this study. Data were analyzed by wilcoxon signed rank test to compare the ordinal data pre and post intervention and mann withney u-test that compare between intervention group and control  group with level of signifi cance of α ≤ 0.05. Result: The result of speech development that analyzed by Wilcoxon signed rank test showed that controlled group had p = 0.157 and intervention group had p = 0.005 and the result of mann whitney test was p = 0.03. The result of kinesthetic development by wilcoxon signed rank test showed that controlled group has p = 0.317 and intervention group has p = 0.005, and analyzed by mann whitney test in kinesthetic development showed the result of p = 0.02. Discussion: Educative playing instrument (picture cards, play dough, origami and meronce increased speech and fine motoric development of preschool children 4–5 years old in Mojo Indah Kindergarten of Surabaya. Educative playing instrument is the activity that makes the playing function optimally in child development and this activity can increase the child development such as physical, speech, cognitive and social adaptation.

  3. Hippocampal low-frequency stimulation inhibits afterdischarge and increases GABA (A) receptor expression in amygdala-kindled pharmacoresistant epileptic rats.

    Science.gov (United States)

    Wu, Guofeng; Wang, Likun; Hong, Zhen; Ren, Siying; Zhou, Feng

    2017-08-01

    The purpose of the present study was to observe the effects of hippocampal low-frequency stimulation (Hip-LFS) on amygdala afterdischarge and GABA (A) receptor expression in pharmacoresistant epileptic (PRE) rats. A total of 110 healthy adult male Wistar rats were used to generate a model of epilepsy by chronic stimulation of the amygdala. Sixteen PRE rats were selected from 70 amygdala-kindled rats by testing their response to Phenytoin and Phenobarbital, and they were randomly assigned to a pharmacoresistant stimulation group (PRS group, 8 rats) or a pharmacoresistant control group (PRC group, 8 rats). A stimulation electrode was implanted into the hippocampus of all of the rats. Hip-LFS was administered twice per day in the PRS group for two weeks. Simultaneously, amygdala stimulus-induced seizures and afterdischarge were recorded. After the hippocampal stimulation was terminated, the brain tissues were obtained to determine the GABA (A) receptors by a method of immumohistochemistry and a real-time polymerase chain reaction. The stages and duration of the amygdala stimulus-induced epileptic seizures were decreased in the PRS group. The afterdischarge threshold was increased and the duration as well as the afterdischarge frequency was decreased. Simultaneously, the GABA (A) expression was significantly increased in the PRS group. Hip-LFS may inhibit amygdala stimulus-induced epileptic seizures and up-regulate GABA (A) receptor expression in PRE rats. The antiepileptic effects of hippocampal stimulation may be partly achieved by increasing the GABA (A) receptor.

  4. Elimination of oral candidiasis may increase stimulated whole salivary flow rate.

    Science.gov (United States)

    Ohga, Noritaka; Yamazaki, Yutaka; Sato, Jun; Asaka, Takuya; Morimoto, Masahiro; Hata, Hironobu; Satoh, Chiharu; Kitagawa, Yoshimasa

    2016-11-01

    Candida infections are frequently encountered fungal infections in the oral mucosa. This study aimed to evaluate the effect of eliminating Candida spp. on stimulated whole salivary flow rate (SWS) in patients with oral candidiasis. This study involved 66 patients with oral candidiasis. Fifty-two consecutive patients, successfully treated by antifungal therapy, were available to examine the effect of elimination of oral Candida spp. on SWS (success group); the 14 patients who tested positive for Candida after therapy were retrospectively included (control group). SWS were used to measure saliva production. Moreover, tongue pain and xerostomia were evaluated using visual analog score (VAS). By eliminating oral Candida spp., SWS significantly increased in the success group after antifungal therapy [SWS: mean value 0.89±0.51ml/min (median 0.82ml/min: 0.15-2.14) to mean value 1.16±0.58ml/min (median 1.05ml/min: 0.2-2.93), Poral Candida spp. in patients with oral candidiasis. Copyright © 2016. Published by Elsevier Ltd.

  5. Follicle stimulating hormone increases spermatogonial stem cell colonization during in vitro co - culture

    Directory of Open Access Journals (Sweden)

    Reza Narenji Sani

    2013-03-01

    Full Text Available The complex process of spermatogenesis is regulated by various factors. Studies onspermatogonial stem cells(SCCshave provided very important tool to improve herd geneticand different field. 0.2 to 0.3 percent of total cells of seminiferous tubules is consist ofspermatogonial stem cells. To investigate and biomanipulation of these cells, proliferationand viability rate of cells should be increasedin vitro, at first. Follicle stimulating hormone(FSH has been suggested to play a determinant role in the survival of germ cells in additionto increasing spermatogonial proliferation. In this study, thein vitroeffects ofFSHonspermatogonial cell colony formation were investigated. Sertoli and spermatogonial cellswere isolated from 3-5 months old calves. The identity of theSertoli cells and spermatogonialstem cells were confirmed through immunocytochemistry and colony morphology,respectively. Co-cultured Sertoli and spermatogonial cells were treatedwithFSHin differentdose of10, 20 and 40 IU mL-1FSH, before colony assay.Results indicated that,FSHincreasedin vitrocolonization of spermatogonial cells in comparison with control group. In conclusion,usingFSHprovided proper bovine spermatogonial stem cell culture medium forin vitrostudy of these cells.

  6. Clinical experience with the radiosensitizer misonidazole

    International Nuclear Information System (INIS)

    Kogelnik, D.; Szepesi, T.; Kaercher, K.H.; Seitz, W.

    1979-01-01

    From April 1976 to June 1978, 74 cancer patients were treated with multiple doses of misonidazole at the University Clinic for Radiotherapy and Radiobiology of Vienna. Thirtyone patients had inoperable brain tumors or high-grade astrocytomas, the remaining patients suffered from late stages of various extracerebral malignancies. All patients were hospitalized and thoroughly examined for possible side-effects of this currently most promising hypoxic cell radiosensitizer. Neurotoxicity, principally the development of peripheral neuropathies, is the most important limiting factor in the clinical application of misonidazole. With total doses of 12 g/m 2 of surface area a low and acceptable incidence of neuropathies is seen. By extension of the over-all treatment time to 6-8 weeks the total dose may be increased to 15 g/m 2 . (orig.) 891 MG/orig. 892 RDG [de

  7. Comparative study of radiosensitivity of normal and regenerating tissues

    International Nuclear Information System (INIS)

    Samokhvalova, H.S.; Popova, M.F.

    1983-01-01

    A comparative study of radiosensitivity of cells of normal and regenerating tissues of bone marrow and spleen has demonstrated that single exposure to X-rays produces a lesser damaging effect on regenerating tissues than on normal ones. The data obtained indicate that the increase in radioresistance of the organism during active regeneration of the haemopoietic organs is due not merely to the increase in the dividing cell pool of these organs but also to qualitative changes in their functional state

  8. Does the Longer Application of Anodal-Transcranial Direct Current Stimulation Increase Corticomotor Excitability Further? A Pilot Study

    Directory of Open Access Journals (Sweden)

    Shapour Jaberzadeh

    2012-08-01

    Full Text Available Introduction: Anodal transcranial direct current stimulation (a-tDCS of the primary motor cortex (M1 has been shown to be effective in increasing corticomotor excitability.  Methods: We investigated whether longer applications of a-tDCS coincide with greater increases in corticomotor excitability compared to shorter application of a-tDCS. Ten right-handed healthy participants received one session of a-tDCS (1mA current with shorter (10 min and longer (10+10 min stimulation durations applied to the left M1 of extensor carpi radialis muscle (ECR. Corticomotor excitability following application of a-tDCS was assessed at rest with transcranial magnetic stimulation (TMS elicited motor evoked potentials (MEP and compared with baseline data for each participant.  Results: MEP amplitudes were increased following 10 min of a-tDCS by 67% (p = 0.001 with a further increase (32% after the second 10 min of a-tDCS (p = 0.005. MEP amplitudes remained elevated at 15 min post stimulation compared to baseline values by 65% (p = 0.02.  Discussion: The results demonstrate that longer application of a-tDCS within the recommended safety limits, increases corticomotor excitability with after effects of up to 15 minutes post stimulation.

  9. Does the Longer Application of Anodal-Transcranial Direct Current Stimulation Increase Corticomotor Excitability Further? A Pilot Study

    Directory of Open Access Journals (Sweden)

    Shapour Jaberzadeh

    2012-09-01

    Full Text Available Introduction: Anodal transcranial direct current stimulation (a-tDCS of the primary motor cortex (M1 has been shown to be effective in increasing corticomotor excitability.Methods: We investigated whether longer applications of a-tDCS coincide with greater increases in corticomotor excitability compared to shorter application of a-tDCS. Ten right-handed healthy participants received one session of a-tDCS(1mA current with shorter (10 min and longer (10+10 min stimulation durationsapplied to the left M1 of extensor carpi radialis muscle (ECR. Corticomotorexcitability following application of a-tDCS was assessed at rest with transcranial magnetic stimulation (TMS elicited motor evoked otentials (MEP and compared with baseline data for each participant.Results: MEP amplitudes were increased following 10 min of a-tDCS by 67%(p = 0.001 with a further increase (32% after the second 10 min of a-tDCS (p = 0.005. MEP amplitudes remained elevated at 15 min post stimulation compared to baseline values by 65% (p = 0.02.Discussion: The results demonstrate that longer application of a-tDCS within the recommended safety limits, increases corticomotor excitability with after effects of up to 15 minutes post stimulation.

  10. Lymphocyte colony forming units and its application to the study of radiosensitivity

    International Nuclear Information System (INIS)

    Ma Xiangrui; Wang Tao; Wang Hongyun

    1991-07-01

    Kinetics and radiosensitivity of human lymphocytes were studied by the techniques of monolayer agar culture and liquid culture in vitro. In the experiments of lymphocyte kinetics, PHA was designated as a motogen for T lymphocyte. LPS, MEBC and BSA were chosen as mitogens for B lymphocyte. The data from thses experiments showed that under the alone or combination stimulation of LPS, MRBC and BSA, B lymphocytes developed to form colonies in agar culture (0.3%) with the same manner. The stimulation of LPS to B lymphocytes was most significant. By the day 6 after seeding, the numbers of colonies in agar culture were maximal. Whereas the numbers decreased significantly by the day 8. The number of T lymphocyte colonies increased with culture time within 12 days. The peak of 3 H-TdR incorporation into T lymphocytes in liquid culture occured at 5th day after seeding. The data above-mentioned demonstrated that the kinetics of lymphocytes cultured in two kinds of environments were different. The studies of the radiosensitivity of T lymphocytes showed that the decreasing in the number of colonies and rate of 3 H-TdR incorporation varied in different dose ranges. In the range of 0∼1.0 Gy, r = -0.96, D 0 value was 1.71 Gy for TL-CFC in agar culture, r = -.96, D 0 value was 4.34 Gy for the proliferation T lymphocytes in liquid culture. In the range of 1.0∼6.0 Gy, r were -0.99 and -0.98, the D 0 were 5.88 and 7.36 Gy respectively. The declining tendency in colonies formed by BL-CFC was the same as that of TL-CFC, r = -0.97, for the range of 0∼1.0 Gy, r = -0.97, for the range of 1.0∼3.0, the D 0 values were 1.35 and 4.36 Gy respectively. The results from these experiments shown that the colony technique was a good method for the study in radiosensitivity

  11. Paraquat-induced radiosensitization of mammalian cells

    International Nuclear Information System (INIS)

    Miller, R.C.; Fujikura, Toshio; Hiraoka, Toshio; Tenou, Hiromi.

    1983-06-01

    The herbicide, paraquat (methyl viologen, 1-1' dimethy1-4, 4'-bipyridinium dichloride), stimulates the production of superoxide anion (O 2 sup(-.)) in aerobic cells and therefore mimics some effects of ionizing radiation. In addition, concentrations of cellular glutathione are reduced by reaction with O 2 sup(-.). It is reported here that paraquat, toxic in its own right to aerobic cells, acts as a radiosensitizer when cells are exposed to nontoxic concentrations of the drug prior to and during irradiation. The radiomimetic effect of paraquat, alone and in combination with X-rays, was examined. Paraquat affects aerated cells (hamster lung V79 cells) in a dose-dependent manner. Doses in excess of 1 mM for two hours cause significant cell killing. In combination with radiation, sublethal doses of paraquat, given for two hours prior to irradiation, enhance the lethal effects of radiation. However, if cells are exposed to the same concentration of paraquat following irradiation, no additional lethal effect is observed. Paraquat is a useful tool to study the effects of O 2 sup(-.) and may lead to better understanding of the mechanisms of radiation-induced energy deposition in cells. (author)

  12. Radiosensitivity of Bombyx mori embryos and its modification by thermal shock

    International Nuclear Information System (INIS)

    Agaev, F.A.; Zakrzhevskaya, D.T.; Yusifov, N.I.; Gaziev, A.I.; AN Azerbajdzhanskoj SSR, Baku

    1991-01-01

    Radiosensitivity of Bombyx mori embryos on days 3-4 of their development is more than 10 times higher than that of 7-9 day embryos. The rate of DNA synthesis in the embryos correlates with their radiosensitivity. Heat treatment (40 deg C, 60 min) of embryos just before γ-irradiation increases their radioresistance (DMF=+1.6), whereas such a treatment immediately after irradiation reduces the survival rate of embryos as compared to the controls irradiated without heat treatment (DMA=-1.5). The radiomodifying effect of the thermal shock on the Bombyx mori embryos is the same with exposure at both the radioresistant and the radiosensitive stage of their development. However, it is more pronounced at the radiosensitive stage

  13. Radiosensitivity of soft tissue sarcomas

    International Nuclear Information System (INIS)

    Hirano, Toru; Iwasaki, Katsuro; Suzuki, Ryohei; Monzen, Yoshio; Hombo, Zenichiro

    1989-01-01

    The correlation between the effectiveness of radiation therapy and the histology of soft tissue sarcomas was investigated. Of 31 cases with a soft tissue sarcoma of an extremity treated by conservative surgery and postoperative radiation of 3,000-6,000 cGy, local recurrence occurred in 12; 5 out of 7 synovial sarcomas, 4 of 9 MFH, one of 8 liposarcomas, none of 4 rhabdomyosarcomas and 2 of 3 others. As for the histological subtyping, the 31 soft tissue sarcomas were divided into spindle cell, pleomorphic cell, myxoid and round cell type, and recurrence rates were 75%, 33.3%, 16.7% and 0%, respectively. From the remarkable difference in recurrent rate, it was suggested that round cell and myxoid type of soft tissue sarcomas showed a high radiosensitivity compared to the spindle cell type with low sensitivity. Clarifying the degree of radiosensitivity is helpful in deciding on the management of limb salvage in soft tissue sarcomas of an extremity. (author)

  14. In vivo radiosensitization by diethyldithiocarbamate

    International Nuclear Information System (INIS)

    Kent, C.R.; Blekkenhorst, G.H.

    1988-01-01

    Diethyldithiocarbamate (DDC) has been suggested to have both radiosensitizing (due to superoxide dismutase (SOD) inhibition) and radioprotective properties. We have studied the activity of SOD up to 24 h after intratumoral administration of 50, 100, 150, and 300 mg/kg DDC in 3-methylcholanthrene-induced tumors in BALB/c mice. Maximal inhibition of SOD (8% of control) was obtained 1 h after administration of 100 mg/kg DDC. Tumor response to DDC and X irradiation was assessed using a tumor growth-delay assay, after 11 Gy 100-kVp X rays given up to 24 h after DDC administration. Radiation-induced tumor growth delay (7.11 +/- 1.76 days) was enhanced only when tumors were irradiated 2-4 h after 50 mg/kg DDC. When higher doses of DDC were used, tumor cure was noted when DDC was injected 1-6 h before irradiation. We suggest our findings are consistent with radiosensitization being due to SOD inhibition, but that if insufficient time is allowed between DDC injection and irradiation, the sensitization is masked by a radioprotective effect. We believe that further investigations as to the therapeutic potential of DDC in human patients with cancer are warranted

  15. ß-Adrenergic stimulation increases RyR2 activity via intracellular Ca2+ and Mg2+ regulation.

    Directory of Open Access Journals (Sweden)

    Jiao Li

    Full Text Available Here we investigate how ß-adrenergic stimulation of the heart alters regulation of ryanodine receptors (RyRs by intracellular Ca(2+ and Mg(2+ and the role of these changes in SR Ca(2+ release. RyRs were isolated from rat hearts, perfused in a Langendorff apparatus for 5 min and subject to 1 min perfusion with 1 µM isoproterenol or without (control and snap frozen in liquid N2 to capture their phosphorylation state. Western Blots show that RyR2 phosphorylation was increased by isoproterenol, confirming that RyR2 were subject to normal ß-adrenergic signaling. Under basal conditions, S2808 and S2814 had phosphorylation levels of 69% and 15%, respectively. These levels were increased to 83% and 60%, respectively, after 60 s of ß-adrenergic stimulation consistent with other reports that ß-adrenergic stimulation of the heart can phosphorylate RyRs at specific residues including S2808 and S2814 causing an increase in RyR activity. At cytoplasmic [Ca(2+] 1 µM, ß-adrenergic stimulation only decreased cytoplasmic Mg(2+ and Ca(2+ inhibition of RyRs. The Ka and maximum levels of cytoplasmic Ca(2+ activation site were not affected by ß-adrenergic stimulation. Our RyR2 gating model was fitted to the single channel data. It predicted that in diastole, ß-adrenergic stimulation is mediated by 1 increasing the activating potency of Ca(2+ binding to the luminal Ca(2+ site and decreasing its affinity for luminal Mg(2+ and 2 decreasing affinity of the low-affinity Ca(2+/Mg(2+ cytoplasmic inhibition site. However in systole, ß-adrenergic stimulation is mediated mainly by the latter.

  16. Transvenous stimulation of the renal sympathetic nerves increases systemic blood pressure: a potential new treatment option for neurocardiogenic syncope.

    Science.gov (United States)

    Madhavan, Malini; Desimone, Christopher V; Ebrille, Elisa; Mulpuru, Siva K; Mikell, Susan B; Johnson, Susan B; Suddendorf, Scott H; Ladewig, Dorothy J; Gilles, Emily J; Danielsen, Andrew J; Asirvatham, Samuel J

    2014-10-01

    Neurocardiogenic syncope (NCS) is a common and sometimes debilitating disorder, with no consistently effective treatment. NCS is due to a combination of bradycardia and vasodilation leading to syncope. Although pacemaker devices have been tried in treating the bradycardic aspect of NCS, no device-based therapy exists to treat the coexistent vasodilation that occurs. The renal sympathetic innervation has been the target of denervation to treat hypertension. We hypothesized that stimulation of the renal sympathetic nerves can increase blood pressure and counteract vasodilation in NCS. High-frequency stimulation (800-900 pps, 10 V, 30-200 seconds) was performed using a quadripolar catheter in the renal vein of 7 dogs and 1 baboon. A significant increase in blood pressure (BP; mean [SD] systolic BP 117 [±28] vs. 128 [±33], diastolic BP 75 [±19] vs. 87 [±29] mmHg) was noted during the stimulation, which returned to baseline after cessation of stimulation. The mean increase in systolic and diastolic BP was 13.0 (±3.3) (P = 0.006) and 10.2 (±4.6) (P = 0.08), respectively. We report the first ever study of feasibility and safety of high-frequency electrical stimulation of the renal sympathetic innervation to increase BP in animal models. This has potential applications in the treatment of hypotensive states such as NCS. © 2014 Wiley Periodicals, Inc.

  17. Pro-inflammatory stimulation of meniscus cells increases production of matrix metalloproteinases and additional catabolic factors involved in osteoarthritis pathogenesis

    Science.gov (United States)

    Stone, Austin V.; Loeser, Richard F.; Vanderman, Kadie S.; Long, David L.; Clark, Stephanie C.; Ferguson, Cristin M.

    2014-01-01

    Objective Meniscus injury increases the risk of osteoarthritis; however, the biologic mechanism remains unknown. We hypothesized that pro-inflammatory stimulation of meniscus would increase production of matrix-degrading enzymes, cytokines and chemokines which cause joint tissue destruction and could contribute to osteoarthritis development. Design Meniscus and cartilage tissue from healthy tissue donors and total knee arthroplasties was cultured. Primary cell cultures were stimulated with pro-inflammatory factors [IL-1β, IL-6, or fibronectin fragments (FnF)] and cellular responses were analyzed by real-time PCR, protein arrays and immunoblots. To determine if NF-κB was required for MMP production, meniscus cultures were treated with inflammatory factors with and without the NF-κB inhibitor, hypoestoxide. Results Normal and osteoarthritic meniscus cells increased their MMP secretion in response to stimulation, but specific patterns emerged that were unique to each stimulus with the greatest number of MMPs expressed in response to FnF. Meniscus collagen and connective tissue growth factor gene expression was reduced. Expression of cytokines (IL-1α, IL-1β, IL-6), chemokines (IL-8, CXCL1, CXCL2, CSF1) and components of the NF-κB and tumor necrosis factor (TNF) family were significantly increased. Cytokine and chemokine protein production was also increased by stimulation. When primary cell cultures were treated with hypoestoxide in conjunction with pro-inflammatory stimulation, p65 activation was reduced as were MMP-1 and MMP-3 production. Conclusions Pro-inflammatory stimulation of meniscus cells increased matrix metalloproteinase production and catabolic gene expression. The meniscus could have an active biologic role in osteoarthritis development following joint injury through increased production of cytokines, chemokines, and matrix-degrading enzymes. PMID:24315792

  18. Effect of retinoic acid on the radiosensitivity of normal human oral keratinocyte

    International Nuclear Information System (INIS)

    Lee, Jean; Heo, Min Suk; Lee, Sam Sun; Oh, Sung Ook; Choi, Soon Chul; Park, Tae Won; Lee, Sul Mi; Choi, Hang Moon

    2003-01-01

    To evaluate the effect of all-trans-retinotic acid (ATRA) on the radiosensitivity of normal human oral keratinocyte (NHOK). Relative cell survival fraction including SF2 (survival fraction at 2 Gy) was calculated on the basis of colony formation assay. Data were fitted to the linear-quadratic model to establish the survival curve and calculate α and β values. Using flow cytometry at 1, 2, 3, 4, and 5 days after exposure to 2 and 10 Gy irradiation, cell cycle arrest and apoptosis were analysed. To understand the molecular mechanism of the radiosensitization of ATRA on NHOK, proteins related with apoptosis and cell cycle arrest were investigated by Western blot analysis. Treatment with ATRA resulted in a significant decrease of SF2 value for NHOK from 0.63 to 0.27, and increased α and β value, indicating that ATRA increased radiosensitivity of NHOK. ATRA increased LDH significantly, but increasing irradiation dose decreased LDH, suggesting that the radiosensitizing effect of ATRA is not directly related with increasing cell necrosis by ATRA. ATRA did not induce appotosis but increased G2 arrest after 10 Gy irradiation, implying that the increased radiosensitivity of NHOK may be due to a decrease in mitosis caused by increasing G2 arrest. ATRA inhibited the reduction of p53 at 3 days after 10 Gy irradiation and increased p21 at 1 day after 10 Gy irradiation. Further study is required to determine the precise relationship between this effect and the radiosensitizing effect of ATRA. These results suggested that ATRA increase radiosensitivity by inhibiting mitosis caused by increasing G2 arrest.

  19. Electrical stimulation enhanced remyelination of injured sciatic nerves by increasing neurotrophins.

    Science.gov (United States)

    Wan, L D; Xia, R; Ding, W L

    2010-09-01

    Previous studies have demonstrated that electrical stimulation (ES) enhances axonal regeneration following central and peripheral nerve injury. However, the effect of ES on peripheral remyelination after nerve damage has been investigated less, and the mechanism underlying its action remains unclear. In the present study, neuron/Schwann cell (SC) co-cultures in vitro and crush-injured sciatic nerves in rats were subjected to 1 h of continuous ES (20 Hz, 100 micros, 3 V). Electron microscopy and nerve morphometry were performed to investigate the extent of regenerated nerve myelination. The expression profiles of P0, Par-3 and brain-derived neurotrophic factor (BDNF) in vitro and in vivo were examined by western blotting. We reported that 20 Hz ES increased the number of regenerated and myelinated axons at 4 and 8 weeks after injury. P0 level in the ES-treated groups, as well as myelin sheath thickness, were enhanced compared with the controls. The earlier peak Par-3 in the ES-treated groups indicated earlier initiation of SC myelination. Moreover, the similar results were achieved in the cell co-culture. Additionally, brief ES significantly elevated BDNF expression in co-cultured cells and nerve tissues. In conclusion, ES of the site of nerve injury potentiates axonal regrowth and myelin maturation during peripheral nerve regeneration. Further, the therapeutic actions of ES on myelination that is mediated via enhanced BDNF signals, which driving the promyelination effect on SCs at the onset of myelination. Copyright (c) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

  20. Rats with decreased brain cholecystokinin levels show increased responsiveness to peripheral electrical stimulation-induced analgesia.

    Science.gov (United States)

    Zhang, L X; Li, X L; Wang, L; Han, J S

    1997-01-16

    Using the P77PMC strain of rat, which is genetically prone to audiogenic seizures, and also has decreased levels of cholecystokinin (CCK), we examined the analgesic response to peripheral electrical stimulation, which is, in part, opiate-mediated. A number of studies have suggested that CCK may function as an antagonist to endogenous opiate effects. Therefore, we hypothesized that the P77PMC animals would show an enhanced analgesic response based on their decreased CCK levels producing a diminished endogenous opiate antagonism. We found that the analgesic effect on tail flick latency produced by 100 Hz peripheral electrical stimulation was more potent and longer lasting in P77PMC rats than in control rats. Moreover, the potency of the stimulation-produced analgesia correlated with the vulnerability to audiogenic seizures in these rats. We were able to block the peripheral electrical stimulation-induced analgesia (PSIA) using a cholecystokinin octapeptide (CCK-8) administered parenterally. Radioimmunoassay showed that the content of CCK-8 in cerebral cortex, hippocampus and periaqueductal gray was much lower in P77PMC rat than in controls. These results suggest that low CCK-8 content in the central nervous system of the P77PMC rats may be related to the high analgesic response to peripheral electrical stimulation, and further support the notion that CCK may be endogenous opiate antagonist.

  1. Glyoxylic compounds as radiosensitizers of hypoxic cells

    International Nuclear Information System (INIS)

    Cornago, M.P.; Lopez Zumel, M.C.; Alvarez, M.V.; Izquierdo, M.C.

    1990-01-01

    The radiosensitizing effect of five glyoxal derivatives on the survival of TC-SV40 cells has been measured, under aerobic and hypoxic conditions. A toxicity study was previously performed in order to use nontoxic concentrations. The OER for the TC-SV40 cells was 2.74. None of the glyoxylic compounds showed radiosensitizing activity under aerobic conditions while in hypoxia their radiosensitizing factors decreased in the order phenylglyoxylic acid (1.68 at 8 x 10(-3) mole dm-3) greater than phenylglyoxal (1.55 at 5 x 10(-6) mole dm-3) greater than 2-2' furil (1.48 at 5 x 10(-5) mole dm-3) greater than glyoxylic acid (1.39 at 1 x 10(-3) mole dm-3) greater than glyoxal (1.30 at 5 x 10(-5) mole dm-3). The dose-modifying factors were also determined at two equimolar concentrations 5 x 10(-5) and 5 x 10(-6) mole dm-3. A concentration effect was noticed for all the compounds although their relative radiosensitizing activity kept, independently of the concentration, the same order noted above. Glyoxals with aromatic or heterocyclic rings exert a greater radiosensitization than the others. The acidic compounds have less radiosensitizing activity than their aldehydic counterparts. Interaction of these glyoxals with NPSH cellular groups was tested and the low degree of inhibition shows that this mechanism would contribute very little, if any, to the radiosensitization effect

  2. The radiosensitivity of nile tilapia (Oreochromis niloticus) fingerlings

    International Nuclear Information System (INIS)

    Reyes, Michael Joseph T.; Velasco, Pia Victoria V.

    2000-04-01

    The nile tilapia (Oreochromis niloticus), a very popular fish commercially in the Philippines, was studied to determine its radiosensitivity and to see its potential as a biological indicator in aquatic ecosystems. Nile tilapia was seen to be radiosensitive. The fish were exposed to gamma-irradiation and chromosomal aberrations were induced. The various types of aberrations seen were chromatid gaps, chromosome gaps, chromatid fragments, dicentric rings, fusions, despiralizations and translocations. Among the aberrations observed, dicentric rings, fusions and chromosome gaps were strongly correlated with dosage, with only the dicentric rings increasing steadily with increasing dosage. In the course of the study, the lethal dosage 50 for nile tilapia with 18 days was determined and it was observed at 2.0 krad. The modal chromosome number was also established at 2n=44 with a karyotype exhibiting 22 pairs of acrocentric chromosomes with 2 pairs of marker chromosomes present. (Author)

  3. Glutathione in the modulation of radiosensitivity: a review

    International Nuclear Information System (INIS)

    Umadevi, P.; Prasanna, P.G.S.

    1993-01-01

    Glutathione (γ - glutamyl cysteinyl glycine, GSH) constitutes the major low molecular weight thiol compound in the mammalian cells. GSH has been assigned an important role in determining the inherent radiosensitivity of cells. Endogenous GSH involved in a number of radiation induced chemical processes, which help in the repair of radiation injury to the target molecules. Experimental evidence suggests that GSH competes with molecular oxygen in the cells to prevent fixation of DNA damage. Certain chemicals like buthionine sulfoximine are found to deplete the cellular GSH content by interactions at specific sites in the GSH cycle. It may be possible to take advantage of this phenomenon by increasing the radiosensitivity of hypoxic tumor cells, without seriously affecting the normal cells, so as to increase the therapeutic efficiency of radiation treatment. (author). 52 refs., 1 fig

  4. The radiosensitivity of nile tilapia (Oreochromis niloticus) fingerlings

    Energy Technology Data Exchange (ETDEWEB)

    Reyes, Michael Joseph T; Velasco, Pia Victoria V

    2000-04-01

    The nile tilapia (Oreochromis niloticus), a very popular fish commercially in the Philippines, was studied to determine its radiosensitivity and to see its potential as a biological indicator in aquatic ecosystems. Nile tilapia was seen to be radiosensitive. The fish were exposed to gamma-irradiation and chromosomal aberrations were induced. The various types of aberrations seen were chromatid gaps, chromosome gaps, chromatid fragments, dicentric rings, fusions, despiralizations and translocations. Among the aberrations observed, dicentric rings, fusions and chromosome gaps were strongly correlated with dosage, with only the dicentric rings increasing steadily with increasing dosage. In the course of the study, the lethal dosage{sub 50} for nile tilapia with 18 days was determined and it was observed at 2.0 krad. The modal chromosome number was also established at 2n=44 with a karyotype exhibiting 22 pairs of acrocentric chromosomes with 2 pairs of marker chromosomes present. (Author)

  5. Normal cellular radiosensitivity in an adult Fanconi anaemia patient with marked clinical radiosensitivity

    International Nuclear Information System (INIS)

    Marcou, Yiola; D'Andrea, Andrew; Jeggo, Penelope A.; Plowman, Piers N.

    2001-01-01

    Background: Fanconi anaemia is a rare disease associated with cellular sensitivity to chemicals (e.g. mitomycin C and diepoxybutane); variable but mild cellular radiosensitivity has also been reported. Materials and methods: A 32-year-old patient with Fanconi anaemia and tonsillar carcinoma, treated by radiotherapy, was found to exhibit profound clinical radiosensitivity. Confluent, ulcerating oropharyngeal mucositis developed after a conventionally fractionated dose of 34 Gy and healing was incomplete by 2 months after cessation of therapy. Results: Cellular radiosensitivity assays and RPLD studies from this patient did not suggest any major detectable radiosensitivity. Conclusion: There is a discrepancy between the observed clinical radiosensitivity and the usual 'predictive' radiosensitivity assays in this patient with Fanconi anaemia

  6. Radiogenomics: predicting clinical normal tissue radiosensitivity

    DEFF Research Database (Denmark)

    Alsner, Jan

    2006-01-01

    Studies on the genetic basis of normal tissue radiosensitivity, or  'radiogenomics', aims at predicting clinical radiosensitivity and optimize treatment from individual genetic profiles. Several studies have now reported links between variations in certain genes related to the biological response...... to radiation injury and risk of normal tissue morbidity in cancer patients treated with radiotherapy. However, after these initial association studies including few genes, we are still far from being able to predict clinical radiosensitivity on an individual level. Recent data from our own studies on risk...

  7. Radiosensitivity of mesothelioma cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Haekkinen, A.M. [Dept. of Oncology, Univ. Central Hospital, Helsinki (Finland); Laasonen, A. [Dept. of Pathology, Central Hospital of Etelae-Pohjanmaa, Seinaejoki (Finland); Linnainmaa, K. [Dept. of Industrial Hygiene and Toxicology, Inst. of Occupational Health, Helsinki (Finland); Mattson, K. [Dept. Pulmonary Medicine, Univ. Central Hospital, Helsinki (Finland); Pyrhoenen, S. [Dept. of Oncology, Univ. Central Hospital, Helsinki (Finland)

    1996-10-01

    The present study was carried out in order to examine the radiosensitivity of malignant pleural mesothelioma cell lines. Cell kinetics, radiation-induced delay of the cell cycle and DNA ploidy of the cell lines were also determined. For comparison an HeLa and a human foetal fibroblast cell line were simultaneously explored. Six previously cytogenetically and histologically characterized mesothelioma tumor cell lines were applied. A rapid tiazolyl blue microtiter (MTT) assay was used to analyze radiosensitivity and cell kinetics and DNA ploidy of the cultured cells were determined by flow cytometry. The survival fraction after a dose of 2 Gy (SF2), parameters {alpha} and {beta} of the linear quadratic model (LQ-model) and mean inactivation dose (D{sub MID}) were also estimated. The DNA index of four cell lines equaled 1.0 and two cell lines equaled 1.5 and 1.6. Different mesothelioma cell lines showed a great variation in radiosensitivity. Mean survival fraction after a radiation dose of 2 Gy (SF2) was 0.60 and ranged from 0.36 to 0.81 and mean {alpha} value was 0.26 (range 0.48-0.083). The SF2 of the most sensitive diploid mesothelioma cell line was 0.36: Less than that of the foetal fibroblast cell line (0.49). The survival fractions (0.81 and 0.74) of the two most resistant cell lines, which also were aneuploid, were equal to that of the HeLa cell line (0.78). The {alpha}/{beta} ratios of the most sensitive cell lines were almost an order of magnitude greater than those of the two most resistant cell lines. Radiation-induced delay of the most resistant aneuploid cell line was similar to that of HeLa cells but in the most sensitive (diploid cells) there was practically no entry into the G1 phase following the 2 Gy radiation dose during 36 h. (orig.).

  8. Effects of glutathione depletion by buthionine sulfoximine on radiosensitization by oxygen and misonidazole in vitro

    International Nuclear Information System (INIS)

    Shrieve, D.C.; Denekamp, J.; Minchinton, A.I.

    1985-01-01

    Buthionine sulfoximine (BSO) has been used to deplete glutathione (GSH) in V79-379A cells in vitro, and the effect on the efficiency of oxygen and misonidazole (MISO) as radiosensitizers has been determined. Treatment with 50 or 500 μM BSO caused a rapid decline in GSH content to less than 5% of control values after 10 hr of exposure. Removal of BSO resulted in a rapid regeneration of GSH after 50 μM BSO, but little regeneration was observed over the subsequent 10-hr period after 500 μM. Cells irradiated in monolayer on glass had an oxygen enhancement ratio (OER) of 3.1. After 10-14 hr pretreatment with 50 μM BSO, washed cells were radiosensitized by GSH depletion at all oxygen tensions tested. The OER was reduced to 2.6, due to greater radiosensitization of hypoxic cells than aerated ones by GSH depletion. In similar experiments performed with MISO, an enhancement ratio of 2.0 could be achieved with 0.2 mM MISO in anoxic BSO-pretreated cells, compared to 2.7 mM MISO in non-BSO-treated cells. These apparent increases in radiosensitizer efficiency in GSH-depleted cells could be explained on the basis of radiosensitization of hypoxic cells by GSH depletion alone. These results are consistent with hypoxic cell radiosensitization by GSH depletion and by MISO or oxygen acting by separate mechanisms

  9. Effect of Gamma Radiation on Amino Acid Based Vesicle Carrying Radiosensitizer

    International Nuclear Information System (INIS)

    Nur Ratasha Alia Mohd Rosli; Faizal Mohamed; Muhammad Amir Syafiq Mohd Sah; Irman Abdul Rahman

    2014-01-01

    Vesicles has been developed and studied to be used as a medium to transport radiosensitizer in treating cancer cells by increasing its sensitivity effectively towards the radiation given during radiotherapy. This study was conducted to investigate the effect of gamma radiation on amino acid-based vesicle carrying radiosensitizer. Amino acid based vesicles carrying radiosensitizer were synthesized using sonication method with sodium N-lauroylsarcosinate hydrate and decanol being the primary surfactant, while hydrogen peroxide and sodium hyaluronate as the encapsulated radiosensitizer. The synthesized vesicle was then irradiated at radiation doses equivalent to those given during radiotherapy. Irradiated vesicle carrying radiosensitizer were then characterized using Transmission Electron Microscopy (TEM), Fourier Transform Infrared Spectroscopy (FTIR) and Polarized Light Microscope. Results obtained shows that there were no significant changes in morphology and molecular conformation of the synthesized vesicle after irradiation. Even at higher radiation dose of 100 Gray and 200 Gray, the results remained unchanged. This indicates that the synthesized vesicle carrying radiosensitizer is morphologically and spectroscopically stable even at high radiation doses. (author)

  10. Radiosensitivity of mouse germ cells

    International Nuclear Information System (INIS)

    Matsuda, Yoichi; Takeuchi, Toyoko; Maemori, Mamiko; Seki, Naohiko; Tobari, Izuo

    1991-01-01

    To estimate radiosensitivity of mouse germ cells the analysis of chromosome aberrations was performed at diakinesis-metaphase I of spermatocytes and first-cleavage metaphase of one-cell embryos after exposure to radiations at various stages of primary spermatocytes and spermatids. The result provided evidence that there are two major types of DNA damage in X-irradiated sperm : (1) short-lived DNA lesions ; the lesions are subject to repair inhibition by agents added in G 1 , and are converted into chromosome-type aberrations during G 1 , and (2) long-lived DNA lesions ; the lesions persist until S phase and repair of the lesions is inhibited by caffeine, hydroxyurea and arabinofuranosyl cytosine in G 2 . The characteristic of X-ray damage induced in spermiogenic stage and repair mechanism for the damage in the fertilized egg were discussed comparing with the results with two chemicals, methyl methanesulfonate (MMS) and mitomycin C (MMC). (J.P.N.)

  11. The dependence of fibroblast radiosensitivity on cell pH

    International Nuclear Information System (INIS)

    Veksler, A.M.; Kublik, L.N.; Degtyareva, O.V.; Ehjdus, L.Kh.

    1983-01-01

    The problem of the change of radiosensitivity of Chinese hamster fibroblasts, irradiated under aerobic and hypoxic conditions in the course of intracellular pH (pHsub(intr.)) change by means of a phosphate buffer has been studied. It has been found that pHsub(intr.) reduction considerably increases the radiosensitivity, the effect being more pronounced on hypoxic cells which is essential for radiotherapy of tumors. The survival rate of cell irradiated under hypoxia conditions does not depend on season while cell resistance in case of irradiation in open air in spring and autumn is different. The effect discovery in case of pHsub(intr.) reduction upon irradiation shows up the influence of the studied factor on repair processes

  12. The inherited basis of human radiosensitivity

    Energy Technology Data Exchange (ETDEWEB)

    Gatti, R.A. [Univ. of California, School of Medicine, Los Angeles, CA (United States). Experimental Pathology

    2001-11-01

    Certain individuals cannot tolerate 'conventional' doses of radiation therapy. This is known to be true of patients with ataxia-telangiectasia and ligase IV deficiency. Although in vitro testing may not correlate completely with clinical radiosensitivity, fibroblasts and lymphoblasts from patients with both of these disorders have been clearly shown to be radiosensitive. Using a colony survival assay (CSA) to test lymphoblastoid cells after irradiation with 1 Gy, a variety of other genetic disorders have been identified as strong candidates for clinical radiosensitivity, such as Nijmegen breakage syndrome, Mre11 deficiency, and Fanconi's anemia. These data are presented and considered as a starting-point for the inherited basis of human radiosensitivity.

  13. Comparative radiosensitivity in the class insecta

    International Nuclear Information System (INIS)

    Willard, W.K.; Cherry, D.S.

    1975-01-01

    A 'radiosensitivity index' (LT 50 /mean longevity) was correlated with the mean longevity and dry weight of 37 insect species (both sexes of 12 species) representing eight orders. Curvilinear regression analysis relating radiosensitivity to mean longevity and mean dry weight indicated that 46.3% of the observed variation could be attributed to longevity and 32.6% to the dry weight of the species. In general, large long-lived adults were more radiosensitive than small short-lived adults. Correlation of the phylogeny of insect orders and order groupings with the radio-sensitivity index was found to be poor. However, when the index was related to longevity, there was a tendency for species comprising the major orders investigated to occur in groups along the predicted curve. (author)

  14. Radiosensitization: enhancing the radiation inactivation of foodborne bacteria

    Science.gov (United States)

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

    2004-09-01

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

  15. Misonidazole radiosensitization in vivo: A therapeutic gain by penicillin pretreatment

    International Nuclear Information System (INIS)

    Sheldon, P.W.; Clarke, C.; Dawson, K.B.; Simpson, W.; Simmons, D.J.C.; Adams, G.E.

    1984-01-01

    Because intestinal microflora have the potential to metabolize nitroimidazole compounds (possibly to toxic species), the authors investigated their influence on the pharmacological, neurotoxic and radiosensitizing properties of misonidazole (MIS) in mice. This was done by comparing the responses obtained in 'normal' mice to those obtained in mice whose microflora had been depleted by pretreatment for 7-14 days with penicillin (PEN) at the rate of 0.5g/1 of drinking water. Bacteriological studies showed this treatment to C57B1 mice eliminated more than 99% of the flora from the caeca and, furthermore, this efficacy of penicillin was not interfered with by MIS administered IP at 0.3mg/g between days 7-14. This pretreatment resulted not only in the elimination of the caecal flora, but also in an increase in the pharmacokinetic exposure to MIS, an increase in Lewis lung tumour radiosensitization by MIS and a decrease in MIS-induced neurotoxicity. The authors conclude pretreatment with PEN can give a therapeutic gain with MIS radiosensitization. Further, assuming no direct interaction between the PEN and MIS, these findings indicate that the intestinal flora may produce neurotoxic species by their metabolism of MIS

  16. Radiosensitization: enhancing the radiation inactivation of foodborne bacteria

    Energy Technology Data Exchange (ETDEWEB)

    Borsa, J. E-mail: jborsa@mds.nordion.com; Lacroix, M.; Ouattara, B.; Chiasson, F

    2004-10-01

    Irradiation of meat products to kill pathogens can be limited by radiation-induced detriment of sensory quality. Since such detriment is directly related to dose, one approach to reduce it is by devising means to lower the dose of radiation required for processing. Increasing the radiation sensitivity of the target microorganisms would lower the dose required for a given level of microbial kill. In this work, the radiation sensitivities of inoculated Escherichia coli and Salmonella typhi in ground beef were examined under a variety of conditions. Results showed that specific manipulations of treatment conditions significantly increased the radiation sensitivity of the test organisms, ranging from a few percent to several-fold reduction in D{sub 10}. In particular, radiation sensitization could be effected by certain additives, including carvacrol, thymol and trans-cinnamaldehyde, and also by certain compositions of modified atmosphere in the package headspace. A combination of additives and modified atmosphere effected a greater radiosensitization effect than could be achieved by either factor applied alone. Radiosensitization could be demonstrated with irradiation of either fresh or frozen ground meat. The radiosensitization phenomenon may be of practical utility in enhancing the technical effectiveness and feasibility of irradiation of a variety of meat and other food products.

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

    Science.gov (United States)

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

    2015-11-01

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

  18. Intermittent Theta-Burst Stimulation of the Lateral Cerebellum Increases Functional Connectivity of the Default Network

    Science.gov (United States)

    Farzan, Faranak; Eldaief, Mark C.; Schmahmann, Jeremy D.; Pascual-Leone, Alvaro

    2014-01-01

    Cerebral cortical intrinsic connectivity networks share topographically arranged functional connectivity with the cerebellum. However, the contribution of cerebellar nodes to distributed network organization and function remains poorly understood. In humans, we applied theta-burst transcranial magnetic stimulation, guided by subject-specific connectivity, to regions of the cerebellum to evaluate the functional relevance of connections between cerebellar and cerebral cortical nodes in different networks. We demonstrate that changing activity in the human lateral cerebellar Crus I/II modulates the cerebral default mode network, whereas vermal lobule VII stimulation influences the cerebral dorsal attention system. These results provide novel insights into the distributed, but anatomically specific, modulatory impact of cerebellar effects on large-scale neural network function. PMID:25186750

  19. Hypertrophic stimulation increases beta-actin dynamics in adult feline cardiomyocytes.

    Directory of Open Access Journals (Sweden)

    Sundaravadivel Balasubramanian

    2010-07-01

    Full Text Available The myocardium responds to hemodynamic stress through cellular growth and organ hypertrophy. The impact of cytoskeletal elements on this process, however, is not fully understood. While alpha-actin in cardiomyocytes governs muscle contraction in combination with the myosin motor, the exact role of beta-actin has not been established. We hypothesized that in adult cardiomyocytes, as in non-myocytes, beta-actin can facilitate cytoskeletal rearrangement within cytoskeletal structures such as Z-discs. Using a feline right ventricular pressure overload (RVPO model, we measured the level and distribution of beta-actin in normal and pressure overloaded myocardium. Resulting data demonstrated enriched levels of beta-actin and enhanced translocation to the Triton-insoluble cytoskeletal and membrane skeletal complexes. In addition, RVPO in vivo and in vitro hypertrophic stimulation with endothelin (ET or insulin in isolated adult cardiomyocytes enhanced the content of polymerized fraction (F-actin of beta-actin. To determine the localization and dynamics of beta-actin, we adenovirally expressed GFP-tagged beta-actin in isolated adult cardiomyocytes. The ectopically expressed beta-actin-GFP localized to the Z-discs, costameres, and cell termini. Fluorescence recovery after photobleaching (FRAP measurements of beta-actin dynamics revealed that beta-actin at the Z-discs is constantly being exchanged with beta-actin from cytoplasmic pools and that this exchange is faster upon hypertrophic stimulation with ET or insulin. In addition, in electrically stimulated isolated adult cardiomyocytes, while beta-actin overexpression improved cardiomyocyte contractility, immunoneutralization of beta-actin resulted in a reduced contractility suggesting that beta-actin could be important for the contractile function of adult cardiomyocytes. These studies demonstrate the presence and dynamics of beta-actin in the adult cardiomyocyte and reinforce its usefulness in measuring

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

    International Nuclear Information System (INIS)

    Jacquet, P.; Grinfeld, S.

    1990-01-01

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

  1. A novel magnetic stimulator increases experimental pain tolerance in healthy volunteers - a double-blind sham-controlled crossover study.

    Directory of Open Access Journals (Sweden)

    Rudie Kortekaas

    Full Text Available UNLABELLED: The 'complex neural pulse'(TM (CNP is a neuromodulation protocol employing weak pulsed electromagnetic fields (PEMF. A pioneering paper reported an analgesic effect in healthy humans after 30 minutes of CNP-stimulation using three nested whole head coils. We aimed to devise and validate a stimulator with a novel design entailing a multitude of small coils at known anatomical positions on a head cap, to improve applicability. The main hypothesis was that CNP delivery with this novel device would also increase heat pain thresholds. Twenty healthy volunteers were enrolled in this double-blind, sham-controlled, crossover study. Thirty minutes of PEMF (CNP or sham was applied to the head. After one week the other treatment was given. Before and after each treatment, primary and secondary outcomes were measured. Primary outcome was heat pain threshold (HPT measured with thermal quantitative sensory testing. Other outcomes were warmth detection threshold, and aspects of cognition, emotion and motor performance. As hypothesized heat pain threshold was significantly increased after the PEMF stimulation. All other outcomes were unaltered by the PEMF but there was a trend level reduction of cognitive performance after PEMF stimulation as measured by the digit-symbol substitution task. Results from this pilot study suggest that our device is able to stimulate the brain and to modulate its function. This is in agreement with previous studies that used similar magnetic field strengths to stimulate the brain. Specifically, pain control may be achieved with PEMF and for this analgesic effect, coil design does not appear to play a dominant role. In addition, the flexible configuration with small coils on a head cap improves clinical applicability. TRIAL REGISTRATION: Dutch Cochrane Centre NTR1093.

  2. AMRI-59 has a role of radiosensitizer via enhancement of γ-ionizing radiation-induced apoptotic cell death

    Energy Technology Data Exchange (ETDEWEB)

    Hong, Wan Gi; Cho, Jeong Hyun; Kim, Ju Yeon; Hwang, Sang Gu; Um, Hong Duck; Park, Jong Kuk [KAERI, Daejeon (Korea, Republic of)

    2016-05-15

    Recent in vitro studies have suggested that may increase the invasiveness of some cancer cells (e.g., glioma, hepatocellular carcinoma, and pancreatic cancer cells) by stimulating several intracellular signaling pathways and in vivo studies have found that radiotherapy of primary tumor sites may promote metastasis. Thus, in addition to having therapeutic effects, IR might promote the malignant traits of surviving cancer cells. The existing efforts to develop radiosensitizing agents have focused on overcoming radioresistance and reducing damage to normal tissues. Recently, concepts of personalized- or precision medicine are developed due to advancement of mega data technique, which provide new targets to develop new anti-cancer drugs. In this study, we sought to identify the radiosensitizer effect of AMRI-59 in vitro and in vivo., which is recently developed specific inhibitor of peroxiredoxin (Prx) I. AMRI-59 enhanced radiation-induced cell death and its mean calculated dose enhancement ratio was 1.26. We also found combination of AMRI-59 and IR In a xenograft assay, the combined PHCM and radiation group showed 14.3 days of growth delay versus the control in terms of tumor growth. The enhancement factor of this combined treatment was determined to be 2.03.

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

    Energy Technology Data Exchange (ETDEWEB)

    Kleiman, Norman Jay [Columbia University

    2013-11-30

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

  4. Study of radiosensitization of chloroquine on esophageal cancer cell line

    International Nuclear Information System (INIS)

    Yuan Xiaoli; Li Tao; Huang Jianming; Zha Xiao; Deng Bifang; Lang Jinyi

    2014-01-01

    Objective: To investigate the possibility of chloroquine radiosensitization of esophageal cancer cell line TE-1 and its further mechanism. Methods: Effect of chloroquine on cell viability of TE-1 cells was determined by MTT method. Expression of LC3, Beclin-1 and formation of acidic vesicular organelles (AVOs) were determined by Western blot, and fluorescence staining with Lyso-Tracker Red DND-99, respectively. Clonogenic survival of TE-1 cells was examined by clonogenic forming assay. Results: Chloroquine showed dose-dependent inhibition of TE-1 cell growth, and its values of IC_5_0 and IC_1_0 were (72.33±5.28) and (15.42±3.33) μmol/L, respectively. The expression of Beclin-1 and LC3-II/I markedly increased in irradiated TE-1 cells. The addition of chloroquine with IC_1_0 concentration significantly reduced the fluorescence and intensity of AVOs accumulation in the cytoplasm of TE-1 cells. Clonogenic survival fraction decreased obviously in TE-1 cells with addition of chloroquine after radiation and the value of SERD0 was 1.439. Conclusions: Chloroquine could radiosensitize esophageal cancer cells by blocking autophagy-lysosomal pathway and be used as a potential radiosensitizing strategy. (authors)

  5. Increasing the Stimulation Dose of rFSH in Unexpected Poor Responders Is Not Associated with Better IVF Outcome

    Directory of Open Access Journals (Sweden)

    Levent Tutuncu

    2012-01-01

    Full Text Available The aim of this retrospective study is to determine whether increasing the stimulation dose of rFSH in unexpected poor responders is associated with better in vitro fertilization (IVF outcome or not. A total of forty eligible women who fulfilled our definition of poor responders and who did not achieve an ongoing pregnancy in the first cycle and returned for a second higher rFSH dose IVF cycle with a long-agonist protocol were included to the study. The first low-dose cycles and the second high-dose cycles were compared to each other. Main outcome measures of the study were duration of stimulation, number of follicles, number of oocytes retrieved, number of embryos, and E2 level on day of hCG injection. There were no significant differences in duration of stimulation, number of follicles, number of oocytes retrieved, number of embryos, and E2 level on day of hCG injection between the first low- and second high-dose cycles. Daily dose and total dose of rFSH were significantly higher in the second high-dose cycles. Increasing the dose of rFSH in a second stimulation cycle after first unsuccessful treatment cycle will add only to the cost and discomfort of the treatment and might adversely affect pregnancy rates.

  6. Red kidney bean (Phaseolus vulgaris lectin stimulation increases the number of enterochromaffin cells in the small intestine of suckling piglets

    Directory of Open Access Journals (Sweden)

    Zacharko-Siembida Anna

    2014-06-01

    Full Text Available The quantities and distribution patterns of serotonin-immunoreactive (serotonin-IR enterochromaffin cells (EC were studied immunohistochemically in the small intestine of suckling piglets stimulated with red kidney bean lectin, and in nonstimulated, control animals. The co-expression patterns of serotonin with somatostatin (SOM or corticotropin releasing-factor (CRF were also studied. After the lectin treatment, the increased numbers of EC were noted in the duodenum of experimental animals. Lectin stimulation did not change the proportions of EC in the jejunum and ileum. In the duodenal epithelium of the lectin-stimulated piglets, the vast majority of serotonin-IR EC were distributed at the basis of crypts. After the lectin administration, the proportions of serotonin-IR/SOM-IR EC were statistically similar in all sections of the small intestine. No upregulation of CRF was found in duodenal, jejunal, and ileal EC of lectin-treated animals. The findings demonstrated that red kidney bean lectin increased the serotonin reservoir in the duodenum, and thus may be an effective stimulant of the gut maturation in suckling mammals.

  7. THE IMPACT OF FERTILIZATION AND FOLIAR STIMULATION PRODUCTS BOTH ON INCREASING THE RESISTANCE TO MAJOR PHYTOPATHOGENS ATTACKS, AND ON INCREASING THE QUANTITY AND QUALITY OF WINE GRAPES HARVEST

    Directory of Open Access Journals (Sweden)

    Cristina BUNESCU

    2014-12-01

    Full Text Available The paper aimed to demonstrate the impact of fertilization and foliar stimulation products both on increasing the resistance to major phytopathogens attacks, and on increasing the quantity and quality of wine grapes harvest. Applying the foliar fertilizer products Plonvit Kali (c1, Tytanit (c2 and Optysil (c3 to vines, for a period of three years (2011/2013, in phenophases of intensive growth of shoots and grapes at approved dosages, simultaneously with pesticide treatment, not only a reduction of pathogenic fungi attack was obtained, but also and an increase of harvest without diminishing the quality of the grapes.

  8. Quinapril treatment increases insulin-stimulated endothelial function and adiponectin gene expression in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Hermann, Thomas S; Li, Weijie; Dominguez, Helena

    2005-01-01

    OBJECTIVE: Angiotensin-converting enzyme inhibitors reduce cardiovascular mortality and improve endothelial function in type 2 diabetic patients. We hypothesized that 2 months of quinapril treatment would improve insulin-stimulated endothelial function and glucose uptake in type 2 diabetic subjects...... and simultaneously increase the expression of genes that are pertinent for endothelial function and metabolism. METHODS: Twenty-four type 2 diabetic subjects were randomized to receive 2 months of quinapril 20 mg daily or no treatment in an open parallel study. Endothelium-dependent and -independent vasodilation...... occlusion plethysmography. Gene expression was measured by real-time PCR. RESULTS: Quinapril treatment increased insulin-stimulated endothelial function in the type 2 diabetic subjects (P = 0.005), whereas forearm glucose uptake was unchanged. Endothelial function was also increased by quinapril (P = 0...

  9. Functioning heterotopic grey matter? Increased blood flow with voluntary movement and sensory stimulation

    International Nuclear Information System (INIS)

    Shimodozono, M.; Kawahira, K.; Tanaka, N.

    1995-01-01

    Heterotopic grey matter has never been reported to have any neuronal function other than as an epileptic focus. However, recent advances in measurement of regional cerebral blood flow (rCBF) and cerebral metabolism have enabled us to assess localised function and functional changes of the brain. We saw a patient with cerebral haemorrhage with bilateral heterotopic grey matter. No neurological deficits or seizures were present before the haemorrhage. To establish the function of the heterotopic grey matter, we studied changes in their rCBF during voluntary movement and sensory stimulation of unilateral extremities using xenon-CT (Xe-CT). (orig.)

  10. Increased electrical nerve stimulation threshold of the sciatic nerve in patients with diabetic foot gangrene: a prospective parallel cohort study.

    Science.gov (United States)

    Keyl, Cornelius; Held, Tanja; Albiez, Georg; Schmack, Astrid; Wiesenack, Christoph

    2013-07-01

    Peripheral neuropathy may affect nerve conduction in patients with diabetes mellitus. This study was designed to test the hypothesis that the electrical stimulation threshold for a motor response of the sciatic nerve is increased in patients suffering from diabetic foot gangrene compared to non-diabetic patients. Prospective non-randomised trial with two parallel groups. Two university-affiliated hospitals. Patients scheduled for surgical treatment of diabetic foot gangrene (n = 30) and non-diabetic patients (n = 30) displaying no risk factors for neuropathy undergoing orthopaedic foot or ankle surgery. The minimum current intensity required to elicit a typical motor response (dorsiflexion or eversion of the foot) at a pulse width of 0.1 ms and a stimulation frequency of 1 Hz when the needle tip was positioned under ultrasound control directly adjacent to the peroneal component of the sciatic nerve. The non-diabetic patients were younger [64 (SD 12) vs. 74 (SD 7) years] and predominantly female (23 vs. 8). The geometric mean of the motor stimulation threshold was 0.26 [95% confidence interval (95% CI) 0.24 to 0.28] mA in non-diabetic and 1.9 (95% CI 1.6 to 2.2) mA in diabetic patients. The geometric mean of the electrical stimulation threshold was significantly (P diabetic compared to non-diabetic patients. The electrical stimulation threshold for a motor response of the sciatic nerve is increased by a factor of 7.2 in patients with diabetic foot gangrene, which might hamper nerve identification.

  11. Increased resistance to sudden noise by audio stimulation during early ontogeny in German shepherd puppies.

    Directory of Open Access Journals (Sweden)

    Helena Chaloupková

    Full Text Available The period of early ontogeny constitutes a time when the physical immaturity of an organism is highly susceptible to external stimuli. Thus, early development plays a major role in shaping later adult behavior. The aim of the study was to check whether stimulating puppies at this early stage in life with sound would improve their responsiveness towards unfamiliar noises during the selection process of the police behavioral test for puppies. The cohort comprised 37 puppies from the litters of three mothers. At the commencement of the experiment the dogs were aged 16 days, rising to the age of 32 days at its close. The mothers and litters of the treatment group were either exposed to radio broadcasts, (see below; three litters totaling 19 puppies, while the control group was not exposed to any radio programs (eight litters totaling 18 puppies. All three mothers had previously experienced both auditory circumstances, as described herein. Ordinary radio broadcasts were played to the puppies in the treatment group three times a day for 20 minute periods, always during feeding time. The cohort was subjected to the so-called Puppy Test, i.e. analysis of the potential of each animal, once the dogs had reached the age of 7 weeks. Such tests included exposure to a sudden noise caused by a shovel (100 dB, noise when alone in a room, and response to loud distracting stimuli (the latter two at 70 dB. Said tasks were rated by the same analyst on a scale of 0-5 points; the better the response of the dog, the higher the score given. The differences between the treatment and control groups were analyzed via Mixed Models (PROC MIXED in SAS. The animals comprising the treatment group responded with a higher score to the sudden noise caused by the shovel than the control dogs (P<0.01. Interestingly, gender was seen to affect response, with the males scoring more than the females (P<0.1. In conclusion, the results suggested that audio stimulation early in life

  12. The potential role of G2- but not of G0-radiosensitivity for predisposition of prostate cancer

    International Nuclear Information System (INIS)

    Borgmann, Kerstin; Raabe, Annette; Reuther, Sebastian; Szymczak, Silke; Schlomm, Thorsten; Isbarn, Hendrik; Gomolka, Maria; Busjahn, Andreas; Bonin, Michael; Ziegler, Andreas; Dikomey, Ekkehard

    2010-01-01

    Purpose: Comparing the chromosomal radiosensitivity of prostate cancer patients with that of healthy donors. Materials and methods: The study was performed on 81 prostate cancer patients characterised by a clinical stage of predominantly pT2c or pT3a and a median age of 67 years. As healthy donors 60 male monozygotic twin pairs were recruited with a median age of 28 years. Chromosomal radiosensitivity was measured using both G0- and G2-assay. Results: No difference between healthy donors and prostate cancer patients was detected concerning G0-radiosensitivity, since medians were similar (Hodges-Lehmann estimate: -0.05, 95% CI: -0.18-0.08, p = 0.4167). However, a pronounced difference was determined for G2-radiosensitivity with prostate cancer patients showing a significantly higher sensitivity compared to healthy donors (Hodges-Lehmann estimate: -0.41, 95% CI: -0.53 to -0.30, p = 1.75 -9 ). Using the 90% quantile of G2-radiosensitivity in healthy donors as a threshold for discrimination the fraction of prostate cancer patients with elevated radiosensitivity increased to 49%. Conclusion: G2-, but not G0-radiosensitivity is a promising marker for predisposition of prostate cancer.

  13. Iodine stimulates estrogen receptor singling and its systemic level is increased in surgical patients due to topical absorption.

    Science.gov (United States)

    He, Shaohua; Wang, Bingchan; Lu, Xiyi; Miao, Suyu; Yang, Fengming; Zava, Theodore; Ding, Qiang; Zhang, Shijiang; Liu, Jiayin; Zava, David; Shi, Yuenian Eric

    2018-01-02

    Iodine is crucial for thyroid hormone production. However, recent epidemiologic studies have shown that breast cancer patients have an elevated risk of developing thyroid cancer and vice versa. A notable finding in this study is that iodine stimulated the transcriptional activity of estrogen receptor-α (ER-α) in breast cancer cells. Iodine stimulated expression of several ER-α regulated gene including PS2 , Cathepsin D , CyclinD1 , and PR both in vitro and in nude mice, which is consistent with its stimulation of both anchorage-dependent and -independent growth of ER-α positive breast cancer cells and the effect to dampen tumor shrinkage of MCF-7 xenograft in ovariectomized nude mice. Analyses of clinical urine samples from breast cancer patients undergoing surgery demonstrated that urinary iodine levels were significantly higher than that in controls; and this increased level is due to the antiseptic use of iodine during breast surgery. The present study indicates that excess iodine intake may be an unfavorable factor in breast cancer by stimulation of ER-α transcriptional activity.

  14. Increases in cellular calcium concentration stimulate pepsinogen secretion from dispersed chief cells

    International Nuclear Information System (INIS)

    Raufman, J.P.; Berger, S.; Cosowsky, L.; Straus, E.

    1986-01-01

    Intracellular calcium concentration ([Ca]i) and pepsinogen secretion from dispersed chief cells from guinea pig stomach were determined before and after stimulation with calcium ionophores. [Ca]i was measured using the fluorescent probe quin2. Basal [Ca]i was 105 +/- 4 nM. Pepsinogen secretion was measured with a new assay using 125 I-albumin substrate. This assay is 1000-fold more sensitive than the widely-used spectrophotometric assay, technically easy to perform, rapid, and relatively inexpensive. The kinetics and stoichiometry of ionophore-induced changes in [Ca]i and pepsinogen secretion were similar. These data support a role for calcium as a cellular mediator of pepsinogen secretion

  15. Herbivorous snails can increase water clarity by stimulating growth of benthic algae.

    Science.gov (United States)

    Zhang, Xiufeng; Taylor, William D; Rudstam, Lars G

    2017-11-01

    Eutrophication in shallow lakes is characterized by a switch from benthic to pelagic dominance of primary productivity that leads to turbid water, while benthification is characterized by a shift in primary production from the pelagic zone to the benthos associated with clear water. A 12-week mesocosm experiment tested the hypothesis that the herbivorous snail Bellamya aeruginosa stimulates the growth of pelagic algae through grazing on benthic algae and through accelerating nutrient release from sediment. A tube-microcosm experiment using 32 P-PO 4 as a tracer tested the effects of the snails on the release of sediment phosphorus (P). The mesocosm experiment recorded greater total nitrogen (TN) concentrations and a higher ratio of TN:TP in the overlying water, and a higher light intensity and biomass of benthic algae as measured by chlorophyll a (Chl a) in the snail treatment than in the control. Concentrations of total phosphorus (TP), total suspended solids (TSSs), and inorganic suspended solids (ISSs) in the overlying water were lower in the snail treatment than in the control, though no significant difference in Chl a of pelagic algae between the snail treatment and control was observed. In the microcosm experiment, 32 P activity in the overlying water was higher in the snail treatment than in the control, indicating that snails accelerated P release from the sediment. Our interpretation of these results is that snails enhanced growth of benthic algae and thereby improved water clarity despite grazing on the benthic algae and enhancing P release from the sediment. The rehabilitation of native snail populations may therefore enhance the recovery of eutrophic shallow lakes to a clear water state by stimulating growth of benthic algae.

  16. Comparison of side effects of pentagastrin test and calcium stimulation test in patients with increased basal calcitonin concentration: the gender-specific differences.

    Science.gov (United States)

    Ubl, Philipp; Gincu, Tatiana; Keilani, Mohammad; Ponhold, Lothar; Crevenna, Richard; Niederle, Bruno; Hacker, Marcus; Li, Shuren

    2014-08-01

    The aim of this study was to compare the side effects of the pentagastrin test and the calcium stimulation test in patients with increased basal calcitonin concentration, especially the gender-specific differences of side effects. A total of 256 patients (123 females and 133 males, mean age of 56 ± 27 years, range 21-83 years) had both pentagastrin and calcium stimulation tests. All patients filled in a questionnaire regarding the side effects within 30 min after completion of the stimulation tests. The differences of side effects between female and male patients as well as between the pentagastrin stimulation test and the calcium stimulation test were evaluated. Warmth feeling was the most frequent occurring side effect in all patients who had both pentagastrin and calcium stimulation tests, followed by nausea, altered gustatory sensation, and dizziness. The incidences of urgency to micturate (p stimulation test. Significant higher incidences of urgency to micturate (p stimulation test as compared with those by pentagastrin test in female patients. The incidences of nausea (p stimulation test than by calcium stimulation test. There is a significant gender-specific difference in side effects induced by calcium stimulation test. Female patients have fewer side effects by pentagastrin test than by calcium stimulation test. Male patients may tolerate the calcium stimulation test better than the pentagastrin test.

  17. Pronounced radiosensitization of cultured human cancer cells by COX inhibitor under acidic microenvironment

    International Nuclear Information System (INIS)

    Shah, Tushar; Ryu, Samuel; Lee, Ho Jun; Brown, Stephen; Kim, Jae Ho

    2002-01-01

    Purpose: To demonstrate the influence of pH on the cytotoxicity and radiosensitization by COX (cyclooxygenase) -1 and -2 inhibitors using established human cancer cells in culture. Methods and Materials: Nonselective COX inhibitor, ibuprofen (IB), and selective COX-2 inhibitor, SC-236, were used to determine the cytotoxicity and radiosensitization at varying pH of culture media. Human colon carcinoma cell line (HT-29) was exposed to the drug alone and in combination with radiation at different pH of the cell culture media. The end point was clonogenic ability of the single-plated cells after the treatment. Results: Cytotoxicity and radiosensitization of IB increased with higher drug concentration and longer exposure time. The most significant radiosensitization was seen with IB (1.5 mM) for 2-h treatment at pH 6.7 before irradiation. The dose-modifying factor as defined by the ratio of radiation doses required to achieve the same effect on cell survival was 1.8 at 10% survival level. In contrast, SC-236 (50 μM for 2-8 h) showed no pH-dependent cytotoxicity. There was modest increase in the cell killing at lower doses of radiation. Conclusion: An acidic pH was an important factor affecting the increased cytotoxicity and radiosensitization by ibuprofen. Radiation response was enhanced at shoulder portion of the cell survival curve by selective COX-2 inhibitor

  18. Radiosensitivity in cultured human fibroblasts

    International Nuclear Information System (INIS)

    Cox, R.; Masson, W.K.

    1980-01-01

    Caution is urged in the use of freshly isolated cultures of human diploid fibroblasts for quantitative studies of radiosensitivity. The distribution of x ray sensitivities of 'normal' human fibroblast cultures of foetal origin (10 subjects, skin or lung biopsy) and post-foetal origin (34 subjects, skin biopsy) are compared with the distribution in 12 patients with ataxia telangiectasia (probability of including any one of these in a normal post-foetal distribution is 0.01%). Cultures from nominally normal subjects showed a broad distribution of D 0 range of 98 +- 160 rad and assuming normal distribution, a mean +- one standard deviation of 122 +- 17 rad. Mean D 0 values for foetal origin cultures were 117 +- 12; values for post-foetal cultures D 0 were 124 +- 18. No systematic variation in D 0 was observed for age of donor, number of cell divisions in culture or for cloning efficiency. For ataxia telangiectasia D 0 values were 46 +- 7 rad. (U.K.)

  19. DNA damage repair and radiosensitivity

    International Nuclear Information System (INIS)

    Suzuki, Norio

    2003-01-01

    Tailored treatment is not new in radiotherapy; it has been the major subject for the last 20-30 years. Radiation responses and RBE (relative biological effectiveness) depend on assay systems, endpoints, type of tissues and tumors, radiation quality, dose rate, dose fractionation, physiological and environmental factors etc, Latent times to develop damages also differ among tissues and endpoints depending on doses and radiation quality. Recent progress in clarification of radiation induced cell death, especially of apoptotic cell death, is quite important for understanding radiosensitivity of tumor cure process as well as of tumorigenesis. Apoptotic cell death as well as dormant cells had been unaccounted and missed into a part of reproductive cell death. Another area of major progress has been made in clarifying repair mechanisms of radiation damage, i.e., non-homologous end joining (NHEJ) and homologous recombinational repair (HRR). New approaches and developments such as cDNA or protein micro arrays and so called informatics in addition to basic molecular biological analysis are expected to aid identifying molecules and their roles in signal transduction pathways, which are multi-factorial and interactive each other being involved in radiation responses. (authors)

  20. Impact of homologous recombination on individual cellular radiosensitivity

    International Nuclear Information System (INIS)

    Koch, Kerstin; Wrona, Agnieszka; Dikomey, Ekkehard; Borgmann, Kerstin

    2009-01-01

    Purpose: Individual radiosensitivity as measured with in vitro irradiated lymphocytes using metaphase analysis can predict the risk of normal tissue effects after radiotherapy. This parameter is considered to be primarily determined by the cellular repair capacity of DNA double-strand breaks (DSBs). It is now tested to which extent this capacity also depends on homologous recombination (HR), which is a pathway available when cells are in S/G2 phase. Methods: Experiments were performed with CHO K1 cells, in which HR was suppressed via knock-down of RAD51 using RNA interference (RNAi). RAD51 was measured via western and foci formation, cell survival by colony forming, DSBs by γH2AX foci formation, and chromosomal damage using PCC, G0 or G2 assay. Results: In quiescent G1 cells DSB repair is completed 6 h after irradiation. But there is still a substantial fraction of non-repaired DSBs. Most of these DSBs are repaired when G1 cells are stimulated into cell cycle. Suppression of HR by down-regulation of RAD51 did not affect this repair. In contrast, repair was inhibited when cells were irradiated in late S/G2. In line with these data down-regulation of HR did affect survival of cells irradiated in late S/G2, but not in G1. Conclusions: Individual radiosensitivity as measured for G0/1 cells using metaphase analysis does not depend on homologous recombination

  1. Hyperthermic radiosensitization : mode of action and clinical relevance

    NARCIS (Netherlands)

    Kampinga, HH; Dikomey, E

    Purpose: To provide an update on the recent knowledge about the molecular mechanisms of thermal radiosensitization and its possible relevance to thermoradiotherapy. Summary: Hyperthermia is probably the most potent cellular radiosensitizer known to date. Heat interacts with radiation and potentiates

  2. Radiosensitization by PARP inhibition to proton beam irradiation in cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Hirai, Takahisa [Department of Radiation Oncology, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo (Japan); Division of Chemotherapy and Clinical Cancer Research, National Cancer Center Research Institute, Chuo-ku, Tokyo (Japan); Saito, Soichiro; Fujimori, Hiroaki [Division of Chemotherapy and Clinical Cancer Research, National Cancer Center Research Institute, Chuo-ku, Tokyo (Japan); Matsushita, Keiichiro; Nishio, Teiji [Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima-shi, Hiroshima (Japan); Okayasu, Ryuichi [International Open Laboratory, National Institute of Radiological Science, Chiba-shi, Chiba (Japan); Masutani, Mitsuko, E-mail: mmasutan@nagasaki-u.ac.jp [Division of Chemotherapy and Clinical Cancer Research, National Cancer Center Research Institute, Chuo-ku, Tokyo (Japan); Department of Frontier Life Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki (Japan)

    2016-09-09

    The poly(ADP-ribose) polymerase (PARP)-1 regulates DNA damage responses and promotes base excision repair. PARP inhibitors have been shown to enhance the cytotoxicity of ionizing radiation in various cancer cells and animal models. We have demonstrated that the PARP inhibitor (PARPi) AZD2281 is also an effective radiosensitizer for carbon-ion radiation; thus, we speculated that the PARPi could be applied to a wide therapeutic range of linear energy transfer (LET) radiation as a radiosensitizer. Institutes for biological experiments using proton beam are limited worldwide. This study was performed as a cooperative research at heavy ion medical accelerator in Chiba (HIMAC) in National Institute of Radiological Sciences. HIMAC can generate various ion beams; this enabled us to compare the radiosensitization effect of the PARPi on cells subjected to proton and carbon-ion beams from the same beam line. After physical optimization of proton beam irradiation, the radiosensitization effect of the PARPi was assessed in the human lung cancer cell line, A549, and the pancreatic cancer cell line, MIA PaCa-2. The effect of the PARPi, AZD2281, on radiosensitization to Bragg peak was more significant than that to entrance region. The PARPi increased the number of phosphorylated H2AX (γ-H2AX) foci and enhanced G2/M arrest after proton beam irradiation. This result supports our hypothesis that a PARPi could be applied to a wide therapeutic range of LET radiation by blocking the DNA repair response. - Highlights: • Effective radiosensitizers for particle radiation therapy have not been reported. • PARP inhibitor treatment radiosensitized after proton beam irradiation. • The sensitization at Bragg peak was greater than that at entrance region. • DSB induction and G2/M arrest is involved in the sensitization mechanism.

  3. Effect of cisplatin on the clinically relevant radiosensitivity of human cervical carcinoma cell lines

    International Nuclear Information System (INIS)

    Britten, Richard A.; Evans, Andrew J.; Allalunis-Turner, M. Joan; Pearcey, Robert G.

    1996-01-01

    Purpose: To evaluate the effect of clinically relevant levels of cisplatin on the radiosensitivity of human cervical tumor cells, and to estimate what changes in local control rates might be expected to accrue from the concomitant use of cisplatin during fractionated radiotherapy. Methods and Materials: The effects of concomitant cisplatin (1 μg/ml, a typical intratumor concentration) on the clinically relevant radiosensitivity, i.e., surviving fraction after 2 G (SF 2 ) values, was determined in 19 cloned human cervical tumor cell lines. These early passage cell lines had SF 2 values ranging from 0.26 to 0.87. Results: The concomitant administration of cisplatin reduced the clinically relevant radiosensitivity in the majority (11 out of 19) of the human tumor cell lines investigated. In only 4 out of 19 was any radiosensitization observed, and in 4 out of 19 cell lines there was no significant change in radiosensitivity. However, the sum of the independent cell killing by radiation and cisplatin, was approximately twofold higher than after radiation alone. There was no apparent dependence of the cisplatin-induced changes in SF 2 values upon the level of cell killing by cisplatin. However, there is a suggestion that concomitant cisplatin administration may have a differential effect in inherently radiosensitive and resistant human tumor cell lines. Conclusions: Our data suggest that concomitant cisplatin/radiotherapy regimens may result in a higher level of local tumor control, but primarily through additive toxicity and not through radiosensitization. Future improvements in local tumor control may, thus, be derived by increasing the total dose of cisplatin

  4. Increased resistance to sudden noise by audio stimulation during early ontogeny in German shepherd puppies.

    Science.gov (United States)

    Chaloupková, Helena; Svobodová, Ivona; Vápeník, Pavel; Bartoš, Luděk

    2018-01-01

    The period of early ontogeny constitutes a time when the physical immaturity of an organism is highly susceptible to external stimuli. Thus, early development plays a major role in shaping later adult behavior. The aim of the study was to check whether stimulating puppies at this early stage in life with sound would improve their responsiveness towards unfamiliar noises during the selection process of the police behavioral test for puppies. The cohort comprised 37 puppies from the litters of three mothers. At the commencement of the experiment the dogs were aged 16 days, rising to the age of 32 days at its close. The mothers and litters of the treatment group were either exposed to radio broadcasts, (see below; three litters totaling 19 puppies), while the control group was not exposed to any radio programs (eight litters totaling 18 puppies). All three mothers had previously experienced both auditory circumstances, as described herein. Ordinary radio broadcasts were played to the puppies in the treatment group three times a day for 20 minute periods, always during feeding time. The cohort was subjected to the so-called Puppy Test, i.e. analysis of the potential of each animal, once the dogs had reached the age of 7 weeks. Such tests included exposure to a sudden noise caused by a shovel (100 dB), noise when alone in a room, and response to loud distracting stimuli (the latter two at 70 dB). Said tasks were rated by the same analyst on a scale of 0-5 points; the better the response of the dog, the higher the score given. The differences between the treatment and control groups were analyzed via Mixed Models (PROC MIXED) in SAS. The animals comprising the treatment group responded with a higher score to the sudden noise caused by the shovel than the control dogs (Pshovel. Therefore, acoustic stimulation during the very early period of life has the potential to raise the necessary skills of dogs for military and police purposes, or civilian life.

  5. Evaluation of Radiosensitivity of HeLa Cells Infected with Polio Virus Irradiated by Co 60

    Directory of Open Access Journals (Sweden)

    F Seif

    2008-04-01

    Full Text Available ABSTRACT: Introduction & Objective: The main purpose of radiotherapy is exposing enough doses of radiation to tumor tissue and protecting the normal tissues around it. Tumor dose for each session in radiotherapy will be considered based on radiosensitivity of the tissues. The presence of viral diseases in tumoral area can affect the radiosensitivity of cells. This study aimed to evaluate the radiosensitivity of Hela cells infected with poliomyelitis virus irradiated by Co 60. Materials & Methods: In this study, the radiosensitivity of HeLa cells, with or without the viral infection, after gamma radiation of cobalt 60, was assessed. Results: Results of comparison of the radisensitivity of infected and uninfected cells indicates that after 2 Gy irradiation by Co 60, polio infection in low, moderate and high virus load, increases the cell death by 20-30%, 30-40% and 70-90% respectively. Conclusion : Radiosensitivity of tumoral cells increase when they are infected with viral agents. Results of this study showed that non cancer diseases should be considered when prescribing dose fraction in radiotherapy of cancers.

  6. Radiosensitivity, radio-curability and DNA repair

    International Nuclear Information System (INIS)

    Vogin, G.

    2011-01-01

    Improvements in accuracy stand as the heart of the success of today's radiotherapy. The dose may be delivered with a sub millimetric accuracy, may also conform to complex shapes, or track external and internal organ motions. In parallel, we may increase the tumour's radio-curability by modulating the biological effects generated by ionizing radiation into the patient. It was precisely the topic of the 2009 Lucien-Mallet prize organized by the French Society for Radiation Oncology (SFRO) and the Centre Antoine-Beclere under the auspices of the Fondation de France. In this review we will precisely describe the integrated molecular response to ionizing radiations. Starting from early observations, we are going to introduce the concept of cellular radiosensitivity as the global response of the irradiated cell. We will then focus into the cell and especially its nucleus. We will describe here the most complex and deleterious radioinduced damages. In the next chapter, we will dissect the molecular pathway that aims to detect and repair the previous lesions. The last part of the review will finally deal with the diagnostic, prognostic and therapeutic impacts emerging from the alliance between clinical and molecular radiobiology. (author)

  7. ErythropoieSIS stimulating agent (ESA use is increased following missed dialysis sessions

    Directory of Open Access Journals (Sweden)

    T. Christopher Bond

    2012-06-01

    Missed session episodes result in significant increases in ESA utilization in the post-miss period, and also in total monthly ESA use. Such increases should be considered in any assessment of impact of missed sessions: both clinical and economic.

  8. Prior AICAR stimulation increases insulin sensitivity in mouse skeletal muscle in an AMPK-dependent manner

    DEFF Research Database (Denmark)

    Kjøbsted, Rasmus; Treebak, Jonas Thue; Fentz, Joachim

    2015-01-01

    Acute exercise increases glucose uptake in skeletal muscle by an insulin-independent mechanism. In the period after exercise insulin sensitivity to increase glucose uptake is enhanced. The molecular mechanisms underpinning this phenomenon are poorly understood, but appear to involve an increased ...

  9. Application of bio-marker to study on tumor radiosensitivity

    International Nuclear Information System (INIS)

    Guo Wanfeng; Ding Guirong; Han Liangfu

    2001-01-01

    To definite tumor radiosensitivity is important for applying the schedules of individualization of patient radiotherapy. Many laboratories were carrying on the research which predict the tumor radiosensitivity with one bio-marker or/and multi-bio-marker in various levels. At present has not witnessed the specific bio-marker, but it provides an excellent model for predicting tumor radiosensitivity

  10. Differential radiosensitivity on a tissue level in Delphinium ajacis

    Energy Technology Data Exchange (ETDEWEB)

    Mandal, S K; Basu, R K [Bose Research Inst., Calcutta (India). Cryogenetics Lab.

    1980-09-01

    Root, leaf, pollen mother cell and endosperm of D.ajacis showed differential sensitivity as measured by X-ray-induced chromosomal aberrations at mitotic anaphase and telophase stages of the first and second division cycles after irradiation. These tissues differed significantly in Interphase Chromosome Volume (ICV) values. In all the tissues the percentage of aberrant cells increased linearly with increase in X-ray dose. Though endosperm had the largest ICV value it was the most radioresistant tissue tested. The relative radiosensitivity of the other 3 tissues was positively correlated with ICV value. The radioresistance of endosperm is probably due to factors unique to this tissue which remained obscure.

  11. Radiosensitizers in cervical cancer. Cisplatin and beyond

    International Nuclear Information System (INIS)

    Candelaria, Myrna; Garcia-Arias, Alicia; Cetina, Lucely; Dueñas-Gonzalez, Alfonso

    2006-01-01

    Cervical cancer continues to be a significant health burden worldwide. Globally, the majority of cancers are locally advanced at diagnosis; hence, radiation remains the most frequently used therapeutical modality. Currently, the value of adding cisplatin or cisplatin-based chemotherapy to radiation for treatment of locally advanced cervical cancer is strongly supported by randomized studies and meta-analyses. Nevertheless, despite these significant achievements, therapeutic results are far from optimal; thus, novel therapies need to be assayed. A strategy currently being investigated is the use of newer radiosensitizers alone or in combination with platinum compounds. In the present work, we present preclinical information on known and newer cytotoxic agents as radiosensitizers on cervical cancer models, as well as the clinical information emanating from early phase trials that incorporate them to the cervical cancer management. In addition, we present the perspectives on the combined approach of radiation therapy and molecular target-based drugs with proven radiosensitizing capacity

  12. On the Path to Seeking Novel Radiosensitizers

    International Nuclear Information System (INIS)

    Katz, David; Ito, Emma; Liu Feifei

    2009-01-01

    Radiation therapy is a highly effective cancer treatment modality, and extensive investigations have been undertaken over the years to augment its efficacy in the clinic. This review summarizes the current understanding of the biologic bases underpinning many of the clinically used radiosensitizers. In addition, this review illustrates how the advent of innovative, high-throughput technologies with integration of different disciplines could be harnessed for an expeditious discovery process for novel radiosensitizers, providing an exciting future for such pursuits in radiation biology and oncology

  13. Gonadotropin stimulates oocyte translation by increasing magnesium activity through intracellular potassium-magnesium exchange

    International Nuclear Information System (INIS)

    Horowitz, S.B.; Tluczek, L.J.

    1989-01-01

    We previously showed that gonadotropin increases the K + activity in Xenopus oocytes and that this is a signal for increased translation. However, K + need not act to control synthesis directly but may act through an unidentified downstream effector. Using microinjection to vary the salt content of oocytes and concomitantly measuring [ 3 H]leucine incorporation, we found that small changes in Mg 2+ greatly affect translation rates. (Ca 2+ had little influence.) By measuring intracellular ion activities, we found that oocyte cations existed in a buffer-like (ion-exchange) equilibrium in which K + and Mg 2+ are the preponderant monovalent and divalent cations. Hence, increasing cellular K + activity might increase translation by causing Mg 2+ activity to rise. If so, the increased translation rates produced by hormone treatment or K + injection would be prevented by EDTA, a Mg 2+ chelating agent. This prediction was tested and confirmed. We conclude that, when gonadotropin increases K + activity, the cell's internal ion-exchange equilibrium is altered thereby increasing Mg 2+ activity and this up-regulates translation

  14. Anodal Stimulation of the Left DLPFC Increases IGT Scores and Decreases Delay Discounting Rate in Healthy Males

    Directory of Open Access Journals (Sweden)

    Qinghua He

    2016-09-01

    Full Text Available Previous correlational imaging studies have implicated the dorsolateral prefrontal cortex (DLPFC in decision making. Using High-Definition Transcranial Direct Current Stimulation (HD-tDCS, the present study directly investigated the causal role of the DLPFC in performing the Iowa Gambling Task (IGT and the Inter-Temporal Choice (ITC task. Three experiments were conducted: Exp. 1 (N = 41 to study the left DLPFC, Exp. 2 (N = 49 to study the right DLPFC, and Exp. 3 (N = 20, a subset of those in Exp. 1 to switch the experimental and control conditions. All participants were healthy male college students. For Exps. 1 and 2, participants were randomly assigned to either the HD- tDCS or the sham stimulation condition. For Exp. 3, participants were assigned to the condition they were not in during Exp. 1. Results showed that HD-tDCS over the left DLPFC increased IGT score, decreased the recency parameter in IGT, and lowered delay discounting rate (k in the ITC task. We discussed the potential roles of impulse control and time perception in mediating the effect of tDCS stimulation of left DLPFC on decision making. Our results have clinical implications for the treatment of disorders involving poor decision-making, such as addictions.

  15. Stimulation of muscle protein synthesis by somatotropin in pigs is independent of the somatotropin-induced increase in circulating insulin.

    Science.gov (United States)

    Wilson, Fiona A; Orellana, Renán A; Suryawan, Agus; Nguyen, Hanh V; Jeyapalan, Asumthia S; Frank, Jason; Davis, Teresa A

    2008-07-01

    Chronic treatment of growing pigs with porcine somatotropin (pST) promotes protein synthesis and doubles postprandial levels of insulin, a hormone that stimulates translation initiation. This study aimed to determine whether the pST-induced increase in skeletal muscle protein synthesis was mediated through an insulin-induced stimulation of translation initiation. After 7-10 days of pST (150 microg x kg(-1) x day(-1)) or control saline treatment, pancreatic glucose-amino acid clamps were performed in overnight-fasted pigs to reproduce 1) fasted (5 microU/ml), 2) fed control (25 microU/ml), and 3) fed pST-treated (50 microU/ml) insulin levels while glucose and amino acids were maintained at baseline fasting levels. Fractional protein synthesis rates and indexes of translation initiation were examined in skeletal muscle. Effectiveness of pST treatment was confirmed by reduced urea nitrogen and elevated insulin-like growth factor I levels in plasma. Skeletal muscle protein synthesis was independently increased by both insulin and pST. Insulin increased the phosphorylation of protein kinase B and the downstream effectors of the mammalian target of rapamycin, ribosomal protein S6 kinase, and eukaryotic initiation factor (eIF)4E-binding protein-1 (4E-BP1). Furthermore, insulin reduced inactive 4E-BP1.eIF4E complex association and increased active eIF4E.eIF4G complex formation, indicating enhanced eIF4F complex assembly. However, pST treatment did not alter translation initiation factor activation. We conclude that the pST-induced stimulation of skeletal muscle protein synthesis in growing pigs is independent of the insulin-associated activation of translation initiation.

  16. In vitro and in vivo study of a nanoliposomal cisplatin as a radiosensitizer

    Directory of Open Access Journals (Sweden)

    Xiaomeng Zhang

    2011-02-01

    Full Text Available Xiaomeng Zhang1*, Huanjun Yang1*, Ke Gu1, Jian Chen2, Mengjie Rui2, Guo-Liang Jiang11Departments of Radiation Oncology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College,Fudan University,Shanghai, People’s Republic of China; 2School of Pharmacy, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; *Xiaomeng Zhang and Huanjun Yang share the first authorshipObjective: To investigate the in vitro and in vivo radiosensitization effect of an institutionally designed nanoliposome encapsulated cisplatin (NLE-CDDP.Materials and methods: NLE-CDDP was developed by our institute. In vitro radiosensitization of NLE-CDDP was evaluated by colony forming assay in A549 cells. In vivo radiosensitization was studied with tumor growth delay (TGD in Lewis lung carcinoma. The radiosensitization for normal tissue was investigated by jejunal crypt survival. The radiosensitization studies were carried out with a 72 h interval between drug administration and irradiation. The mice were treated with 6 mg/kg of NLE-CDDP or CDDP followed by single doses of 2 Gy, 6 Gy, 16 Gy, and 28 Gy. Sensitization enhancement ratio (SER was calculated by D0s of cell survival curves for A549 cells, doses needed to yield TGD of 20 days in Lewis lung carcinoma, or D0s of survival curves in crypt cells in radiation alone and radiation plus drug groups.Results: Our NLE-CDDP could inhibit A549 cells in vitro with half maximal inhibitory concentration of 1.12 µg/mL, and its toxicity was 2.35 times that observed in CDDP. For in vitro studies of A549 cells, SERs of NLE-CDDP and CDDP were 1.40 and 1.14, respectively, when combined with irradiation. For in vivo studies of Lewis lung carcinoma, the strongest radiosensitization was found in the 72 h interval between NLE-CDDP and irradiation. When given 72 h prior to irradiation, NLE-CDDP yielded higher radiosensitization than CDDP (SER of 4.92 vs 3.21 and slightly increased injury in jejunal

  17. Sucralose Increases Antimicrobial Resistance and Stimulates Recovery of Escherichia coli Mutants.

    Science.gov (United States)

    Qu, Yilin; Li, Rongyan; Jiang, Mingshan; Wang, Xiuhong

    2017-07-01

    Because of heavy use of antimicrobials, antimicrobial resistance in bacteria has become of great concern. The effect of some widely used food additives such as sucralose on bacteria in the gut and the environment has also drawn increasing attention. In this study, we investigated the interaction between antimicrobials and sucralose impacting antimicrobial resistance and mutation of Escherichia coli (E. coli). To examine antimicrobial resistance and mutation frequency, different subinhibitory concentrations of sucralose were added to cultures of E.coli BW25113 that were then treated with antimicrobials, oxolinic acid, or moxifloxacin. Then the E.coli were assayed for bacterial survival and recovery of mutants resistant to an unrelated antimicrobial, rifampicin. Pre-treatment of E.coli BW25113 with 1/2 minimal inhibitory concentration (MIC) of sucralose increased the survival rate in oxolinic acid or moxifloxacin. A 1/3 MIC of sucralose increased rifampicin-resistant mutation rate of E.coli BW25113 after 72 h, while rifampicin-resistant mutation rate was increased when co-treated with 1/8 MIC, 1/4 MIC, 1/3 MIC sucralose, and oxolinic acid after 24 h. Sucralose can increase the antimicrobial resistance and mutation frequency of E.coli to some antimicrobials.

  18. Wounding stimulates ALLENE OXIDE SYNTHASE gene and increases the level of jasmonic acid in Ipomoea nil cotyledons

    Directory of Open Access Journals (Sweden)

    Emilia Wilmowicz

    2016-03-01

    Full Text Available Allene oxide synthase (AOS encodes the first enzyme in the lipoxygenase pathway, which is responsible for jasmonic acid (JA formation. In this study we report the molecular cloning and characterization of InAOS from Ipomoea nil. The full-length gene is composed of 1662 bp and encodes for 519 amino acids. The predicted InAOS contains PLN02648 motif, which is evolutionarily conserved and characteristic for functional enzymatic proteins. We have shown that wounding led to a strong stimulation of the examined gene activity in cotyledons and an increase in JA level, which suggest that this compound may be a modulator of stress responses in I. nil.

  19. Pioglitazone treatment increases spontaneous growth hormone (GH) secretion and stimulated GH levels in polycystic ovary syndrome

    DEFF Research Database (Denmark)

    Glintborg, Dorte; Støving, René Klinkby; Hagen, Claus

    2005-01-01

    BACKGROUND: Low GH levels, probably due to insulin resistance and increased abdominal fat mass, are well described in polycystic ovary syndrome (PCOS). GH acts as an important ovarian cogonadotropin, and GH disturbances may be an additional pathogenic factor in PCOS. Decreased abdominal fat mass...

  20. Optokinetic stimulation increases limb pain and forehead hyperalgesia in complex regional pain syndrome

    DEFF Research Database (Denmark)

    Knudsen, Lone F.; Drummond, Peter D.

    2015-01-01

    BACKGROUND: Ambiguous visual stimuli increase limb pain in patients with complex regional pain syndrome (CRPS), possibly due to afferent sensory feedback conflicts. Conflicting sensory stimuli can also generate unpleasant sensations in healthy people such as during motion sickness. We wanted to i...

  1. Radiosensitization effect of CMNa on hypoxic pancreatic cancer cell in vitro

    International Nuclear Information System (INIS)

    Yin Lijie; Zhang Li; Ding Tiangui; Peng Zhaoxiang; Yu Huan; Gao Yuwei

    2006-01-01

    Objective: To investigate the effects of glycodidazolum natrium (CMNa) on pancreatic cancer cells under hypoxic condition. Methods: The human pancreatic cancer Panc-1 cells were exposed to a single fraction of high-dose γ-ray radiation either with CMNa or under hypoxic condition. The percentage of dead cells was detected with a multiwell plated reader, and fluorescence intensities of propidium iodide were measured before and after digitonin treatment. The sensitizing effect of CMNa on cell killing induced by high-dose irradiation was evaluated by time and concentration dependence. The selective radiosensitive effect of CMNa on hypoxia was evaluated by flow cytometry. Results: The death rate of pancreatic cancer Panc-1 cells paralleled with the increasing concentration of CMNa under hypoxic condition after 30 gray irradiation. The selective radiosensitive effect of CMNa on hypoxia was time-dependent. Conclusions: CMNa can enhance the radiosensitivity of pancreatic cancer Pane-1 cells under hypoxic condition with high-dose irradiation. (authors)

  2. Effects of heat-shock treatment and genotype on radiosensitivity of maize seeds

    International Nuclear Information System (INIS)

    Yamagata, Hirotada; Tanisaka, Takatoshi; Harima, Kunio

    1975-01-01

    In order to clarify the internal and external factors responsible for radiosensitivity of seed, and to induce mutations more effectively, two experiments were conducted using maize. (1) Seeds of an inbred line were irradiated with γ rays at an extremely low temperature (-70 0 C) and then dipped in hot water (60 0 C, 30 sec.). Through such heat-shock treatment the radiosensitivity of maize seeds was remarkably reduced: LD 50 and RD 50 for growth rose as high as about three times and about twice, respectively. (2) Seeds of seven strains including four inbred lines, two single-cross hybrids and one double-cross hybrid were exposed to γ rays by the ordinary procedure. Hybrids, regardless of whether they were single cross or double cross, were clearly proved to surpass their parental strains in radiation tolerance, both in survival rate and in culm length. These descents of radiosensitivity were considered to be due mainly to the increased heterozygosity. (auth.)

  3. Effect of Quercetin on radio-sensitivity of HeLa cells

    International Nuclear Information System (INIS)

    Wu Xiaofen; Hong Chengjiao; Guo Wenxiu; Pan Yanling; Zhang Baoguo

    2011-01-01

    In order to investigate the mechanism of Quercetin on radio-sensitivity of human Uterine Cervix Cancer HeLa cells, HeLa cells were cultured in different concentrations of Quercetin and different doses of irradiation. The clonogenic assay was used to observe the cell survival rate. The repair of DNA double-strand breaks and effect of Quercetin combination of radiation on the cell cycle were detected by flow cytometry. The results show that the radio-sensitivity of Quercetin on HeLa cells was obvious and the unrepaired DSBs after irradiation increased, but did not decrease G2/M cell cycle arrest. From this it can be inferred that the effect on HeLa cell radio-sensitivity may be related to the inhibition of the repair of DNA double-strand breaks induced by Quercetin, but it dose not reveal a significant relation with the cell cycle and G2/M arrest. (authors)

  4. Caffeine stimulates voluntary wheel running in mice without increasing aerobic capacity.

    Science.gov (United States)

    Claghorn, Gerald C; Thompson, Zoe; Wi, Kristianna; Van, Lindsay; Garland, Theodore

    2017-03-01

    The "energy drink" Red Bull and the "sports drink" Gatorade are often marketed to athletes, with claims that they cause performance gains. However, both are high in sugars, and also consumed by non-athletes. Few studies have addressed the effects of these drinks or their biologically active components in rodent exercise models. We used three experiments to test effects on both voluntary exercise behavior and maximal aerobic capacity in lines of mice known to differ in "athletic" traits. Mice from four replicate High Runner (HR) lines have been selectively bred for voluntary running on wheels, and run approximately three times as many revolutions per day as do mice from four non-selected Control (C) lines. HR mice also have higher endurance and maximal oxygen consumption (VO 2 max) during forced treadmill exercise. In Experiment 1, we tested the hypothesis that Gatorade or Red Bull might cause or allow mice to increase their voluntary wheel running. On days 5 and 6 of 6days of wheel access, as is used to select breeders, HR mice ran 3.3-fold more than C, and females ran 1.2-fold more than males, with no linetype by sex interaction. On day 7, mice were administered Gatorade, Red Bull or tap water. During the subsequent 19-hour period, Gatorade had no statistical effect on running, but Red Bull significantly increased distance run by both sexes and in both HR and C lines. The increase in distance run caused by Red Bull was attributable to time spent running, not an increase in mean (or maximum) speed. As previous studies have found that sucrose alone does not generally increase wheel running, we tested two other active ingredients in Red Bull, caffeine and taurine, in Experiment 2. With a similar testing protocol, caffeine alone and caffeine+taurine increased running by about half the magnitude of Red Bull. In Experiment 3, we tested the hypothesis that Red Bull or caffeine alone can increase physiological performance ability during aerobic exercise, measured as VO 2

  5. Fertilization stimulates an increase in inositol trisphosphate and inositol lipid levels in Xenopus eggs.

    Science.gov (United States)

    Snow, P; Yim, D L; Leibow, J D; Saini, S; Nuccitelli, R

    1996-11-25

    Previous experiments from our lab have suggested that the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) is required for sperm-induced egg activation in Xenopus laevis. Here we measure the endogenous production of both Ins(1,4,5)P3 and PIP2 during the sperm-induced and ionomycin-induced calcium wave in the egg and find that both increase following fertilization. Ins(1,4,5)P3 increases 3.2-fold from an unfertilized egg level of 0.13 pmole per egg (0.29 microM) to a peak of 0.42 pmole per egg (0.93 microM) as the calcium wave reaches the antipode in the fertilized egg. This continuous production of Ins(1,4,5)P3 during the time that the Ca2+ wave is propagating across the egg suggests the involvement of Ins(1,4,5)P3 in wave propagation. This increase in Ins(1,4,5)P3 is smaller in ionomycin-activated eggs than in sperm-activated eggs, suggesting that the sperm-induced production of Ins(1,4,5)P3 involves a PIP2 hydrolysis pathway that is not simply raising intracellular Ca2+. While one might expect PIP2 levels to fall as a result of hydrolysis, we find that PIP2 actually increases 2-fold. The total lipid fraction in unfertilized egg exhibits 0.8 pmole PIP2 per egg and this increases to 1.5 pmole as the calcium wave reaches the antipode. The PIP2 concentration peaks 2 min after the completion of the calcium wave at 1.8 pmole per egg. The amount of PIP2 in the animal and vegetal hemispheres of the egg was also measured by cutting frozen eggs in half. The vegetal hemisphere contained twice the amount of PIP2 as the animal hemisphere but it also contained twice the amount of lipid. Thus, there was an equivalent amount of PIP2 normalized to lipid in each hemisphere. Isolated animal and vegetal hemisphere cortices exhibit similar PIP2 concentrations, suggesting that the 2-fold higher total PIP2 in the vegetal half is not due to a gradient of PIP2 in the plasma membrane, but rather implies that cytoplasmic organelle membranes also contain PIP2.

  6. Radiosensitivity of str.fecalis in presence of some substances being contained in meat cans

    International Nuclear Information System (INIS)

    Stojchev, M.; Brankova, G.; Dzhezheva, G.

    1974-01-01

    This study was designed to assess the effects of some organic and inorganic substances present in canned meats on the radiosensitivity of Streptococcus faecalis exposed to different doses of gamma rays. It was found that the death rate of irradiated S.faecalis depends on the radiation dose, the time elapsed after irradiation, and the medium in which the cells are suspended. Adding lactic and ascorbic acids and glucose to the model solution decreased the radiosensitivity and increased the post-irradiation effects. (E.T.)

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

    International Nuclear Information System (INIS)

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

    1987-01-01

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

  8. Radiosensitivity of quince seeds (Cydonia oblonga Mill.)

    International Nuclear Information System (INIS)

    Dall'Orto, F.A.C.; Ojima, M.; Hiroce, R.; Igue, T.; Ferraz, E.S.B.; Nascimento Filho, V.F. do; Menten, J.O.M.; Tulmann Neto, A.; Ando, A.

    1984-01-01

    The investigation with quince seeds (Cydonia oblonga Mill.) radiosensitivity and the mineral composition of the plants obtained for mutation breeding are related. The concentration of some macro and micronutrients in quince seedlings obtained from irradiated seeds are studied. (M.A.C.) [pt

  9. Radiosensitivity of human lymphocytes and thymocytes

    International Nuclear Information System (INIS)

    Kwan, D.K.; Norman, A.

    1977-01-01

    The in vitro survival of human peripheral blood lymphocytes and thymocytes was measured 4 days following graded doses of γ radiation. Results indicate considerable heterogeneity among lymphocyte subpopulations with respect to radiosensitivity. Total T lymphocytes were characterized by rosette formation with neuraminidase-treated sheep red blood cells (nSRBC); early T (T/sub E/) cells, by early rosettes; and B cells, by their inability to form nSRBC rosettes. Late T (T/sub L/) cells were defined as T -- T/sub E/. Survival curves of T, T/sub E/, and B cells are biphasic. The radiosensitive and radioresistant components of T, T/sub E/, and B cells all have a D 0 of about 50 and 550 rad, respectively. B cells appeared to be slightly more radiosensitive than T cells. T/sub L/ cells and thymocytes, however, appeared to be homogeneous with respect to radiosensitivity, both having D 0 values of about 135 rad. The survival of T cells in mixed T and B cell cultures resembled that of separated T cells, suggesting that ionizing radiation has no significant effect on rosette formation. It also indicates that interactions of T and B cells do not significantly affect their radiation responses

  10. Osmotic homeostasis and NKLy lymphoma cells radiosensitivity

    International Nuclear Information System (INIS)

    Tishchenko, V.V.; Magda, I.N.

    1992-01-01

    In experiments with cells of ascites NKLy lymphoma differing in ploidy and position in the cell cycle, a study was made of the radiosensitivity, osmotic homeostasis peculiarities and thermoradiation changes in potassium content. It was shown that the resistance of osmotic homeostasis of NKLy cells to thermoradiation correlated with their radioresistance

  11. Hexachlorobenzene stimulates uroporphyria in low affinity AHR mice without increasing CYP1A2

    International Nuclear Information System (INIS)

    Gorman, Nadia; Trask, Heidi S.; Robinson, Susan W.; Sinclair, Jacqueline F.; Gerhard, Glenn S.; Smith, Andrew G.; Sinclair, Peter R.

    2007-01-01

    Hexachlorobenzene (HCB), a weak ligand of the aryl hydrocarbon receptor (AHR), causes hepatic uroporphyrin (URO) accumulation (uroporphyria) in humans and animals. CYP1A2 has been shown to be necessary in the development of uroporphyria in mice. Using mice expressing the low affinity form of the AH receptor (AHRd), we investigated whether the enhancement of uroporphyria by HCB involves an obligatory increase in CYP1A2 as measured by specific enzyme assays and immunoblotting. We compared the ability of HCB, in combination with iron dextran and the porphyrin precursor, 5-aminolevulinate (ALA), to cause uroporphyria in a strain of mice (C57BL/6) which expresses the high affinity form of the receptor (AHRb 1 ), with three strains of mice (SWR and two 129 sublines) expressing the low affinity AHRd. In C57BL/6 mice, HCB-enhanced uroporphyria was associated with a doubling of CYP1A2. HCB treatment produced uroporphyria in iron-loaded mice expressing AHRd, even though there was little or no increase in CYP1A2. Cyp1a2(-/-) mice in a 129 background were completely resistant to HCB-induced uroporphyria, and female Hfe(-/-) 129 mice, in which the levels of hepatic CYP1A2 were half of those of the male levels, responded poorly. The effect of exogenous iron, administered in the form of iron dextran, on HCB enhancement of uroporphryia could be replicated utilizing the endogenous hepatic iron accumulated in 129 Hfe(-/-) mice. In conclusion, some minimal basal expression of CYP1A2 is essential for HCB-mediated enhancement of uroporphyria, but increases in CYP1A2 above that level are not essential

  12. Integrin inhibitor (Cilengitide) as radiosensitization strategy for malignant tumors

    International Nuclear Information System (INIS)

    Silva, Felipe Henrique de Souza

    2017-01-01

    Radiotherapy is effective in tumor control, but several tumors have molecular characteristics that lead to radioresistance and possible posttreatment recurrence. Many tumors have overexpression of integrin receptors. Integrins play a central role in growth, motility, regulation of adhesion and survival, leading to increased proliferation, invasion and metastasis of tumors, making these receptors excellent targets for the development of new therapies. Studies have shown that inhibiting the interaction of matrix proteins with integrin receptors may increase the cytotoxic effect of ionizing radiation by demonstrating the radiosensitizing potential of combination therapy in tumoral lines. Cilengitide an inhibitor of integrins receptors α Vβ3 and αVβ5 stands out for its great antitumor potential against gliomas. Thus, the combination of ionizing radiation with cilengitide is an alternative therapeutic strategy. However, the effect of this combination is little studied in Glioblastomas (U87 and T98) and not studied in melanoma (UACC). The objective of this study was to evaluate the radiosensitising potential of the RGD molecule cilengitida by means of the combined treatment with gamma radiation in different tumor lines, as well as to compare the effect of this combination therapy with cisplatin, a molecule already used in clinical practice. Our panel of tumor cell lines was composed of U87 (wild-type p53 malignant glioblastoma) T98 (malignant glioblastoma mutant p53), MCF7 (mammary carcinoma) and UACC (melanoma). The radiosensitizer effect of cilengitide was evaluated by the quantification of metabolic cell viability through the MTT assay. Inhibition of colony formation was investigated in clonogenicity assays. The flow cytometer was used to investigate cell cycle distribution and the type of cell death induced. We observed that in all cell lines examined, cilengitida promoted detachment, metabolic alterations and reduction of proliferation, as well as alteration of

  13. Radiosensitization of hypoxic tumor cells by simultaneous administration of hyperthermia and nitroimidazoles

    International Nuclear Information System (INIS)

    Hofer, K.G.; Hofer, M.G.; Ieracitano, J.; McLaughlin, W.H.

    1977-01-01

    The radiation response of oxygenated and hypoxic L1210 leukemia cells subjected to in vivo treatments with hyperthermia and/or chemical radiosensitizers was evaluated with the [ 125 I]iododeoxyuridine prelabeling assay. X irradiation of L1210 cells at body temperatures of 41 0 C or higher resulted in strongly enhanced tumor cell death. The magnitude of this thermal effect increased with increasing temperatures. Hypoxic L1210 cells were particularly sensitive to heat induced enhancement of radiation damage, i.e., the sensitizing effects were more pronounced and occurred at lower temperatures. Chemical radiosensitizers (metronidazole, Ro 7-0582) selectively sensitized hypoxic L1210 populations; fully oxygenated cells were not affected. Considerable radiosensitization was achieved at nontoxic dose levels of the two sensitizers. Experiments designed to determine the degree of radiosensititization as a function of drug dose showed that Ro 7-0582 was consistently more effective than metronidazole in sensitizing hypoxic tumor populations. At the highest drug dose used (3 mg/g body wt) the DMF was 2.2 for metronidazole and 2.8 for Ro 7-0582. Combined administration of hyperthermia and Ro 7-0582 (or metronidazole) produced synergistic potentiation of radiation damage in hypoxic L1210 populations (DMF of 4.2). Under optimal conditions, hypoxic L1210 cells subjected simultaneously to both modes of radiosensitization became more radiosensitive than untreated, fully oxygenated L1210 cells. Experiments on two other tumor lines (BP-8 murine sarcoma and Ehrlich ascites cells) indicate that such synergistic radiosensitization effects are not unique to L1210 cells

  14. Stimulation of Toll-like receptor-1/2 combined with Velcade increases cytotoxicity to human multiple myeloma cells

    International Nuclear Information System (INIS)

    Abdi, J; Mutis, T; Garssen, J; Redegeld, F

    2013-01-01

    An increasing body of evidence supports the important role of adhesion to bone marrow microenvironment components for survival and drug resistance of multiple myeloma (MM) cells. Previous studies suggested that stimulation of Toll-like receptors by endogenous ligands released during inflammation and tissue damage may be pro-tumorigenic, but no studies have been performed in relation to modulation of cell adhesion and drug cytotoxicity. Here, we investigated the effect of TLR1/2 activation on adhesion of human myeloma cells to fibronectin, and their sensitivity to the proteasome inhibitor Velcade. It was found that TLR1/2 activation with Pam3CSK4 increased the cytotoxicity of Velcade in L363, OPM-2 and U266 human myeloma cells. This effect was not related to a decreased adhesion of the cells to fibronectin, but TLR1/2 activation stimulated the caspase-3 activity in Velcade-treated myeloma cells, which may be responsible for the enhanced cell death. Inhibitors of NF-κB and MAPK reduced the stimulatory effect. These findings indicate that TLR activation of MM cells could bypass protective effects of cell adhesion and suggest that TLR signaling may also have antitumorigenic potential

  15. Quercetin suppresses DNA double-strand break repair and enhances the radiosensitivity of human ovarian cancer cells via p53-dependent endoplasmic reticulum stress pathway

    Directory of Open Access Journals (Sweden)

    Gong C

    2017-12-01

    Full Text Available Cheng Gong,1 Zongyuan Yang,1 Lingyun Zhang,2 Yuehua Wang,2 Wei Gong,2 Yi Liu3 1Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 2Department of Oncology, XiangYang Central Hospital, Hubei University of Arts and Science, XiangYang, 3Department of Medicinal Chemistry, School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, China Abstract: Quercetin is proven to have anticancer effects for many cancers. However, the role of tumor suppressor p53 on quercetin’s radiosensitization and regulation of endoplasmic reticulum (ER stress response in this process remains obscure. Here, quercetin exposure resulted in ER stress, prolonged DNA repair, and the expression of p53 protein; phosphorylation on serine 15 and 20 increased in combination with X-irradiation. Quercetin pretreatment could potentiate radiation-induced cell death. The combination of irradiation and quercetin treatment aggravated DNA damages and caused typical apoptotic cell death; as well the expression of Bax and p21 elevated and the expression of Bcl-2 decreased. Knocking down of p53 could reverse all the above effects under quercetin in combination with radiation. In addition, quercetin-induced radiosensitization was through stimulation of ATM phosphorylation. In human ovarian cancer xenograft model, combined treatment of quercetin and radiation significantly restrained the growth of tumors, accompanied with the activation of p53, CCAAT/enhancer-binding protein homologous protein, and γ-H2AX. Overall, these results indicated that quercetin acted as a promising radiosensitizer through p53-dependent ER stress signals. Keywords: quercetin, p53, endoplasmic reticulum stress, DNA double-strand breaks, eIF-2α (eukaryotic initiation factor 2α, ATM kinase

  16. Phytochemicals radiosensitize cancer cells by inhibiting DNA repair

    International Nuclear Information System (INIS)

    Singh, Rana P.

    2017-01-01

    Solid tumors are mostly treated with radiotherapy. Radiotherapy is toxic to normal tissues and also promote the invasiveness and radioresistance in cancer cells. The resistance against radiotherapy and adverse effects to normal cells reduce the overall therapeutic effects of the treatment. Radiosensitizing agents usually show limited success during clinical trials. Therefore, the search and development of new radiosensitizers showing selective response to only cancer cells is desirable. We analyzed the radiosensitizing effects including cell death effect of silibinin, a phytochemical on prostate cancer cells. Silibinin enhanced gamma radiation (2.5-10 Gy) induced inhibition in colony formation selectively in prostate cancer cells. In cell cycle progression, G2/M phase is the most sensitive phase for radiation-induced damage which was delayed by the compound treatment in radiation exposed cells. The lower concentrations of silibinin substantially enhanced radiation-induced apoptosis. A prolonged reactive oxygen species production was also observed in these treatments EGFR signaling pathway can contribute to radiation-induced pro-survival mechanisms and to the therapeutic resistance. Agent treatment reduced the IR-induced EGFR phosphorylation and consequently reversed the resistance mediating mechanisms within the cancer cell. Thus, inhibiting DNA repair in cancer cells would enhance therapeutic response of radiation in cancer cells. Silibinin affected the localization of EGFR and DNA-dependent protein kinase, the DNA-PK is known to be an important mediator of DSB repair in human cells, and showed increased number of pH2AX (ser139) foci, and thus indicating lower DNA repair in these cancer cells. This was also confirmed in the tumor xenograft study. Our findings suggest that a combination of silibinin with radiation could be an effective treatment of radioresistant human prostate cancer and warrants further investigation. (author)

  17. Electron microscopic study on radiosensitivity of uterine cervical cancer

    Energy Technology Data Exchange (ETDEWEB)

    Iwai, S; Shiozawa, K; Tsukamoto, T; Noguchi, H; Tsukahara, Y [Shinshu Univ., Matsumoto, Nagano (Japan). Faculty of Medicine

    1974-11-01

    The effects of 1000 R of tele-cobalt upon the changes in the primary lesions of uterine cervical cancer with time were studied with an electron microscope. In addition, twenty cases which were proven to have cancer tissues (10 cases of IInd stage of cancer, 8 cases of IIIrd stage of cancer and 2 cases of IVth stage of cancer) were studied. Four cases were favourably sensitive, 7 cases moderately sensitive and 9 cases unfavourably sensitive to radiation. In favourably radio-sensitive cases, the changes in the cancer cells first appeared in the nucleus. There were other changes such as local clumping of chromatin and, specifically, vacuolization of the nucleus. The changes in the endoplasmic reticulum appeared somewhat late. In addition, the disturbance of mitochondria and the decrease or disappearance of ribosomes were specifically due to radiation injury. From the point of view of changes with time, Golgi's apparatus was enlarged and the membrane of the endoplasmic reticulum was degenerated at the 1st day. At the 3rd day, vacuolization of the nucleus appeared, the nuclear corpuscles were increased, the nucleoplasm became thin, and mitochondria was enlarged and degenerated. At the 5th day, the nuclear membrane disappeared, the nucleus was destroyed, large vacuolization of the endoplasmic reticulum was seen, free ribosomes were decreased, and changes around the endoplasmic reticulum were observed. At the 7th day, collagen around the endoplasmic reticulum appeared. In favourably radiosensitive cases, individual tumor cells showed the same degeneration, which fairly corresponded to that evaluated by the histological observation. The disturbance of the cells was caused by radiation, so-called ''burning'' of the cells. Radiation protection of the cells against burning was considered in terms of their radiosensitivity.

  18. Dopaminergic stimulation increases selfish behavior in the absence of punishment threat.

    Science.gov (United States)

    Pedroni, Andreas; Eisenegger, Christoph; Hartmann, Matthias N; Fischbacher, Urs; Knoch, Daria

    2014-01-01

    People often face decisions that pit self-interested behavior aimed at maximizing personal reward against normative behavior such as acting cooperatively, which benefits others. The threat of social sanctions for defying the fairness norm prevents people from behaving overly selfish. Thus, normative behavior is influenced by both seeking rewards and avoiding punishment. However, the neurochemical processes mediating the impact of these influences remain unknown. Several lines of evidence link the dopaminergic system to reward and punishment processing, respectively, but this evidence stems from studies in non-social contexts. The present study investigates dopaminergic drug effects on individuals' reward seeking and punishment avoidance in social interaction. Two-hundred one healthy male participants were randomly assigned to receive 300 mg of L-3,4-dihydroxyphenylalanine (L-DOPA) or a placebo before playing an economic bargaining game. This game involved two conditions, one in which unfair behavior could be punished and one in which unfair behavior could not be punished. In the absence of punishment threats, L-DOPA administration led to more selfish behavior, likely mediated through an increase in reward seeking. In contrast, L-DOPA administration had no significant effect on behavior when faced with punishment threats. The results of this study broaden the role of the dopaminergic system in reward seeking to human social interactions. We could show that even a single dose of a dopaminergic drug may bring selfish behavior to the fore, which in turn may shed new light on potential causal relationships between the dopaminergic system and norm abiding behaviors in certain clinical subpopulations.

  19. Increased heart rate caused by atrial pacing with the closed-loop stimulation function prevented micturition syncope

    Directory of Open Access Journals (Sweden)

    Tatsuo Haraki, MD,PhD

    2013-10-01

    Full Text Available A 70-year-old man had been experiencing syncope several times a year. We implanted a DDD pacemaker with closed-loop stimulation (CLS function. When he urinated early in the morning, his increased atrial pacing rates elevated his heart rate (HR during and after micturition. After implantation of the DDD-CLS mode, he did not experience symptoms. In contrast, in the DDD-R mode, his intrinsic HR changed to atrial pacing after micturition but decreased to the basal rate within 2 min, and he experienced a sense of cold perspiration and presyncope. Increased HRs caused by atrial pacing with the CLS function were useful in the prevention of micturition syncope.

  20. Increased BOLD Signals Elicited by High Gamma Auditory Stimulation of the Left Auditory Cortex in Acute State Schizophrenia

    Directory of Open Access Journals (Sweden)

    Hironori Kuga, M.D.

    2016-10-01

    We acquired BOLD responses elicited by click trains of 20, 30, 40 and 80-Hz frequencies from 15 patients with acute episode schizophrenia (AESZ, 14 symptom-severity-matched patients with non-acute episode schizophrenia (NASZ, and 24 healthy controls (HC, assessed via a standard general linear-model-based analysis. The AESZ group showed significantly increased ASSR-BOLD signals to 80-Hz stimuli in the left auditory cortex compared with the HC and NASZ groups. In addition, enhanced 80-Hz ASSR-BOLD signals were associated with more severe auditory hallucination experiences in AESZ participants. The present results indicate that neural over activation occurs during 80-Hz auditory stimulation of the left auditory cortex in individuals with acute state schizophrenia. Given the possible association between abnormal gamma activity and increased glutamate levels, our data may reflect glutamate toxicity in the auditory cortex in the acute state of schizophrenia, which might lead to progressive changes in the left transverse temporal gyrus.

  1. Effect of constitutive androstane receptor on radiosensitization of mictomycin C and its homologoue-629

    International Nuclear Information System (INIS)

    Zhang Jianghong; Jin Yizun

    2008-01-01

    The object of this work is to evaluate radiosensitization of MMC and its analogue 5-(aziridin-l-yl)-3- hydroxymethyl-1-methylindole-4,7-dione(629) and how transfection of constitutive androstane receptor (CAR) affect their biological effects. The expressions of CAR mRNA and CYP2B6 mRNA in HepG2 cells and g2car cells were detected by RT-PCR. The radiosensitization of MMC and 629 in vitro were evaluated in HepG2 cells and g2car cells by colony formation under anaerobic and aerobic condition. The effect of 629 on cell cycle and apoptosis of HepG2 cells and g2car cells were assayed by flow cytometry. It was found that plasmid mCAR1/pCR3 was transfected into g2car cells successfully and target CYP2B6 was transactivated by CAR. To compare with aerobic and anaerobic, the radiosensitization of MMC and 629 to HepG2 cells and g2car cells had significantly enhanced, the radiosensitization of 629 was stronger than its parent compound-MMC under aerobic and anaerobic condition, and transfect CAR gene could improve the radiosensitization of MMC and 629. Furthermore, CYP2B6 is one master enzyme for the metabolism of MMC and 629. Transfection of CAR can increase expression of CYP2B6 mRNA in HepG2 cells, and can affect radiosensitization of MMC and 629. (authors)

  2. Radiosensitization and relative mechanisms of vanillin derivative BVAN08 on human glioma U-251 cells

    International Nuclear Information System (INIS)

    Wang Shubin; Zhang Bo; Sun Weijian; Wang Yu; Liu Xiaodan; Xu Qinzhi; Zhou Pingkun

    2010-01-01

    Objective: To provide more convincing evidences and experimental data for exploring vanillin derivative BVAN08, 6-bromine-5-hydroxy-4-methoxy-benzaldehyde, as a new anticancer drug, and to investigate the effect on the growth, radiosensitization of human glioma cell line U-251 and the relative mechanism. Methods: The effect of BVAN08 on cell proliferation of U-251 and radiosensitivity to 60 Co γ-rays (irradiation dose rate 2.3 Gy/min) were analyzed with MTT and colony-forming ability assay. Change in cellular morphology was observed by using light microscope. Change in cell cycle and apoptosis was detected with flow cytometry. The autophagy was observed by using TEM (irradiation dose rate is transmission electron microscope). DNA-PKcs protein level was detected through Western blot analysis. Results: BVAN08 exhibited a dose- and time-dependent inhibition on the proliferation of U-251 cells during the concentration range of 10-100 mol/L (t=1.83-3.07, P 50 at 48 h and 72 h after administration with BVAN08 were 55.3 and 52.7 mol/L, respectively. Obvious G 2 /M arrest was induced in U-251 cells after 4 h administration with BVAN08, and reached peck at 12 h. The G 2 /M population reached 63.3% in U-251 cells after 12 h administration of 60 μmol/L BVAN08 and kept increasing with the time, while both apoptosis and autophagic cell death were induced. The most effective radiosensitization time for BVAN08 treatment was 12 h before irradiation. The enhancement ratio of radiosensitivity was 3.14 for 20 μmol/L of BVAN08 12 h before 2 Gy irradiation. Conclusions: BVAN08 can induce apoptosis as radiosensitizing effect might be associated with the induction of G 2 /M arrest and inhibition of DNA-PKcs expression. BVAN08 seemed to be a promising radiosensitizing anticancer drug. (authors)

  3. Cytogenetic radiosensitivity of G0-lymphocytes of breast and esophageal cancer patients as determined by micronucleus assay

    International Nuclear Information System (INIS)

    Mozdarani, H.; Mansouri, Z.; Haeri, S.A.

    2005-01-01

    Enhanced chromosomal radiosensitivity is a feature of many cancer predisposition conditions, indicative of the important role of chromosomal alterations in carcinogenesis. In this study the cytokinesis-blocked micronucleous assay was used to compare the radiosensitivity of blood lymphocytes obtained from Iranian breast or esophageal cancer patients (n=50, n=16; respectively) with that of control individuals (n=40). For each sample, one thousand binucleate lymphocytes were analyzed before and after in vitro exposure to 3 Gy of γ rays. The radiation-induced frequency of micronucleus was significantly higher in the breast cancer group (261/1,000 binucleated cells) than in esophageal cancer group (241/1,000 binucleated cells, P<0.01) or in the control group (240/1,000 binucleated cells, P<0.01). The results indicate that breast cancer patients are more radiosensitive compared to normal healthy individuals or esophageal cancer patients. Increased radiosensitivity could be due to defects in DNA repair genes involved in breast cancer formation. Since patients with esophageal cancer did not show elevated radiosensitivity, it is assumed that the contribution of radiosensitivity-related genes to the development of esophageal cancer may be smaller than the contribution of those genes to breast cancer. (author)

  4. Lung cancer radiosensitization by CMNa in vitro and in vivo

    International Nuclear Information System (INIS)

    Zhang Xia; Ouyang Xienong; Ji Hongbing; Chen Zhonghua; Yang Rujun

    2005-01-01

    Objective: To probe into the radiosensitization effect of CMNa on lung tumor cell lines after γ-irradiation combined with γ-knife to treat patients suffering from lung cancer. Methods: 1. Cells of small cell lung cancer cell line NCI-H446 and non-small cell lung cancer cell line NCI-H596 irradiated with 60 Co γ-rays combined with or without CMNa were counted using trypan blue exclusion methods, and cell survival rate curves were depicted. 2. Patients suffering from lung cancer at different clinical stages were treated using γ-knife combined with or without CMNa, and the curative effect was evaluated 6 weeks after one cycle of treatment. Results: CMNa could significantly increase the sensitivity of lung cancer cell lines to γ-irradiation. Curative effect increased significantly by γ-knife treatment combined with CMNa i. e., the CR+PR rates for these two groups were 47.22% and 37.67% separately (P 0.05). Conclusion: CMNa could significantly increase the radiation sensitivity of lung cancer cell line cells in vitro and tumors in vivo, therefore, it could be used as a radiosensitization agent in clinical treatment of lung cancer. (authors)

  5. α-Naphthoflavone Increases Lipid Accumulation in Mature Adipocytes and Enhances Adipocyte-Stimulated Endothelial Tube Formation

    Directory of Open Access Journals (Sweden)

    Mei-Lin Wang

    2015-04-01

    Full Text Available The aryl hydrocarbon receptor (AhR is a ligand-activated factor that regulates biological effects associated with obesity. The AhR agonists, such as environmental contaminants 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD and β-naphthoflavone (BNF, inhibit preadipocyte differentiation and interfere with the functions of adipose tissue, whereas the antagonist may have opposite or protective effects in obesity. This study investigated the effects of α-naphthoflavone (α-NF, an AhR antagonist, on adipogenesis- and angiogenesis-associated factors in mature adipocytes and on cross-talk of mature adipocytes with endothelial cells (ECs. Besides, the roles of the AhR on lipid accumulation and on secretion of vascular endothelial growth factor were also determined by introducing siRNA of AhR. Differentiated 3T3-L1 cells were treated with α-naphthoflavone (α-NF (1–5 μM for 16 h. Lipid accumulation and the expressions of AhR-associated factors in the cells were determined. The interaction between adipocytes and ECs was investigated by cultivating ECs with conditioned medium (CM from α-NF-treated mature adipocytes, followed by the determination of endothelial tube formation. The results showed that α-NF significantly increased triglyceride (TG accumulation in mature adipocytes, which was associated with increased expression of hormone-sensitive lipase (HSL, estrogen receptor (ER, as well as decreased expression of AhR, AhR nuclear translocator (ARNT, cytochrome P4501B1 (CYP1B1, and nuclear factor erythroid-2-related factor (NRF-2 proteins. In addition, CM stimulated formation of tube-like structures in ECs, and α-NF further enhanced such stimulation in association with modulated the secretions of various angiogenic mediators by mature adipocytes. Similarly, increased TG accumulation and vascular endothelial growth factor (VEGF secretion were observed in AhR-knockout cells. In conclusion, α-NF increased TG accumulation in mature adipocytes and

  6. Triiodothyronine Acutely Stimulates Glucose Transport into L6 Muscle Cells Without Increasing Surface GLUT4, GLUT1, or GLUT3

    Science.gov (United States)

    Teixeira, Silvania Silva; Tamrakar, Akhilesh K.; Goulart-Silva, Francemilson; Serrano-Nascimento, Caroline; Klip, Amira

    2012-01-01

    Background Thyroid hormones (THs) act genomically to stimulate glucose transport by elevating glucose transporter (Slc2a) expression and glucose utilization by cells. However, nongenomic effects of THs are now emerging. Here, we assess how triiodothyronine (T3) acutely affects glucose transport and the content of GLUT4, GLUT1, and GLUT3 at the surface of muscle cells, and possible interactions between T3 and insulin action. Methods Differentiated L6 myotubes transfected with myc-tagged Slc2a4 (L6-GLUT4myc) or Slc2a1 (L6-GLUT1myc) and wild-type L6 myotubes were studied in the following conditions: control, hypothyroid (Tx), Tx plus T3, Tx plus insulin, and Tx plus insulin and T3. Results Glucose uptake and GLUT4 content at the cell surface decreased in the Tx group relative to controls. T3 treatment for 30 minutes increased glucose transport into L6-GLUT4myc cells without altering surface GLUT4 content, which increased only thereafter. The total amount of GLUT4 protein remained unchanged among the groups studied. The surface GLUT1 content of L6-GLUT1myc cells also remained unaltered after T3 treatment; however, in these cells glucose transport was not stimulated by T3. In wild-type L6 cells, although T3 treatment increased the total amount of GLUT3, it did not change the surface GLUT3 content. Moreover, within 30 minutes, T3 stimulation of glucose uptake was additive to that of insulin in L6-GLUT4myc cells. As expected, insulin elevated surface GLUT4 content and glucose uptake. However, interestingly, surface GLUT4 content remained unchanged or even dropped with T3 plus insulin. Conclusions These data reveal that T3 rapidly increases glucose uptake in L6-GLUT4myc cells, which, at least for 30 minutes, did not depend on an increment in GLUT4 at the cell surface yet potentiates insulin action. We propose that this rapid T3 effect involves activation of GLUT4 transporters at the cell surface, but cannot discount the involvement of an unknown GLUT. PMID:22663547

  7. Genotype dependent radiosensitivity of autotetraploids in Trigonella foenum-graecum L

    Energy Technology Data Exchange (ETDEWEB)

    Raghuvanshi, S S; Singh, A K

    1980-01-01

    Different diploids of Trigonella foenum-graecum L. and their corresponding autotetraploids were seedtreated with 40 krad of ..gamma..-rays, and parameters such as germination, survival, growth reduction, pollen fertility, pod setting, etc. were recorded. A stimulation of seed germination due to the irradiation could be observed. Contrary to the general rule that polyploids are more radioresistant than their corresponding diploids, one 4x strain was completely killed while the 2x version survived comparatively well. Apparently gene reduplication is not the overall protective mechanism as was once earlier believed. The importance of genotypic influence on radiosensitivity was demonstrated at both the 2x and 4x level. The limitation of interphase chromosome volume and degree of ploidy in predicting radiosensitivity is discussed.

  8. Potential in a single cancer cell to produce heterogeneous morphology, radiosensitivity and gene expression

    International Nuclear Information System (INIS)

    Ban, Sadayuki; Ishikawa, Ken-ichi; Kawai, Seiko; Koyama-Saegusa, Kumiko; Ishikawa, Atsuko; Imai, Takashi; Shimada, Yutaka; Inazawa, Johji

    2005-01-01

    Morphologically heterogeneous colonies were formed from a cultured cell line (KYSE70) established from one human esophageal carcinoma tissue. Two subclones were separated from a single clone (clone 13) of KYSE70 cells. One subclone (clone 13-3G) formed mainly mounding colonies and the other (clone 13-6G) formed flat, diffusive colonies. X-irradiation stimulated the cells to dedifferentiate from the mounding state to the flat, diffusive state. Clone 13-6G cells were more radiosensitive than the other 3 cell lines. Clustering analysis for gene expression level by oligonucleotide microarray demonstrated that in the radiosensitive clone 13-6G cells, expression of genes involved in cell adhesion was upregulated, but genes involved in the response to DNA damage stimulus were downregulated. The data demonstrated that a single cancer cell had the potential to produce progeny heterogeneous in terms of morphology, radiation sensitivity and gene expression, and irradiation enhanced the dedifferentiation of cancer cells. (author)

  9. Increased thalamic gamma band activity correlates with symptom relief following deep brain stimulation in humans with Tourette's syndrome.

    Directory of Open Access Journals (Sweden)

    Nicholas Maling

    Full Text Available Tourette syndrome (TS is an idiopathic, childhood-onset neuropsychiatric disorder, which is marked by persistent multiple motor and phonic tics. The disorder is highly disruptive and in some cases completely debilitating. For those with severe, treatment-refractory TS, deep brain stimulation (DBS has emerged as a possible option, although its mechanism of action is not fully understood. We performed a longitudinal study of the effects of DBS on TS symptomatology while concomitantly examining neurophysiological dynamics. We present the first report of the clinical correlation between the presence of gamma band activity and decreased tic severity. Local field potential recordings from five subjects implanted in the centromedian nucleus (CM of the thalamus revealed a temporal correlation between the power of gamma band activity and the clinical metrics of symptomatology as measured by the Yale Global Tic Severity Scale and the Modified Rush Tic Rating Scale. Additional studies utilizing short-term stimulation also produced increases in gamma power. Our results suggest that modulation of gamma band activity in both long-term and short-term DBS of the CM is a key factor in mitigating the pathophysiology associated with TS.

  10. Sleep deprivation prevents stimulation-induced increases of levels of P-CREB and BDNF: protection by caffeine.

    Science.gov (United States)

    Alhaider, Ibrahim A; Aleisa, Abdulaziz M; Tran, Trinh T; Alkadhi, Karim A

    2011-04-01

    It is well known that caffeine and sleep deprivation have opposing effects on learning and memory; therefore, this study was undertaken to determine the effects of chronic (4wks) caffeine treatment (0.3g/l in drinking water) on long-term memory deficit associated with 24h sleep deprivation. Animals were sleep deprived using the modified multiple platform method. The results showed that chronic caffeine treatment prevented the impairment of long-term memory as measured by performance in the radial arm water maze task and normalized L-LTP in area CA1 of the hippocampi of sleep-deprived anesthetized rats. Sleep deprivation prevents the high frequency stimulation-induced increases in the levels of phosphorylated-cAMP response element binding protein (P-CREB) and brain-derived neurotrophic factor (BDNF) seen during the expression of late phase long-term potentiation (L-LTP). However, chronic caffeine treatment prevented the effect of sleep-deprivation on the stimulated levels of P-CREB and BDNF. The results suggest that chronic caffeine treatment may protect the sleep-deprived brain probably by preserving the levels of P-CREB and BDNF. Copyright © 2011 Elsevier Inc. All rights reserved.

  11. Increased androgen levels in rats impair glucose-stimulated insulin secretion through disruption of pancreatic beta cell mitochondrial function.

    Science.gov (United States)

    Wang, Hongdong; Wang, Xiaping; Zhu, Yunxia; Chen, Fang; Sun, Yujie; Han, Xiao

    2015-11-01

    Although insulin resistance is recognized to contribute to the reproductive and metabolic phenotypes of polycystic ovary syndrome (PCOS), pancreatic beta cell dysfunction plays an essential role in the progression from PCOS to the development of type 2 diabetes. However, the role of insulin secretory abnormalities in PCOS has received little attention. In addition, the precise changes in beta cells and the underlying mechanisms remain unclear. In this study, we therefore attempted to elucidate potential mechanisms involved in beta cell alterations in a rat model of PCOS. Glucose-induced insulin secretion was measured in islets isolated from DHT-treated and control rats. Oxygen consumption rate (OCR), ATP production, and mitochondrial copy number were assayed to evaluate mitochondrial function. Glucose-stimulated insulin secretion is significantly decreased in islets from DHT-treated rats. On the other hand, significant reductions are observed in the expression levels of several key genes involved in mitochondrial biogenesis and in mitochondrial OCR and ATP production in DHT-treated rat islets. Meanwhile, we found that androgens can directly impair beta cell function by inducing mitochondrial dysfunction in vitro in an androgen receptor dependent manner. For the first time, our study demonstrates that increased androgens in female rats can impair glucose-stimulated insulin secretion partly through disruption of pancreatic beta cell mitochondrial function. This work has significance for hyperandrogenic women with PCOS: excess activation of the androgen receptor by androgens may provoke beta cell dysfunction via mitochondrial dysfunction. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. Genetic components for radiosensitivity. Gene expression in radiosensitive monocygotic twins. Final report

    International Nuclear Information System (INIS)

    Dikomey, Ekkehard

    2012-01-01

    The underlying hypothesis of this project was that the variation of individual radiosensitivity is determined by the different expression of single gens. This concept was tested using 60 monozygotic twin pairs, followed by an evaluation with 80 prostate cancer patients. Radiosensitivity was assessed for both G0- as well as G2-phase using chromosomal assays. G0- radiosensitivity is determined by lethal chromosomal aberrations and reflects the individual amount of cell killing, while G2-sensitivity is determined by chromatid breaks and is taken as an indicator of individual cancer risk. For both populations, G0- and G2-radiosensitivity are characterized by substantial variation with a CV of 11 and 14% or 27 and 21%, respectively. While the mean G0-sensitivity is the same for both populations, there is a slight difference for G2. The slightly higher value of G2-sensitivity found for prostate cancer patients might result from the higher age of this group. For both populations gene expression profiles were determined using the Affymetrix chip HG-U133+2.0. Overall gene expression was characterized by a huge variation covering more than four decades. However, for single genes, expression showed little variation with CV generally ranging only between 2 and 8%. Analysis of data using several different methods revealed that variation of both G0- as well as G2-radiosensitivity cannot be ascribed to the different expression of single genes. For twins, random forests can be used to identify 8 to 10 genes than are relevant either for G0- or G2-radiosensitivity. However, these genes cannot be confirmed by an evaluation with 80 prostate cancer patients. This finding clearly demonstrates that the hypothesis, due to which variation of individual radiosensitivity is caused by different expression of single genes, has to be rejected. It appears more likely that this parameter is determined by complex interactions of several genes in functional networks. (orig.)

  13. Andrographolide radiosensitizes human esophageal cancer cell line ECA109 to radiation in vitro.

    Science.gov (United States)

    Wang, Z-M; Kang, Y-H; Yang, X; Wang, J-F; Zhang, Q; Yang, B-X; Zhao, K-L; Xu, L-P; Yang, L-P; Ma, J-X; Huang, G-H; Cai, J; Sun, X-C

    2016-01-01

    To explore the radiosensitivity of andrographolide on esophageal cancer cell line ECA109. The inhibition effects of andrographolide were measured using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium (MTT) assay. Clonogenic survival assay was used to evaluate the effects of andrographolide on the radiosensitivity of esophageal cancer cells. Immunofluorescence was employed to examine Bax expression. The changes in cell cycle distribution and apoptosis were assayed using flow cytometry. The expression of NF-κb/Cleaved-Caspase3/Bax/Bcl-2 was measured using Western blot analysis. DNA damage was detected via γ-H2AX foci counting. With a clear dose and time effects, andrographolide was found to inhibit the proliferation of esophageal cell line ECA109. The results of the clonogenic survival assay show that andrographolide could markedly enhance radiosensitivity (P Andrographolide caused a dose-dependent increase in Cleaved-Caspase3/Bax protein expression and a decrease in Bcl-2/NF-κb expression. Apoptosis in andrographolide-treated ECA-109 increased significantly compared with the apoptosis in the simple drug and radiation combined with drug groups (P andrographolide combined with radiation group increased the number of DNA double chain breaks. Andrographolide can increase the radiosensitivity of esophageal cell line ECA109. This result may be associated with the decrease in the NF-κb level and the induced apoptosis of esophageal cancer cells. © 2014 International Society for Diseases of the Esophagus.

  14. ZnFe2O4 nanoparticles for potential application in radiosensitization

    International Nuclear Information System (INIS)

    Hidayatullah, M; Nurhasanah, I; Budi, W S

    2016-01-01

    Radiosensitizer is a material that can increase the effects of radiation in radiotherapy application. Various materials with high effective atomic number have been developed as a radiosensitizer, such as metal, iron oxide and quantum dot. In this study, ZnFe 2 O 4 nanoparticles are included in iron oxide class were synthesized by precipitation method from the solution of zinc nitrate and ferrite nitrate and followed by calcination at 700° C for 3 hours. The XRD pattern shows that most of the observed peaks can be indexed to the cubic phase of ZnFe 2 O 4 with a lattice parameter of 8.424 Å. SEM image reveals that nanoparticles are the sphere-like shape with size in the range 84-107 nm. The ability of ZnFe 2 O 4 nanoparticles as radiosensitizer was examined by loading those nanoparticles into Escherichia coli cell culture which irradiated with photon energy of 6 MV at a dose of 2 Gy. ZnFe 2 O 4 nanoparticles showed ability to increase the absorbed dose by 0.5 to 1.0 cGy/g. In addition, the presence of 1 g/L ZnFe 2 O 4 nanoparticles resulted in an increase radiation effect by 6.3% higher than if exposed to radiation only. These results indicated that ZnFe 2 O 4 nanoparticles can be used as the radiosensitizer for increasing radiation effect in radiotherapy. (paper)

  15. Neonatal Nicotine Exposure Increases Excitatory Synaptic Transmission and Attenuates Nicotine-stimulated GABA release in the Adult Rat Hippocampus

    Science.gov (United States)

    Damborsky, Joanne C.; Griffith, William H.; Winzer-Serhan, Ursula H.

    2014-01-01

    Developmental exposure to nicotine has been linked to long-lasting changes in synaptic transmission which may contribute to behavioral abnormalities seen in offspring of women who smoke during pregnancy. Here, we examined the long-lasting effects of developmental nicotine exposure on glutamatergic and GABAergic neurotransmission, and on acute nicotine-induced glutamate and GABA release in the adult hippocampus, a structure important in cognitive and emotional behaviors. We utilized a chronic neonatal nicotine treatment model to administer nicotine (6 mg/kg/day) to rat pups from postnatal day (P) 1–7, a period that falls developmentally into the third human trimester. Using whole-cell voltage clamp recordings from CA1 pyramidal neurons in hippocampal slices, we measured excitatory and inhibitory postsynaptic currents in neonatally control- and nicotine-treated young adult males. Neonatal nicotine exposure significantly increased AMPA receptor-mediated spontaneous and evoked excitatory signaling, with no change in glutamate release probability in adults. Conversely, there was no increase in spontaneous GABAergic neurotransmission in nicotine-males. Chronic neonatal nicotine treatment had no effect on acute nicotine-stimulated glutamate release in adults, but acute nicotine-stimulated GABA release was significantly attenuated. Thus, neonatal nicotine exposure results in a persistent net increase in excitation and a concurrent loss of nicotinic acetylcholine receptor (nAChR)-mediated regulation of presynaptic GABA but not glutamate release, which would exacerbate excitation following endogenous or exogenous nAChR activation. Our data underscore an important role for nAChRs in hippocampal excitatory synapse development, and suggest selective long-term changes at specific presynaptic nAChRs which together could explain some of the behavioral abnormalities associated with maternal smoking. PMID:24950455

  16. Radiosensitivity of peripheral blood lymphocytes in autoimmune disease

    Energy Technology Data Exchange (ETDEWEB)

    Harris, G [Kennedy Inst. of Rheumatology, London (UK). Div. of Experimental Pathology; Cramp, W A; Edwards, J C; George, A M; Sabovljev, S A; Hart, L; Hughes, G R.V. [Hammersmith Hospital, London (UK); Denman, A M [Northwich Park Hospital, Harrow (UK); Yatvin, M B [Wisconsin Clinical Cancer Center, Madison (USA)

    1985-06-01

    The proliferation of peripheral blood lymphocytes, cultured with Con A, can be inhibited by ionizing radiation. Lymphocytes from patients with conditions associated with autoimmunity, such as rheumatoid arthritis, systemic lupus erythematosus and polymyositis, are more radiosensitive than those from healthy volunteers or patients with conditions not associated with autoimmunity. Nuclear material isolated from the lymphocytes of patients with autoimmune diseases is, on average, lighter in density than the nuclear material from most healthy controls. This difference in density is not related to increased sensitivity to ionizing radiation but the degree of post-irradiation change in density (lightening) is proportional to the initial density, i.e. more dense nuclear material always shows a greater upward shift after radiation. The recovery of pre-irradiation density of nuclear material, 1 h after radiation exposure, taken as an indication of DNA repair, correlates with the radiosensitivity of lymphocyte proliferation (Con A response); failure to return to pre-irradiation density being associated with increased sensitivity of proliferative response. These results require extension but, taken with previously reported studied of the effects of DNA methylating agents, support the idea that DNA damage and its defective repair could be important in the aetio-pathogenesis of autoimmune disease.

  17. Effect of misonidazole on radiosensitivity of Ehrlich ascites tumor cells

    International Nuclear Information System (INIS)

    Takeuchi, Hiroshi

    1986-01-01

    The effect of Misonidazole on radiosensitivity of Ehrlich ascites tumor cells was studied in vivo. Ehrlich ascites tumor cells growing intraperitoneally (ICR/SIC mice) for either 1, 4, 6 or 10 days were irradiated in vivo (whole body irradiation) with or without Misonidazole. Immediately after irradiation tumor cells were transplanted intraperitoneally into new animals. Four days later, the propagated surviving cells were removed and counted for analyses. Enhancement ratio of Misonidazole at the surviving fraction of 0.1 were 1.0 (for 1-day-old), 1.3 (for 4-day-old), 1.9 (for 6-day-old), 1.9 (for 10-day-old) and 2.8 (for anoxic cells) respectively. The gradual increase of the enhancement ratio of the ascites tumore cells during intraperitoneal growth from 1 through 10 days might be attributed to an increase of hypoxic tumor cells. Cytotoxicity was not observed at 0.1 mg per gram body weight of Misonidazole but was at 1 mg per gram body weight of Misonidazole in 6-day-old and 10-day-old Ehrlich ascites tumor cells which were supposed to contain hypoxic cells. These results suggest that Misonidazole may prove an effective radiosensitizer for hypoxic tumor cells. (author)

  18. Radiosensitivity of lymphocytes in vitro

    International Nuclear Information System (INIS)

    Albrecht, S.

    1979-01-01

    The radiation-induced impairment of human T-lymphocytes was studied after in vitro exposure to 25.8 - 825.6 mC/kg (100 - 3200 R) of 60 Co γ-radiation by ascertaining the change in lymphocyte response to phytohaemagglutin stimulation. Following methods were used: (1) measurement of 3 H-thymidine uptake, (2) E-rosette test, and (3) morphological examination of transformed T-cells. The results revealed a dose-dependent decline in T-cell number which was still somewhat more marked with lymphocytes purified over Ficoll-Isopaque prior to irradiation. (author)

  19. Does stimulation of NaCl secretion in in vitro perfused rectal gland tubules of Squalus acanthias increase membrane capacitance?

    Science.gov (United States)

    Greger, R; Thiele, I; Warth, R; Bleich, M

    1998-07-01

    NaCl secretion in rectal gland tubules (RGT) of Squalus acanthias requires the activation of Cl– channels in the luminal membrane. The RGT and its mechanism of activation are an early evolutionary paradigm of exocrine secretion. The respective Cl– channels probably resemble the shark equivalent of the cystic fibrosis transmembrane conductance regulator (CFTR). Activation of these Cl– channels occurs via cAMP. It has been hypothesized that the activation of CFTR occurs via exocytosis or inhibited endocytosis. To examine this question directly by electrical measurements we have performed whole-cell patch-clamp analyses of in vitro perfused RGT. NaCl secretion was stimulated by a solution (Stim) containing forskolin (10 µmol/l), dibutyryl-cAMP (0.5 mmol/l) and adenosine (0.5 mmol/l). This led to the expected strong depolarization and an increase in membrane conductance (G m). The membrane capacitance (C m) was measured by a newly devised two-frequency synchronous detector method. It was increased by Stim significantly from 5.00±0.22 to 5.17±0.21 pF (n=50). The increase in C m correlated with the increase in G m with a slope of 51 fF/nS. Next the effect of furosemide (500 µmol/l) was examined in previously stimulated RGT. Furosemide was supposed to inhibit coupled Na+2Cl–K+ uptake and to reduce cell volume but not membrane trafficking of Cl– channels. Furosemide reduced G m slightly (due to the fall in cytosolic Cl– concentration) and C m to the same extent by which Stim had increased it. Both changes were statistically significant, and the slope of ΔC m/ΔG m was similar to that caused by Stim. Inhibitors of microtubules or actin (colchicine, phalloidin and cytochalasin D added at 10 µmol/l to the pipette solution and dialysed for >10 min) did not alter cell voltage, G m or C m, nor did these inhibitors abolish the stimulatory effect of cAMP. These data suggest that the small C m changes observed with Stim reflect a minor cell volume increase and an

  20. CRF1 receptor activation increases the response of neurons in the basolateral nucleus of the amygdala to afferent stimulation

    Directory of Open Access Journals (Sweden)

    2008-07-01

    Full Text Available The basolateral nucleus (BLA of the amygdala contributes to the consolidation of memories for emotional or stressful events. The nucleus contains a high density of CRF1 receptors that are activated by corticotropin-releasing factor (CRF. Modulation of the excitability of neurons in the BLA by CRF may regulate the immediate response to stressful events and the formation of associated memories. In the present study, CRF was found to increase the amplitude of field potentials recorded in the BLA following excitatory afferent stimulation, in vitro. The increase was mediated by CRF1 receptors, since it could be blocked by the selective, non-peptide antagonists, NBI30775 and NBI35583, but not by the CRF2-selective antagonist, astressin 2B. Furthermore, the CRF2-selective agonist, urocortin II had no effect on field potential amplitude. The increase induced by CRF was long-lasting, could not be reversed by subsequent administration of NBI35583, and required the activation of protein kinase C. This effect of CRF in the BLA may be important for increasing the salience of aversive stimuli under stressful conditions, and for enhancing the consolidation of associated memories. The results provide further justification for studying the efficacy of selective antagonists of the CRF1 receptor to reduce memory formation linked to emotional or traumatic events, and suggest that these compounds might be useful as prophylactic treatment for stress-related illness such as post-traumatic stress disorder.

  1. Evaluation of a MTT assay in measurement of radiosensitizing effect

    International Nuclear Information System (INIS)

    Higuchi, Keiko; Mitsuhashi, Norio; Saitoh, Jun-ichi; Maebayashi, Katsuya; Sakurai, Hideyuki; Akimoto, Tetsuo; Niibe, Hideo

    1999-01-01

    The usefulness of a MTT assay by measuring the radiosensitizing effect of caffeine on rat yolk sac tumor cell line with a mutant-type p53 in vitro was evaluated. A rat yolk sac tumor cell line with a mutant-type p53, NMT-1R, was used in this study. The radiosensitivity of NMT-1R with or without caffeine was measured with a MTT assay. The results were compared with those by a clonogenic assay. Caffeine at a concentration of 2.0 mM which released radiation-induced G 2 block demonstrated a radiosensitizing effect, but caffeine at a concentration of 0.5 mM did not. The radiosensitizing effect of caffeine measured by a MTT assay correlated with that measured by a clonogenic assay. A MTT assay was useful to measure radiosensitivity and/or a radiosensitizing effect in vitro. (author)

  2. Gamma radiosensitivity of a common bean cultivar

    International Nuclear Information System (INIS)

    Colaco, W.; Martinez, C.R.

    1995-01-01

    A preliminary experiment was conducted to evaluate the radiosensitivity of common bean (Phaseolous vulgaris L.), cultivar to gamma rays from a 60 Co source. Sets of seeds (60 seed/sample) irradiated with 50, 100, 150, 200, and 250 Gy, were compared to a control without irradiation (0 Gy), under greenhouse conditions. The radiosensitivity was evaluated through seedling height reduction, determined at 15 days after emergence (DAE), and also through seedling survival, root length, and dry matter production of leaves, shoots and roots. Seedling height was significantly reduced for the treatments with 150 and 250 Gy, in relation to the control. The dose causing reduction of 50% seedling height was between 150 and 200 Gy. Survival rates corresponding to these doses, were, respectively, 85% and 60%. Root length and dry matter of leaves, shoots and roots, were inversely related to the doses. (author). 15 refs, 3 figs, 1 tab

  3. Radiosensitivity study of salmonella enteritidis in chickens

    International Nuclear Information System (INIS)

    Fernandez Gianotti, Tomas

    1997-01-01

    One of the applications of ionizing radiations in food is the inactivation of vegetative phatogenic bacteria (radicidation) such as Salmonella, Shigella, Campylobacter, Vibro and Listeria. These bacteria are associated with the diseases transmitted by food (ETA). Fresh and frozen farmyard fowls can be contaminated with pathogenic microorganisms, between them Salmonella. In Argentine, between years 1987-1990, Salmonella enteritidis was the main cause of salmonellosis. In food irradiation, with the aim of improving and assuring its hygienic quality, it is important to know the radiosensitivity of microorganisms to be inactivated. Inactivation of a determined microorganism shall depend, between others factors, of the species, strain, number and of the irradiation conditions (temperature, media, etc.). D 10 value is a very useful data in order to compare radiosensitivities between the microorganisms and the influence of different factors in their sensitivities. In this paper, it was determined the sensitivity to the gamma radiation of Salmonella enteritidis in fresh and frozen chickens

  4. Gamma radiosensitivity in common bean plant and cowpea

    International Nuclear Information System (INIS)

    Guimaraes, Sandra da Silva; Colaco, Waldeciro

    2002-01-01

    An indispensable step in mutation induction experiments is the determination of the sensitivity to mutagens to be used. Taking this into consideration the radiosensitivity of bean cultivars Carioca, Princesa (P. vulgaris L.), and IPA-206 [V. unguiculata (L.) Walp] to gamma rays from a 60 Co source was evaluated. Sets of seeds (40 seeds/sample) were irradiated with 100, 150, 200, 250 Gy, and compared to a control without irradiation (0 Gy), under greenhouse conditions. Bean and cowpea seeds were respectively inoculated with a suspension of Rhizobium (SEMIA-4077) and Bradyrhizobium (SEMIA-6145) strains. The radiosensitivity was evaluated through seedling height reduction determined at 15 days after emergence (15-DAE), and also through dry matter yield of above-ground part and root nodules at 40-DAE. Seedling height was significantly reduced with increased dose of radiation in relation to the control. The dose causing reduction of 50% seedling height for P. vulgaris cultivar Princesa was set up between 150-250 Gy. Cowpea (IPA-206) was less sensitive to radiation than common bean cultivars, considering the dose range of radiation studied, and a 75% seedling height reduction was reached in the range of 150-250 Gy. Dry mater yield of the above-ground part, root and nodule, were inversely related to the doses. It is recommended a dose range of 300-350 Gy for mutation breeding purposes using the cowpea cultivar (IPA-206). (author)

  5. ATM induction insufficiency in a radiosensitive breast-cancer patient

    International Nuclear Information System (INIS)

    Clarke, R.A.; Fang, Z.H.; Marr, P.J.; Kearsley, J.H.; Papadatos, G.; Lee, C.S.; University of Sydney, Camperdown, NSW

    2002-01-01

    ATM induction insufficiency in a radiosensitive breast-cancer patient The ataxia telangiectasia (A-T) gene (ATM) is a dominant breast cancer gene with tumour suppressor activity. ATM also regulates cellular sensitivity to ionising radiation (IR) presumably through its role as a facilitator of DNA repair. In normal cells and tissues the ATM protein is rapidly induced by IR to threshold/maximum levels. The kinase function of the ATM protein is also rapidly activated in response to IR. The fact that women carriers of ATM mutations can have an increased risk of developing breast cancer and that many sporadic breast tumours have reduced levels of the ATM protein broadens the scope of ATM's tumour suppressor within the breast. This report describes the downregulation of ATM protein levels in a radiosensitive breast cancer patient. Postinduction ATM levels were up to tenfold lower in the patient's fresh tissues compared to normal controls. These results might indicate a much broader role for ATM anomalies in breast cancer aetiology. Copyright (2002) Blackwell Science Pty Ltd

  6. Radiosensitivity of red flour beetle tribolium castaneum

    International Nuclear Information System (INIS)

    Sattar, A.; Khattak, S.; Hamed, M.

    1992-07-01

    In this report radiosensitivity of red beetle has been discussed. Red flour beetle is the most injurious pest causing great losses to stored grain. Radiation is one of the best tools of insect control. Different radiation doses (50 to 200 krads) were employed for different age groups from 1 to 60 days. It is concluded from these results that 200 krad radiation dose caused 100% mortality in red beetle in all age group. (A.B.)

  7. 53BP1 loss suppresses the radiosensitizing effect of icotinib hydrochloride in colorectal cancer cells.

    Science.gov (United States)

    Huang, Ai; Yao, Jing; Liu, Tao; Lin, Zhenyu; Zhang, Sheng; Zhang, Tao; Ma, Hong

    2018-04-01

    This study aimed to investigate the influence of the expression of P53-binding protein 1 (53BP1), a key component in DNA damage repair pathways, on the radiosensitizing effect of icotinib hydrochloride in colorectal cancer and to elucidate the mechanisms underlying this influence. Real-time RT-PCR and Western blotting were performed to verify the gene-knockout effect of 53BP1 small hairpin RNA (ShRNA), and colony formation assay was employed to investigate the influence of 53BP1 downregulation on the radiosensitizing effect of icotinib hydrochloride in HCT116 cells. Cell apoptosis, cell cycle distributions, and histone H2AX (γ-H2AX) fluorescence foci after 53BP1 knockdown were evaluated. Relative protein expression in the ataxia telangiectasia mutated kinase (ATM)-checkpoint kinase-2 (CHK2)-P53 pathway was measured by Western blot analysis to unravel the molecular mechanisms linking the pathway to the above phenomena. Icotinib hydrochloride increased the radiosensitivity of HCT116 cells; however, this effect was suppressed by the downregulation of 53BP1 expression, a change that inhibited cell apoptosis, increased the percentage of HCT116 cells arrested in S-phase and inhibited the protein expression of key molecules in the ATM-CHK2-P53 apoptotic pathway. Our studies confirmed that the loss of 53BP1 serves as a negative regulator of the radiosensitizing effect of icotinib in part by suppressing the ATM-CHK2-P53 apoptotic pathway.

  8. Effect of allicin on the radiosensitivity of human pancreatic carcinoma BXPC3 cells

    International Nuclear Information System (INIS)

    Ma Hongbing; Di Zhengli; He Na; Wen Jiao; Ke Yue

    2014-01-01

    Objective: To study the effect of allicin on the growth and radiosensitivity of human pancreatic carcinoma BXPC3 cells. Methods: BXPC3 cells were exposed to X-rays in the presence or absence of allicin. Cell proliferation was measured by MTT assay. Cell cycle distribution and apoptosis were detected by flow cytometry assay. Cell radiosensitivity and the influence of allicin on it was evaluated by colony formation assay. The expressions of Bax and Bcl-2 proteins were assayed by RT-PCR and Western blot. Results: IC 50 values of allicin on cell growth were 76.24, 58.34 and 43.58 μmol/L under 12, 24 and 48 h treatment, respectively. Treatment of cells with allicin obviously inhibited cell growth after irradiation and hence increased radiosensitivity (t = 2.74, P < 0.05). This treament also enhanced radiation-induced cell cycle arrest at G 2 /M phase (t = 11.41, P < 0.05), apoptosis induction (t = 12.36, P < 0.05), and Bax expression (t = 4.83, P < 0.05), but it decreased Bcl-2 expression (t = 3.69, P < 0.05). Conclusions: Allicin could inhibit cell growth, induce cell cycle arrest and apoptosis via Bax/Bcl-2 pathway and hence increases radiosensitivity of BXPC3 cells. (authors)

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

    Energy Technology Data Exchange (ETDEWEB)

    Meng, Zhen [Central Laboratory, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081 (China); Department of Oral & Maxillofacial Surgery, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081 (China); Gan, Ye-Hua, E-mail: kqyehuagan@bjmu.edu.cn [Central Laboratory, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081 (China); Department of Oral & Maxillofacial Surgery, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081 (China)

    2015-05-01

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

  10. Leucine deprivation stimulates fat loss via increasing CRH expression in the hypothalamus and activating the sympathetic nervous system.

    Science.gov (United States)

    Cheng, Ying; Zhang, Qian; Meng, Qingshu; Xia, Tingting; Huang, Zhiying; Wang, Chunxia; Liu, Bin; Chen, Shanghai; Xiao, Fei; Du, Ying; Guo, Feifan

    2011-09-01

    We previously showed that leucine deprivation decreases abdominal fat mass largely by increasing energy expenditure, as demonstrated by increased lipolysis in white adipose tissue (WAT) and uncoupling protein 1 (UCP1) expression in brown adipose tissue (BAT). The goal of the present study was to investigate the possible involvement of central nervous system (CNS) in this regulation and elucidate underlying molecular mechanisms. For this purpose, levels of genes and proteins related to lipolysis in WAT and UCP1 expression in BAT were analyzed in wild-type mice after intracerebroventricular administration of leucine or corticotrophin-releasing hormone antibodies, or in mice deleted for three β-adrenergic receptors, after being maintained on a leucine-deficient diet for 7 d. Here, we show that intracerebroventricular administration of leucine significantly attenuates abdominal fat loss and blocks activation of hormone sensitive lipase in WAT and induction of UCP1 in BAT in leucine-deprived mice. Furthermore, we provide evidence that leucine deprivation stimulates fat loss by increasing expression of corticotrophin-releasing hormone in the hypothalamus via activation of stimulatory G protein/cAMP/protein kinase A/cAMP response element-binding protein pathway. Finally, we show that the effect of leucine deprivation on fat loss is mediated by activation of the sympathetic nervous system. These results suggest that CNS plays an important role in regulating fat loss under leucine deprivation and thereby provide novel and important insights concerning the importance of CNS leucine in the regulation of energy homeostasis.

  11. Effects of Increasing Neuromuscular Electrical Stimulation Current Intensity on Cortical Sensorimotor Network Activation: A Time Domain fNIRS Study.

    Directory of Open Access Journals (Sweden)

    Makii Muthalib

    Full Text Available Neuroimaging studies have shown neuromuscular electrical stimulation (NMES-evoked movements activate regions of the cortical sensorimotor network, including the primary sensorimotor cortex (SMC, premotor cortex (PMC, supplementary motor area (SMA, and secondary somatosensory area (S2, as well as regions of the prefrontal cortex (PFC known to be involved in pain processing. The aim of this study, on nine healthy subjects, was to compare the cortical network activation profile and pain ratings during NMES of the right forearm wrist extensor muscles at increasing current intensities up to and slightly over the individual maximal tolerated intensity (MTI, and with reference to voluntary (VOL wrist extension movements. By exploiting the capability of the multi-channel time domain functional near-infrared spectroscopy technique to relate depth information to the photon time-of-flight, the cortical and superficial oxygenated (O2Hb and deoxygenated (HHb hemoglobin concentrations were estimated. The O2Hb and HHb maps obtained using the General Linear Model (NIRS-SPM analysis method, showed that the VOL and NMES-evoked movements significantly increased activation (i.e., increase in O2Hb and corresponding decrease in HHb in the cortical layer of the contralateral sensorimotor network (SMC, PMC/SMA, and S2. However, the level and area of contralateral sensorimotor network (including PFC activation was significantly greater for NMES than VOL. Furthermore, there was greater bilateral sensorimotor network activation with the high NMES current intensities which corresponded with increased pain ratings. In conclusion, our findings suggest that greater bilateral sensorimotor network activation profile with high NMES current intensities could be in part attributable to increased attentional/pain processing and to increased bilateral sensorimotor integration in these cortical regions.

  12. Effects of Increasing Neuromuscular Electrical Stimulation Current Intensity on Cortical Sensorimotor Network Activation: A Time Domain fNIRS Study.

    Science.gov (United States)

    Muthalib, Makii; Re, Rebecca; Zucchelli, Lucia; Perrey, Stephane; Contini, Davide; Caffini, Matteo; Spinelli, Lorenzo; Kerr, Graham; Quaresima, Valentina; Ferrari, Marco; Torricelli, Alessandro

    2015-01-01

    Neuroimaging studies have shown neuromuscular electrical stimulation (NMES)-evoked movements activate regions of the cortical sensorimotor network, including the primary sensorimotor cortex (SMC), premotor cortex (PMC), supplementary motor area (SMA), and secondary somatosensory area (S2), as well as regions of the prefrontal cortex (PFC) known to be involved in pain processing. The aim of this study, on nine healthy subjects, was to compare the cortical network activation profile and pain ratings during NMES of the right forearm wrist extensor muscles at increasing current intensities up to and slightly over the individual maximal tolerated intensity (MTI), and with reference to voluntary (VOL) wrist extension movements. By exploiting the capability of the multi-channel time domain functional near-infrared spectroscopy technique to relate depth information to the photon time-of-flight, the cortical and superficial oxygenated (O2Hb) and deoxygenated (HHb) hemoglobin concentrations were estimated. The O2Hb and HHb maps obtained using the General Linear Model (NIRS-SPM) analysis method, showed that the VOL and NMES-evoked movements significantly increased activation (i.e., increase in O2Hb and corresponding decrease in HHb) in the cortical layer of the contralateral sensorimotor network (SMC, PMC/SMA, and S2). However, the level and area of contralateral sensorimotor network (including PFC) activation was significantly greater for NMES than VOL. Furthermore, there was greater bilateral sensorimotor network activation with the high NMES current intensities which corresponded with increased pain ratings. In conclusion, our findings suggest that greater bilateral sensorimotor network activation profile with high NMES current intensities could be in part attributable to increased attentional/pain processing and to increased bilateral sensorimotor integration in these cortical regions.

  13. Liposome based radiosensitizer cancer therapy

    DEFF Research Database (Denmark)

    Pourhassan, Houman

    Liposome-encapsulated chemotherapeutics have been used in the treatment of a variety of cancers and are feasible for use as mono-therapeutics as well as for combination therapy in conjunction with other modalities. Despite widespread use of liposomal drugs in cancer patient care, insufficient drug...... biomolecules. By modulating the liposomal membrane, liposomes can become sensitive towards enzymatically-driven destabilization and/or functionalization, thereby allowing control of the release of encapsulated therapeutics within the diseased tissue upon intrinsic stimulation from tumor-associated enzymes...... in tumor-bearing mice.The safety and efficacy of sPLA2-sensitive liposomal L-OHP was assessed in sPLA2-deficient FaDu hypopharyngeal squamous cell carcinoma and sPLA2-expressing Colo205 colorectal adenocarcinoma. Also, the feasibility of multimodal cancer therapy employing L-OHP encapsulated in MMP...

  14. Comparison of Transcutaneous Electrical Nerve Stimulation and Cryotherapy for Increasing Quadriceps Activation in Patients With Knee Pathologies.

    Science.gov (United States)

    Gabler, Conrad M; Lepley, Adam S; Uhl, Tim L; Mattacola, Carl G

    2016-08-01

    Proper neuromuscular activation of the quadriceps muscle is essential for maintaining quadriceps (quad) strength and lower-extremity function. Quad activation (QA) failure is a common characteristic observed in patients with knee pathologies, defined as an inability to voluntarily activate the entire alpha-motor-neuron pool innervating the quad. One of the more popular techniques used to assess QA is the superimposed burst (SIB) technique, a force-based technique that uses a supramaximal, percutaneous electrical stimulation to activate all of the motor units in the quad during a maximal, voluntary isometric contraction. Central activation ratio (CAR) is the formula used to calculate QA level (CAR = voluntary force/SIB force) with the SIB technique. People who can voluntarily activate 95% or more (CAR = 0.95-1.0) of their motor units are defined as being fully activated. Therapeutic exercises aimed at improving quad strength in patients with knee pathologies are limited in their effectiveness due to a failure to fully activate the muscle. Within the past decade, several disinhibitory interventions have been introduced to treat QA failure in patients with knee pathologies. Transcutaneous electrical nerve stimulation (TENS) and cryotherapy are sensory-targeted modalities traditionally used to treat pain, but they have been shown to be 2 of the most successful treatments for increasing QA levels in patients with QA failure. Both modalities are hypothesized to positively affect voluntary QA by disinhibiting the motor-neuron pool of the quad. In essence, these modalities provide excitatory afferent stimuli to the spinal cord, which thereby overrides the inhibitory afferent signaling that arises from the involved joint. However, it remains unknown whether 1 is more effective than the other for restoring QA levels in patients with knee pathologies. By knowing the capabilities of each disinhibitory modality, clinicians can tailor treatments based on the rehabilitation goals

  15. Clinical studies on radiosensitization of cervical cancer by cisplatinum

    International Nuclear Information System (INIS)

    Yu Shiying; Chen Yuan; Xu Zhiqiang

    1993-01-01

    A prospective randomized clinical trial on the radiosensitizing effect of cisplatinum was carried out in 60 patients with cervical cancer, of whom 30 were given cisplatinum in combination with radiotherapy (radiosensitizing group) and the remaining 30 radiotherapy alone (control group). The results showed that the length of time of immediate CR and PR was shorter in the radiosensitizing group than in the control group. The sensitive enhancement ratio was 1.846. No toxicity was observed in the radiosensitizing group, and the treatment was well tolerated by the patients

  16. Electrical Stimulation During Gait Promotes Increase of Muscle Cross-sectional Area in Quadriplegics: A Preliminary Study

    Science.gov (United States)

    Cliquet, Alberto; Rondina, Jane Maryan; Cendes, Fernando

    2008-01-01

    Increases in muscular cross-sectional area (CSA) occur in quadriplegics after training, but the effects of neuromuscular electrical stimulation (NMES) along with training are unknown. Thus, we addressed two questions: (1) Does NMES during treadmill gait training increase the quadriceps CSA in complete quadriplegics?; and (2) Is treadmill gait training alone enough to observe an increase in CSA? Fifteen quadriplegics were divided into gait (n = 8) and control (n = 7) groups. The gait group performed training with NMES for 6 months twice a week for 20 minutes each time. After 6 months of traditional therapy, the control group received the same gait training protocol but without NMES for an additional 6 months. Axial images of the thigh were acquired at the beginning of the study, at 6 months (for both groups), and at 12 months for the control group to determine the average quadriceps CSA. After 6 months, there was an increase of CSA in the gait group (from 49.8 ± 9.4 cm2 to 57.3 ± 10.3 cm2), but not in the control group (from 43.6 ± 7.6 cm2 to 41.8 ± 8.4 cm2). After another 6 months of gait without NMES in the control group, the CSA did not change (from 41.8 ± 8.4 cm2 to 41.7 ± 7.9 cm2). The increase in quadriceps CSA after gait training in patients with chronic complete quadriplegia appears associated with NMES. PMID:18791775

  17. Sensing radiosensitivity of human epidermal stem cells

    International Nuclear Information System (INIS)

    Rachidi, Walid; Harfourche, Ghida; Lemaitre, Gilles; Amiot, Franck; Vaigot, Pierre; Martin, Michele T.

    2007-01-01

    Purpose: Radiosensitivity of stem cells is a matter of debate. For mouse somatic stem cells, both radiosensitive and radioresistant stem cells have been described. By contrast, the response of human stem cells to radiation has been poorly studied. As epidermis is a radiosensitive tissue, we evaluated in the present work the radiosensitivity of cell populations enriched for epithelial stem cells of human epidermis. Methods and materials: The total keratinocyte population was enzymatically isolated from normal human skin. We used flow cytometry and antibodies against cell surface markers to isolate basal cell populations from human foreskin. Cell survival was measured after a dose of 2 Gy with the XTT assay at 72 h after exposure and with a clonogenic assay at 2 weeks. Transcriptome analysis using oligonucleotide microarrays was performed to assess the genomic cell responses to radiation. Results: Cell sorting based on two membrane proteins, α6 integrin and the transferrin receptor CD71, allowed isolation of keratinocyte populations enriched for the two types of cells found in the basal layer of epidermis: stem cells and progenitors. Both the XTT assay and the clonogenic assay showed that the stem cells were radioresistant whereas the progenitors were radiosensitive. We made the hypothesis that upstream DNA damage signalling might be different in the stem cells and used microarray technology to test this hypothesis. The stem cells exhibited a much more reduced gene response to a dose of 2 Gy than the progenitors, as we found that 6% of the spotted genes were regulated in the stem cells and 20% in the progenitors. Using Ingenuity Pathway Analysis software, we found that radiation exposure induced very specific pathways in the stem cells. The most striking responses were the repression of a network of genes involved in apoptosis and the induction of a network of cytokines and growth factors. Conclusion: These results show for the first time that keratinocyte

  18. Addition of Wollastonite Fibers to Calcium Phosphate Cement Increases Cell Viability and Stimulates Differentiation of Osteoblast-Like Cells

    Directory of Open Access Journals (Sweden)

    Juliana Almeida Domingues

    2017-01-01

    Full Text Available Calcium phosphate cement (CPC that is based on α-tricalcium phosphate (α-TCP is considered desirable for bone tissue engineering because of its relatively rapid degradation properties. However, such cement is relatively weak, restricting its use to areas of low mechanical stress. Wollastonite fibers (WF have been used to improve the mechanical strength of biomaterials. However, the biological properties of WF remain poorly understood. Here, we tested the response of osteoblast-like cells to being cultured on CPC reinforced with 5% of WF (CPC-WF. We found that both types of cement studied achieved an ion balance for calcium and phosphate after 3 days of immersion in culture medium and this allowed subsequent long-term cell culture. CPC-WF increased cell viability and stimulated cell differentiation, compared to nonreinforced CPC. We hypothesize that late silicon release by CPC-WF induces increased cell proliferation and differentiation. Based on our findings, we propose that CPC-WF is a promising material for bone tissue engineering applications.

  19. Increased biological activity of deglycosylated recombinant human granulocyte/macrophage colony-stimulating factor produced by yeast or animal cells

    International Nuclear Information System (INIS)

    Moonen, P.; Mermod, J.J.; Ernst, J.F.; Hirschi, M.; DeLamarter, J.F.

    1987-01-01

    Human granulocyte/macrophage colony-stimulating factor (hGM-CSF) produced by several recombinant sources including Escherichia coli, yeast, and animal cells was studied. Recombinant animal cells produced hGM-CSF in low quantities and in multiple forms of varying size. Mammalian hGM-CSF was purified 200,000-fold using immunoaffinity and lectin chromatography. Partially purified proteins produced in yeast and mammalian cells were assayed for the effects of deglycosylation. Following enzymatic deglycosylation, immunoreactivity was measured by radioimmunoassay and biological activity was measured in vitro on responsive human primary cells. Removal of N-linked oligosaccharides from both proteins increased their immunoreactivities by 4- to 8-fold. Removal of these oligosaccharides also increased their specific biological activities about 20-fold, to reach approximately the specific activity of recombinant hGM-CSF from E. coli. The E. coli produced-protein-lacking any carbohydrate- had by far the highest specific activity observed for the recombinant hGM-CSFs

  20. Radiosensitivity of grapevines. Empirical modelling of the radiosensitivity of some clones to x-ray irradiation. Pt. 1

    International Nuclear Information System (INIS)

    Koeroesi, F.; Jezierska-Szabo, E.

    1999-01-01

    Empirical and formal (Poisson) models were utilized, applying experimental growth data to characterize the radiosensitivity of six grapevine clones to X-ray irradiation. According to the radiosensitivity constants (k), target numbers (n) and volumes, GR 37 doses and energy deposition, the following radiosensitivity order has been found for various vine brands: Chardonnay clone type < Harslevelue K. 9 < Koevidinka K. 8 < Muscat Ottonel clone type < Irsai Oliver K. 11 < Cabernet Sauvignon E. 153. The model can be expanded to describe the radiosensitivity of other plant species and varieties, and also the efficiency of various radioprotecting agents and conditions. (author)

  1. Effect of gonadotropin secretion rate on the radiosensitivity of the rat luteinizing hormone-releasing hormone neuron and gonadotroph

    International Nuclear Information System (INIS)

    Winterer, J.; Barnes, K.M.; Lichter, A.S.; Deluca, A.M.; Loriaux, D.L.; Cutler, G.B. Jr.

    1988-01-01

    To test the hypothesis that the functional state of hypothalamic LHRH neurons and pituitary gonadotrophs might alter their radiosensitivity, we determined the experimental conditions under which the gonadotropin response to castration could be impaired by a single dose of cranial irradiation. Single doses of cranial irradiation greater than 2000 rads were lethal to unshielded rats. Shielding of the oropharynx and esophagus allowed the animals to survive doses up to 5000 rads. Doses between 2000 and 5000 rads had no effect on basal gonadotropin levels for as long as 3 months after irradiation. Irradiation caused a dose- and time-dependent impairment, however, in the gonadotropin response to castration. Impairment of the gonadotropin levels of castrate animals occurred in animals that were irradiated either before or after castration. However, rats irradiated in the castrate state showed a decreased susceptibility to irradiation damage. Additionally, stimulation of the pituitary by LHRH agonist (LHRHa) 3 h before irradiation significantly reduced the impairment of gonadotropin secretion 12-20 weeks after irradiation (P less than 0.05). Thus, increased functional activity of the rat hypothalamus or pituitary at the time of irradiation, induced by either castration or acute LHRHa administration, was associated with some protection against the gonadotropin-lowering effect of irradiation. Based upon these data, we hypothesize that stimulation of gonadotropin secretion at the time of therapeutic cranial irradiation in humans might protect against subsequent impairment of gonadotropin secretion

  2. Silencing the Girdin gene enhances radio-sensitivity of hepatocellular carcinoma via suppression of glycolytic metabolism.

    Science.gov (United States)

    Yu, Li; Sun, Yifan; Li, Jingjing; Wang, Yan; Zhu, Yuxing; Shi, Yong; Fan, Xiaojun; Zhou, Jianda; Bao, Ying; Xiao, Jie; Cao, Ke; Cao, Peiguo

    2017-08-15

    Radiotherapy has been used increasingly to treat primary hepatocellular carcinoma. Clinically, the main cause of radiotherapy failure is cellular radioresistance, conferred via glycolytic metabolism. Our previous study demonstrated that Girdin is upregulated in primary hepatocellular carcinoma and promotes the invasion and metastasis of tumor cells. However, whether Girdin underlies the radio-sensitivity of hepatocellular carcinoma remains unclear. A short hairpin RNA (shRNA) was used to silence CCDC88A (encoding Girdin), and real-time PCR was performed to determine CCDC88A mRNA expression. Then, cell proliferation, colony formation, flow cytometric, scratch, and transwell assays were to examine the influence of Girdin silencing on cellular radiosensitivity. Glycolysis assays were conducted to exam cell glycolysis process. Western blotting was performed to explore the signaling pathway downstream of Girdin. Finally, animal experiments were performed to demonstrate the effect of CCDC88A silencing on the radiosensitivity of hepatoma in vivo. shRNA-induced Girdin silencing suppressed glycolysis and enhanced the radio-sensitivity of hepatic cell lines, HepG2 and Huh-7. Furthermore, silencing of Girdin inhibited the PI3K/AKT/HIF-1α signaling pathway, which is a central regulator of glycolysis. Girdin can regulate glycolysis in hepatocellular carcinoma cells through the PI3K/AKT/HIF-1α signaling pathway, which decreases the sensitivity of tumor cells to radiotherapy.

  3. Curcumin enhances the radiosensitivity of renal cancer cells by suppressing NF-κB signaling pathway.

    Science.gov (United States)

    Li, Gang; Wang, Ziming; Chong, Tie; Yang, Jie; Li, Hongliang; Chen, Haiwen

    2017-10-01

    The radiation resistance of renal cell carcinoma (RCC) remains the primary obstacle to improve patient survival. This study aimed to investigate the effects of curcumin on the radiosensitivity of RCC cells. Human RCC cell (ACHN) was exposed to irradiation (IR) and/or curcumin treatment. Cell viability, DNA repair, cell cycle, and apoptosis, were evaluated by MTT, immunofluoresence staining and flow cytometry. Moreover, ACHN cells were xenografted into nude mice and subjected to IR and/or curcumin treatment. The expression of NF-κB signaling related proteins in ACHN cells and xenografts was detected by western blot analysis. The results showed that curcumin significantly increased radiosensitivity of ACHN cells by inhibiting the cell proliferation and DNA damage repair, causing cell cycle arrest at G2/M phase, inducing apoptosis in vitro, and suppressing the growth of xenografts in vivo. In addition, curcumin enhanced radiosensitivity was through markedly inhibiting IR-induced NF-κB signaling by modulating the related protein expressions including NF-κBP65, I-κB, VEGF, COX2, and Bcl-2 in ACHN cells, which was further strengthened by NF-κB inhibitor PDTC treatment. Thus, curcumin may confer radiosensitivity on RCC via inhibition of NF-κB activation and its downstream regulars, suggesting the potential application of curcumin as an adjuvant in radiotherapy of RCC. Copyright © 2017. Published by Elsevier Masson SAS.

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

    International Nuclear Information System (INIS)

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

    2010-01-01

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

  5. Study on the relationship between DNA-PKcs and genomic instability and hyper-radiosensitivity

    International Nuclear Information System (INIS)

    Yang Kang; Zhu Jiayun; Ding Nan; Li Junhong; Hu Wentao; Su Fengtao; He Jinpeng; Li Sha

    2010-01-01

    To investigate the relationship between DNA-PKcs and genome instability and hyper-radiosensitivity, human glioma cell lines M059K and M059J, as a model expressing wild-type DNA-PKcs and a model defective in DNA-PKcs activity, were exposed to low doses of X-rays. Cells survival fractions were assessed by colony-forming assay and Cytochalasin-B micronucleus assay was employed to detect the genomic instability happening in each single irradiated colony. It has been found that as the post-incubation time increased, M059K cells expressing wild-type DNA-PKcs exhibited low-dose hyper-radiosensitivity and showed a similar genomic instability after 0.2 Gy and 0.6 Gy irradiations, but the M059J cells lacking in DNA-PKcs didn't present low-dose hyper-radiosensitivity and showed a higher genomic instability of 0.6 Gy than that of 0.2 Gy. The results indicate that DNA-PKcs may act as one of the key factors that lead to low-dose hyper-radiosensitivity. (authors)

  6. Transcranial alternating current stimulation (tACS increases risk taking behavior in the Balloon Analogue Risk Task

    Directory of Open Access Journals (Sweden)

    Tal eSela

    2012-02-01

    Full Text Available The process of evaluating risks and benefits involves a complex neural network that includes the dorsolateral prefrontal cortex (DLPFC. It has been proposed that in conflict and reward situations, theta-band (4–8 Hz oscillatory activity in the frontal cortex may reflect an electrophysiological mechanism for coordinating neural networks monitoring behavior, as well as facilitating task-specific adaptive changes. The goal of the present study was to investigate the hypothesis that theta-band oscillatory balance between right and left frontal and prefrontal regions, with a predominance role to the right hemisphere, is crucial for regulatory control during decision-making under risk. In order to explore this hypothesis, we used transcranial Alternating Current Stimulation (tACS, a novel technique that provides the opportunity to explore the functional role of neuronal oscillatory activities and to establish a causal link between specific oscillations and functional lateralization in risky decision-making situations. For this aim, healthy participants were randomly allocated to one of three stimulation groups (LH stimulation / RH stimulation / Sham stimulation, with active AC stimulation delivered in a frequency-dependent manner (at 6.5 Hz; 1mA peak to-peak. During the AC stimulation, participants performed the Balloon Analog Risk Task. This experiment revealed that participants receiving LH stimulation displayed riskier decision-making style compared to sham and RH stimulation groups. However, there was no difference in decision-making behaviors between sham and RH stimulation groups. The current study extends the notion that DLPFC activity is critical for adaptive decision-making in the context of risk-taking and emphasis the role of theta-band oscillatory activity during risky decision-making situations.

  7. Paired motor cortex and cervical epidural electrical stimulation timed to converge in the spinal cord promotes lasting increases in motor responses.

    Science.gov (United States)

    Mishra, Asht M; Pal, Ajay; Gupta, Disha; Carmel, Jason B

    2017-11-15

    Pairing motor cortex stimulation and spinal cord epidural stimulation produced large augmentation in motor cortex evoked potentials if they were timed to converge in the spinal cord. The modulation of cortical evoked potentials by spinal cord stimulation was largest when the spinal electrodes were placed over the dorsal root entry zone. Repeated pairing of motor cortex and spinal cord stimulation caused lasting increases in evoked potentials from both sites, but only if the time between the stimuli was optimal. Both immediate and lasting effects of paired stimulation are likely mediated by convergence of descending motor circuits and large diameter afferents onto common interneurons in the cervical spinal cord. Convergent activity in neural circuits can generate changes at their intersection. The rules of paired electrical stimulation are best understood for protocols that stimulate input circuits and their targets. We took a different approach by targeting the interaction of descending motor pathways and large diameter afferents in the spinal cord. We hypothesized that pairing stimulation of motor cortex and cervical spinal cord would strengthen motor responses through their convergence. We placed epidural electrodes over motor cortex and the dorsal cervical spinal cord in rats; motor evoked potentials (MEPs) were measured from biceps. MEPs evoked from motor cortex were robustly augmented with spinal epidural stimulation delivered at an intensity below the threshold for provoking an MEP. Augmentation was critically dependent on the timing and position of spinal stimulation. When the spinal stimulation was timed to coincide with the descending volley from motor cortex stimulation, MEPs were more than doubled. We then tested the effect of repeated pairing of motor cortex and spinal stimulation. Repetitive pairing caused strong augmentation of cortical MEPs and spinal excitability that lasted up to an hour after just 5 min of pairing. Additional physiology

  8. Radiation could induce p53-independent and cell cycle - unrelated apoptosis in 5-fluorouracil radiosensitized head and neck carcinoma cells

    International Nuclear Information System (INIS)

    Didelot, C.; Mirjolet, J.F.; Barberi-Heyob, M.; Ramacci, C.; Merlin, J.L.

    2002-01-01

    The effect of chemoresistance induction in radio sensitivity and cellular behavior after irradiation remains misunderstood. This study was designed to understand the relationship between radiation-induced cell cycle arrest, apoptosis, and radiosensitivity in KB cell line and KB3 subline selected after 5-fluorouracil (5FU) exposure. Exposure of KB cells to 5FU led to an increase in radiosensitivity. G 2 /M cell cycle arrest was observed in the two cell lines after irradiation. The radioresistant KB cell line reached the maximum arrest two hours before KB3. The cellular exit from this arrest was found to be related to the wild type p53 protein expression induction. After irradiation, only KB3 cell line underwent apoptosis. This apoptosis induction seemed to be independent of G 2 /M arrest exit, which was carried out later. The difference in radiosensitivity between KB and KB3 subline may result therefore from both a difference in apoptosis induction and a difference in G 2 /M arrest maximum duration. Moreover, 5FU exposure has led to an increase in constitutive p53 protein expression, which may be associated with an increase in basal apoptosis cell fraction. Given the existing correlation between radiosensitivity and the percentage of basal apoptosis. the constitutive p53 protein expression may be related to intrinsic radiosensitivity in our cellular model. (author)

  9. Root carbon inputs to the rhizosphere stimulate extracellular enzyme activity and increase nitrogen availability in temperate forest soils

    Science.gov (United States)

    Brzostek, E. R.; Phillips, R.; Dragoni, D.; Drake, J. E.; Finzi, A. C.

    2011-12-01

    The mobilization of nitrogen (N) from soil organic matter in temperate forest soils is controlled by the microbial production and activity of extracellular enzymes. The exudation of carbon (C) by tree roots into the rhizosphere may subsidize the microbial production of extracellular enzymes in the rhizosphere and increase the access of roots to N. The objective of this research was to investigate whether rates of root exudation and the resulting stimulation of extracellular enzyme activity in the rhizosphere (i.e., rhizosphere effect) differs between tree species that form associations with ectomycorrhizal (ECM) or arbuscular mycorrhizal (AM) fungi. This research was conducted at two temperate forest sites, the Harvard Forest (HF) in Central MA and the Morgan Monroe State Forest (MMSF) in Southern IN. At the HF, we measured rates of root exudation and the rhizosphere effects on enzyme activity, N cycling, and C mineralization in AM and ECM soils. At the MMSF, we recently girdled AM and ECM dominated plots to examine the impact of severing belowground C allocation on rhizosphere processes. At both sites, the rhizosphere effect on proteolytic, chitinolytic and ligninolytic enzyme activities was greater in ECM soils than in AM soils. In particular, higher rates of proteolytic enzyme activity increased the availability of amino acid-N in ECM rhizospheres relative to the bulk soils. Further, this stimulation of enzyme activity was directly correlated with higher rates of C mineralization in the rhizosphere than in the bulk soil. Although not significantly different between species, root exudation of C comprised 3-10% of annual gross primary production at the HF. At the MMSF, experimental girdling led to a larger decline in soil respiration and enzyme activity in ECM plots than in AM plots. In both ECM and AM soils, however, girdling resulted in equivalent rates of enzyme activity in rhizosphere and corresponding bulk soils. The results of this study contribute to the

  10. Targeting Mcl-1 for Radiosensitization of Pancreatic Cancers

    Directory of Open Access Journals (Sweden)

    Dongping Wei

    2015-02-01

    Full Text Available In order to identify targets whose inhibition may enhance the efficacy of chemoradiation in pancreatic cancer, we previously conducted an RNAi library screen of 8,800 genes. We identified Mcl-1 (myeloid cell leukemia-1, an anti-apoptotic member of the Bcl-2 family, as a target for sensitizing pancreatic cancer cells to chemoradiation. In the present study we investigated Mcl-1 inhibition by either genetic or pharmacological approaches as a radiosensitizing strategy in pancreatic cancer cells. Mcl-1 depletion by siRNA produced significant radiosensitization in BxPC-3 and Panc-1 cells in association with Caspase-3 activation and PARP cleavage, but only minimal radiosensitization in MiaPaCa-2 cells. We next tested the ability of the recently identified, selective, small molecule inhibitor of Mcl-1, UMI77, to radiosensitize in pancreatic cancer cells. UMI77 caused dissociation of Mcl-1 from the pro-apoptotic protein Bak and produced significant radiosensitization in BxPC-3 and Panc-1 cells, but minimal radiosensitization in MiaPaCa-2 cells. Radiosensitization by UMI77 was associated with Caspase-3 activation and PARP cleavage. Importantly, UMI77 did not radiosensitize normal small intestinal cells. In contrast, ABT-737, an established inhibitor of Bcl-2, Bcl-XL, and Bcl-w, failed to radiosensitize pancreatic cancer cells suggesting the unique importance of Mcl-1 relative to other Bcl-2 family members to radiation survival in pancreatic cancer cells. Taken together, these results validate Mcl-1 as a target for radiosensitization of pancreatic cancer cells and demonstrate the ability of small molecules which bind the canonical BH3 groove of Mcl-1, causing displacement of Mcl-1 from Bak, to selectively radiosensitize pancreatic cancer cells.

  11. Low-intensity repetitive magnetic stimulation lowers action potential threshold and increases spike firing in layer 5 pyramidal neurons in vitro.

    Science.gov (United States)

    Tang, Alexander D; Hong, Ivan; Boddington, Laura J; Garrett, Andrew R; Etherington, Sarah; Reynolds, John N J; Rodger, Jennifer

    2016-10-29

    Repetitive transcranial magnetic stimulation (rTMS) has become a popular method of modulating neural plasticity in humans. Clinically, rTMS is delivered at high intensities to modulate neuronal excitability. While the high-intensity magnetic field can be targeted to stimulate specific cortical regions, areas adjacent to the targeted area receive stimulation at a lower intensity and may contribute to the overall plasticity induced by rTMS. We have previously shown that low-intensity rTMS induces molecular and structural plasticity in vivo, but the effects on membrane properties and neural excitability have not been investigated. Here we investigated the acute effect of low-intensity repetitive magnetic stimulation (LI-rMS) on neuronal excitability and potential changes on the passive and active electrophysiological properties of layer 5 pyramidal neurons in vitro. Whole-cell current clamp recordings were made at baseline prior to subthreshold LI-rMS (600 pulses of iTBS, n=9 cells from 7 animals) or sham (n=10 cells from 9 animals), immediately after stimulation, as well as 10 and 20min post-stimulation. Our results show that LI-rMS does not alter passive membrane properties (resting membrane potential and input resistance) but hyperpolarises action potential threshold and increases evoked spike-firing frequency. Increases in spike firing frequency were present throughout the 20min post-stimulation whereas action potential (AP) threshold hyperpolarization was present immediately after stimulation and at 20min post-stimulation. These results provide evidence that LI-rMS alters neuronal excitability of excitatory neurons. We suggest that regions outside the targeted region of high-intensity rTMS are susceptible to neuromodulation and may contribute to rTMS-induced plasticity. Copyright © 2016 IBRO. All rights reserved.

  12. Melanogenesis stimulation in B16-F10 melanoma cells induces cell cycle alterations, increased ROS levels and a differential expression of proteins as revealed by proteomic analysis

    Energy Technology Data Exchange (ETDEWEB)

    Cunha, Elizabeth S.; Kawahara, Rebeca [Departamento de Bioquimica e Biologia Molecular, Setor de Ciencias Biologicas, Universidade Federal do Parana, P.O. Box 19046, CEP 81531-990, Curitiba, PR (Brazil); Kadowaki, Marina K. [Universidade Estadual do Oeste do Parana, Cascavel, PR (Brazil); Amstalden, Hudson G.; Noleto, Guilhermina R.; Cadena, Silvia Maria S.C.; Winnischofer, Sheila M.B. [Departamento de Bioquimica e Biologia Molecular, Setor de Ciencias Biologicas, Universidade Federal do Parana, P.O. Box 19046, CEP 81531-990, Curitiba, PR (Brazil); Martinez, Glaucia R., E-mail: grmartinez@ufpr.br [Departamento de Bioquimica e Biologia Molecular, Setor de Ciencias Biologicas, Universidade Federal do Parana, P.O. Box 19046, CEP 81531-990, Curitiba, PR (Brazil)

    2012-09-10

    Considering that stimulation of melanogenesis may lead to alterations of cellular responses, besides melanin production, our main goal was to study the cellular effects of melanogenesis stimulation of B16-F10 melanoma cells. Our results show increased levels of the reactive oxygen species after 15 h of melanogenesis stimulation. Following 48 h of melanogenesis stimulation, proliferation was inhibited (by induction of cell cycle arrest in the G1 phase) and the expression levels of p21 mRNA were increased. In addition, melanogenesis stimulation did not induce cellular senescence. Proteomic analysis demonstrated the involvement of proteins from other pathways besides those related to the cell cycle, including protein disulfide isomerase A3, heat-shock protein 70, and fructose biphosphate aldolase A (all up-regulated), and lactate dehydrogenase (down-regulated). In RT-qPCR experiments, the levels of pyruvate kinase M2 mRNA dropped, whereas the levels of ATP synthase (beta-F1) mRNA increased. These data indicate that melanogenesis stimulation of B16-F10 cells leads to alterations in metabolism and cell cycle progression that may contribute to an induction of cell quiescence, which may provide a mechanism of resistance against cellular injury promoted by melanin synthesis. -- Highlights: Black-Right-Pointing-Pointer Melanogenesis stimulation by L-tyrosine+NH{sub 4}Cl in B16-F10 melanoma cells increases ROS levels. Black-Right-Pointing-Pointer Melanogenesis inhibits cell proliferation, and induced cell cycle arrest in the G1 phase. Black-Right-Pointing-Pointer Proteomic analysis showed alterations in proteins of the cell cycle and glucose metabolism. Black-Right-Pointing-Pointer RT-qPCR analysis confirmed alterations of metabolic targets after melanogenesis stimulation.

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

    Science.gov (United States)

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

    2014-01-01

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

  14. Can repetitive transcranial magnetic stimulation increase muscle strength in functional neurological paresis? A proof-of-principle study.

    Science.gov (United States)

    Broersma, M; Koops, E A; Vroomen, P C; Van der Hoeven, J H; Aleman, A; Leenders, K L; Maurits, N M; van Beilen, M

    2015-05-01

    Therapeutic options are limited in functional neurological paresis disorder. Earlier intervention studies did not control for a placebo effect, hampering assessment of effectivity. A proof-of-principle investigation was conducted into the therapeutic potential of repetitive transcranial magnetic stimulation (rTMS), using a single-blind two-period placebo-controlled cross-over design. Eleven patients received active 15 Hz rTMS over the contralateral motor cortex (hand area), in two periods of 5 days, for 30 min once a day at 80% of resting motor threshold, with a train length of 2 s and an intertrain interval of 4 s. Eight of these eleven patients were also included in the placebo treatment condition. Primary outcome measure was change in muscle strength as measured by dynamometry after treatment. Secondary outcome measure was the subjective change in muscle strength after treatment. In patients who received both treatments, active rTMS induced a significantly larger median increase in objectively measured muscle strength (24%) compared to placebo rTMS (6%; P difference due to treatment, i.e. patients did not perceive these objectively measured motor improvements (P = 0.40). Our findings suggest that rTMS by itself can potentially improve muscle weakness in functional neurological paresis disorder. Whereas patients' muscle strength increased as measured with dynamometry, patients did not report increased functioning of the affected hand, subjectively. The results may indicate that decreased muscle strength is not the core symptom and that rTMS should be added to behavioral approaches in functional neurological paresis. © 2015 EAN.

  15. Increased cell motility and invasion upon knockdown of lipolysis stimulated lipoprotein receptor (LSR in SW780 bladder cancer cells

    Directory of Open Access Journals (Sweden)

    Ørntoft Torben F

    2008-07-01

    Full Text Available Abstract Background Mechanisms underlying the malignant development in bladder cancer are still not well understood. Lipolysis stimulated lipoprotein receptor (LSR has previously been found to be upregulated by P53. Furthermore, we have previously found LSR to be differentially expressed in bladder cancer. Here we investigated the role of LSR in bladder cancer. Methods A time course siRNA knock down experiment was performed to investigate the functional role of LSR in SW780 bladder cancer cells. Since LSR was previously shown to be regulated by P53, siRNA against TP53 was included in the experimental setup. We used Affymetrix GeneChips for measuring gene expression changes and we used Ingenuity Pathway Analysis to investigate the relationship among differentially expressed genes upon siRNA knockdown. Results By Ingenuity Pathway analysis of the microarray data from the different timepoints we identified six gene networks containing genes mainly related to the functional categories "cancer", "cell death", and "cellular movement". We determined that genes annotated to the functional category "cellular movement" including "invasion" and "cell motility" were highly significantly overrepresented. A matrigel assay showed that 24 h after transfection the invasion capacity was significantly increased 3-fold (p Conclusion We conclude that LSR may impair bladder cancer cells from gaining invasive properties.

  16. Dimethoxycurcumin, a metabolically stable analogue of curcumin enhances the radiosensitivity of cancer cells: Possible involvement of ROS and thioredoxin reductase

    Energy Technology Data Exchange (ETDEWEB)

    Jayakumar, Sundarraj; Patwardhan, R.S.; Pal, Debojyoti [Radiation Biology & Health Sciences Division, Modular Laboratories, Bhabha Atomic Research Centre, Trombay, Mumbai 400085 (India); Sharma, Deepak [Radiation Biology & Health Sciences Division, Modular Laboratories, Bhabha Atomic Research Centre, Trombay, Mumbai 400085 (India); Homi Bhabha National Institute, Anushaktinagar, Mumbai 400094 (India); Sandur, Santosh K., E-mail: sskumar@barc.gov.in [Radiation Biology & Health Sciences Division, Modular Laboratories, Bhabha Atomic Research Centre, Trombay, Mumbai 400085 (India); Homi Bhabha National Institute, Anushaktinagar, Mumbai 400094 (India)

    2016-09-09

    Dimethoxycurcumin (DIMC), a structural analogue of curcumin, has been shown to have more stability, bioavailability, and effectiveness than its parent molecule curcumin. In this paper the radiosensitizing effect of DIMC has been investigated in A549 lung cancer cells. As compared to its parent molecule curcumin, DIMC showed a very potent radiosensitizing effect as seen by clonogenic survival assay. DIMC in combination with radiation significantly increased the apoptosis and mitotic death in A549 cells. This combinatorial treatment also lead to effective elimination of cancer stem cells. Further, there was a significant increase in cellular ROS, decrease in GSH to GSSG ratio and also significant slowdown in DNA repair when DIMC was combined with radiation. In silico docking studies and in vitro studies showed inhibition of thioredoxin reductase enzyme by DIMC. Overexpression of thioredoxin lead to the abrogation of radiosensitizing effect of DIMC underscoring the role of thioredoxin reductase in radiosensitization. Our results clearly demonstrate that DIMC can synergistically enhance the cancer cell killing when combined with radiation by targeting thioredoxin system. - Highlights: • DIMC enhances radiosensitivity of cancer cells by inducing cell death. • DIMC with radiation disrupted the cellular redox and targeted cancer stem cells. • DNA repair is hampered when cells are treated with DIMC. • DIMC inhibited thioredoxin reductase in cancer cells.

  17. Dimethoxycurcumin, a metabolically stable analogue of curcumin enhances the radiosensitivity of cancer cells: Possible involvement of ROS and thioredoxin reductase

    International Nuclear Information System (INIS)

    Jayakumar, Sundarraj; Patwardhan, R.S.; Pal, Debojyoti; Sharma, Deepak; Sandur, Santosh K.

    2016-01-01

    Dimethoxycurcumin (DIMC), a structural analogue of curcumin, has been shown to have more stability, bioavailability, and effectiveness than its parent molecule curcumin. In this paper the radiosensitizing effect of DIMC has been investigated in A549 lung cancer cells. As compared to its parent molecule curcumin, DIMC showed a very potent radiosensitizing effect as seen by clonogenic survival assay. DIMC in combination with radiation significantly increased the apoptosis and mitotic death in A549 cells. This combinatorial treatment also lead to effective elimination of cancer stem cells. Further, there was a significant increase in cellular ROS, decrease in GSH to GSSG ratio and also significant slowdown in DNA repair when DIMC was combined with radiation. In silico docking studies and in vitro studies showed inhibition of thioredoxin reductase enzyme by DIMC. Overexpression of thioredoxin lead to the abrogation of radiosensitizing effect of DIMC underscoring the role of thioredoxin reductase in radiosensitization. Our results clearly demonstrate that DIMC can synergistically enhance the cancer cell killing when combined with radiation by targeting thioredoxin system. - Highlights: • DIMC enhances radiosensitivity of cancer cells by inducing cell death. • DIMC with radiation disrupted the cellular redox and targeted cancer stem cells. • DNA repair is hampered when cells are treated with DIMC. • DIMC inhibited thioredoxin reductase in cancer cells.

  18. Efficacy of radiosensitizing doped titania nanoparticles under hypoxia and preparation of an embolic microparticle

    Directory of Open Access Journals (Sweden)

    Morrison RA

    2017-05-01

    Full Text Available Rachel A Morrison,1,* Malgorzata J Rybak-Smith,1,* James M Thompson,2 Bénédicte Thiebaut,3 Mark A Hill,2 Helen E Townley1,4 1Department of Engineering Science, 2Gray Laboratories, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, 3Johnson Matthey, Technology Centre, Reading, Berkshire, 4Nuffield Department of Obstetrics and Gynaecology, John Radcliffe Hospital, University of Oxford, Oxford, UK *These authors have contributed equally to this work Abstract: The aim of this study was to develop a manufacturing protocol for large-scale production of doped titania radiosensitizing nanoparticles (NPs to establish their activity under hypoxia and to produce a multimodal radiosensitizing embolic particle for cancer treatment. We have previously shown that radiosensitizing NPs can be synthesized from titania doped with rare earth elements, especially gadolinium. To translate this technology to the clinic, a crucial step is to find a suitable, scalable, high-throughput method. Herein, we have described the use of flame spray pyrolysis (FSP to generate NPs from titanium and gadolinium precursors to produce titania NPs doped with 5 at% gadolinium. The NPs were fully characterized, and their capacity to act as radiosensitizers was confirmed by clonogenic assays. The integrity of the NPs in vitro was also ascertained due to the potentially adverse effects of free gadolinium in the body. The activity of the NPs was then studied under hypoxia since this is often a barrier to effective radiotherapy. In vitro radiosensitization experiments were performed with both the hypoxia mimetics deferoxamine and cobalt chloride and also under true hypoxia (oxygen concentration of 0.2%. It was shown that the radiosensitizing NPs were able to cause a significant increase in cell death even after irradiation under hypoxic conditions such as those found in tumors. Subsequently, the synthesized NPs were used to modify polystyrene embolization

  19. Validation of a radiosensitivity molecular signature in breast cancer

    NARCIS (Netherlands)

    S.A. Eschrich (Steven); C. Fulp (Carl); Y. Pawitan (Yudi); J.A. Foekens (John); M. Smid (Marcel); J.W.M. Martens (John); M. Echevarria (Michelle); P.S. Kamath (Patrick); J.-H. Lee (Ji-Hyun); E.E. Harris (Eleanor); J. Bergh (Jonas); J.F. Torres-Roca (Javier)

    2012-01-01

    textabstractPurpose: Previously, we developed a radiosensitivity molecular signature [radiosensitivity index (RSI)] that was clinically validated in 3 independent datasets (rectal, esophageal, and head and neck) in 118 patients. Here, we test RSI in radiotherapy (RT)-treated breast cancer patients.

  20. Radiosensitizing effects of 9401 on mice bearing H22 hepatoma

    International Nuclear Information System (INIS)

    Liu Xiaoqiu; Wang Qin; Zhou Zewei; Han Ying; Wang Dezhi; Shen Xiu

    2013-01-01

    Objective: To investigate the radiosensitizing effects of 9401 on mice bearing H22 hepatoma. Methods: Mouse model bearing H22 hepatoma cells were established. Mice were randomly divided into six groups, the control group,the radiation group and four treatment groups including 9401 at high, medium and low dosages and nicotinamide combined with radiation. After irradiated, the growth of tumor was observed, the time of tumor growth was recorded, the delay time of tumor growth and enhancement factor (EF) were calculated. After 28 days, the mice were killed, the tumors were stripped and inhibition rate was calculated. Results: Groups of 9401 combined with radiation could postpone tumor growth. The difference was statistically significant between 9401 groups at high, medium dosages combined with radiation and nicotinamide combined with radiation group (t=24.7 and 7.5, both P<0.01). Compared with radiation alone group, groups of 9401 combined with radiation had significant radiosensitizing effect. The enhancement factor of 9401 combined with radiation groups at high and medium dosages were 2.13 and 1.73 respectively, they were significant higher than nicotinamide combined with radiation group (t=2.26 and 9.04, both P<0.05). The inhibition rate of 9401 groups at high, medium and low dosages combined with radiation were 64.5%, 50.9% and 42.6% respectively. The inhibition rate of nicotinamide group combined radiation was 53.2%. The inhibition rate of 9401 at high dosage combined with radiation had significant difference with nicotinamide combined radiation (t =2.8, P<0.05). Nicotinamide combined with radiation group, 9401 combined with radiation groups could significant inhibit the growth of tumors compared with radiation alone group (t=5.7, 4.0 and 2.2, all P<0.05). Conclusion: 9401 can inhibit the tumor growth and the inhibition effect increases gradually with the drug dose increasing. It also has radiosensitizing effects on mice bearing H22 hepatoma and present broadly

  1. [Does transcutaneous electrical nerve stimulation or therapeutic ultrasound increase the effectiveness of exercise for knee osteoarthritis: a randomized controlled study].

    Science.gov (United States)

    Eyigör, Sibel; Karapolat, Hale; Ibisoğlu, Uğur; Durmaz, Berrin

    2008-01-01

    The aim of this study was to determine if transcutaneous electrical nerve stimulation (TENS) or therapeutic ultrasound (US) increase the effectiveness of exercise on pain, function, muscle strength and quality of life for knee osteoarthritis (OA). Forty-five patients with primary knee OA diagnosis according to American College Rheumatology criteria were sequentially divided into 3 random groups. The patients in group 1 received TENS (with superficial heat and exercise), group 2 received US (with superficial heat and exercise), and group 3 acted as controls (superficial heat and exercise). Outcome measures were included as visual analog scale (VAS), a 20-meter walking test, Lequesne index, WOMAC scores, isokinetic muscle testing, and the Short Form 36 (SF 36). All treatment groups, physical modalities were carried out for a total fifteen sessions. All of the patients were subjected to six weeks of exercise program. All of the treatment groups had significant improvement on activity VAS, 20 meter walking test, Lequesne index, WOMAC scores, and most of the sub-scores of SF36 when compared with their initial status (p0.05). All of the treatment groups were effective on pain, function, muscle strength and quality of life in patients with knee OA. Statistically significant differences could not be found between the treatment groups. The exercise program, as it is cheaper, more easily performed and efficient, may be preferable for the treatment of knee OA. It is difficult to say, TENS or US could increase the effectiveness of isokinetic exercise for pain, function, muscle strength and quality of life of knee OA in this study.

  2. Increase in cortical pyramidal cell excitability accompanies depression-like behavior in mice: a transcranial magnetic stimulation study.

    Science.gov (United States)

    Sun, Peng; Wang, Furong; Wang, Li; Zhang, Yu; Yamamoto, Ryo; Sugai, Tokio; Zhang, Qing; Wang, Zhengda; Kato, Nobuo

    2011-11-09

    Clinical evidence suggests that cortical excitability is increased in depressives. We investigated its cellular basis in a mouse model of depression. In a modified version of forced swimming (FS), mice were initially forced to swim for 5 consecutive days and then were treated daily with repetitive transcranial magnetic stimulation (rTMS) or sham treatment for the following 4 weeks without swimming. On day 2 through day 5, the mice manifested depression-like behaviors. The next and last FS was performed 4 weeks later, which revealed a 4 week maintenance of depression-like behavior in the sham mice. In slices from the sham controls, excitability in cingulate cortex pyramidal cells was elevated in terms of membrane potential and frequencies of spikes evoked by current injection. Depolarized resting potential was shown to depend on suppression of large conductance calcium-activated potassium (BK) channels. This BK channel suppression was confirmed by measuring spike width, which depends on BK channels. Chronic rTMS treatment during the 4 week period significantly reduced the depression-like behavior. In slices obtained from the rTMS mice, normal excitability and BK channel activity were recovered. Expression of a scaffold protein Homer1a was reduced by the FS and reversed by rTMS in the cingulate cortex. Similar recovery in the same behavioral, electrophysiological, and biochemical features was observed after chronic imipramine treatment. The present study demonstrated that manifestation and disappearance of depression-like behavior are in parallel with increase and decrease in cortical neuronal excitability in mice and suggested that regulation of BK channels by Homer1a is involved in this parallelism.

  3. Prostate-Specific Natural Health Products (Dietary Supplements) Radiosensitize Normal Prostate Cells

    International Nuclear Information System (INIS)

    Hasan, Yasmin; Schoenherr, Diane; Martinez, Alvaro A.; Wilson, George D.; Marples, Brian

    2010-01-01

    Purpose: Prostate-specific health products (dietary supplements) are taken by cancer patients to alleviate the symptoms linked with poor prostate health. However, the effect of these agents on evidence-based radiotherapy practice is poorly understood. The present study aimed to determine whether dietary supplements radiosensitized normal prostate or prostate cancer cell lines. Methods and Materials: Three well-known prostate-specific dietary supplements were purchased from commercial sources available to patients (Trinovin, Provelex, and Prostate Rx). The cells used in the study included normal prostate lines (RWPE-1 and PWR-1E), prostate tumor lines (PC3, DU145, and LNCaP), and a normal nonprostate line (HaCaT). Supplement toxicity was assessed using cell proliferation assays [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] and cellular radiosensitivity using conventional clonogenic assays (0.5-4Gy). Cell cycle kinetics were assessed using the bromodeoxyuridine/propidium iodide pulse-labeling technique, apoptosis by scoring caspase-3 activation, and DNA repair by assessing γH2AX. Results: The cell growth and radiosensitivity of the malignant PC3, DU145, and LNcaP cells were not affected by any of the dietary prostate supplements (Provelex [2μg/mL], Trinovin [10μg/mL], and Prostate Rx [50 μg/mL]). However, both Trinovin (10μg/mL) and Prostate Rx (6μg/mL) inhibited the growth rate of the normal prostate cell lines. Prostate Rx increased cellular radiosensitivity of RWPE-1 cells through the inhibition of DNA repair. Conclusion: The use of prostate-specific dietary supplements should be discouraged during radiotherapy owing to the preferential radiosensitization of normal prostate cells.

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

    Directory of Open Access Journals (Sweden)

    M Emmy M Dolman

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

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

    Science.gov (United States)

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

    2015-01-01

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

  6. Radiosensitization by overexpression of the nonphosphorylation form of IκB-α in human glioma cells

    International Nuclear Information System (INIS)

    Honda, Naoko; Yagi, Kasumi; Ding, Gui-Rong; Miyakoshi, Junji

    2002-01-01

    To assess the role of NF-κB in cellular radiosensitivity, we constructed mutated IκB expression plasmids for SY-IκB (with mutations at residues of 32, 36 and 42) expression in human malignant glioma cells (radiosensitive MO54 and radioresistant T98 cells), giving respective cell types referred to as MO54-SY4 and T98-SY14. Both of the clones expressing SY-IκB became radiosensitive, compared with the parental MO54 and T98 cells. A treatment with herbimycin A or genistein did not change the radiosensitivity of cells expressing SY-IκB, but made both the MO54 and T98 parental cells more sensitive to ionizing radiation. A treatment with TNF-α induced DNA fragmentation and apoptosis in cells expressing SY-IκB, but not in MO54 and T98 cells. The survival after X-ray exposure of the parental MO54 cells was slightly increased by a TNF-α treatment, but that of the parental T98 cells did not change. The change in sensitivity to ultra-violet (UV) radiation and adriamycin in MO54-SY4 cells was very similar to that for X-ray sensitivity, but no change was observed in T98-SY14 cells. Significant sublethal damage repair was observed in T98 cells, whereas MO54 cells showed little repair activity. The expression of p53 was enhanced in the parental MO54 cells, while the p53 levels in the MO54-SY4, and in the parent and clonal T98 cells, did not change. Our data suggest that the serine and tyrosine phosphorylation of IκB-α may play a role in determining the radiosensitivity of malignant glioma cells. (author)

  7. DNMT (DNA methyltransferase) inhibitors radiosensitize human cancer cells by suppressing DNA repair activity

    International Nuclear Information System (INIS)

    Kim, Hak Jae; Kim, Jin Ho; Chie, Eui Kyu; Da Young, Park; Kim, In Ah; Kim, Il Han

    2012-01-01

    Histone modifications and DNA methylation are two major factors in epigenetic phenomenon. Unlike the histone deacetylase inhibitors, which are known to exert radiosensitizing effects, there have only been a few studies thus far concerning the role of DNA methyltransferase (DNMT) inhibitors as radiosensitizers. The principal objective of this study was to evaluate the effects of DNMT inhibitors on the radiosensitivity of human cancer cell lines, and to elucidate the mechanisms relevant to that process. A549 (lung cancer) and U373MG (glioblastoma) cells were exposed to radiation with or without six DNMT inhibitors (5-azacytidine, 5-aza-2'-deoxycytidine, zebularine, hydralazine, epigallocatechin gallate, and psammaplin A) for 18 hours prior to radiation, after which cell survival was evaluated via clonogenic assays. Cell cycle and apoptosis were analyzed via flow cytometry. Expressions of DNMT1, 3A/3B, and cleaved caspase-3 were detected via Western blotting. Expression of γH2AX, a marker of radiation-induced DNA double-strand break, was examined by immunocytochemistry. Pretreatment with psammaplin A, 5-aza-2'-deoxycytidine, and zebularine radiosensitized both A549 and U373MG cells. Pretreatment with psammaplin A increased the sub-G1 fraction of A549 cells, as compared to cells exposed to radiation alone. Prolongation of γH2AX expression was observed in the cells treated with DNMT inhibitors prior to radiation as compared with those treated by radiation alone. Psammaplin A, 5-aza-2'-deoxycytidine, and zebularine induce radiosensitivity in both A549 and U373MG cell lines, and suggest that this effect might be associated with the inhibition of DNA repair

  8. Differential radiosensitivity of seeds, seedlings and callus cultures of Petunia inflata

    International Nuclear Information System (INIS)

    Bapat, V.A.; Rao, P.S.

    1976-01-01

    A comparative study of the effects of γ-irradiation on seeds, seedlings and callus cultures of Petunia inflata showed striking differences in radiosensitivity as reflected in differences in mean fresh and dry weights, seedling height and morphology. Seeds subjected to low doses (4-6 kR) of irradiation showed stimulation of seedling height. Direct exposure of seedlings to high doses (10 kR) of irradiation caused inhibition in their development. Callus cultures, however, were more radioresistant compared to seeds and seedlings. Tissues grown on either an irradiated nutrient medium or on a medium in which sucrose alone had been irradiated, showed a marked inhibition in their growth potential

  9. Taxane-mediated radiosensitization derives from chromosomal missegregation on tripolar mitotic spindles orchestrated by AURKA and TPX2.

    Science.gov (United States)

    Orth, M; Unger, K; Schoetz, U; Belka, C; Lauber, K

    2018-01-04

    Taxane-based radiochemotherapy is a central treatment option for various cancer entities in locally advanced stages. The therapeutic synergism of this combined modality approach due to taxane-mediated radiosensitization of cancer cells is well-known. However, the underlying molecular mechanisms remain largely elusive, and mechanism-derived predictive markers of taxane-based radiochemotherapy are currently not available. Here, we show that clinically relevant doses of Paclitaxel, the prototype taxane, stimulate a tripolar mode of mitosis leading to chromosomal missegregation and aneuploidization rather than interfering with cell cycle progression. This distinct mitotic phenotype was interlinked with Paclitaxel-mediated radiosensitization via overexpression of mitotic Aurora kinase A (AURKA) and its cofactor TPX2 whose knockdown rescued the bipolar mode of cell division and largely attenuated the radiosensitizing effects of Paclitaxel. In the cancer genome atlas (TCGA) lung adenocarcinoma cohort, high expression levels of AURKA and TPX2 were associated with specifically improved overall survival upon taxane-based radiochemotherapy, but not in case of non-taxane-based radiochemotherapy, chemo- or radiotherapy only. Thus, our data provide insights into Paclitaxel-mediated radiosensitization on a mechanistic and molecular level and identify AURKA and TPX2 as the first potential mechanism-based, predictive markers of taxane-based radiochemotherapy.

  10. Modern concepts for basic radiobiological factors characterizing tumor tissue radiosensitivity

    International Nuclear Information System (INIS)

    Gocheva, L.; Sergieva, K.

    2002-01-01

    Traditionally radiotherapy is prescribed at doses consistent with the expected therapeutic response and tolerance of tumor and normal tissues without consideration to individual differences in radiosensitivity. However, the basic radiobiological knowledge and clinical experience along this line point to significant variations in the observed therapeutic results. It has been established that cells and tissues under experimental and clinical conditions manifest a wide spectrum of individual radiosensitivity. The aim of this survey is to outline the current concepts for the basic radiobiological factors influencing tumor radiosensitivity. A thorough discussion is done of the essence, mechanisms of action, methods of determination and measurement, and effect on the prognosis in patients with malignant diseases of a number of radiobiological factors, such as: tumor-cell proliferation, apoptosis, tumor hypoxia and neovascularization. Although the knowledge of the mechanisms of radiosensitivity is constantly expanding, its clinical implementation is still rather limited. The true role of radiosensitivity in predicting the therapeutic response should be more accurately defined. (authors)

  11. Chromosomal radiosensitivity in patients with multiple sclerosis

    International Nuclear Information System (INIS)

    Milenkova, Maria; Milanov, Ivan; Kmetska, Ksenia; Deleva, Sofia; Popova, Ljubomira; Hadjidekova, Valeria; Groudeva, Violeta; Hadjidekova, Savina; Domínguez, Inmaculada

    2013-01-01

    Highlights: • We studied radiosensitivity to in vitro γ-irradiated lymphocytes from MS patients. • Immunotherapy in RRMS patients reduced the yield of radiation induced MN. • The group of treated RRMS accounts for the low radiosensitivity in MS patients. • Spontaneous yield of MN was similar in treated and untreated RRMS patients. - Abstract: Multiple sclerosis is a clinically heterogeneous autoimmune disease leading to severe neurological disability. Although during the last years many disease-modifying agents as treatment options for multiple sclerosis have been made available, their mechanisms of action are still not fully determined. In the present study radiosensitivity in lymphocytes of patients with relapsing–remitting multiple sclerosis, secondary progressive multiple sclerosis and healthy controls was investigated. Whole blood cultures from multiple sclerosis patients and healthy controls were used to analyze the spontaneous and radiation-induced micronuclei in binucleated lymphocytes. A subgroup of patients with relapsing–remitting multiple sclerosis was treated with immunomodulatory agents, interferon β or glatiramer acetate. The secondary progressive multiple sclerosis patients group was not receiving any treatment. Our results reveal that the basal DNA damage was not different between relapsing–remitting and secondary progressive multiple sclerosis patients, and healthy controls. No differences between gamma-irradiation induced micronuclei frequencies in binucleated cells from relapsing–remitting and secondary progressive multiple sclerosis patients, and healthy controls were found either. Nevertheless, when we compared the radiation induced DNA damage in binucleated cells from healthy individuals with the whole group of patients, a reduction in the frequency of micronuclei was obtained in the patients group. Induced micronuclei yield was significantly lower in the irradiated samples from treated relapsing–remitting multiple

  12. Taxonomic and developmental aspects of radiosensitivity

    International Nuclear Information System (INIS)

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

    1996-11-01

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

  13. Chromosomal radiosensitivity in patients with multiple sclerosis

    Energy Technology Data Exchange (ETDEWEB)

    Milenkova, Maria; Milanov, Ivan; Kmetska, Ksenia [III Neurological Clinic, University Hospital Saint Naum, Sofia (Bulgaria); Deleva, Sofia; Popova, Ljubomira; Hadjidekova, Valeria [Laboratory of Radiation Genetics, NCRRP, Sofia (Bulgaria); Groudeva, Violeta [Department of Diagnostic Imaging, University Hospital St. Ekaterina, Sofia (Bulgaria); Hadjidekova, Savina [Department of Medical Genetics, Medical University, Sofia (Bulgaria); Domínguez, Inmaculada, E-mail: idomin@us.es [Department of Cell Biology, Faculty of Biology, University of Seville, Avda. Reina Mercedes 6, 41012 (Spain)

    2013-09-15

    Highlights: • We studied radiosensitivity to in vitro γ-irradiated lymphocytes from MS patients. • Immunotherapy in RRMS patients reduced the yield of radiation induced MN. • The group of treated RRMS accounts for the low radiosensitivity in MS patients. • Spontaneous yield of MN was similar in treated and untreated RRMS patients. - Abstract: Multiple sclerosis is a clinically heterogeneous autoimmune disease leading to severe neurological disability. Although during the last years many disease-modifying agents as treatment options for multiple sclerosis have been made available, their mechanisms of action are still not fully determined. In the present study radiosensitivity in lymphocytes of patients with relapsing–remitting multiple sclerosis, secondary progressive multiple sclerosis and healthy controls was investigated. Whole blood cultures from multiple sclerosis patients and healthy controls were used to analyze the spontaneous and radiation-induced micronuclei in binucleated lymphocytes. A subgroup of patients with relapsing–remitting multiple sclerosis was treated with immunomodulatory agents, interferon β or glatiramer acetate. The secondary progressive multiple sclerosis patients group was not receiving any treatment. Our results reveal that the basal DNA damage was not different between relapsing–remitting and secondary progressive multiple sclerosis patients, and healthy controls. No differences between gamma-irradiation induced micronuclei frequencies in binucleated cells from relapsing–remitting and secondary progressive multiple sclerosis patients, and healthy controls were found either. Nevertheless, when we compared the radiation induced DNA damage in binucleated cells from healthy individuals with the whole group of patients, a reduction in the frequency of micronuclei was obtained in the patients group. Induced micronuclei yield was significantly lower in the irradiated samples from treated relapsing–remitting multiple

  14. Taxonomic and developmental aspects of radiosensitivity

    Energy Technology Data Exchange (ETDEWEB)

    Harrison, F.L. [Lawrence Livermore National Lab., CA (United States); Anderson, S.L. [Lawrence Berkeley National Lab., CA (United States)

    1996-11-01

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

  15. Individual radiosensitivity and its relevance to health physics

    International Nuclear Information System (INIS)

    Schnarr, K.; Dayes, I.; Sathya, J.; Boreham, D.

    2006-01-01

    Full text: In the radiation protection industry, dose limits are developed to keep the workers safe. These limits assume that people have equal responses to ionizing radiation and that there is no variation in radiation risk. In radiotherapy, where patients receive large doses of radiation to their tumours and the surrounding tissue volume, 5-10% of individuals are sensitive to the treatment (adverse reactions). A radiation sensitive individual may have increased toxicity in the tissue around the tumour. This can result in necrosis, loss of organ function or even death. The cause of this sensitivity is only speculative. We postulate that this variation is due to the individual's intrinsic cellular response to radiation. Therefore, this systemic predisposition results in a lack of ability for damaged cells to be eliminated properly or repaired and consequently causes an adverse reaction. Understanding this phenomenon is crucial for radiation protection practices, since these radiosensitive individuals may also be at increased risk to high occupational or medical exposures. We have investigated individual radiosensitivity using a number of different biological endpoints. Apoptosis, or programmed cell death, was measured in human lymphocytes after receiving in vitro doses of 0, 2, 4, and 8Gy. At high doses (8Gy), radiation induced apoptosis showed a wide range of responses (mean = 34% apoptosis, o = 8.2) with z-scores ranging from -1.5 to 2.4. Low dose responses (mGy range) were also studied measuring apoptosis, DNA double strand break induction and repair in human lymphocytes exposed in vivo when patients a whole body radiation dose during diagnostic PET scans. The results showed varied individual responses and indicates that individuals may be at increased risk due to differences in DNA repair capabilities. Being able to measure radiation sensitivity would allow the radiation protection industry to tailor dose limits to an individual, reducing risk to the worker

  16. A small interfering RNA screen of genes involved in DNA repair identifies tumor-specific radiosensitization by POLQ knockdown

    DEFF Research Database (Denmark)

    Higgins, Geoff S; Prevo, Remko; Lee, Yin-Fai

    2010-01-01

    The effectiveness of radiotherapy treatment could be significantly improved if tumor cells could be rendered more sensitive to ionizing radiation (IR) without altering the sensitivity of normal tissues. However, many of the key therapeutically exploitable mechanisms that determine intrinsic tumor...... radiosensitivity are largely unknown. We have conducted a small interfering RNA (siRNA) screen of 200 genes involved in DNA damage repair aimed at identifying genes whose knockdown increased tumor radiosensitivity. Parallel siRNA screens were conducted in irradiated and unirradiated tumor cells (SQ20B......) and irradiated normal tissue cells (MRC5). Using gammaH2AX foci at 24 hours after IR, we identified several genes, such as BRCA2, Lig IV, and XRCC5, whose knockdown is known to cause increased cell radiosensitivity, thereby validating the primary screening end point. In addition, we identified POLQ (DNA...

  17. Chemical radiosensitizers with special reference to metronidazole

    International Nuclear Information System (INIS)

    Sharma, R.; Purohit, O.P.; Nair, C.R.; Dutta, T.K.

    1982-01-01

    An attempt at rationalisation of drug dose schedule for a radiosensitizer in a cancer clinic is attempted. A prospective analysis of tissue tolerance, response data and complications of the two groups of patients (treated by oral and high intermittent rectal routes) was made with matched control. The study group has definite use of metronidazole. It is further highlighted that there is an additional advantage of the rectal administration route of the drug as compared to that of the oral route. This is a preliminary communication. (author)

  18. Radiosensitization of thymidine in deaerated aqueous solution

    International Nuclear Information System (INIS)

    Berger, Maurice.

    1982-09-01

    This work investigates the mode of action of various radiosensitizing agents on the radio-induced degradation of thymidine in deaerated aqueous solution. A special effort was devoted to the separation of addition products formed by one of these substances (a stable nitroxide radical: TAN) with the radio-induced neutral radicals of thymidine. The complex mixture of different diastereoisomers resulting from the covalent addition of the TAN molecule on the thymidine carbons C (5) or C (6) was resolved by HPLC. The structural determination of these adducts (absolute configuration) was achieved by various spectroscopic techniques and specific chemical syntheses. A conformational study has been undertaken [fr

  19. Analysis of mice radiosensitivity depending on age

    International Nuclear Information System (INIS)

    Bogatyrev, A.V.; Timoshenko, S.I.; Nikanorova, N.G.; Sverdlov, A.G.

    1979-01-01

    In order to elucidate mechanisms of age variations in radiosensitivity of mice a study was made of the sensitivity of in vitro irradiated bone marrow stem cells, taken from animals of different age, and postradiation recovery of leukocyte content of peripheral blood and cellularity of bone marrow and spleen. Using the method of spleen colonies similar affections were revealed in bone marrow cells of animals of different age. The degree of recovery of the hemopoietic cell pool was significantly lower in newborn mice than in adults after exposure to a dose (LDsub(50/30)) equally effective with respect to mortality

  20. Radiosensitivity study in rice (Oriza Sativa Lin.)

    International Nuclear Information System (INIS)

    Gonzalez, M.; Santana, N.; Diaz, R.

    1987-01-01

    Four rice varieties (J-104, Amistad-82, 6066 and IR-1529) were irradiated at doses of 10,15,20,25,30,35,40,45,50 and 55 Krad of gamma rays so as to determine radiosensitivity curves for each of the varieties for the following factors; seed germination percentage; survival percentage; height of the plant; length of roots. It was determined that IR-1529 variety is the one with the highest sensitivity and that radiations over 35 Krad should not be used for none of the varieties above mentioned

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

    International Nuclear Information System (INIS)

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

    1985-01-01

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

  2. Triolimus: A Multi-Drug Loaded Polymeric Micelle Containing Paclitaxel, 17-AAG, and Rapamycin as a Novel Radiosensitizer.

    Science.gov (United States)

    Tomoda, Keishiro; Tam, Yu Tong; Cho, Hyunah; Buehler, Darya; Kozak, Kevin R; Kwon, Glen S

    2017-01-01

    Triolimus is a multi-drug loaded polymeric micelle containing paclitaxel (PTX), 17-allylamino-17-demethoxygeldanamycin (17-AAG), and rapamycin (RAP). This study examines the radiosensitizing effect of Triolimus in vitro and in vivo. Radiosensitizing effects of Triolimus on A549 cells are dose dependent and at 2 × 10 -9 m, Triolimus shows significant radiosensitization even at low radiation doses (2 Gy). By sensitivity enhancement ratio, PTX alone, dual drug combinations, and Triolimus treatment at 2 × 10 -9 m have radiosensitizing effects with potency as follows: PTX alone (PTX) > PTX and RAP (P/R) > Triolimus (TRIO) > PTX and 17-AAG (P/17) >17-AAG and RAP (17/R). In vivo, fractionated radiation of 15 Gy preceded by infusion of PTX alone, dual drug combinations, or an intermediate dose of Triolimus (Int. TRIO: PTX/17-AAG/RAP at 15/15/7.5 mg kg -1 ) strongly inhibits A549 tumor growth. Notably, pretreatment with high dose of Triolimus (High TRIO: PTX/17-AAG/RAP at 60/60/30 mg kg -1 ) before the fractionated radiation leads to tumor control for up to 24 weeks. An enhanced radiosensitizing effect is observed without an increase in acute toxicity compared to PTX alone or radiation alone. These results suggest that further investigations of Triolimus in combination with radiation therapy are merited. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  3. DNA-PK. The major target for wortmannin-mediated radiosensitization by the inhibition of DSB repair via NHEJ pathway

    International Nuclear Information System (INIS)

    Hashimoto, Mitsumasa; Rao, S.; Tokuno, Osamu; Utsumi, Hiroshi; Takeda, Shunichi

    2003-01-01

    The effect of wortmannin posttreatment was studied in cells derived from different species (hamster, mouse, chicken, and human) with normal and defective DNA-dependent protein kinase (DNA-PK) activity, cells with and without the ataxia telangiectasia mutated (ATM) gene, and cells lacking other regulatory proteins involved in the DNA double-strand break (DSB) repair pathways. Clonogenic assays were used to obtain all results. Wortmannin radiosensitization was observed in Chinese hamster cells (V79-B310H, CHO-K1), mouse mammary carcinoma cells (SR-1), transformed human fibroblast (N2KYSV), chicken B lymphocyte wild-type cells (DT40), and chicken Rad54 knockout cells (Rad54 -/- ). However, mouse mammary carcinoma cells (SX9) with defects in the DNA-PK and chicken DNA-PK catalytic subunit (DNA-PKcs) knockout cells (DNA-PKcs -/-/- ) failed to exhibit wortmannin radiosensitization. On the other hand, severe combined immunodeficiency (SCID) mouse cells (SC3VA2) exposed to wortmannin exhibited significant increases in radiosensitivity, possibly because of some residual function of DNA-PKcs. Moreover, the transformed human cells derived from AT patients (AT2KYSV) and chicken ATM knockout cells (ATM -/- ) showed pronounced wortmannin radiosensitization. These studies demonstrate confirm that the mechanism underlying wortmannin radiosensitization is the inhibition of DNA-PK, but not of ATM, thereby resulting in the inhibition of DSB repair via nonhomologous endjoining (NHEJ). (author)

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

    International Nuclear Information System (INIS)

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

    2009-01-01

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

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

    International Nuclear Information System (INIS)

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

    1982-01-01

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

  6. ATM-induced radiosensitization in vitro and in vivo

    International Nuclear Information System (INIS)

    Song, C. W.; Griffin, R. J.; Park, H. J.; Chung, H. S.; Choi, E. K.; Ahn, S. D.; Rhee, Y. H.; Ha, S. W.

    2002-01-01

    It has been known that ATM plays a central role in response of cells to ionizing radiation by enhancing DNA repair. Based in large part on studies of the homologous proteins in yeast, it is predicted that ATM function as proximal signal transducers in G1, S, and G2 checkpoint pathways. With the exception of p53, the downstream components of these pathways remain largely undefined. We have investigated the feasibility of increasing radiosensitivity of tumor cells with the use of ATM inhibitors such as caffeine, pentoxifylline, and wortmannin. Also in an effort to examine and understand the molecular mechanism by which ATM might exert its cellular effects, we have expressed the full length wild type ATM in RKO cells

  7. Dipolar sources of the early scalp somatosensory evoked potentials to upper limb stimulation. Effect of increasing stimulus rates.

    Science.gov (United States)

    Valeriani, M; Restuccia, D; Di Lazzaro, V; Le Pera, D; Barba, C; Tonali, P; Mauguiere, F

    1998-06-01

    Brain electrical source analysis (BESA) of the scalp electroencephalographic activity is well adapted to distinguish neighbouring cerebral generators precisely. Therefore, we performed dipolar source modelling in scalp medium nerve somatosensory evoked potentials (SEPs) recorded at 1.5-Hz stimulation rate, where all the early components should be identifiable. We built a four-dipole model, which was issued from the grand average, and applied it also to recordings from single individuals. Our model included a dipole at the base of the skull and three other perirolandic dipoles. The first of the latter dipoles was tangentially oriented and was active at the same latencies as the N20/P20 potential and, with opposite polarity, the P24/N24 response. The second perirolandic dipole showed an initial peak of activity slightly earlier than that of the N20/P20 dipolar source and, later, it was active at the same latency as the central P22 potential. Lastly, the third perirolandic dipole explaining the fronto-central N30 potential scalp distribution was constantly more posterior than the first one. In order to evaluate the effect of an increasing repetition frequency on the activity of SEP dipolar sources, we applied the model built from 1.5-Hz SEPs to traces recorded at 3-Hz and 10-Hz repetition rates. We found that the 10-Hz stimulus frequency reduced selectively the later of the two activity phases of the first perirolandic dipole. The decrement in strength of this dipolar source can be explained if we assume that: (a) the later activity of the first perirolandic dipole can represent the inhibitory phase of a "primary response"; (b) two different clusters of cells generate the opposite activities of the tangential perirolandic dipole. An additional finding in our model was that two different perirolandic dipoles contribute to the centro-parietal N20 potential generation.

  8. Early sepsis does not stimulate reactive oxygen species production and does not reduce cardiac function despite an increased inflammation status.

    Science.gov (United States)

    Léger, Thibault; Charrier, Alice; Moreau, Clarisse; Hininger-Favier, Isabelle; Mourmoura, Evangelia; Rigaudière, Jean-Paul; Pitois, Elodie; Bouvier, Damien; Sapin, Vincent; Pereira, Bruno; Azarnoush, Kasra; Demaison, Luc

    2017-07-01

    If it is sustained for several days, sepsis can trigger severe abnormalities of cardiac function which leads to death in 50% of cases. This probably occurs through activation of toll-like receptor-9 by bacterial lipopolysaccharides and overproduction of proinflammatory cytokines such as TNF- α and IL-1 β In contrast, early sepsis is characterized by the development of tachycardia. This study aimed at determining the early changes in the cardiac function during sepsis and at finding the mechanism responsible for the observed changes. Sixty male Wistar rats were randomly assigned to two groups, the first one being made septic by cecal ligation and puncture (sepsis group) and the second one being subjected to the same surgery without cecal ligation and puncture (sham-operated group). The cardiac function was assessed in vivo and ex vivo in standard conditions. Several parameters involved in the oxidative stress and inflammation were determined in the plasma and heart. As evidenced by the plasma level of TNF- α and gene expression of IL-1 β and TNF- α in the heart, inflammation was developed in the sepsis group. The cardiac function was also slightly stimulated by sepsis in the in vivo and ex vivo situations. This was associated with unchanged levels of oxidative stress, but several parameters indicated a lower cardiac production of reactive oxygen species in the septic group. In conclusion, despite the development of inflammation, early sepsis did not increase reactive oxygen species production and did not reduce myocardial function. The depressant effect of TNF- α and IL-1 β on the cardiac function is known to occur at very high concentrations. The influence of low- to moderate-grade inflammation on the myocardial mechanical behavior must thus be revisited. © 2017 French National Institute of Agronomical Research (INRA). Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

  9. Moderate (20%) fructose-enriched diet stimulates salt-sensitive hypertension with increased salt retention and decreased renal nitric oxide.

    Science.gov (United States)

    Gordish, Kevin L; Kassem, Kamal M; Ortiz, Pablo A; Beierwaltes, William H

    2017-04-01

    Previously, we reported that 20% fructose diet causes salt-sensitive hypertension. In this study, we hypothesized that a high salt diet supplemented with 20% fructose (in drinking water) stimulates salt-sensitive hypertension by increasing salt retention through decreasing renal nitric oxide. Rats in metabolic cages consumed normal rat chow for 5 days (baseline), then either: (1) normal salt for 2 weeks, (2) 20% fructose in drinking water for 2 weeks, (3) 20% fructose for 1 week, then fructose + high salt (4% NaCl) for 1 week, (4) normal chow for 1 week, then high salt for 1 week, (5) 20% glucose for 1 week, then glucose + high salt for 1 week. Blood pressure, sodium excretion, and cumulative sodium balance were measured. Systolic blood pressure was unchanged by 20% fructose or high salt diet. 20% fructose + high salt increased systolic blood pressure from 125 ± 1 to 140 ± 2 mmHg ( P  fructose + high salt than either high salt, or glucose + high salt (114.2 ± 4.4 vs. 103.6 ± 2.2 and 98.6 ± 5.6 mEq/Day19; P  fructose + high salt group compared to high salt only: 5.33 ± 0.21 versus 7.67 ± 0.31 mmol/24 h; P  fructose + high salt group (2139 ± 178  μ mol /24 hrs P  fructose predisposes rats to salt-sensitivity and, combined with a high salt diet, leads to sodium retention, increased blood pressure, and impaired renal nitric oxide availability. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

  10. Defensive peripersonal space: the blink reflex evoked by hand stimulation is increased when the hand is near the face.

    Science.gov (United States)

    Sambo, C F; Liang, M; Cruccu, G; Iannetti, G D

    2012-02-01

    Electrical stimulation of the median nerve at the wrist may elicit a blink reflex [hand blink reflex (HBR)] mediated by a neural circuit at brain stem level. As, in a Sherringtonian sense, the blink reflex is a defensive response, in a series of experiments we tested, in healthy volunteers, whether and how the HBR is modulated by the proximity of the stimulated hand to the face. Electromyographic activity was recorded from the orbicularis oculi, bilaterally. We observed that the HBR is enhanced when the stimulated hand is inside the peripersonal space of the face, compared with when it is outside, irrespective of whether the proximity of the hand to the face is manipulated by changing the position of the arm (experiment 1) or by rotating the head while keeping the arm position constant (experiment 3). Experiment 2 showed that such HBR enhancement has similar magnitude when the participants have their eyes closed. Experiments 4 and 5 showed, respectively, that the blink reflex elicited by the electrical stimulation of the supraorbital nerve, as well as the N20 wave of the somatosensory evoked potentials elicited by the median nerve stimulation, are entirely unaffected by hand position. Taken together, our results provide compelling evidence that the brain stem circuits mediating the HBR in humans undergo tonic and selective top-down modulation from higher order cortical areas responsible for encoding the location of somatosensory stimuli in external space coordinates. These findings support the existence of a "defensive" peripersonal space, representing a safety margin advantageous for survival.

  11. Doranidazole (PR-350), a hypoxic cell radiosensitizer, radiosensitizes human lung tumors (RERF-LC- AI) and causes changes in tumor oxygenation

    International Nuclear Information System (INIS)

    Kubota, N.; Griffin, R.J.; Williams, B.W.; Song, C.W.; Yahiro, T.

    2003-01-01

    Full text: We previously have reported the radiosensitizing capability of Doranidazole (PR-350) on SCCVII cells and tumors (Puerto Rico, 2001). In the present study, we have investigated the efficacy of PR-350 as a hypoxic cell radiosensitizer using human lung cancer cells (RERF-LC-AI) in vitro and also RERF-LC-AI tumors grown s.c. in Balb/c nude mice. Using the micronucleus assay method, we determined the effect of PR-350 on the response of RERF-LC-AI cells to radiation under hypoxic conditions and enhancement ratios (ER) of 1.45∼2.26 were obtained. The in vivo radiosensitizing effect was studied by irradiating RERF-LC-AI tumors with 15 Gy at 20 min. after i.v. injection of PR-350 (200mg/kg) and measuring the tumor growth delay. Significant growth delay occurred after i.v. injection of PR-350 before irradiation compared to radiation alone. We measured tumor pO 2 at 3, 7 and 14 days after treatment using an Eppendorf pO 2 histograph. The frequency of pO 2 values 2 in tumors treated with radiation plus PR-350 were higher than that in tumors treated with radiation plus saline. These data suggest that the O 2 consumption in tumors treated with radiation plus PR-350 was less than that in tumors treated with radiation plus saline due to greater drug and radiation-induced cell death. This hypothesis is supported by the fact that the tumor size in the combined treatment group was smaller than in radiation alone. These results suggest that PR-350 may improve the response of tumors to radiotherapy not only by increasing the radiosensitivity of hypoxic cells but also by improving tumor oxygenation over many days during fractionated radiotherapy

  12. Evaluation of nitrobenzimidazoles as hypoxic cell radiosensitizers

    International Nuclear Information System (INIS)

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

    1983-01-01

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

  13. Evaluation of nitrobenzimidazoles as hypoxic cell radiosensitizers

    International Nuclear Information System (INIS)

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

    1983-01-01

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

  14. Molecular mechanism of radiosensitization by nitro compounds

    International Nuclear Information System (INIS)

    Kagiya, T.; Wada, T.; Nishimoto, S.I.

    1984-01-01

    In this chapter a molecular mechanism of radiosensitization by electron-affinic nitro compounds is discussed, mainly on the basis of the results of the radiation-induced chemical studies of DNA-related compounds in aqueous solutions. In Section II the general aspects of the radiation chemistry of organic compounds in the absence and presence of oxygen in aqueous solution are shown in order to demonstrate characteristic differences between radiation chemical reactions in hypoxic and oxic cells. The effects of nitro compounds on the radiolysis yields of DNA-related compounds in aqueous solutions are described in Section III. In Section IV the retardation effects of misonidazole on the radiation chemical processes of DNA-related compounds are shown along with the reaction characteristics of misonidazole with hydroxyl radical ( . OH) and hydrated electron (e/sub aq/-bar) produced by the radiolysis of water. The promotion of radiation-induced oxidation of thymine into thymine glycol (TG) by nitro radiosensitizers in deoxygenated solution and the relations between the activity of nitro compound for the thymine glycol formation and the enhancement activity measured in vitro are described in Section V. Finally, the protection against radiation-induced damage of thymine by a sulfhydryl compound of glutathione and the ability of electron-affinic compounds to decompose the intracellular radioprotector are described in Section VI

  15. Electrical Stimulation of Low-Threshold Proprioceptive Fibers in the Adult Rat Increases Density of Glutamatergic and Cholinergic Terminals on Ankle Extensor α-Motoneurons.

    Directory of Open Access Journals (Sweden)

    Olga Gajewska-Woźniak

    Full Text Available The effects of stimulation of low-threshold proprioceptive afferents in the tibial nerve on two types of excitatory inputs to α-motoneurons were tested. The first input is formed by glutamatergic Ia sensory afferents contacting monosynaptically α-motoneurons. The second one is the cholinergic input originating from V0c-interneurons, located in lamina X of the spinal cord, modulating activity of α-motoneurons via C-terminals. Our aim was to clarify whether enhancement of signaling to ankle extensor α-motoneurons, via direct electrical stimulation addressed predominantly to low-threshold proprioceptive fibers in the tibial nerve of awake rats, will affect Ia glutamatergic and cholinergic innervation of α-motoneurons of lateral gastrocnemius (LG. LG motoneurons were identified with True Blue tracer injected intramuscularly. Tibial nerve was stimulated for 7 days with continuous bursts of three pulses applied in four 20 min sessions daily. The Hoffmann reflex and motor responses recorded from the soleus muscle, LG synergist, allowed controlling stimulation. Ia terminals and C-terminals abutting on LG-labeled α-motoneurons were detected by immunofluorescence (IF using input-specific anti- VGLUT1 and anti-VAChT antibodies, respectively. Quantitative analysis of confocal images revealed that the number of VGLUT1 IF and VAChT IF terminals contacting the soma of LG α-motoneurons increased after stimulation by 35% and by 26%, respectively, comparing to the sham-stimulated side. The aggregate volume of VGLUT1 IF and VAChT IF terminals increased by 35% and by 30%, respectively. Labeling intensity of boutons was also increased, suggesting an increase of signaling to LG α-motoneurons after stimulation. To conclude, one week of continuous burst stimulation of proprioceptive input to LG α-motoneurons is effective in enrichment of their direct glutamatergic but also indirect cholinergic inputs. The effectiveness of such and longer stimulation in models

  16. Modification of bone marrow radiosensitivity by medicinal plant extracts

    Energy Technology Data Exchange (ETDEWEB)

    Ganasoundari, A.; Zare, S. M.; Uma Devi, P. [Department of Radiobiology, Kasturba Medical College, Manipal 576 119 (India)

    1997-07-01

    Withaferin A (WA), a steroidal lactone, and Plumbagin (Pi), a naphthoquinone, from the roots of Withania somnifera and Plumbage rosea, respectively, have been shows to possess growth inhibitory and radiosensitizing effects on experimental mouse tumours. An aqueous extract of the leaves of Ocimum sanctum (OE) was found to protect mice against radiation lethality. Therefore, the radiomodifying effects of the above plant products on the bone marrow of the adult Swiss mouse was studied. Single doses of WA (30 mg kg{sup -1}) or P1 (5 mg kg{sup -1}) were injected intraperitoneally tip) and OE (10 mg kg{sup -1}) was injected ip once daily for five consecutive days. Administration of extracts was followed by 2 Gy whole body gamma irradiation. Bone marrow stem cell survival was studied by an exogenous spleen colony unit (CFU-S) assay. The effects of WA and P1 were compared with that of cyclophosphamide (CP) and radioprotection by OE was compared with that of WR-2721 (WR). Radiation reduced the CFU-S to less than 50% of normal. WA, CP and P1 significantly enhanced this effect and reduced the CFU-S to almost the same extent (to <20% of normal), although individually WA and P1 were less cytotoxic than CP. These results indicate that radiosensitization by WE and P1 is not tumour specific. OE significantly increased CFU-S compared with radiotherapy (RT) alone. OE + RT gave a higher stem cell survival (p < 0.05) than that produced by WR + RT. While WR alone had a toxic effect, OE treatment showed no such effect, suggesting that the latter may have an advantage over WR in clinical application. (author)

  17. Potential of radiosensitizing agents in cancer chemo-radiotherapy

    Directory of Open Access Journals (Sweden)

    Girdhani S

    2005-01-01

    Full Text Available Potential of herbs and other plant-based formulations have been increasingly recognized in prevention and treatment of human diseases including cancer. There exist enormous prospect for screening and evaluation of herbal/plant products for developing effective radiosensitization and radioprotection relevant to nuclear research program. Investigations in our laboratory have focused on the mechanism of activity of variety of anticancer and antioxidant agents, namely, Eugenol, (EU, Ellagic acid (EA, Triphala (TPL, Tocopherol Succinate (TOS and Arachidonic acid on normal and cancer cells with view to design effective protocols in practical radioprotection and cancer radiotherapy. This paper is mainly focused on studies on cytotoxic effects on cancer cell lines. Results have shown that these agents produced radiosensitizing action involving oxidative damage, membrane alteration and damage to nucleic acid in various human cell lines. Studies were performed employing fluorescence probes and electron spin resonance methods and gel electrophoresis protocols. It has been found that cytotoxic effect was induced by initiating membrane oxidative damage and by triggering intracellular generation of reactive oxygen species (ROS by gamma radiation in combination with phytochemicals like TPL, EA and TOS in tumor cell line Ehrlich Ascites (EAC, Human cervical (HeLa and breast (MCF-7 cells. Membrane damage and ROS generation was measured by DPH and DCF-FDA fluorescent probes respectively after exposure to low to moderate doses of gamma radiation. This talk will present the cytotoxic effects of phytochemicals in combination with ionizing radiation. It is emphasized that modulation of membrane peroxidative damage and intra cellular ROS may help achieve efficient killing of cancer cells which may provide a new approach to developing effective treatment of cancer.

  18. Radiosensitizing effect of epothilone B on human epithelial cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Baumgart, T.; Kriesen, S.; Hildebrandt, G.; Manda, K. [Univ. of Rostock (Germany). Dept. of Radiotherapy and Radiation Oncology; Klautke, G.; Fietkau, R. [Friedrich-Alexander-Univ. Erlangen-Nuernberg, Erlangen (Germany). Dept. of Radiation Oncology; Kuznetsov, S.A.; Weiss, D.G. [Univ. of Rostock (Germany). Inst. of Biological Sciences, Cell Biology, and Biosystems Technology

    2012-02-15

    A combined modality treatment employing radiation and chemotherapy plays a central role in the management of solid tumors. In our study, we examined the cytotoxic and radiosensitive effect of the microtubule stabilizer epothilone B on two human epithelial tumor cell lines in vitro and its influence on the microtubule assembly. Cancer cells were treated with epothilone B in proliferation assays and in combination with radiation in colony-forming assays. For the analysis of ionizing radiation-induced DNA damage and the influence of the drug on its repair a {gamma}H2AX foci assay was used. To determine the effect of epothilone B on the microtubule assembly in cells and on purified tubulin, immunofluorescence staining and tubulin polymerization assay, respectively, were conducted. Epothilone B induced a concentration- and application-dependent antiproliferative effect on the cells, with IC{sub 50} values in the low nanomolar range. Colony forming assays showed a synergistic radiosensitive effect on both cell lines which was dependent on incubation time and applied concentration of epothilone B. The {gamma}H2AX assays demonstrated that ionizing radiation combined with the drug resulted in a concentration-dependent increase in the number of double-strand breaks and suggested a reduction in DNA repair capacity. Epothilone B produced enhanced microtubule bundling and abnormal spindle formation as revealed by immunofluorescence microscopy and caused microtubule formation from purified tubulin. The results of this study showed that epothilone B displays cytotoxic antitumor activity at low nanomolar concentrations and also enhances the radiation response in the tumor cells tested; this may be induced by a reduced DNA repair capacity triggered by epothilone B. It was also demonstrated that epothilone B in fact targets microtubules in a more effective manner than paclitaxel. (orig.)

  19. Cellular radiosensitivity and DNA damage in primary human fibroblasts

    International Nuclear Information System (INIS)

    Wurm, R.; Burnet, N.G.; Duggal, N.

    1994-01-01

    To evaluate the relationship between radiation-induced cell survival and DNA damage in primary human fibroblasts to decide whether the initial or residual DNA damage levels are more predictive of normal tissue cellular radiosensitivity. Five primary human nonsyndromic and two primary ataxia telangiectasia fibroblast strains grown in monolayer were studied. Cell survival was assessed by clonogenic assay. Irradiation was given at high dose rate (HDR) 1-2 Gy/min. DNA damage was measured in stationary phase cells and expressed as fraction released from the well by pulsed-field gel electrophoresis (PFGE). For initial damage, cells were embedded in agarose and irradiated at HDR on ice. Residual DNA damage was measured in monolayer by allowing a 4-h repair period after HDR irradiation. Following HDR irradiation, cell survival varied between SF 2 0.025 to 0.23. Measurement of initial DNA damage demonstrated linear induction up to 30 Gy, with small differences in the slope of the dose-response curve between strains. No correlation between cell survival and initial damage was found. Residual damage increased linearly up to 80 Gy with a variation in slope by a factor of 3.2. Cell survival correlated with the slope of the dose-response curves for residual damage of the different strains (p = 0.003). The relationship between radiation-induced cell survival and DNA damage in primary human fibroblasts of differing radiosensitivity is closest with the amount of DNA damage remaining after repair. If assays of DNA damage are to be used as predictors of normal tissue response to radiation, residual DNA damage provides the most likely correlation with cell survival. 52 refs., 5 figs., 2 tabs

  20. Wnt activation affects proliferation, invasiveness and radiosensitivity in medulloblastoma.

    Science.gov (United States)

    Salaroli, Roberta; Ronchi, Alice; Buttarelli, Francesca Romana; Cortesi, Filippo; Marchese, Valeria; Della Bella, Elena; Renna, Cristiano; Baldi, Caterina; Giangaspero, Felice; Cenacchi, Giovanna

    2015-01-01

    Medulloblastomas (MBs) associated with the Wnt activation represent a subgroup with a favorable prognosis, but it remains unclear whether Wnt activation confers a less aggressive phenotype and/or enhances radiosensitivity. To investigate this issue, we evaluated the biological behavior of an MB cell line, UW228-1, stably transfected with human β-catenin cDNA encoding a nondegradable form of β-catenin (UW-B) in standard culture conditions and after radiation treatment. We evaluated the expression, transcriptional activity, and localization of β-catenin in the stably transfected cells using immunofluorescence and WB. We performed morphological analysis using light and electron microscopy. We then analyzed changes in the invasiveness, growth, and mortality in standard culture conditions and after radiation. We demonstrated that (A) Wnt activation inhibited 97 % of the invasion capability of the cells, (B) the growth of the UW-B cells was statistically significantly lower than that of all the other control cells (p < 0.01), (C) the mortality of irradiated UW-B cells was statistically significantly higher than that of the controls and their nonirradiated counterparts (p < 0.05), and (D) morphological features of neuronal differentiation were observed in the Wnt-activated cells. In tissue samples, the Ki-67 labeling index (LI) was lower in β-catenin-positive samples compared to non-β-catenin positive ones. The Ki-67 LI median (LI = 40) of the nuclear β-catenin-positive tumor samples was lower than that of non-nuclear β-catenin-positive samples (LI = 50), but the difference was not statistically significant. Overall, our data suggest that activation of the Wnt pathway reduces the proliferation and invasion of MBs and increases the tumor's radiosensitivity.

  1. Insulin does not stimulate muscle protein synthesis during increased plasma branched-chain amino acids alone but still decreases whole body proteolysis in humans.

    Science.gov (United States)

    Everman, Sarah; Meyer, Christian; Tran, Lee; Hoffman, Nyssa; Carroll, Chad C; Dedmon, William L; Katsanos, Christos S

    2016-10-01

    Insulin stimulates muscle protein synthesis when the levels of total amino acids, or at least the essential amino acids, are at or above their postabsorptive concentrations. Among the essential amino acids, branched-chain amino acids (BCAA) have the primary role in stimulating muscle protein synthesis and are commonly sought alone to stimulate muscle protein synthesis in humans. Fourteen healthy young subjects were studied before and after insulin infusion to examine whether insulin stimulates muscle protein synthesis in relation to the availability of BCAA alone. One half of the subjects were studied in the presence of postabsorptive BCAA concentrations (control) and the other half in the presence of increased plasma BCAA (BCAA). Compared with that prior to the initiation of the insulin infusion, fractional synthesis rate of muscle protein (%/h) did not change (P > 0.05) during insulin in either the control (0.04 ± 0.01 vs 0.05 ± 0.01) or the BCAA (0.05 ± 0.02 vs. 0.05 ± 0.01) experiments. Insulin decreased (P BCAA (0.89 ± 0.07 vs 0.61 ± 0.03) experiments, but the change was not different between the two experiments (P > 0.05). In conclusion, insulin does not stimulate muscle protein synthesis in the presence of increased circulating levels of plasma BCAA alone. Insulin's suppressive effect on proteolysis is observed independently of the levels of circulating plasma BCAA. Copyright © 2016 the American Physiological Society.

  2. A Novel Magnetic Stimulator Increases Experimental Pain Tolerance in Healthy Volunteers : A Double-Blind Sham-Controlled Crossover Study

    NARCIS (Netherlands)

    Kortekaas, R.; van Nierop, L.E.; Baas, V.G.; Konopka, K.H.; Harbers, M.; van der Hoeven, J.H.; van Wijhe, M.; Aleman, A.; Maurits, N.M.

    2013-01-01

    The 'complex neural pulse'(TM) (CNP) is a neuromodulation protocol employing weak pulsed electromagnetic fields (PEMF). A pioneering paper reported an analgesic effect in healthy humans after 30 minutes of CNP-stimulation using three nested whole head coils. We aimed to devise and validate a

  3. Tissue factor pathway inhibitor (TFPI) release after heparin stimulation is increased in Type 1 diabetic patients with albuminuria

    NARCIS (Netherlands)

    Leurs, PB; van Oerle, R; Hamulyak, K; Wolffenbuttel, BHR

    Aims To study heparin-stimulated TFPI release in relation to complications in Type 1 diabetic patients. Subjects and methods Nineteen uncomplicated Type 1 diabetic patients (group I) were compared with 18 patients with retinopathy (group II), and nine patients with retinopathy and albuminuria (group

  4. Increases in frontostriatal connectivity are associated with response to dorsomedial repetitive transcranial magnetic stimulation in refractory binge/purge behaviors

    Directory of Open Access Journals (Sweden)

    Katharine Dunlop

    2015-01-01

    Conclusions: Enhanced frontostriatal connectivity was associated with responders to dmPFC-rTMS for binge/purge behavior. rTMS caused paradoxical suppression of frontostriatal connectivity in nonresponders. rs-fMRI could prove critical for optimizing stimulation parameters in a future sham-controlled trial of rTMS in disordered eating.

  5. Increased cell motility and invasion upon knockdown of lipolysis stimulated lipoprotein receptor (LSR) in SW780 bladder cancer cells

    DEFF Research Database (Denmark)

    Herbsleb, Malene; Birkenkamp-Demtroder, Karin; Thykjaer, Thomas

    2008-01-01

    Mechanisms underlying the malignant development in bladder cancer are still not well understood. Lipolysis stimulated lipoprotein receptor (LSR) has previously been found to be upregulated by P53. Furthermore, we have previously found LSR to be differentially expressed in bladder cancer. Here we...... investigated the role of LSR in bladder cancer....

  6. Radiosensitization of human prostate cell line LNCAP by [6]- gingerol

    Energy Technology Data Exchange (ETDEWEB)

    Silva, Josias Paulino Leal; Bellini, Maria Helena [Instituto de Pesquisas Energéticas e Nucleares (IPEN/CNEN-SP), São Paulo, SP (Brazil)

    2017-07-01

    significant. Results: Our results demonstrated that [6]-Gingerol treatment induced a dose-dependent decrease in the cell viability. Compared with the vehicle control, the cell viabilities were 75.99 ± 3.56% and 43.06 ± 7.82% when the cells were exposed to 150 μg/mL and 300 μg/mL of [6]-Gingerol, respectively. Therefore, we observed a significant difference between the treatment groups; (P<0.01). Then, the effect of [6]-Gingerol (300 μg/mL) on cell radiosensitivity was evaluated. The clonogenic cell survival assay showed a significant difference between dose-survival curves of group (A) and (B), (P<0.05) and between the group (C) and (D), (P<0.05). Therefore, [6]-Gingerol treatment increased the radiosensitivity of LNCaP cells. Conclusions: The results demonstrated that, besides inducing a dose-dependent apoptosis in LNCaP human prostate cancer cells, [6]-Gingerol showed a radiosensitizing activity. These findings suggests it potential as candidate phytochemical agent for combined therapy for prostate cancer. (author)

  7. Radiosensitization of human prostate cell line LNCAP by [6]- gingerol

    International Nuclear Information System (INIS)

    Silva, Josias Paulino Leal; Bellini, Maria Helena

    2017-01-01

    significant. Results: Our results demonstrated that [6]-Gingerol treatment induced a dose-dependent decrease in the cell viability. Compared with the vehicle control, the cell viabilities were 75.99 ± 3.56% and 43.06 ± 7.82% when the cells were exposed to 150 μg/mL and 300 μg/mL of [6]-Gingerol, respectively. Therefore, we observed a significant difference between the treatment groups; (P<0.01). Then, the effect of [6]-Gingerol (300 μg/mL) on cell radiosensitivity was evaluated. The clonogenic cell survival assay showed a significant difference between dose-survival curves of group (A) and (B), (P<0.05) and between the group (C) and (D), (P<0.05). Therefore, [6]-Gingerol treatment increased the radiosensitivity of LNCaP cells. Conclusions: The results demonstrated that, besides inducing a dose-dependent apoptosis in LNCaP human prostate cancer cells, [6]-Gingerol showed a radiosensitizing activity. These findings suggests it potential as candidate phytochemical agent for combined therapy for prostate cancer. (author)

  8. Radiosensitizing potential of gemcitabine (2',2'-difluoro-2'-deoxycytidine) within the cell cycle in vitro

    International Nuclear Information System (INIS)

    Latz, Detlev; Fleckenstein, Katharina; Eble, Michael; Blatter, Johannes; Wannenmacher, Michael; Weber, Klaus J.

    1998-01-01

    Purpose: Gemcitabine (2',2'-difluorodeoxycytidine; dFdCyd) is a new deoxycitidine analog which exhibits substantial activity against solid tumors and radiosensitizing properties in vitro. To examine cell cycle-specific effects of a combined treatment with gemcitabine and radiation, the in vitro clonogenic survival of two different cell lines was measured for cells from log-phase culture, G1 and S-phase cells. Methods and Materials: Chinese hamster (V79) and human colon carcinoma (Widr) cells were exposed to different radiation doses and for different points of time relative to gemcitabine treatment (2 h). Experiments were also carried out with different cell-cycle populations obtained after mitotic selection (V79) or after serum stimulation of plateau-phase cells (Widr). The resulting survival curves were analyzed according to the LQ model, and mean inactivation doses (MID) and the cell cycle-specific enhancement ratios (ER) were calculated from the survival curve parameters. Results: Effectiveness of combined treatment of log-phase cells was greatest when cells were irradiated at the end of the gemcitabine exposure [ER: 1.28 (V79), 1.24 (Widr)]. For later times after the removal of the drug, radiosensitization declined, approaching independent toxicity. From the time course of interactive-type damage decay half-life values of 75 min (V79) and 92 min (Widr) were derived. Gemcitabine did not radiosensitize G1 Widr cells or V79 cells from the G1/S border, but substantial radiosensitization was observed for the S-phase cell preparations [ER: 1.45 (V79-lateS), 1.57 (Widr)]. Conclusions: Treatment of cells with gemcitabine immediately before irradiation eliminates, or at least greatly reduces, the variation in radiosensitivity during the cell cycle that is manifested by radioresistance during S phase. This reversal of S-phase radioresistance could imply that gemcitabine interferes with the potentially lethal damage repair/fixation pathway. Other approaches have been

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

    Directory of Open Access Journals (Sweden)

    Rahman WN

    2014-05-01

    Full Text Available Wan Nordiana Rahman,1,2 Stéphanie Corde,3,4 Naoto Yagi,5 Siti Aishah Abdul Aziz,1 Nathan Annabell,2 Moshi Geso21School of Health Sciences, Universiti Sains Malaysia, Kelantan, Malaysia; 2Division of Medical Radiation, School of Medical Sciences, Royal Melbourne Institute of Technology, Bundoora, VIC, 3Radiation Oncology, Prince of Wales Hospital, High Street, Randwick, 4Centre for Medical Radiation Physics, University of Wollongong, Wollongong, NSW, Australia; 5Japanese Synchrotron Radiation Research Institute, Sayo-gun, Hyogo, JapanAbstract: Gold nanoparticles have been shown to enhance radiation doses delivered to biological targets due to the high absorption coefficient of gold atoms, stemming from their high atomic number (Z and physical density. These properties significantly increase the likelihood of photoelectric effects and Compton scattering interactions. Gold nanoparticles are a novel radiosensitizing agent that can potentially be used to increase the effectiveness of current radiation therapy techniques and improve the diagnosis and treatment of cancer. However, the optimum radiosensitization effect of gold nanoparticles is strongly dependent on photon energy, which theoretically is predicted to occur in the kilovoltage range of energy. In this research, synchrotron-generated monoenergetic X-rays in the 30–100 keV range were used to investigate the energy dependence of radiosensitization by gold nanoparticles and also to determine the photon energy that produces optimum effects. This investigation was conducted using cells in culture to measure dose enhancement. Bovine aortic endothelial cells with and without gold nanoparticles were irradiated with X-rays at energies of 30, 40, 50, 60, 70, 81, and 100 keV. Trypan blue exclusion assays were performed after irradiation to determine cell viability. Cell radiosensitivity enhancement was indicated by the dose enhancement factor which was found to be maximum at 40 keV with a value of 3

  10. An increase in alpha band frequency in resting state EEG after electrical stimulation of the ear in tinnitus patients - a pilot study

    Directory of Open Access Journals (Sweden)

    Marzena Mielczarek

    2016-10-01

    Full Text Available In our clinic invasive transtympanal promontory positive DC stimulations were first used, with a success rate of 42%. However, non-invasive hydrotransmissive negative DC stimulations are now favoured, with improvement being obtained in 37.8% directly after the treatment, and 51.3% in a follow up one month after treatment. The further improvement after one month may be due to neuroplastic changes at central level as a result of altered peripheral input. The aim of the study was to determine how a single electrical stimulation of the ear influences cortical activity, and whether changes observed in tinnitus after electrical stimulation are associated with any changes in cortical activity recorded in EEG.The study included 12 tinnitus patients(F–6, M-6 divided into two groups. Group I comprised six patients with unilateral tinnitus - unilateral, ipsilateral ES was performed. Group II comprised six patients with bilateral tinnitus - bilateral ES was performed.Electrical stimulation was performed using a custom-made apparatus.The active, silver probe – was immersed inside the external ear canal filled with saline. The passive electrode was placed on the forehead. The stimulating frequency was 250Hz, the intensity ranged from 0.14 to 1.08 mA. The voltage was kept constant at 3V. The duration of stimulation was four minutes. The EEG recording (Deymed QEST 32 was performed before and after electrical stimulation. We assessed the intensity of tinnitus on the visual analogue scale (1-10. Results.In both groups an improvement in VAS was observed– in group I - in five ears (83.3%, in group II - in seven ears (58.3%. In Group I,a significant increase in the upper and lower limits of the alpha frequency range was observed in the left central temporal and left frontal regions following electrical stimulation. These changes, however, were not correlated with improvement in tinnitus. No significant changes were observed in the beta and theta bands and in

  11. Exercise training favors increased insulin-stimulated glucose uptake in skeletal muscle in contrast to adipose tissue: a randomized study using FDG PET imaging

    DEFF Research Database (Denmark)

    Reichkendler, M. H.; Auerbach, P.; Rosenkilde, M.

    2013-01-01

    abdominal SAT compared with CON but not in either intra- or retroperitoneal VAT. Total adipose tissue mass decreased in both exercise groups, and the decrease was distributed equally among subcutaneous and intra-abdominal depots. In conclusion, aerobic exercise training increases insulin-stimulated glucose...

  12. Effects of taurolidine on radiosensitivity of murine melanoma cells and its mechanism

    International Nuclear Information System (INIS)

    Sun Baosheng; Liu Shixin; Wang Tiejun; Liu Linlin; Huang Guomin; Gong Shouliang

    2008-01-01

    Objective: To observe the effects of taurolidine on radiosensitivity of B16-F10 cells of murine melanoma via the enhancement of Bax and Bad proteins and induction of Bcl-2 protein. Methods: The apoptosis of B16-F10 cells was assessed after treated with 0, 10, 25, 50, 100 and 150 μmol·L -1 taurolidine, clone survival assay was used to detect the radiosensitivity of B16-F10 cells, and protein expressions were determined by Western blotting. Results: The apoptosis of 5% cells was induced in a dose-and time-dependent manner after B16-F10 cells were treated with 50 μmol·L -1 taurolidine. The survival rate decreased after treated with tautolidine in combination with 2 Gy X-irradiation with the increase of taurolidine concentration and doses of irradiation (P 0 and SER D q ) also increased with the increase of its concentration, there was significant difference between 50 μmol·L -1 taurolidine group and 10 μmol·L -1 taurolidine group (P<0.05); meantime, the level of proapototic protein Bax and Bad increased and the level of antiapoptotic protein Bcl-2 reduced. Conclusion: Taurolidine in combination with irradiation can enhance the radiosensitivity by the mediation of Bcl-2 family protein. (authors)

  13. The development of genes associated with radiosensitivity of cervical cancer

    International Nuclear Information System (INIS)

    Li Hongyan; Chen Zhihua; He Guifang

    2007-01-01

    It has a good application prospect to predict effects of radiotherapy by examining radiosensitivity of patients with cervical cancers before their radiotherapy. Prediction of tumor cell radiosensitivity according to their level of gene expression and gene therapy to reverse radio-resistance prior to radiation on cervical cancers are heated researches on tumor therapy. The expression of some proliferation-related genes, apoptosis-related genes and hypoxia-related genes can inerease the radiosensitivity of cervical cancer. Microarray technology may have more direct applications to the study of biological pathway contributing to radiation resistance and may lead to development of alternative treatment modalities. (authors)

  14. Correlation between the organism response to acute hypoxia and individual radiosensitivity of rats

    International Nuclear Information System (INIS)

    Grigor'ev, A.Yu.; Silin, D.Ya.

    1988-01-01

    A study was made of a correlation between the response of basal metabolism to acute hypoxia and the life span of rats after irradiation resulting in the development of a cerebral form of radiation sickness. The more radiosensitive animals consumed a larger amount of oxygen, exhaled a smaller amount of carbon dioxide and showd an increased normal expiratory exchange per minute. After the effect of acure hypoxia all the indices under study revealed an opposite picture

  15. Comparative radiosensitivity of amino acids during γ-radiolysis in aqueous solutions

    International Nuclear Information System (INIS)

    Duzhenkova, N.A.; Savich, A.V.

    1977-01-01

    The radiosensitivity of amino acids contained in proteins has been compared. The γ-radiolysis of aqueous solutions of amino acids has studied over a wide range of concentrations in the presence of air, the dose rate being 60 rad/sec, and the dose, 100 krad. Radiation-chemical yields of amino acid decay and ammonia accumulation are given. An increase in yields with amino acid concentration has been established. Assumptions concerning some peculiarities of the amino acid decay mechanism are made

  16. The effects of BSO on GSH contents and radiosensitivity of retinoblastoma cells

    International Nuclear Information System (INIS)

    Yi Xanjin; Ding Li; Jin Yizun; Ni Chuo; Wang Wenji; Yi Yuzhen

    1995-01-01

    The radiobiological effects of thiol modifier BSO on retinoblastoma were studied using cultured retinoblastoma cell lines Y-79 and So-Rb 50 and retinoblastoma bearing nude mouse. The preliminary results showed that BSO can deplete intracellular GSH contents of retinoblastoma cells in vitro and vivo. In vitro data demonstrated that low and nontoxic concentration BSO increased the retinoblastoma cells radiosensitivity especially under the hypoxic condition

  17. Radiosensitivity of California Wonder pepper variety to Co-60 gamma rays

    International Nuclear Information System (INIS)

    Puertas Arias, Ana Leonor; Gonzalez Nunez, Luis Manuel; Ramirez Fernandez, Ramiro

    1998-01-01

    Seeds of California wonder pepper variety were irradiated with dosages among 100-800 Gy, to intervals of 100 Gy, in a source of Co 60 gamma rays, with the objective of determining its radiosensitivity and to establish the adequate interval of dosage for the mutation breeding. A decrease of the growing indicators, productivity and plant fertility was observed with the increasing of irradiation dosages and the interval among 130-460 Gy was established as the most adequate

  18. Proliferation activity and radiosensitivity of CFU-S in their decreased compartments in continuously irradiated rats

    International Nuclear Information System (INIS)

    Kalina, I.; Vacek, A.; Brezani, P.

    1984-01-01

    Effects of the continuous irradiation (0.25 Gy/day) on proliferation activity and radiosensitivity (D 0 ) of CFU-S were studied in rats after accumulated doses of 1.75 Gy and 15 Gy, resp. The proliferation activity of CFU-S in continuously irradiated groups was increased 4 - 5 fold compared with the control group. D 0 values for CFU-S in their decreased compartments were not changed after long-term irradiation compared with the controls. (author)

  19. Mechanical stimulation of C2C12 cells increases m-calpain expression and activity, focal adhesion plaque degradation and cell fusion

    DEFF Research Database (Denmark)

    Grossi, Alberto; Karlsson, Anders Hans; Lawson, Moira A.

    2005-01-01

    Abstract Mechanical Stimulation of C2C12 Cells Increases m-calpain Expression and Activity, Focal Adhesion Plaque Degradation and Cell Fusion A. Grossi, A. H. Karlsson, M. A. Lawson; Department of Dairy and Food Science, Royal Veterinary and Agricultural University, Frederiksberg C, Denmark...... Myogenesis is a complex sequence of events, including the irreversible transition from the proliferation-competent myoblast stage into fused, multinucleated myotubes. During embryonic development, myogenic differentiation is regulated by positive and negative signals from surrounding tissues. Stimulation due...... to the activity of ubiquitous proteolytic enzymes known as calpains has been reported. Whether there is a link between stretch- or load induced signaling and calpain expression and activation is not known. Using a magnetic bead stimulation assay and C2C12 mouse myoblasts cell population, we have demonstrated...

  20. Increasing the effectiveness of hematopoiesis in myelodysplastic syndromes: erythropoiesis-stimulating agents and transforming growth factor-β superfamily inhibitors.

    Science.gov (United States)

    Mies, Anna; Platzbecker, Uwe

    2017-07-01

    Patients with lower-risk myelodysplastic syndromes (MDS) are mainly affected by chronic anemia and fatigue. Treatment strategies aim to improve anemia and quality of life, as well as iron overload due to red blood cell transfusion support. To promote proliferation and differentiation of erythropoiesis, erythropoiesis-stimulating agents (ESAs) such as erythropoietin (EPO) and mimetics are applied as first-line therapy in a large fraction of lower-risk MDS patients. In general, ESAs yield favorable responses in about half of the patients, although responses are often short-lived. In fact, many ESA-refractory patients harbor defects in late-stage erythropoiesis downstream of EPO action. Novel transforming growth factor (TGF)-β superfamily inhibitors sotatercept and luspatercept represent a promising approach to alleviate anemia by stimulating erythroid differentiation. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Repeated 6-Hz Corneal Stimulation Progressively Increases FosB/ΔFosB Levels in the Lateral Amygdala and Induces Seizure Generalization to the Hippocampus.

    Directory of Open Access Journals (Sweden)

    Carmela Giordano

    Full Text Available Exposure to repetitive seizures is known to promote convulsions which depend on specific patterns of network activity. We aimed at evaluating the changes in seizure phenotype and neuronal network activation caused by a modified 6-Hz corneal stimulation model of psychomotor seizures. Mice received up to 4 sessions of 6-Hz corneal stimulation with fixed current amplitude of 32 mA and inter-stimulation interval of 72 h. Video-electroencephalography showed that evoked seizures were characterized by a motor component and a non-motor component. Seizures always appeared in frontal cortex, but only at the fourth stimulation they involved the hippocampus, suggesting the establishment of an epileptogenic process. Duration of seizure non-motor component progressively decreased after the second session, whereas convulsive seizures remained unchanged. In addition, a more severe seizure phenotype, consisting of tonic-clonic generalized convulsions, was predominant after the second session. Immunohistochemistry and double immunofluorescence experiments revealed a significant increase in neuronal activity occurring in the lateral amygdala after the fourth session, most likely due to activity of principal cells. These findings indicate a predominant role of amygdala in promoting progressively more severe convulsions as well as the late recruitment of the hippocampus in the seizure spread. We propose that the repeated 6-Hz corneal stimulation model may be used to investigate some mechanisms of epileptogenesis and to test putative antiepileptogenic drugs.

  2. Polymers for IUdR radiosensitization of experimental glioblastoma

    International Nuclear Information System (INIS)

    Williams, Jeffery A.; Xuan Yuan; Brem, Henry

    1997-01-01

    Purpose: For the radiosensitization of human malignant gliomas, the potential of polymers for the local, controlled release of 5-iodo-2'-deoxyuridine (IUdR) remains unexplored. We tested a synthetic, implantable biodegradable polymer for the controlled in vitro release of IUdR, the resultant in vivo cellular labeling and subsequent radiosensitization of experimental intracranial (i.c.) U251 human glioblastoma xenografts. Materials and Methods: In vitro: Release: To measure release, increasing (10%, 30%, 50%) proportions of IUdR in synthetic [(poly(bis(p-carboxyphenoxy)-propane) (PCPP):sebacic acid (SA) (PCPP:SA ratio 20:80)] polymer discs (1x1x3 mm: 10 mg) were incubated in 0.1 M phosphate-buffered saline. The supernatant fractions were periodically removed and IUdR was measured via quantitative spectrophotometry. Radiosensitization: To confirm sensitization, U251 cells had 0 (control), 0.1, 1.0 or 10 uM exposure to IUdR for 72 hours and acute irradiation (0, 2.5, 5.0, or 10 Gy). Cells were trypsinized, replated and scored for colony formation. In vivo: To confirm in vivo i.c. release, 5 mice (male nu/nu, 6 weeks) had right frontal i.c. implantation of single polymer discs having 200 uCi 125-IUdR. The decay-corrected activity (cpm) vs. time (days) was serially measured via a calibrated, collimated scintillation detector. To measure i.c. diffusion of IUdR from polymers to GBM xenografts, groups of 5 mice had i.c. inoculation of 2 x 10 5 U251 cells (Day 0) and subsequent (Day 5) implantation of polymer discs having 50% IUdR loadings. Four or 8 days after IUdR polymer implantation, mice were sacrificed and the intact brains bearing the tumor and IUdR polymer were excised, fixed and cut coronally 0 (in plane of polymer), 1 or 2 mm anterior to the polymer in tumor using a cryostat. To quantify the percentage labeling of the tumor cells vs. distance from polymers via quantitative immunohistochemistry, triplicate high-powered fields of tumors were scored for nuclear IUd

  3. Sulfoxide stimulation of chondrogenesis in limb mesenchyme is accompanied by an increase in type II collagen enhancer activity

    International Nuclear Information System (INIS)

    Horton, W.E. Jr.; Higginbotham, J.D.

    1991-01-01

    We have utilized a modification of the limb bud mesenchyme micromass culture system to screen compounds that might stimulate chondrogenesis. Two compounds in the sulfoxide family (methylphenylsulfoxide and p-chlorophenyl methyl sulfoxide) were stimulatory at 10(-2) M and 10(-3) M, respectively; whereas other sulfoxides and organic solvents were not active at these concentrations. In addition, specific growth factors (basic FGF, IGF-I, IGF-II) were not chondroinductive at concentrations that are active in other cell systems. Both sulfoxide compounds stimulated cartilage nodule formation, [ 35 S]sulfate incorporation, and activity of the regulatory sequences of the collagen II gene. In contrast, transforming growth factor beta-1 (10 ng/ml) stimulated sulfate incorporation but produced only a diffuse deposition of cartilage matrix and reduced the ability of the cells to utilize the regulatory sequences of the collagen II gene. The sulfoxides appear to promote the differentiation of limb bud cells to chondrocytes and thus exhibit chondroinductive activity

  4. Transcranial direct current stimulation generates a transient increase of small-world in brain connectivity: an EEG graph theoretical analysis.

    Science.gov (United States)

    Vecchio, Fabrizio; Di Iorio, Riccardo; Miraglia, Francesca; Granata, Giuseppe; Romanello, Roberto; Bramanti, Placido; Rossini, Paolo Maria

    2018-04-01

    Transcranial direct current stimulation (tDCS) is a non-invasive technique able to modulate cortical excitability in a polarity-dependent way. At present, only few studies investigated the effects of tDCS on the modulation of functional connectivity between remote cortical areas. The aim of this study was to investigate-through graph theory analysis-how bipolar tDCS modulate cortical networks high-density EEG recordings were acquired before and after bipolar cathodal, anodal and sham tDCS involving the primary motor and pre-motor cortices of the dominant hemispherein 14 healthy subjects. Results showed that, after bipolar anodal tDCS stimulation, brain networks presented a less evident "small world" organization with a global tendency to be more random in its functional connections with respect to prestimulus condition in both hemispheres. Results suggest that tDCS globally modulates the cortical connectivity of the brain, modifying the underlying functional organization of the stimulated networks, which might be related to changes in synaptic efficiency of the motor network and related brain areas. This study demonstrated that graph analysis approach to EEG recordings is able to intercept changes in cortical functions mediated by bipolar anodal tDCS mainly involving the dominant M1 and related motor areas. Concluding, tDCS could be an useful technique to help understanding brain rhythms and their topographic functional organization and specificity.

  5. Alterations in growth phenotype and radiosensitivity after fractionated irradiation of breast carcinoma cells from a single patient

    International Nuclear Information System (INIS)

    Wazer, D.E.; Joyce, M.; Jung, L.; Band, V.

    1993-01-01

    The purpose was to investigate growth regulation and radiosensitivity in surviving clonogens after fractionated irradiation. Four breast carcinoma cell lines isolated from the primary tumor (21NT, 21PT) and metastases (21MT-1, 21MT-2) of a single patient were exposed to cumulative radiation doses of 30 Gy yielding cell lines designated -IR with respect to their parent. The irradiated lines were then compared to their parent for serum- and growth factor-requirements under defined media conditions, ability to proliferate in soft agar, concentration of TGF-alpha in conditioned medium, and radiosensitivity. The irradiated lines showed no change in proliferative doubling times under serum- and growth factor-supplemented media conditions. A single line, 21MT-1-IR, acquired a limited ability to proliferate in serum- and growth factor-deplete medium with a day 2-4 doubling time of 44.5 hr. Three lines, 21MT-1-IR, 21MT-2-IR, and 21NT-IR, formed colonies in soft agar in contrast to none of the unirradiated parent lines. There were significant 6-8 fold increases in conditioned media TGF-alpha concentrations for 21MT-2-IR and 21NT-IR cells. The 21MT-1-IR and 21NT-IR cells were significantly less radiosensitive than their respective parent lines. This decrease in radiosensitivity appeared to be at least partially mediated by a released factor as the radiosensitivity of 21MT-1 cells was significantly decreased by pre-incubation with conditioned medium from 21MT-1-IR cells. Radiation-induced changes in growth phenotype vary with respect to clonal origin of the cell line and may influence the radiosensitivity of surviving clonogens after fractionated treatment. 18 refs., 4 figs., 3 tabs

  6. Experimental studies on the radiosensitizing agents against cultured human glioblastoma and human neurinoma

    International Nuclear Information System (INIS)

    Sawatari, Yutaka

    1976-01-01

    The radiosensitivity increasing effect of bromo-2'-deoxyuridine (BUdR) and 5-fluorouracil (5-FU), alone and in combination, was studied comparatively using tissue culture of brain tumor cells (No. 60 cells originating in human glioblastoma and N cells originating in human neurinoma) with colony formation and growth curve as the quantitative indices and the phase contrast microscope and scanning electron microscope for morphological observation. The inhibitive effect of BUdR on growth of the N cells was above 4μg/ml, while 3000μg/ml was required in the case of the No. 60 cells. This indicates that there is a large difference between the sensitivities of these two cell types against BUdR. Increased sensitivity can be anticipated by pretreatment of the No. 60 cells or the N cells with BUdR with a dose of no growth inhibition effect. N cells have a lower radiosensitivity than No. 60 cells; but when both cells are pretreated with BUdR, N cells have a higher radiosensitivity than No. 60 cells. This increasing radiosensitivity of the N cells, which is clinically benign, suggests the possibility of wider application for radiotherapy in the future. A dose of 2μg/ml of 5-FU alone showed no growth inhibiting effect on either the N cells or the No. 60 cells, but it intensified the effect of BUdR. Using a phase contrast microscope and a scanning electron microscope for morphological observation of the No. 60 cells and the N cells which had been exposed to BUdR+5-FU+X-ray, unique findings were observed on the surface structures of these two kinds of cells. (J.P.N.)

  7. SHP1-mediated cell cycle redistribution inhibits radiosensitivity of non-small cell lung cancer

    International Nuclear Information System (INIS)

    Cao, Rubo; Ding, Qian; Li, Pindong; Xue, Jun; Zou, Zhenwei; Huang, Jing; Peng, Gang

    2013-01-01

    Radioresistance is the common cause for radiotherapy failure in non-small cell lung cancer (NSCLC), and the degree of radiosensitivity of tumor cells is different during different cell cycle phases. The objective of the present study was to investigate the effects of cell cycle redistribution in the establishment of radioresistance in NSCLC, as well as the signaling pathway of SH2 containing Tyrosine Phosphatase (SHP1). A NSCLC subtype cell line, radioresistant A549 (A549S1), was induced by high-dose hypofractionated ionizing radiations. Radiosensitivity-related parameters, cell cycle distribution and expression of cell cycle-related proteins and SHP1 were investigated. siRNA was designed to down-regulate SHP1expression. Compared with native A549 cells, the proportion of cells in the S phase was increased, and cells in the G0/G1 phase were consequently decreased, however, the proportion of cells in the G2/M phase did not change in A549S1 cells. Moreover, the expression of SHP1, CDK4 and CylinD1 were significantly increased, while p16 was significantly down-regulated in A549S1 cells compared with native A549 cells. Furthermore, inhibition of SHP1 by siRNA increased the radiosensitivity of A549S1 cells, induced a G0/G1 phase arrest, down-regulated CDK4 and CylinD1expressions, and up-regulated p16 expression. SHP1 decreases the radiosensitivity of NSCLC cells through affecting cell cycle distribution. This finding could unravel the molecular mechanism involved in NSCLC radioresistance

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

    International Nuclear Information System (INIS)

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

    2015-01-01

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

  9. Prediction of radiosensitivity of oral cancers by serial cytological assay of nuclear changes

    International Nuclear Information System (INIS)

    Bhattathiri, N.V.; Nair, K.M.; Bharathykkutty, C.; Prathapan, R.; Chirayathmanjiyil, D.A.

    1998-01-01

    Background and purpose: To identify the relationship between the radiosensitivity of oral cancers and the induction of micronucleation, nuclear budding and multinucleation (polynucleation) evaluated by serial cytology during fractionated radiotherapy. Materials and methods: Forty-four patients with epidermoid cancer of the oral cavity receiving radiotherapy (60 Gy in 25 fractions over 5 weeks) were studied. Serial scrape smears were taken from the tumour before and during radiotherapy and stained by Giemsa and the frequency of micronucleated cells (MNC), nuclear budded cells (NBC) and multinucleated cells (PNC) was evaluated by light microscopy. After a minimum follow-up period of 30 months the patients were classified as having resistant or sensitive tumours, depending on whether the primary tumour had recurred or not within that time. Within-group and between-group analysis on the induction of the above individual parameters and two combined parameters, the micro- or multinucleated cell (MPC) count and the abnormally nucleated cell (ANC) count, was done. The counts were expressed per 1000 uni-nucleated cells. Results: In both groups each parameter showed a statistically significant increase with dose, the increase being higher in the sensitive group. The ANC count showed the greatest increase, the mean counts before treatment and after 28.8 Gy being 24.3 and 157.8 (P<0.0005), respectively, in the sensitive group and 21.0 and 65.2 (P<0.0005), respectively, in the resistant group. After 28.8 Gy the sensitive tumours had significantly higher ANC (P=0.01), MPC (P<0.05) and PNC (P<0.05) counts. Conclusion: The study shows that serial cytological assay of nuclear changes (SCANCing) during radiotherapy is a potentially useful test to predict radiosensitivity. The fact that multinucleation showed the greatest relation with radiosensitivity suggests that injury to the cytokinetic apparatus is important in determining tumour radiosensitivity. (Copyright (c) 1998 Elsevier

  10. Radiosensitivity and chimera formation in Hibiscus syriacus

    International Nuclear Information System (INIS)

    Kwon, S.H.; Won, J.L.

    1980-01-01

    Radiosensitivity of gamma-irradiated Hibiscus syriacus and chimera formation were investigated. The lethal dose-50 percent with respect to seeding and cuttings was 15kR and 2 approximately 3 kR respectively, chlorophyll mutation rate of seeds irradiated with 15 kR being about 13 percent. The degree of chimeric leaf mutants from the buds by radiation treatment depends on the bud position of the branch. Buds of the middle part of V 1 branch seemed to be more multi-cellular condition than the upper and low part when irradiation was made. It is assumed that at least two primordia of V 2 branch were already differentiated from the V 1 branch in Hibiscus syriacus plant. (Author)

  11. Radiosensitivity of cultured insect cells: II. Diptera

    International Nuclear Information System (INIS)

    Koval, T.M.

    1983-01-01

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

  12. The effect of intra- and extracellular GSH depletion on aerobic radiosensitization in three cell lines

    International Nuclear Information System (INIS)

    Clark, E.P.; Epp, E.R.; Morse-Gaudio, M.; Biaglow, J.E.

    1985-01-01

    The effect of changes in the intra- and extracellular glutathione (GSH) concentrations on aerobic radiosensitization was studied in thee cell lines: CHO, V79 and A549. Intracellular GSH was metabolically depleted after the inhibition of GSH synthesis by buthionine sulfoximine (BSO) treatment of attached cell cultures. Extracellular GSH was controlled through the replacement of growth medium with a thiol-free salt solution and, where desired, by the exogenous addition of GSH. Each of the cell lines examined exhibited an enhanced aerobic radioresponse when the intracellular GSH was extensively depleted (GSH < 5% of control after 1.0 mM BSO/24 hr treatment) and the extracellular GSH concentration was zero. However, this enhanced radiosensitivity was eliminated by the addition of exogenous GSH, albeit at a high concentration (5 mM). Most interesting and as yet unexplained is the observation that GSH appears to affect restoration of the control radioresponse without increasing the intracellular GSH concentration

  13. 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.

  14. Time-course mortality and radiosensitivity indices in Tribolium spp. developing from irradiated pupae

    International Nuclear Information System (INIS)

    Hasan, Md Mahbub

    1999-01-01

    Effects of gamma irradiation (1-5 Krad) on the time-course mortality and radiosensitivity indices in adults of Tribolium anaphe, T. brevicornis, T. castaneum, T. destructor, T. freemani developing from irradiated 1 day old and pre-emergence (4-5 day old) pupae were studied. Adult longevity was significantly (P<0.001) affected by irradiation and was linearly dose dependent. T. destructor was markedly more radioresistant than the other species at all dose levels and had a longer life expectancy. The mean survival times of adults developing from irradiated early and late pupae were shorter in females than in males for all the species. The radiosensitivity indices did not vary widely among the species and these values decreased as the dose increased in all the species which clearly indicate that the resistance of the species was dose-dependent. (author)

  15. Chemical radiosensitization and quality of cellular damage in bacteria exposed to gamma rays

    International Nuclear Information System (INIS)

    Nair, C.K.K.; Pradhan, D.S.; Sreenivasan, A.

    1976-01-01

    Iodoacetic acid (IAA) and N-ethylmaleimide (NEM) when present during exposure of Streptococcus faecalis cells to gamma radiation enhance radiation-induced lethality under both anoxic and aerated conditions. The changes brought about by this radiosensitization in cellular functions have been studied with a view to elucidating the mechanism responsible for the increased loss of viability. The quality of cellular damage in chemical radiosensitization was investigated by correlating survival and the biosynthetic capacity of an irradiated cell population. The relationship between surviving fraction and extent of incorporation of 3 H-thymidine into DNA was found to be unaffected regardless of whether the sensitizers (IAA or NEM) were present or absent during irradiation under anoxia. However, under the oxic condition of irradiation the survival--DNA-labeling relationship was completely different in the presence and in the absence of the sensitizers

  16. Modulation of radiosensitivity by growth factors

    International Nuclear Information System (INIS)

    Paris, F.

    2013-01-01

    The full text of the publication follows. For the past 70 years, radiotherapy protocols were defined to target and kill cancer cells. New research developments showed that the tissue or tumor radiosensitivities might be directly modulated by its own microenvironment. Between all the micro-environmental cells, endothelial cells are playing a unique role due to the need of angio-genesis for tumor genesis and to the microvascular endothelial cell apoptosis involved in acute normal tissue and tumor radiosensitivities. Both endothelial behaviours may be controlled by specific growth factors secreted by tumor cells. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are two cytokines involved in angio genesis and endothelial cell survival. Because radiation exposure develops opposite molecular and cellular responses by inhibiting proliferation and by enhancing apoptosis, inhibiting these cytokines has been proposed as a relevant strategy to improve radiotherapy efficiency. Drugs or antibody against VEGF, or other growth factors have been used with success to limit endothelial cell resistance, but also to transiently normalize of blood vessels to improve oxygen distribution into the tumor. However, better characterisation of the role of the cytokines will help to better improve the strategy of the use of their antagonists. We demonstrate that bFGF or sphingosin 1 phosphate (S1P), a lipid endothelial growth factor, protects endothelial cells from radiation stress by inhibiting the pre-mitotic apoptosis through enhancement of pro-survival molecular cascade, such as the Pi3K/AKT pathway, but not post-mitotic death. This discrepancy allowed a specific use of S1P as pharmacological drug protecting quiescent endothelial cells, present in normal tissue blood vessels, but not in proliferating angiogenic blood vessels, majority present in tumor blood vessel. In vivo studies are underway. (author)

  17. Chromosomal radiosensitivity of lymphocytes in South African breast ...

    African Journals Online (AJOL)

    radiosensitivity has been used as an indirect measure of cancer susceptibility. ... studies have shown that breast cancer patients are more sensitive to ionising radiation than healthy individuals. .... There was an effect of ER positivity on the MN.

  18. HLA‐G modulates the radiosensitivity of human neoplastic cells

    International Nuclear Information System (INIS)

    Michelin, Severino; Gallegos, Cristina; Baffa Trasci, Sofía; Dubner, Diana; Favier, B.; Carosella, E.D.

    2011-01-01

    Tumor cells show a very broad range of radiosensitivities. The differential radiosensitivity may depend on many factors, being the efficiency to recognize and/or repair the DNA lesion, and the cell cycle control mechanisms, the most important (Jeggo and Lavin, 2009; Kumala et al., 2003). Human leukocyte antigen‐G (HLA‐G) is a non‐classical HLA class I molecule involved in fetus protection form the maternal immune system, transplant tolerance, and viral and tumoral immune escape (Carosella et al., 2008). It has been determined that gamma radiation modulates HLA‐G expression at the plasma membrane of human melanoma cells. However, its role in tumoral radiosensitivity has not been demonstrated yet. The objective of this work was to determine if the radiosensitivity of human neoplastic cell lines cultured in vitro was mediated by HLA‐G expression. (authors)

  19. The influence of autologous tumor fibroblasts on the radiosensitivity of squamous cell carcinoma megacolonies

    International Nuclear Information System (INIS)

    Kummermehr, Johann; Malinen, Eirik; Freykowski, Sabine; Sund, Malte; Trott, Klaus-Ruediger

    2001-01-01

    Purpose: To study the influence of tumor fibroblasts on radiosensitivity and stem cell fraction of tumor cells in squamous cell carcinoma megacolonies by determining colony cure and clonogen survival. Methods and Materials: Murine squamous cell carcinoma cells (AT478c) grown as flat but multilayered megacolonies were co-cultured with pre-irradiated tumor fibroblasts derived from the same carcinoma, and irradiated with 1, 2, 4, or 8 fractions. Recurrent clones and their growth pattern in situ were recorded. From megacolony cure data and clonogen survival data, the clonogen number and the parameters of cellular radiosensitivity were calculated. Results: The curability of the co-cultured megacolonies, as determined by TCD50 values, was significantly increased compared to the megacolonies without fibroblasts (p<0.01). Both the megacolony cure and clonogen survival data suggested a decrease of the clonogen fraction in the co-cultured megacolonies. Conclusion: The presence of tumor fibroblasts increases megacolony radiosensitivity. This is due to a decrease in the fraction of clonogens in the tumor megacolony, apparently caused by a downregulation of the stem cell fraction of the tumor cells

  20. G{sub 2} radiosensitivity of cells derived from cancer-prone individuals

    Energy Technology Data Exchange (ETDEWEB)

    Darroudi, F.; Vyas, R.C.; Vermeulen, S.; Natarajan, A.T. [J.A. Cohen Institute of Radiopathology and Radiation Protection, Interuniversity Institute, Leiden (Netherlands)

    1995-04-01

    The potential of enhanced chromatid damage, observed after X-irradiation of G{sub 2} phase, has been used to detect individuals genetically predisposed to cancer, utilising fibroblasts/lymphocytes from these patients as well as fibroblasts derived from human tumours. Fibroblasts and/or lymphocyte samples of two autosomal recessive syndromes (xeroderma pigmentosum (XP), Fanconi`s anaemia (FA)) and one congenital or acquired disorder, aplastic anaemia (AA), were employed for the G{sub 2} radiosensitivity assay. In addition, we have estimated the frequencies of spontaneously occurring chromosomal aberrations as well as G{sub 2} radiosensitivity of eight samples of fibroblasts/fibroblast-like cells (two normal, two colorectal carcinoma, two Wilms` tumour, one retinoblastoma and one polyposis coli), and three samples of lymphocytes (two normal and one from a lymphoma patient). The results obtained indicate that there were no differences between fibroblast cells derived from patients or tumours, except FA patients, in the frequency of spontaneously occurring chromosomal aberrations when compared to normal cells. Following X-irradiation we did not observe any significantly increased G{sub 2} radiosensitivity in FA and XP cells. Lymphocytes from AA and lymphoma patients, and all tumour cell lines except retinoblastoma, responded with increased frequencies of aberrations following G{sub 2} X-irradiation in comparison to cells derived from normal individuals. In our hands, the G{sub 2} sensitivity assay could not always discriminate cells from cancer-prone individuals from those of controls.

  1. The toxic effects, GSH depletion and radiosensitivity by BSO on retinoblastoma

    International Nuclear Information System (INIS)

    Xianjin Yi; Li Ding; Yizun Jin; Chuo Ni; Wenji Wang

    1994-01-01

    Retinoblastoma is the most common intraocular malignant tumor in children. Previous investigations have reported that buthionine sulfoximine (BSO) can deplete intracellular glutathione (GSH) by specific inhibition and increase cellular radiosensitivity. The toxic effects, GSH depletion and radiosensitivity effects of BSO on retinoblastoma cells are reported in this paper. GSH content of retinoblastoma cell lines Y-79, So-Rb50 and retinoblastoma xenograft is 2.7 ± 1.3 X 1.0 -12 mmol/cell, 1.4 ± 0.2 X 1.0 -12 mmol/cell, and 2.8 ± 1.2 μmol/g, respectively. The ID 50 of BSO on Y-79 and So-Rb50 in air for 3 h exposure is 2.5 mM and 0.2 mM, respectively. GSH depletion by 0.1 mM BSO for 24 h on Y-79 cells and 0.01 mM BSO for 24 h on So-Rb50 cells is 16.35%, and 4.7% of control. GSH depletion in tumor and other organ tissues in retinoblastoma-bearing nude mice after BSO administration is differential. GSH depletion after BSO exposure in Y-79 cells in vitro decreases the Do value of retinoblastoma cells. The SER of 0.01 mM and 0.05 mM BSO for 24 h under hypoxic conditions is 1.21 and 1.36, respectively. Based on these observations, the authors conclude that BSO toxicity on retinoblastoma cells depends on the characteristics of the cell line and that BSO can increase hypoxic retinoblastoma cells' radiosensitivity in vitro. Further study of BSO radiosensitization on retinoblastoma in vivo using nude mouse xenografts is needed. 25 refs., 3 figs., 3 tabs

  2. The toxic effects, GSH depletion and radiosensitivity by BSO on retinoblastoma

    International Nuclear Information System (INIS)

    Yi Xianjin; Ni Chuo; Wang Wengi; Li Ding; Jin Yizun

    1993-01-01

    Retinoblastoma is the most common intraocular malignant tumor in children. Previous investigations have reported that buthionine sulfoximine (BSO) can deplete intracellular glutathione (GSH) by the specific inhibition and increase cellular radiosensitivity. The toxic effects, GSH depletion and radiosensitivity of BSO on retinoblastoma were reported. GSH content of retinoblastoma cell lines Y-79, So-Rb50 and retinoblastoma xenograft is (2.7 +- 1.3) x 10 -12 mmol/cell, (1.4 +- 0.2) x 10 -12 mmol/cell, and 2.8 +- 1.2 μmol/g respectively. The ID50 of BSO on Y-79 and So-Rb50 in air for 3h exposure is 2.5 mM and 0.2 mM respectively. GSH depletion by 0.1 mM BSO for 24h on Y-79 cells and 0.01 mM BSO for 24 h on So-Rb50 cells is 16.35%, and 4.7% of control. GSH depletion in tumor and other organ tissues in retinoblastoma bearing nude mice after BSO administration is differential. BSH depletion after BSO exposure in Y-79 cells in vitro decrease the D 0 value of retinoblastoma cells. The SER of 0.01 mM and 0.05 mM BSO for 24 h under the hypoxic condition is 1.21 and 1.36 respectively. Based on these observations, the authors conclude that BSO toxicity on retinoblastoma cells depends on the characteristics of cell line and BSO can increase hypoxic retinoblastoma cells radiosensitivity in vitro. Further study of BSO radiosensitization on retinoblastoma in vivo using nude mouse xenograft is needed

  3. Nimotuzumab promotes radiosensitivity of EGFR-overexpression esophageal squamous cell carcinoma cells by upregulating IGFBP-3

    Directory of Open Access Journals (Sweden)

    Zhao Lei

    2012-12-01

    Full Text Available Abstract Background Epidermal growth factor receptor (EGFR is suggested to predict the radiosensitivity and/or prognosis of human esophageal squamous cell carcinoma (ESCC. The objective of this study was to investigate the efficacy of Nimotuzumab (an anti-EGFR monoclonal antibody on ESCC radiotherapy (RT and underlying mechanisms. Methods Nimotuzumab was administrated to 2 ESCC cell lines KYSE30 and TE-1 treated with RT. Cell growth, colony formation and apoptosis were used to measure anti-proliferation effects. The method of RNA interference was used to investigate the role of insulin-like growth factor binding protein-3 (IGFBP-3 in ESCC cells radiosensitivity treated with Nimotuzumab. In vivo effect of Nimotuzumab on ESCC radiotherapy was done using a mouse xenograft model. Results Nimotuzumab enhanced radiation response of KYSE30 cells (with high EGFR expression in vitro, as evidenced by increased radiation-inhibited cell growth and colony formation and radiation-mediated apoptosis. Mechanism study revealed that Nimotuzumab inhibited phosphorylated EGFR (p-EGFR induced by EGF in KYSE30 cells. In addition, knockdown of IGFBP-3 by short hairpin RNA significantly reduced KYSE30 cells radiosensitivity (PP>0.05. In KYSE30 cell xenografts, Nimotuzumab combined with radiation led to significant tumor growth delay, compared with that of radiation alone (P=0.029, and also with IGFBP-3 up-regulation in tumor tissue. Conclusions Nimotuzumab could enhance the RT effect of ESCC cells with a functional active EGFR pathway. In particular, the increased ESCC radiosensitivity by Nimotuzumab might be dependent on the up-regulation of IGFBP-3 through EGFR-dependent pathway.

  4. Study on ionizing radiosensitivity of respiratory deficiency yeast mutants

    International Nuclear Information System (INIS)

    Mao Shuhong; Chinese Academy of Sciences, Beijing; Jin Genming; Wei Zengquan; Xie Hongmei

    2006-01-01

    The radiosensitivity of respiratory deficiency yeast mutants has been studied in this work. The mutants which were screened from the yeasts after ionizing irradiation were irradiated with 12 C 6+ at different doses. Because of the great change in its mitochondria and mitochondrial DNA, the respiratory deficiency yeast mutants show radio-sensitivity at dose less than 1 Gy and radioresistance at doses higher than 1 Gy. (authors)

  5. Cellular radiosensitivity in human severe-combined-immunodeficiency (SCID) syndromes

    International Nuclear Information System (INIS)

    Sproston, Anthony R.M.; West, Catharine M.L.; Hendry, Jolyon H.

    1997-01-01

    Purpose: The aim of the work was to establish to what extent a variety of human severe-combined-immunodeficiency (SCID) disorders are associated with in vitro cellular hypersensitivity to ionizing radiation. Materials and methods: A study was made of fibroblast strains established from individuals with adenosine deaminase deficiency, T(-)B(-) SCID, Omenn's syndrome and a SCID heterozygote. For comparison, an assessment was also made of the radiosensitivity of a series of fibroblast strains derived from: normal donors, a patient with ataxia-telangiectasia (A-T) and an A-T heterozygote. Radiosensitivity was determined using a clonogenic assay following both high (HDR) and low (LDR) dose-rate irradiation. Results: Following HDR irradiation, the fibroblast strains derived from the different human SCID disorders displayed a wide range of radiosensitivity: the adenosine deaminase deficiency cells were similar in radiosensitivity to normal fibroblasts, T(-)B(-) cells were as hypersensitive to radiation as A-T cells and the Omenn's syndrome cells showed intermediate radiosensitivity. However, whereas all four normal cell strains studied showed significant LDR sparing, none of the SCID fibroblasts did. Conclusions: These data indicate that human SCID is variable in terms of radiosensitivity depending on the particular defect. In addition, the lack of LDR sparing of radiation-induced damage suggests the involvement of some form(s) of DNA repair defect in all the human SCID syndromes

  6. Radiosensitivity of in vitro Cultured Banana Shoot-Tips

    International Nuclear Information System (INIS)

    Elagamawy, M.R.

    2002-01-01

    Longitudinally dissected shoot apices of Grand Nain, Williams and Maghrabi banana cultivars were exposed to gamma irradiation with Cobalt 60 source at the doses of 0, 20, 40 and 60 Gy and immediately placed into proliferation medium. A number of micropropagation cycles after irradiation were necessary up to M1 V2 to M1 V4 stage to let mutated sectors developing into non-chimeric shoots. Radiosensitivity was evaluated by the rate of shoot proliferation and by the shoot fresh weight increase. Increasing gamma doses caused reduction in survival rates and average number of shoots. Grand Nain exhibited the highest multiplication- rate (3.1). The lower dose (20 Gy) enhanced shoot multiplication ratio specially in Williams and Maghrabi, which however decreased with increased doses. The doses of 20-40 Gy yielded Ld50, with sensible degree of shoot multiplication, which occurred hardly ever beyond 40 Gy. The dose of 60 Gy resulted 80% lethal shoot growth. Linear decrease in fresh weight was observed in post-irradiation recovery, notably in the Maghrabi. In contradictory vulnerable damage was observed in Williams which showed the highest fresh weight value. Shoot proliferation appeared generally on the surface of the corm. Root formation was observed without additional hormone. The roots were dark colored and was decreased with the increased of dosage

  7. Survivin, a target to modulate the radiosensitivity of Ewing's sarcoma

    International Nuclear Information System (INIS)

    Greve, B.; Sheikh-Mounessi, F.; Ernst, I.; Eich, H.T.; Kemper, B.; Goette, M.

    2012-01-01

    Background and purpose: Radiotherapy constitutes an essential element in the multimodal therapy of Ewing's sarcoma. Compared to other sarcomas, Ewing tumors normally show a good response to radiotherapy. However, there are consistently tumors with a radioresistant phenotype, and the underlying mechanisms are not known in detail. Here we investigated the association between survivin protein expression and the radiosensitivity of Ewing's sarcoma in vitro. Material and methods: An siRNA-based knockdown approach was used to investigate the influence of survivin expression on cell proliferation, double-strand break (DSB) induction and repair, apoptosis and colony-forming ability in four Ewing's sarcoma cell lines with and without irradiation. Results: Survivin protein and mRNA were upregulated in all cell lines tested in a dose-dependent manner. As a result of survivin knockdown, STA-ET-1 cells showed reduced cell proliferation, an increased number of radiation-induced DSBs, and reduced repair. Apoptosis was increased by knockdown alone and increased further in combination with irradiation. Colony formation was significantly reduced by survivin knockdown in combination with irradiation. Conclusion: Survivin is a radiation-inducible protein in Ewing's sarcoma and its down-regulation sensitizes cells toward irradiation. Survivin knockdown in combination with radiation inhibits cell proliferation, repair, and colony formation significantly and increases apoptosis more than each single treatment alone. This might open new perspectives in the radiation treatment of Ewing's sarcoma. (orig.)

  8. Survivin, a target to modulate the radiosensitivity of Ewing's sarcoma.

    Science.gov (United States)

    Greve, B; Sheikh-Mounessi, F; Kemper, B; Ernst, I; Götte, M; Eich, H T

    2012-11-01

    Radiotherapy constitutes an essential element in the multimodal therapy of Ewing's sarcoma. Compared to other sarcomas, Ewing tumors normally show a good response to radiotherapy. However, there are consistently tumors with a radioresistant phenotype, and the underlying mechanisms are not known in detail. Here we investigated the association between survivin protein expression and the radiosensitivity of Ewing's sarcoma in vitro. An siRNA-based knockdown approach was used to investigate the influence of survivin expression on cell proliferation, double-strand break (DSB) induction and repair, apoptosis and colony-forming ability in four Ewing's sarcoma cell lines with and without irradiation. Survivin protein and mRNA were upregulated in all cell lines tested in a dose-dependent manner. As a result of survivin knockdown, STA-ET-1 cells showed reduced cell proliferation, an increased number of radiation-induced DSBs, and reduced repair. Apoptosis was increased by knockdown alone and increased further in combination with irradiation. Colony formation was significantly reduced by survivin knockdown in combination with irradiation. Survivin is a radiation-inducible protein in Ewing's sarcoma and its down-regulation sensitizes cells toward irradiation. Survivin knockdown in combination with radiation inhibits cell proliferation, repair, and colony formation significantly and increases apoptosis more than each single treatment alone. This might open new perspectives in the radiation treatment of Ewing's sarcoma.

  9. Alcohol decreases baseline brain glucose metabolism more in heavy drinkers than controls but has no effect on stimulation-induced metabolic increases.

    Science.gov (United States)

    Volkow, Nora D; Wang, Gene-Jack; Shokri Kojori, Ehsan; Fowler, Joanna S; Benveniste, Helene; Tomasi, Dardo

    2015-02-18

    During alcohol intoxication, the human brain increases metabolism of acetate and decreases metabolism of glucose as energy substrate. Here we hypothesized that chronic heavy drinking facilitates this energy substrate shift both for baseline and stimulation conditions. To test this hypothesis, we compared the effects of alcohol intoxication (0.75 g/kg alcohol vs placebo) on brain glucose metabolism during video stimulation (VS) versus when given with no stimulation (NS), in 25 heavy drinkers (HDs) and 23 healthy controls, each of whom underwent four PET-(18)FDG scans. We showed that resting whole-brain glucose metabolism (placebo-NS) was lower in HD than controls (13%, p = 0.04); that alcohol (compared with placebo) decreased metabolism more in HD (20 ± 13%) than controls (9 ± 11%, p = 0.005) and in proportion to daily alcohol consumption (r = 0.36, p = 0.01) but found that alcohol did not reduce the metabolic increases in visual cortex from VS in either group. Instead, VS reduced alcohol-induced decreases in whole-brain glucose metabolism (10 ± 12%) compared with NS in both groups (15 ± 13%, p = 0.04), consistent with stimulation-related glucose metabolism enhancement. These findings corroborate our hypothesis that heavy alcohol consumption facilitates use of alternative energy substrates (i.e., acetate) for resting activity during intoxication, which might persist through early sobriety, but indicate that glucose is still favored as energy substrate during brain stimulation. Our findings are consistent with reduced reliance on glucose as the main energy substrate for resting brain metabolism during intoxication (presumably shifting to acetate or other ketones) and a priming of this shift in HDs, which might make them vulnerable to energy deficits during withdrawal. Copyright © 2015 the authors 0270-6474/15/353248-08$15.00/0.

  10. Alcohol decreases baseline brain glucose metabolism more in heavy drinkers than controls but has no effect on stimulation-induced metabolic increases

    International Nuclear Information System (INIS)

    Volkow, Nora D.; Fowler, Joanna S.; Wang, Gene-Jack; Kojori, Eshan Shokri; Benveniste, Helene; Tomasi, Dardo

    2015-01-01

    During alcohol intoxication the human brain increases metabolism of acetate and decreases metabolism of glucose as energy substrate. Here we hypothesized that chronic heavy drinking facilitates this energy substrate shift both for baseline and stimulation conditions. To test this hypothesis we compared the effects of alcohol intoxication (0.75g/kg alcohol versus placebo) on brain glucose metabolism during video-stimulation (VS) versus when given with no-stimulation (NS), in 25 heavy drinkers (HD) and 23 healthy controls each of whom underwent four PET- 18 FDG scans. We showed that resting whole-brain glucose metabolism (placebo-NS) was lower in HD than controls (13%, p=0.04); that alcohol (compared to placebo) decreased metabolism more in HD (20±13%) than controls (9±11%, p=0.005) and in proportion to daily alcohol consumption (r=0.36, p=0.01) but found that alcohol did not reduce the metabolic increases in visual cortex from VS in either group. Instead, VS reduced alcohol-induced decreases in whole-brain glucose metabolism (10±12%) compared to NS in both groups (15±13%, p=0.04), consistent with stimulation-related glucose metabolism enhancement. These findings corroborate our hypothesis that heavy alcohol consumption facilitates use of alternative energy substrates (i.e. acetate) for resting activity during intoxication, which might persist through early sobriety, but indicate that glucose is still favored as energy substrate during brain stimulation. Our findings are consistent with reduced reliance on glucose as the main energy substrate for resting brain metabolism during intoxication (presumably shifting to acetate or other ketones) and a priming of this shift in heavy drinkers, which might make them vulnerable to energy deficits during withdrawal

  11. Lack of dependence of 5-fluorodeoxyuridine-mediated radiosensitization on cytotoxicity

    International Nuclear Information System (INIS)

    Lawrence, T.S.; Davis, M.A.; Chang, E.Y.

    1995-01-01

    It has been proposed that fluoropyrimidine-mediated cytotoxicity and radiosensitization are closely correlated. We have shown that HT29 human colon cancer cells transfected with the E. coli dUTPase gene are resistant to 5-fluorodeoxyuridine (FdUrd)-mediated cytotoxicity, presumably through more effective elimination of dUTP. We used these cells to assess the association between radiosensitization and cytotoxicity produced by FdUrd. The radiation sensitivities of the clones expressing elevated dUTPase activity (dutE clones) were similar to those of untransfected HT29 cells or HT29 cells which has been transfected with only the expression vector for the E. coli gene (con clones). We found that FdUrd produced similar increases in radiation sensitivity regardless of dUTPase activity. Levels of dUTPase in the dutE clones remained elevated during the entire period of FdUrd exposure, demonstrating that the lack of difference between dutE and Con clones was not a reflection of down-regulation of dUTPase activity by FdUrd, Flow cytometry showed that all clones progressed past the G 1 /S-phase boundary and into early S phase during FdUrd treatment. These data suggest that the mechanisms of FdUrd-mediated cytotoxicity and radiosensitization are not closely linked. These findings, combined with our previous investigations, are consistent with the hypothesis that radiosensitization occurs in cells which progress past the G 1 /S-phase boundary in the presence of FdUrd. 24 refs., 2 figs., 2 tabs

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

    Science.gov (United States)

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

    2011-03-01

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

  13. MicroRNA-449a enhances radiosensitivity in CL1-0 lung adenocarcinoma cells.

    Directory of Open Access Journals (Sweden)

    Yi-Jyun Liu

    Full Text Available Lung cancer is the leading cause of cancer-related mortality worldwide. Radiotherapy is often applied for treating lung cancer, but it often fails because of the relative non-susceptibility of lung cancer cells to radiation. MicroRNAs (miRNAs have been reported to modulate the radiosensitivity of lung cancer cells and have the potential to improve the efficacy of radiotherapy. The purpose of this study was to identify a miRNA that can adjust radiosensitivity in lung adenocarcinoma cells. Two lung adenocarcinoma cell lines (CL1-0 and CL1-5 with different metastatic ability and radiosensitivity were used. In order to understand the regulatory mechanisms of differential radiosensitivity in these isogenic tumor cells, both CL1-0 and CL1-5 were treated with 10 Gy radiation, and were harvested respectively at 0, 1, 4, and 24 h after radiation exposure. The changes in expression of miRNA upon irradiation were examined using Illumina Human microRNA BeadChips. Twenty-six miRNAs were identified as having differential expression post-irradiation in CL1-0 or CL1-5 cells. Among these miRNAs, miR-449a, which was down-regulated in CL1-0 cells at 24 h after irradiation, was chosen for further investigation. Overexpression of miR-449a in CL1-0 cells effectively increased irradiation-induced DNA damage and apoptosis, altered the cell cycle distribution and eventually led to sensitization of CL1-0 to irradiation.

  14. Impact of various parameters in detecting chromosomal aberrations by FISH to describe radiosensitivity

    International Nuclear Information System (INIS)

    Keller, U.; Mueller, E.; Grabenbauer, G.; Sauer, R.; Distel, L.; Kuechler, A.; Liehr, T.

    2004-01-01

    Background and purpose: analysis of radiation-induced chromosomal aberrations is regarded as the ''gold standard'' for classifying individual radiosensitivity. A variety of different parameters can be used. The crucial question, however, is to explore which parameter is suited best to describe the differences between patients with increased radiosensitivity and healthy individuals. Patients and methods: in this study, five patients with severe radiation-induced late effects of at least grade 3, classified according to the Radiation Therapy Oncology Group (RTOG), and eleven healthy individuals were examined retrospectively. Peripheral blood lymphocytes were irradiated in vitro with 0.7 Gy and 2.0 Gy prior to cultivation and stained by means of three-color fluorescence in situ hybridization (FISH). The detailed analysis was focused on the number of breaks per metaphase, on breaks from complex chromosomal rearrangements per metaphase, as well as on the percentage of translocations, dicentric chromosomes, breaks, and excess acentric fragments - each in comparison with the total number of mitoses analyzed. Results: using the number of breaks from complex chromosomal rearrangements after 2.0 Gy, radiosensitive patients as endpoint were clearly to be distinguished (p = 0.001) from healthy individuals. Translocations (p = 0.001) as well as breaks per metaphase (p = 0.002) were also suitable indicators for detecting differences between patients and healthy individuals. The parameters ''percentage of dicentric chromosomes'', ''breaks'', and ''excess acentric fragments'' in comparison to the total number of mitoses analyzed could neither serve as meaningful nor as significant criteria, since they showed a strong interindividual variability. Conclusion: to detect a difference in chromosomal aberrations between healthy and radiosensitive individuals, the parameters ''frequency of breaks per metaphase'', ''complex chromosomal rearrangements'', and ''translocations'' are most

  15. Radiosensitivity evaluation of Human tumor cell lines by detecting 4977bp deletion in mitochondrial DNA

    International Nuclear Information System (INIS)

    Zhang Yipei

    2009-01-01

    Objective: To explore the feasibility of determining radiosensitivity of human tumor cell lines in vitro using the assay of mtDNA4977bp deletion. Methods: Three human tumor cell lines were selected in this study, HepG 2 , EC-9706 and MCF-7. The surviving fraction(SF), the ratio of mtDNA4977bp deletion and DNA damage were detected by MTT assay and nested PCR technique respectively. Results: MTT assay: The SF of HepG 2 and EC-9706 after irradiated by 2, 4and 8Gy was lower significantly than that of MCF-7, which showed that the radiosensitivity of HepG 2 and EC-9706 was higher than that of MCF-7. But there was no statistical difference of SF between HepG 2 and EC-9706. PCR method:The differences on mtDNA 4977bp deletion in mitochondrial DNA among HepG 2 , EC-9706 and MCF-7 were not significant after 1Gy and 4Gy γ-ray irradiation. The ratio of 4977bp deletion in mitochondrial DNA of HepG 2 and EC-9706 increased while that of MCF-7 decreased after 8Gy irradiation. The ratio of mtDNA 4977bp deletion of HepG 2 and EC-9706 was higher significantly than that of MCF-7, which implies that the radiosensitivity of HepG 2 and EC-9706 was higher than that of MCF -7. Conclusion: As a new biological marker, mtDNA4977bp deletion may be hopeful to evaluate the radiosensitivity of tumor cells more objectively and exactly. (authors)

  16. Uroporphyrinogen decarboxylase is a radiosensitizing target for head and neck cancer.

    Science.gov (United States)

    Ito, Emma; Yue, Shijun; Moriyama, Eduardo H; Hui, Angela B; Kim, Inki; Shi, Wei; Alajez, Nehad M; Bhogal, Nirmal; Li, Guohua; Datti, Alessandro; Schimmer, Aaron D; Wilson, Brian C; Liu, Peter P; Durocher, Daniel; Neel, Benjamin G; O'Sullivan, Brian; Cummings, Bernard; Bristow, Rob; Wrana, Jeff; Liu, Fei-Fei

    2011-01-26

    Head and neck cancer (HNC) is the eighth most common malignancy worldwide, comprising a diverse group of cancers affecting the head and neck region. Despite advances in therapeutic options over the last few decades, treatment toxicities and overall clinical outcomes have remained disappointing, thereby underscoring a need to develop novel therapeutic approaches in HNC treatment. Uroporphyrinogen decarboxylase (UROD), a key regulator of heme biosynthesis, was identified from an RNA interference-based high-throughput screen as a tumor-selective radiosensitizing target for HNC. UROD knockdown plus radiation induced caspase-mediated apoptosis and cell cycle arrest in HNC cells in vitro and suppressed the in vivo tumor-forming capacity of HNC cells, as well as delayed the growth of established tumor xenografts in mice. This radiosensitization appeared to be mediated by alterations in iron homeostasis and increased production of reactive oxygen species, resulting in enhanced tumor oxidative stress. Moreover, UROD was significantly overexpressed in HNC patient biopsies. Lower preradiation UROD mRNA expression correlated with improved disease-free survival, suggesting that UROD could potentially be used to predict radiation response. UROD down-regulation also radiosensitized several different models of human cancer, as well as sensitized tumors to chemotherapeutic agents, including 5-fluorouracil, cisplatin, and paclitaxel. Thus, our study has revealed UROD as a potent tumor-selective sensitizer for both radiation and chemotherapy, with potential relevance to many human malignancies.

  17. Inhibition of DNA synthesis and radiosensitization effects of thalidomide on esophageal carcinoma TE1 cells

    International Nuclear Information System (INIS)

    Yu Jingping; Sun Suping; Sun Zhiqiang; Sun Meiling; Liu Fenju

    2010-01-01

    Objective: To explore the radiosensitization effect of thalidomide combined with X-ray on esophageal carcinoma TE1 cells. Methods: Cell scratch assay was used to detect the inhibition ability of different concentration of Thalidomide on cell invasion and metastasis. H 3 -TdR incorporation assay was used to investigate the inhibition of DNA synthesis in TE1 cells by treated with Thalidomide singly or combination with X-rays. The colony formation assay was used to analyze the radiosensitization of Thalidomide effect on TE1 cells. Results: Thalidomide had obvious inhibition effect on TE1 cell metastasis, DNA synthesis and colony formation, which were correlated with drug concentration. The values D 0 , D q and SF 2 in TE1 cells were gradually decreased with thalidomide concentration increased. When the concentration of thalidomide was 100μg/ml, the SER D 0 and SER D 0 and SER D q were (1.4±0.2) and (1.5±0.1), respectively, While the concentration of thalidomide was 150 μg/ml, the SER D 0 and SER D q were (1.5±0.2) and (1.8±0.2), respectively. Conclusions: Thalidomide could inhibit TE1 cell invasion, metastasis, DNA synthesis, and significantly enhance the radiosensitizing effect on esophageal carcinoma TE1 cells. (authors)

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

    International Nuclear Information System (INIS)

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

    2013-01-01

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

  19. Location of radiosensitive organs, measurement of absorbed dose to radiosensitive organs and use of bismuth shields in paediatric anthropomorphic phantoms

    International Nuclear Information System (INIS)

    Inkoom, S.

    2014-08-01

    The aim of this study was to investigate: firstly, (i) location of radiosensitive organs in the interior of four (4) paediatric anthropomorphic phantoms, and, secondly, (ii) effectiveness of single and double bismuth thyroid shields, distance between shield and phantom surface, during paediatric multi-detector computed tomography (MDCT) using fixed tube current (FTC) and automatic exposure control (AEC) on dose reduction and image quality. Four (4) paediatric anthropomorphic phantoms representing the equivalent of a newborn, 1-, 5-, and 10-y-old child underwent head, thorax and abdomen computed tomography (CT) scans. CT and magnetic resonance imaging scans of all children aged 0-16 y-old performed during a 5-y-period at the University Hospital of Heraklion, Crete, Greece were reviewed, and five hundred and three (503) were found to be eligible for normal anatomy. Anterior-posterior and lateral dimensions of twelve (12) of the above children closely matched that of the phantoms' thoracic and abdominal region in each four (4) phantoms. The mid-sagittal plane (MSP) and mid-coronal plane (MCP) were drawn on selected matching axial images of patients and phantoms. Multiple points outlining large radiosensitive organs and centres of small organs in patient images were identified at each slice level and their orthogonal distances from the MSP and MCP were measured. The outlines and centres of all radiosensitive organs were reproduced using the coordinates of each organ on the corresponding phantom's transverse images. The four (4) phantoms were also subjected to routine head and neck, neck and thorax CT scans on a 16-slice CT system. Each phantom was first scanned with both FTC and AEC for with and without bismuth shields. Each scan was repeated ten (10) times to increase thermoluminescent dosimeters (TLDs) signal and reduce measurement statistical error. For neck CT, the effect of using single and double thickness of bismuth shields and 1-3 cm cotton spacers

  20. An increase level of acylation stimulating protein is correlated with metabolic risk markers in North Indian obese women.

    Science.gov (United States)

    Mishra, Supriya; Gupta, Vani; Mishra, Sameeksha; Gupta, Vandana; Mahdi, Abbas Ali; Sachan, Rekha

    2017-12-01

    The present study was to investigate the association between serum acylation stimulating protein (ASP) level with metabolic risk factors in North Indian obese women. This is a case control study, total n=322 women aged between 20 and 45 years (n=162 with metabolic syndrome & n=160 without metabolic syndrome) were recruited for the study according to National Cholesterol Education Program Treatment Panel (NCEPATP) guidelines. Serum ASP level were determined by enzyme linked immunosorbent assay. Results indicated that circulating ASP and other metabolic risk factors (waist circumference, triglycerides, fasting plasma glucose etc) were significantly higher in women with metabolic syndrome (WmetS) than in women without syndrome (WometS) (pwomen with metabolic syndrome. Conclusively circulating ASP was found to be significantly associated with hyperlipidemia, obesity and obesity related disorders in North Indian obese women. Copyright © 2017 Diabetes India. Published by Elsevier Ltd. All rights reserved.

  1. Tetanic stimulation leads to increased accumulation of Ca2+ calmodulin-dependent protein kinase II via dendritic protein synthesis in hippocampal neurons

    OpenAIRE

    Rosenstein, Alan; Kreiman, Gabriel; Schuman, Erin M; Kennedy, Mary

    1999-01-01

    mRNA for the alpha-subunit of CaMKII is abundant in dendrites of neurons in the forebrain (Steward, 1997). Here we show that tetanic stimulation of the Schaffer collateral pathway causes an increase in the concentration of alpha-CaMKII in the dendrites of postsynaptic neurons. The increase is blocked by anisomycin and