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Sample records for stage mitotic rate

  1. The relationship between mitotic rate and depth of invasion in biopsies of malignant melanoma

    Directory of Open Access Journals (Sweden)

    Ghasemi Basir HR

    2018-03-01

    Full Text Available Hamid Reza Ghasemi Basir,1,2 Pedram Alirezaei,2 Sara Ahovan,3 Abbas Moradi3 1Department of Pathology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran; 2Psoriasis Research Center, Hamadan University of Medical Sciences, Hamadan, Iran; 3School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran Background: Malignant melanoma of the skin is a potentially lethal neoplasm that generally originates from atypical melanocytes in the dermal–epidermal junction. When the neoplasm penetrates into the dermis, several variables can affect the extent of its spread, among which depth of invasion has the most important prognostic value. Mitotic rate is another prognostic factor that reflects the biological behavior of the neoplasm.Objective: This study was designed to evaluate the probable relationship between the depth of invasion of malignant melanoma and its mitotic rate.Materials and methods: This study was performed on 50 excisional biopsy specimens that had received the diagnosis of malignant melanoma histopathologically. Tumor characteristics including Breslow thickness, Clark level, T-stage, and tumor mitotic rate were recorded.Results: We observed that at higher Clark levels and higher T-stages, and the mean mitotic rate was significantly increased. Moreover, there was a positive and significant correlation between Breslow thickness and mitotic rate. We demonstrated that one unit increase in mitotic rate was correlated with 0.8 mm increase in Breslow thickness of the tumor.Conclusion: In malignant melanoma, mitotic activity may probably indicate the depth of tumor invasion. Therefore, in incisional biopsies where depth of invasion cannot be accurately determined, the mitotic activity may be used to estimate Breslow thickness, which is necessary for planning surgical management. Keywords: melanoma, mitosis, Breslow, invasion, thickness, proliferation

  2. The NIMA Kinase Is Required To Execute Stage-Specific Mitotic Functions after Initiation of Mitosis

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    Govindaraghavan, Meera; Lad, Alisha A.

    2014-01-01

    The G2-M transition in Aspergillus nidulans requires the NIMA kinase, the founding member of the Nek kinase family. Inactivation of NIMA results in a late G2 arrest, while overexpression of NIMA is sufficient to promote mitotic events independently of cell cycle phase. Endogenously tagged NIMA-GFP has dynamic mitotic localizations appearing first at the spindle pole body and then at nuclear pore complexes before transitioning to within nuclei and the mitotic spindle and back at the spindle pole bodies at mitotic exit, suggesting that it functions sequentially at these locations. Since NIMA is indispensable for mitotic entry, it has been difficult to determine the requirement of NIMA for subaspects of mitosis. We show here that when NIMA is partially inactivated, although mitosis can be initiated, a proportion of cells fail to successfully generate two daughter nuclei. We further define the mitotic defects to show that normal NIMA function is required for the formation of a bipolar spindle, nuclear pore complex disassembly, completion of chromatin segregation, and the normal structural rearrangements of the nuclear envelope required to generate two nuclei from one. In the remaining population of cells that enter mitosis with inadequate NIMA, two daughter nuclei are generated in a manner dependent on the spindle assembly checkpoint, indicating highly penetrant defects in mitotic progression without sufficient NIMA activity. This study shows that NIMA is required not only for mitotic entry but also sequentially for successful completion of stage-specific mitotic events. PMID:24186954

  3. Mitotic effects of monochromatic ultraviolet radiation at 225, 265, and 280 nm on eleven stages of the cell cycle of the grasshopper neuroblast in culture. II. Changes in progression rate and cell sequence between the stage irradiated and nuclear membrane breakdown

    International Nuclear Information System (INIS)

    Carlson, J.G.

    1976-01-01

    Portions of embryos of the grasshopper, Chortophaga viridifasciata (DeGeer), were cultured in hanging drops under quartz cover slips. Immediately after exposure to 225, 265, or 280 nm radiation, microscope observations at 38 0 C were begun. The morphologically identified stage and the time after treatment of selected neuroblasts were recorded at short-time intervals until prometaphase was reached. Mitotic retardation induced by irradiation of prereplication stages (metaphase, anaphase, or early telophase) or S phase (middle or late telophase, interphase, or very early prophase) is greatest in postreplication stages (early, middle, and late prophase) and absent or minimal in stages morphologically identified as parts of S phase. Ultraviolet irradiation superimposes on the normal diversity of progression rates an additional variation factor, so that cells do not necessarily reach prometaphase in the order of their sequence at the time of treatment. This suggests the need for caution in ascribing particular radiosensitivities to substages of limited duration on the basis of the order in which they attain a subsequent stage

  4. Termini of human chromosomes display elevated rates of mitotic recombination.

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    Cornforth, M N; Eberle, R L

    2001-01-01

    The strand-specific in situ hybridization technique of CO-FISH was used to probe telomeres of human mitotic cells in order to determine the spontaneous frequency of crossover. This approach allowed the detection of recombinational crossovers occurring anywhere along the length of individual chromosomes, including reciprocal events taking place between sister chromatids. Although the process of sister chromatid exchange (SCE) is the most prominent type of recombination in somatic mammalian cells, our results show that SCEs accounted for less than a third of the recombinational events revealed by CO-FISH. It is concluded that chromosomal regions near the termini of chromosome arms undergo extraordinarily high rates of spontaneous recombination, producing terminal crossovers whose small size precludes detection by standard cytogenetic methods. That similar results were observed for transformed epithelial cells, as well as primary fibroblasts, suggests that the phenomenon is a common characteristic of human cells. These findings are noteworthy because, although telomeric and subtelomeric DNA is known to be preferentially involved in certain types of recombination, the tips of somatic mammalian chromosomes have not previously been identified as preferred sites for crossover. Implications of these results are discussed in terms of limitations imposed on CO-FISH for its proposed use in directional hybridization mapping.

  5. The influence of serotonin on the mitotic rate in the colonic crypt epithelium and in colonic adenocarcinoma in rats.

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    Tutton, P J; Barkla, D H

    1978-01-01

    1. The mitotic rate in the crypts of Lieberkühn of the descending colon and in dimethylhydrazine-induced adenocarcinomata of the descending colon of rat was measured using a stathmokinetic technique. 2. Intraperitoneal injection of a small dose (10 microgram/kg) of serotonin resulted in an increase in the tumour cell mitotic rate. 3. Blockade of serotonin receptors by 2-bromolysergic acid diethylamide and depletion of tissue serotonin levels following injection of DL-6-fluorotryptophan both result in a decrease in the tumour cell mitotic rate. 4. Treatment with serotonin, 2-bromolysergic acid diethylamide and DL-6-fluorotryptophan were all without effect on the colonic crypt cell mitotic rate.

  6. Influence of irradiation at different stages of mitotic cycle upon production of sister chromatid exchanges in cultured Chinese hamster cells

    International Nuclear Information System (INIS)

    Antoshina, M.M.; Poryadkova, N.A.; Luchnik, N.V.

    1982-01-01

    Frequency of sister chromatid exchanges (SCE) and microexchanges in Chinese hamster cells has been studied by means of the method of differential staining of chromatids on irradiation at different stages of the mitotic cycle. It is shown that the irradiation enhances frequency of SCE and microexchanges if it is carried out before the end of DNA replication synthesis. Comparison of frequency depenedence of radiation-induced microexchanges and SCE at different stages of the mitotic cycle results in the conclusion that the microexchanges are none other than small SCE

  7. Nitrogen deficiency inhibits leaf blade growth in Lolium perenne by increasing cell cycle duration and decreasing mitotic and post-mitotic growth rates.

    Science.gov (United States)

    Kavanová, Monika; Lattanzi, Fernando Alfredo; Schnyder, Hans

    2008-06-01

    Nitrogen deficiency severely inhibits leaf growth. This response was analysed at the cellular level by growing Lolium perenne L. under 7.5 mM (high) or 1 mM (low) nitrate supply, and performing a kinematic analysis to assess the effect of nitrogen status on cell proliferation and cell growth in the leaf blade epidermis. Low nitrogen supply reduced leaf elongation rate (LER) by 43% through a similar decrease in the cell production rate and final cell length. The former was entirely because of a decreased average cell division rate (0.023 versus 0.032 h(-1)) and thus longer cell cycle duration (30 versus 22 h). Nitrogen status did not affect the number of division cycles of the initial cell's progeny (5.7), and accordingly the meristematic cell number (53). Meristematic cell length was unaffected by nitrogen deficiency, implying that the division and mitotic growth rates were equally impaired. The shorter mature cell length arose from a considerably reduced post-mitotic growth rate (0.033 versus 0.049 h(-1)). But, nitrogen stress did not affect the position where elongation stopped, and increased cell elongation duration. In conclusion, nitrogen deficiency limited leaf growth by increasing the cell cycle duration and decreasing mitotic and post-mitotic elongation rates, delaying cell maturation.

  8. Relationships betwen mitotic delay and the dose rate of X radiation

    International Nuclear Information System (INIS)

    Yi, P.N.; Rha, C.K.; Evans, H.H.; Beer, J.Z.

    1994-01-01

    Upon exposure of cells to radiation delivered at a continuous low dose rate, cell proliferation may be sustained with the cells exhibiting a constant doubling time that is independent of the total dose. The doubling time or mitotic delay under these conditions has been shown to depend on the dose rate in HeLa, V79 and P388F cells. Reanalysis of the data for these particular cell lines shows that there is a threshold dose rate for mitotic delay, and that above the threshold there is a linear relationship between the length of mitotic delay and the logarithm of the dose rate which is referred to as the dose-rate response. We have observed the same relationships for L5178Y (LY)-R and LY-S cells exposed to low-dose-rate radiation. The threshold dose rates for LY-R, LY-S and P388F cells are similar (0.01-0.02 Gy/h) and are much lower than for V79 and HeLa cells. The slope of the dose-rate response curve is the greatest for HeLa cells, followed in order by LY-S, V79 and P388F cells, and finally by LY-R cells. The slopes for HeLa and LY-R cells differ by a factor of 35. 20 refs., 3 figs., 1 tab

  9. Mitotic effects of monochromatic ultraviolet radiation at 225, 265, and 280 nm on eleven stages of the cell cycle of the grasshopper neuroblast in culture. I. Overall retardation from the stage irradiated to nuclear membrane breakdown

    International Nuclear Information System (INIS)

    Carlson, J.G.

    1976-01-01

    Neuroblasts of Chortophaga viridifasciata (DeGeer) in culture were exposed to different doses of 225, 265, or 280 nm ultraviolet radiations at 11 different stages and substages of the mitotic cycle and individually selected cells were timed to breakdown of the nuclear membrane. Comparisons of the effectiveness of different wavelengths on the different stages were based on the dose that reduced the cell progression rate to 67 percent of normal (D 67 ) and the slope of the regression line, i.e., the control to treated time (C/T) ratio change/erg/mm 2 at the D 67 level. Cells of the prereplication period (metaphase + anaphase + early telophase) and the S phase (middle and late telophase + interphase + very early prophase) are equally sensitive to uv and contrast sharply with the much lower sensitivity of those in the postreplication period (early and middle prophase). This can best be interpreted if chromosomal DNA is the chromophore for uv-induced mitotic retardation. Cells in the prereplication period at exposure show no wavelength effect. In the S phase all stages except middle telophase and all stages combined are significantly more sensitive to 265 and 280 nm than to 225 nm. Of the postreplication stages, early prophase is retarded significantly more by 280 than by 225 or 265 nm. The C/T ratio/erg/mm 2 is greater after exposure to 265 nm at all prereplication and replication stages, but exhibits no consistent wavelength pattern during the postreplication period. Evidence based on the orientation of the neuroblast with respect to the uv-source suggests that the chromophore for mitotic retardation does not reside within the centrosome and related structures, but may be present, at least partly, in the nucleolus

  10. Dose rate, mitotic cycle duration, and sensitivity of cell transitions from G1 → S and G2 → M to protracted gamma radiation in root meristems

    International Nuclear Information System (INIS)

    Evans, L.S.; Hof, J.V.

    1975-01-01

    Experiments were designed to determine the relative radiosensitivity of the cell transition points of G1 → S and G2 → M in root meristems of several plant species. Label and mitotic indices and microspectrophotometry were used to measure the proportions of cells in each mitotic cycle stage in root meristems after protracted gamma radiation. The criterion of radiosensitivity was the dose rate needed to produce a tissue with less than 1 percent cells in S and none in M after 3 days of continuous exposure. The results show that DNA is the primary radiation target in proliferative root meristems and that the cycle duration stipulates the time interval of vulnerability. In each species, nonrandom reproducible cell proportions were established with 2C:4C:8C amounts of nuclear DNA after 3 days of exposure. Roots of Helianthus annuus, Crepis capillaris, and Tradescantia clone 02 had 80 percent cells with a 2C amount of DNA and 20 percent had a 4C amount of DNA. In these species the transition point of G1 → S was more radiosensitive than G2 → M. Roots of Pisum sativum and Triticum aestivum had cell proportions at 2C:4C:8C amounts of DNA in frequencies of 0.10 to 0.20:0.40 to 0.60:0.30 to 0.40. In these two species 0.30 to 0.40 cells underwent radiation-induced endoreduplication that resulted from a rapid inhibition of cell transit from G2 → M and a slower impairment of G1 → S. Cells increased from 2C to 4C and from 4C to 8C amounts of DNA during irradiation. The proportions of nuclei with 2C:4C:8C amounts of DNA were dependent in part upon the relative radiosensitivity of the G1 → S and G2 → M control points. The data show the relative radiosensitivity of the transition points from G1 → S and from G2 → M was species specific and unrelated to the cycle duration and mean nuclear DNA content of the plant species

  11. Detection of mitotic figures in thin melanomas--immunohistochemistry does not replace the careful search for mitotic figures in hematoxylin-eosin stain.

    Science.gov (United States)

    Ottmann, Karl; Tronnier, Michael; Mitteldorf, Christina

    2015-10-01

    The mitotic rate is an important prognostic criterion in patients with thin melanoma ≤ 1 mm. The aim of this study was to investigate the reproducibility of the mitotic rate in thin melanoma in hematoxylin-eosin (H&E) stain and compare it with the detection of mitotic figures by immunohistochemistry. The number of mitoses stated in the routine diagnostic report in 190 pT1 melanomas was compared with the number gained from re-evaluation of H&E sections and the number detected after staining with the mitotic marker, phosphohistone H3 (PHH3). Two different approaches were used for choosing the "hot spot" for evaluation (dermal vs epidermal/dermal). Comparing routine H&E-stained slides with re-evaluation slides, the number of mitotic figures was slightly variable. However, findings did not result in a change of the tumor stage. In 34% of the tumors with dermal mitotic figures on H&E, mitoses could not be found in the corresponding PHH3 slide anymore. In 4% of the cases, stage relevant mitoses could only be found by PHH3 immunohistochemistry. This is a single center study. Immunohistochemical staining for mitotic figures does not replace a careful evaluation of H&E-stained slides. Immunohistochemical detection of mitosis is only an additional tool; the time-saving effect is therefore negligible. Copyright © 2015 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

  12. KCNK10, a Tandem Pore Domain Potassium Channel, Is a Regulator of Mitotic Clonal Expansion during the Early Stage of Adipocyte Differentiation

    Directory of Open Access Journals (Sweden)

    Makoto Nishizuka

    2014-12-01

    Full Text Available KCNK10, a member of tandem pore domain potassium channel family, gives rise to leak K+ currents. It plays important roles in stabilizing the negative resting membrane potential and in counterbalancing depolarization. We previously demonstrated that kcnk10 expression is quickly elevated during the early stage of adipogenesis of 3T3-L1 cells and that reduction of kcnk10 expression inhibits adipocyte differentiation. However, the molecular mechanism of KCNK10 in adipocyte differentiation remains unclear. Here we revealed that kcnk10 is induced by 3-isobutyl-1-methylxanthine, a cyclic nucleotide phosphodiesterase inhibitor and a potent inducer of adipogenesis, during the early stage of adipocyte differentiation. We also demonstrated that KCNK10 functions as a positive regulator of mitotic clonal expansion (MCE, a necessary process for terminal differentiation. The reduction of kcnk10 expression repressed the expression levels of CCAAT/enhancer-binding protein β (C/EBPβ and C/EBPδ as well as the phosphorylation level of Akt during the early phase of adipogenesis. In addition, knockdown of kcnk10 expression suppressed insulin-induced Akt phosphorylation. These results indicate that KCNK10 contributes to the regulation of MCE through the control of C/EBPβ and C/EBPδ expression and insulin signaling.

  13. Phosphohistone-H3 (PHH3) is prognostic relevant in Merkel cell carcinomas but Merkel cell polyomavirus is a more powerful prognostic factor than AJCC clinical stage, PHH3, Ki-67 or mitotic indices.

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    Iwasaki, Takeshi; Matsushita, Michiko; Nonaka, Daisuke; Kato, Masako; Nagata, Keiko; Murakami, Ichiro; Hayashi, Kazuhiko

    2015-08-01

    Merkel cell carcinomas (MCCs) associated with Merkel cell polyomavirus (MCPyV) have better prognosis than those without MCPyV. The relationship between mitotic index (MI) and MCC outcome has remained elusive because of the difficulty in differentiating mitotic cells from apoptotic ones. We evaluated the role of phosphohistone-H3 (PHH3) (Ser10), a new mitotic count biomarker, in MCPyV-positive or -negative MCC patients, and assessed its prognostic value in comparison to Ki-67 labeling index or MI using hematoxylin and eosin (HE) staining. We compared the prognostic value of PHH3 mitotic index with that of MI by HE in 19 MCPyV-positive and 9 MCPyV-negative MCC patients. PHH3-positive immunoreactivity was mostly observed in mitotic figures. Multivariate analysis significantly showed that MCPyV status (HR, 0.004; 95% CI 0.0003-0.058) and the American Joint Committee of Cancer (AJCC) stage (HR, 5.02; 95% CI 1.23-20.51) were observed as significantly independent prognostic factors for OS. PHH3-positive cell counts/10 HPF was a slightly significant independent prognostic factor for OS (HR, 4.96; 95% CI 0.93-26.55). PHH3-positive MI and MCPyV status in MCC patients are useful in prognostication, although MCPyV-infection is a more powerful prognostic factor in MCCs than the AJCC scheme on proliferation or mitotic indices. © 2015 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.

  14. Inhibiting effect of plasma from normal and tumour bearing mice on the mitotic rate of regenerating liver.

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    Echave Llanos, J M; Moreno, F R; Badrán, A F

    1986-01-01

    Plasma from normal mice and from mice bearing the ES2 transplantable malignant tumour was injected intraperitoneally at a dose of 0.01 ml/g body weight in partially hepatectomized mice. Control animals were injected with a solution of sodium citrate in saline. The recipients were killed at the first (14:00 hours/48 h). These times are the time of day and the number of h after partial hepatectomy and second (14:00 hours/72 h) peak times after partial hepatectomy. The number of colchicine metaphases per 1000 nuclei was determined for hepatocytes and litoral cells. A different effect was obtained with plasma from tumour-bearing compared with normal mice. Plasma from both sources when injected 26 h after partial hepatectomy (16:00 hours/26 h) inhibited the mitotic activity of hepatocytes at the next peak of regenerative activity (14:00 hours/48 h). The plasma from tumour-bearing mice also inhibited the peak on the following day (14:00 hours/72 h), whereas plasma from normal mice had no inhibitory effect and, indeed, a compensatory wave was observed at this time. Furthermore, plasma from tumour-bearing mice also showed an inhibitory effect at the first peak (14:00 hours/48 h) when injected at the time of partial hepatectomy (14:00 hours/00 h) or at 22 h before partial hepatectomy (16:00 hours/-22 h) whereas the injection of plasma from normal mice at these times had no inhibitory effect. In the litoral cells the injection of plasma from tumour-bearing mice made 22 h before hepatectomy (16:00 hours/-22 h) led to a stimulation of mitotic activity which was controlled at 14:00 hours/48 h.(ABSTRACT TRUNCATED AT 250 WORDS)

  15. Evidence of Selection against Complex Mitotic-Origin Aneuploidy during Preimplantation Development

    Science.gov (United States)

    McCoy, Rajiv C.; Demko, Zachary P.; Ryan, Allison; Banjevic, Milena; Hill, Matthew; Sigurjonsson, Styrmir; Rabinowitz, Matthew; Petrov, Dmitri A.

    2015-01-01

    Whole-chromosome imbalances affect over half of early human embryos and are the leading cause of pregnancy loss. While these errors frequently arise in oocyte meiosis, many such whole-chromosome abnormalities affecting cleavage-stage embryos are the result of chromosome missegregation occurring during the initial mitotic cell divisions. The first wave of zygotic genome activation at the 4–8 cell stage results in the arrest of a large proportion of embryos, the vast majority of which contain whole-chromosome abnormalities. Thus, the full spectrum of meiotic and mitotic errors can only be detected by sampling after the initial cell divisions, but prior to this selective filter. Here, we apply 24-chromosome preimplantation genetic screening (PGS) to 28,052 single-cell day-3 blastomere biopsies and 18,387 multi-cell day-5 trophectoderm biopsies from 6,366 in vitro fertilization (IVF) cycles. We precisely characterize the rates and patterns of whole-chromosome abnormalities at each developmental stage and distinguish errors of meiotic and mitotic origin without embryo disaggregation, based on informative chromosomal signatures. We show that mitotic errors frequently involve multiple chromosome losses that are not biased toward maternal or paternal homologs. This outcome is characteristic of spindle abnormalities and chaotic cell division detected in previous studies. In contrast to meiotic errors, our data also show that mitotic errors are not significantly associated with maternal age. PGS patients referred due to previous IVF failure had elevated rates of mitotic error, while patients referred due to recurrent pregnancy loss had elevated rates of meiotic error, controlling for maternal age. These results support the conclusion that mitotic error is the predominant mechanism contributing to pregnancy losses occurring prior to blastocyst formation. This high-resolution view of the full spectrum of whole-chromosome abnormalities affecting early embryos provides insight

  16. Evidence of Selection against Complex Mitotic-Origin Aneuploidy during Preimplantation Development.

    Directory of Open Access Journals (Sweden)

    Rajiv C McCoy

    2015-10-01

    Full Text Available Whole-chromosome imbalances affect over half of early human embryos and are the leading cause of pregnancy loss. While these errors frequently arise in oocyte meiosis, many such whole-chromosome abnormalities affecting cleavage-stage embryos are the result of chromosome missegregation occurring during the initial mitotic cell divisions. The first wave of zygotic genome activation at the 4-8 cell stage results in the arrest of a large proportion of embryos, the vast majority of which contain whole-chromosome abnormalities. Thus, the full spectrum of meiotic and mitotic errors can only be detected by sampling after the initial cell divisions, but prior to this selective filter. Here, we apply 24-chromosome preimplantation genetic screening (PGS to 28,052 single-cell day-3 blastomere biopsies and 18,387 multi-cell day-5 trophectoderm biopsies from 6,366 in vitro fertilization (IVF cycles. We precisely characterize the rates and patterns of whole-chromosome abnormalities at each developmental stage and distinguish errors of meiotic and mitotic origin without embryo disaggregation, based on informative chromosomal signatures. We show that mitotic errors frequently involve multiple chromosome losses that are not biased toward maternal or paternal homologs. This outcome is characteristic of spindle abnormalities and chaotic cell division detected in previous studies. In contrast to meiotic errors, our data also show that mitotic errors are not significantly associated with maternal age. PGS patients referred due to previous IVF failure had elevated rates of mitotic error, while patients referred due to recurrent pregnancy loss had elevated rates of meiotic error, controlling for maternal age. These results support the conclusion that mitotic error is the predominant mechanism contributing to pregnancy losses occurring prior to blastocyst formation. This high-resolution view of the full spectrum of whole-chromosome abnormalities affecting early embryos

  17. Protein synthesis rate measured with l-[1-11C]tyrosine positron emission tomography correlates with mitotic activity and MIB-1 antibody-detected proliferation in human soft tissue sarcomas

    International Nuclear Information System (INIS)

    Plaat, B.; Mastik, M.; Molenaar, W.; Kole, A.; Vaalburg, W.; Hoekstra, H.

    1999-01-01

    Protein synthesis rate (PSR) can be assessed in vivo using positron emission tomography with l-[1- 11 C]tyrosine (TYR-PET). Biological activity of soft tissue sarcomas (STS) can be measured in vitro by the mitotic rate and number of proliferating cells. In STS the grade of malignancy, in which the mitotic index plays a major role, is considered to be the major standard in predicting biological tumour behaviour. This study was designed to test the validity of TYR-PET in relation to different histopathological features. In 21 patients with untreated STS, the PSR was measured using TYR-PET. The number of mitoses was counted and tumours were graded according to the grading system of Coindre et al. (Cancer 1986; 58:306-309). Proliferative activity was assessed by immunohistological detection of the Ki-67 nuclear antigen using MIB-1 monoclonal antibody. To test the association between the PSR and these tumour parameters, a correlation analysis was performed. A significant (P<0.05) correlation was found between PSR and the Ki-67 proliferation index (R = 0.54), and between PSR and mitotic rate (R = 0.64). There was no correlation between PSR and tumour grade. The present study in malignant soft tissue tumours relates in vivo tumour metabolism as established with TYR-PET to tumour activity measured in vitro and indicates that the non-invasive method of TYR-PET can estimate the mitotic and proliferative activity in STS. (orig.)

  18. Two-Stage Variable Sample-Rate Conversion System

    Science.gov (United States)

    Tkacenko, Andre

    2009-01-01

    A two-stage variable sample-rate conversion (SRC) system has been pro posed as part of a digital signal-processing system in a digital com munication radio receiver that utilizes a variety of data rates. The proposed system would be used as an interface between (1) an analog- todigital converter used in the front end of the receiver to sample an intermediatefrequency signal at a fixed input rate and (2) digita lly implemented tracking loops in subsequent stages that operate at v arious sample rates that are generally lower than the input sample r ate. This Two-Stage System would be capable of converting from an input sample rate to a desired lower output sample rate that could be var iable and not necessarily a rational fraction of the input rate.

  19. Cytologic anaplasia is a prognostic factor in osteosarcoma biopsies, but mitotic rate or extent of spontaneous tumor necrosis are not: a critique of the College of American Pathologists Bone Biopsy template.

    Science.gov (United States)

    Cates, Justin Mm; Dupont, William D

    2017-01-01

    The current College of American Pathologists cancer template for reporting biopsies of bone tumors recommends including information that is of unproven prognostic significance for osteosarcoma, such as the presence of spontaneous tumor necrosis and mitotic rate. Conversely, the degree of cytologic anaplasia (degree of differentiation) is not reported in this template. This retrospective cohort study of 125 patients with high-grade osteosarcoma was performed to evaluate the prognostic impact of these factors in diagnostic biopsy specimens in predicting the clinical outcome and response to neoadjuvant chemotherapy. Multivariate Cox regression was performed to adjust survival analyses for well-established prognostic factors. Multivariate logistic regression was used to determine odds ratios for good chemotherapy response (≥90% tumor necrosis). Osteosarcomas with severe anaplasia were independently associated with increased overall and disease-free survival, but mitotic rate and spontaneous necrosis had no prognostic impact after controlling for other confounding factors. Mitotic rate showed a trend towards increased odds of a good histologic response, but this effect was diminished after controlling for other predictive factors. Neither spontaneous necrosis nor the degree of cytologic anaplasia observed in biopsy specimens was predictive of a good response to chemotherapy. Mitotic rate and spontaneous tumor necrosis observed in pretreatment biopsy specimens of high-grade osteosarcoma are not strong independent prognostic factors for clinical outcome or predictors of response to neoadjuvant chemotherapy. Therefore, reporting these parameters for osteosarcoma, as recommended in the College of American Pathologists Bone Biopsy template, does not appear to have clinical utility. In contrast, histologic grading schemes for osteosarcoma based on the degree of cytologic anaplasia may have independent prognostic value and should continue to be evaluated.

  20. REC46 gene of Saccharomyces cerevisiae controls mitotic chromosomal stability, recombination and sporulation: cell-type and life cycle stage specific expression of the rec46-1 mutation

    International Nuclear Information System (INIS)

    Maleas, D.T.; Bjornstad, K.A.; Holbrook, L.L.; Esposito, M.S.

    1986-01-01

    Studies of chromosomal recombination during mitosis and meiosis of Saccharomyces cerevisiae have demonstrated that recombination at these two distinct stages of the yeast life cycle proceeds by mechanisms that appear similar but involve discrete mitosis-specific and meiosis-specific properties. UV radiation induced REC mutants are being employed as a genetic tool to identify the partial reactions comprising recombination and the involvement of individual REC gene products in mitotic and meiotic recombination. The sequence of molecular events that results in genetic recombination in eukaryotes is presently ill-defined. Genetic characterization of REC gene mutants and biochemical analyses of them for discrete defects in DNA metabolic proteins and enzymes (in collaboration with the laboratory of Junko Hosoda) are beginning to remedy this gap in the authors knowledge. This report summarizes the genetic properties of the rec46-1 mutation

  1. Protein synthesis rate measured with l-[1-{sup 11}C]tyrosine positron emission tomography correlates with mitotic activity and MIB-1 antibody-detected proliferation in human soft tissue sarcomas

    Energy Technology Data Exchange (ETDEWEB)

    Plaat, B.; Mastik, M.; Molenaar, W. [Department of Pathology, University Hospital Groningen (Netherlands); Kole, A.; Vaalburg, W. [PET Centre, University Hospital Groningen (Netherlands); Hoekstra, H. [Department of Surgical Oncology, University Hospital Groningen (Netherlands)

    1999-04-29

    Protein synthesis rate (PSR) can be assessed in vivo using positron emission tomography with l-[1-{sup 11}C]tyrosine (TYR-PET). Biological activity of soft tissue sarcomas (STS) can be measured in vitro by the mitotic rate and number of proliferating cells. In STS the grade of malignancy, in which the mitotic index plays a major role, is considered to be the major standard in predicting biological tumour behaviour. This study was designed to test the validity of TYR-PET in relation to different histopathological features. In 21 patients with untreated STS, the PSR was measured using TYR-PET. The number of mitoses was counted and tumours were graded according to the grading system of Coindre et al. (Cancer 1986; 58:306-309). Proliferative activity was assessed by immunohistological detection of the Ki-67 nuclear antigen using MIB-1 monoclonal antibody. To test the association between the PSR and these tumour parameters, a correlation analysis was performed. A significant (P<0.05) correlation was found between PSR and the Ki-67 proliferation index (R = 0.54), and between PSR and mitotic rate (R = 0.64). There was no correlation between PSR and tumour grade. The present study in malignant soft tissue tumours relates in vivo tumour metabolism as established with TYR-PET to tumour activity measured in vitro and indicates that the non-invasive method of TYR-PET can estimate the mitotic and proliferative activity in STS. (orig.) With 2 figs., 2 tabs., 30 refs.

  2. Senescence rates in patients with end-stage renal disease

    DEFF Research Database (Denmark)

    Koopman, J J E; Rozing, M P; Kramer, Ada

    2011-01-01

    function of the Gompertz equation as a superior descriptor of senescence rate. Here, we tested both measures of the rate of senescence in a population of patients with end-stage renal disease. It is clinical dogma that patients on dialysis experience accelerated senescence, whereas those with a functional...

  3. Bacterial mitotic machineries

    DEFF Research Database (Denmark)

    Gerdes, Kenn; Møller-Jensen, Jakob; Ebersbach, Gitte

    2004-01-01

    Here, we review recent progress that yields fundamental new insight into the molecular mechanisms behind plasmid and chromosome segregation in prokaryotic cells. In particular, we describe how prokaryotic actin homologs form mitotic machineries that segregate DNA before cell division. Thus, the P......M protein of plasmid R1 forms F actin-like filaments that separate and move plasmid DNA from mid-cell to the cell poles. Evidence from three different laboratories indicate that the morphogenetic MreB protein may be involved in segregation of the bacterial chromosome.......Here, we review recent progress that yields fundamental new insight into the molecular mechanisms behind plasmid and chromosome segregation in prokaryotic cells. In particular, we describe how prokaryotic actin homologs form mitotic machineries that segregate DNA before cell division. Thus, the Par...

  4. Fill Rates of Single-Stage and Multistage Supply Systems

    OpenAIRE

    Matthew J. Sobel

    2004-01-01

    A supply system's fill rate is the fraction of demand that is met from on-hand inventory. This paper presents formulas for the fill rate of periodic review supply systems that use base-stock-level policies. The first part of the paper contains fill-rate formulas for a single-stage system and general distributions of demand. When demand is normally distributed, an exact expression uses only the standard normal distribution and density functions, and a good approximation uses only the standard ...

  5. Sleep stage classification with low complexity and low bit rate.

    Science.gov (United States)

    Virkkala, Jussi; Värri, Alpo; Hasan, Joel; Himanen, Sari-Leena; Müller, Kiti

    2009-01-01

    Standard sleep stage classification is based on visual analysis of central (usually also frontal and occipital) EEG, two-channel EOG, and submental EMG signals. The process is complex, using multiple electrodes, and is usually based on relatively high (200-500 Hz) sampling rates. Also at least 12 bit analog to digital conversion is recommended (with 16 bit storage) resulting in total bit rate of at least 12.8 kbit/s. This is not a problem for in-house laboratory sleep studies, but in the case of online wireless self-applicable ambulatory sleep studies, lower complexity and lower bit rates are preferred. In this study we further developed earlier single channel facial EMG/EOG/EEG-based automatic sleep stage classification. An algorithm with a simple decision tree separated 30 s epochs into wakefulness, SREM, S1/S2 and SWS using 18-45 Hz beta power and 0.5-6 Hz amplitude. Improvements included low complexity recursive digital filtering. We also evaluated the effects of a reduced sampling rate, reduced number of quantization steps and reduced dynamic range on the sleep data of 132 training and 131 testing subjects. With the studied algorithm, it was possible to reduce the sampling rate to 50 Hz (having a low pass filter at 90 Hz), and the dynamic range to 244 microV, with an 8 bit resolution resulting in a bit rate of 0.4 kbit/s. Facial electrodes and a low bit rate enables the use of smaller devices for sleep stage classification in home environments.

  6. Mitotic and apoptotic activity in colorectal neoplasia.

    Science.gov (United States)

    Kohoutova, Darina; Pejchal, Jaroslav; Bures, Jan

    2018-05-18

    Colorectal cancer (CRC) is third most commonly diagnosed cancer worldwide. The aim of the prospective study was to evaluate mitosis and apoptosis of epithelial cells at each stage of colorectal neoplasia. A total of 61 persons were enrolled into the study: 18 patients with non-advanced colorectal adenoma (non-a-A), 13 patients with advanced colorectal adenoma (a-A), 13 patients with CRC and 17 controls: individuals with normal findings on colonoscopy. Biopsy samples were taken from pathology (patients) and healthy mucosa (patients and healthy controls). Samples were formalin-fixed paraffin-embedded and stained with haematoxylin-eosin. Mitotic and apoptotic activity were evaluated in lower and upper part of the crypts and in the superficial compartment. Apoptotic activity was also assessed using detection of activated caspase-3. In controls, mitotic activity was present in lower part of crypts, accompanied with low apoptotic activity. Mitotic and apoptotic activity decreased (to almost zero) in upper part of crypts. In superficial compartment, increase in apoptotic activity was observed. Transformation of healthy mucosa into non-a-A was associated with significant increase of mitotic activity in lower and upper part of the crypts and with significant increase of apoptotic activity in all three compartments; p colorectal neoplasia were observed. Detection of activated caspase-3 confirmed the above findings in apoptotic activity. Significant dysregulation of mitosis and apoptosis during the progression of colorectal neoplasia, corresponding with histology, was confirmed. In patients with sporadic colorectal neoplasia, healthy mucosa does not display different mitotic and apoptotic activity compared to mucosa in healthy controls and therefore adequate endoscopic/surgical removal of colorectal neoplasia is sufficient.

  7. ATYPICAL MITOTIC FIGURES AND THE MITOTIC INDEX IN CERVICAL INTRAEPITHELIAL NEOPLASIA

    NARCIS (Netherlands)

    VANLEEUWEN, AM; PIETERS, WJLM; HOLLEMA, H; BURGER, MPM

    1995-01-01

    We surveyed cervical intraepithelial neoplasia (CIN) to quantify the proliferation rate and the presence of normal and atypical mitotic figures. In the cervical tissue specimens of 127 women with CIN, the area with the highest cell proliferation was identified and, at that site, the proliferation

  8. HIGH-DOSE RATE BRACHYTHERAPY IN CARCINOMA CERVIX STAGE IIIB

    Directory of Open Access Journals (Sweden)

    Sathya Maruthavanan

    2016-07-01

    Full Text Available INTRODUCTION Radiotherapy is the standard treatment in locally advanced (IIB-IVA and early inoperable cases. The current standard of practice with curable intent is concurrent chemoradiation in which intracavitary brachytherapy is an integral component of radiotherapy. This study aims at assessing the efficacy of HDR ICBT (High-dose rate intracavitary brachytherapy in terms local response, normal tissue reactions, and feasibility. METHODS AND MATERIALS A total of 20 patients of stage IIIB cancer of the uterine cervix were enrolled in the study and were planned to receive concurrent chemotherapy weekly along with EBRT (external beam radiotherapy to a dose of 50 Gy/25 Fr. Suitability for ICBT was assessed at 40 Gy/20 Fr. 6/20 patients were suitable at 40 Gy and received HDR ICBT with a dose of 5.5 Gy to point A in 4 sessions (5.5 Gy/4 Fr. The remaining 14/20 patients completed 50 Gy and received HDR ICBT with a dose of 6 Gy to point A in 3 sessions (6 Gy/3 Fr. RESULTS A total of 66 intracavitary applications were done and only one application required dose modification due to high bladder dose, the pelvic control rate was 85% (17/20. 10% (2/20 had stable disease and 5% (1/20 had progressive disease at one year of follow up. When toxicity was considered only 15% developed grade I and grade II rectal complications. Patient compliance and acceptability was 100%. Patients were very comfortable with the short treatment time as compared with patients on LDR ICBT (low-dose rate intracavitary brachytherapy treatment interviewed during the same period. CONCLUSION This study proves that HDR brachytherapy is efficacious and feasible in carcinoma of cervix stage IIIB. It also proves that good dose distribution can be achieved with HDR intracavitary facility by the use of dose optimization. The short treatment time in HDR ICBT makes it possible to maintain this optimised dose distribution throughout the treatment providing a gain in the therapeutic ratio and

  9. Variation in sensitivity to #betta#-ray-induced chromosomal aberrations during the mitotic cycle of the sea urchin egg

    International Nuclear Information System (INIS)

    Ejima, Y.; Nakamura, I.; Shiroya, T.

    1982-01-01

    Sea urchin eggs were irradiated with 137 Cs #betta# rays at various stages of the mitotic cycle, and chromosomal aberrations at the first postirradiation mitosis and embryonic abnormalities at later developmental stages were examined. The radiosensitivity of the eggs to both endpoints varied in parallel with the mitotic stage at the time of irradiation, suggesting a possible relationship between chromosomal damage and embryonic abnormalities

  10. Estimation of mortality rates in stage-structured population

    CERN Document Server

    Wood, Simon N

    1991-01-01

    The stated aims of the Lecture Notes in Biomathematics allow for work that is "unfinished or tentative". This volume is offered in that spirit. The problem addressed is one of the classics of statistical ecology, the estimation of mortality rates from stage-frequency data, but in tackling it we found ourselves making use of ideas and techniques very different from those we expected to use, and in which we had no previous experience. Specifically we drifted towards consideration of some rather specific curve and surface fitting and smoothing techniques. We think we have made some progress (otherwise why publish?), but are acutely aware of the conceptual and statistical clumsiness of parts of the work. Readers with sufficient expertise to be offended should regard the monograph as a challenge to do better. The central theme in this book is a somewhat complex algorithm for mortality estimation (detailed at the end of Chapter 4). Because of its complexity, the job of implementing the method is intimidating. Any r...

  11. Micromechanics of human mitotic chromosomes

    International Nuclear Information System (INIS)

    Sun, Mingxuan; Kawamura, Ryo; Marko, John F

    2011-01-01

    Eukaryote cells dramatically reorganize their long chromosomal DNAs to facilitate their physical segregation during mitosis. The internal organization of folded mitotic chromosomes remains a basic mystery of cell biology; its understanding would likely shed light on how chromosomes are separated from one another as well as into chromosome structure between cell divisions. We report biophysical experiments on single mitotic chromosomes from human cells, where we combine micromanipulation, nano-Newton-scale force measurement and biochemical treatments to study chromosome connectivity and topology. Results are in accord with previous experiments on amphibian chromosomes and support the 'chromatin network' model of mitotic chromosome structure. Prospects for studies of chromosome-organizing proteins using siRNA expression knockdowns, as well as for differential studies of chromosomes with and without mutations associated with genetic diseases, are also discussed

  12. A two-stage decentralised system combining high rate activated ...

    African Journals Online (AJOL)

    Total ammonium nitrogen (TAN) and total phosphates (TP) were largely retained in the effluent with average removal percentages of 19.5 and 27.5%, respectively, encouraging reuse for plant growth. Key words: A-stage, sustainable wastewater treatment, resource recovery, developing countries, water reuse, nutrient ...

  13. Axin localizes to mitotic spindles and centrosomes in mitotic cells

    International Nuclear Information System (INIS)

    Kim, Shi-Mun; Choi, Eun-Jin; Song, Ki-Joon; Kim, Sewoon; Seo, Eunjeong; Jho, Eek-Hoon; Kee, Sun-Ho

    2009-01-01

    Wnt signaling plays critical roles in cell proliferation and carcinogenesis. In addition, numerous recent studies have shown that various Wnt signaling components are involved in mitosis and chromosomal instability. However, the role of Axin, a negative regulator of Wnt signaling, in mitosis has remained unclear. Using monoclonal antibodies against Axin, we found that Axin localizes to the centrosome and along mitotic spindles. This localization was suppressed by siRNA specific for Aurora A kinase and by Aurora kinase inhibitor. Interestingly, Axin over-expression altered the subcellular distribution of Plk1 and of phosphorylated glycogen synthase kinase (GSK3β) without producing any notable changes in cellular phenotype. In the presence of Aurora kinase inhibitor, Axin over-expression induced the formation of cleavage furrow-like structures and of prominent astral microtubules lacking midbody formation in a subset of cells. Our results suggest that Axin modulates distribution of Axin-associated proteins such as Plk1 and GSK3β in an expression level-dependent manner and these interactions affect the mitotic process, including cytokinesis under certain conditions, such as in the presence of Aurora kinase inhibitor

  14. Histone phosphorylation during radiation-induced mitotic delay in synchronous plasmodia of Physarum polycephalum

    International Nuclear Information System (INIS)

    Brewer, E.N.; Oleinick, N.L.

    1980-01-01

    Using the nearly perfect synchrony of the mitotic stages in Physarum plasmodia, and making use of 32 P as a tracer, studies were made to define the time course of histone phosphorylation during the late G2 and prophase and the alterations in that time course accompanying radiation-induced mitotic delay. Histone H1 was phosphorylated throughout the last 2-3 hours of the mitotic cycle coincident with the early stages of chromosome condensation. H1 phosphorylation appeared to be reduced in irradiated plasmodia. It is postulated that a longer time period, i.e. the mitotic delay, may be required to obtain the same eventual level of H1-phosphate. In normal cultures, nucleosome core histones were phosphorylated late in G2 and prophase, the peak corresponding closely with the γ-transition point. In irradiated plasmodia, phosphorylation of the core histones had an extended time course similar to H1. (U.K.)

  15. Mitotic chromosome condensation in vertebrates

    International Nuclear Information System (INIS)

    Vagnarelli, Paola

    2012-01-01

    Work from several laboratories over the past 10–15 years has revealed that, within the interphase nucleus, chromosomes are organized into spatially distinct territories [T. Cremer, C. Cremer, Chromosome territories, nuclear architecture and gene regulation in mammalian cells, Nat. Rev. Genet. 2 (2001) 292–301 and T. Cremer, M. Cremer, S. Dietzel, S. Muller, I. Solovei, S. Fakan, Chromosome territories—a functional nuclear landscape, Curr. Opin. Cell Biol. 18 (2006) 307–316]. The overall compaction level and intranuclear location varies as a function of gene density for both entire chromosomes [J.A. Croft, J.M. Bridger, S. Boyle, P. Perry, P. Teague,W.A. Bickmore, Differences in the localization and morphology of chromosomes in the human nucleus, J. Cell Biol. 145 (1999) 1119–1131] and specific chromosomal regions [N.L. Mahy, P.E. Perry, S. Gilchrist, R.A. Baldock, W.A. Bickmore, Spatial organization of active and inactive genes and noncoding DNA within chromosome territories, J. Cell Biol. 157 (2002) 579–589] (Fig. 1A, A'). In prophase, when cyclin B activity reaches a high threshold, chromosome condensation occurs followed by Nuclear Envelope Breakdown (NEB) [1]. At this point vertebrate chromosomes appear as compact structures harboring an attachment point for the spindle microtubules physically recognizable as a primary constriction where the two sister chromatids are held together. The transition from an unshaped interphase chromosome to the highly structured mitotic chromosome (compare Figs. 1A and B) has fascinated researchers for several decades now; however a definite picture of how this process is achieved and regulated is not yet in our hands and it will require more investigation to comprehend the complete process. From a biochemical point of view a vertebrate mitotic chromosomes is composed of DNA, histone proteins (60%) and non-histone proteins (40%) [6]. I will discuss below what is known to date on the contribution of these two different

  16. Mitotic chromosome condensation in vertebrates

    Energy Technology Data Exchange (ETDEWEB)

    Vagnarelli, Paola, E-mail: P.Vagnarelli@ed.ac.uk

    2012-07-15

    Work from several laboratories over the past 10-15 years has revealed that, within the interphase nucleus, chromosomes are organized into spatially distinct territories [T. Cremer, C. Cremer, Chromosome territories, nuclear architecture and gene regulation in mammalian cells, Nat. Rev. Genet. 2 (2001) 292-301 and T. Cremer, M. Cremer, S. Dietzel, S. Muller, I. Solovei, S. Fakan, Chromosome territories-a functional nuclear landscape, Curr. Opin. Cell Biol. 18 (2006) 307-316]. The overall compaction level and intranuclear location varies as a function of gene density for both entire chromosomes [J.A. Croft, J.M. Bridger, S. Boyle, P. Perry, P. Teague,W.A. Bickmore, Differences in the localization and morphology of chromosomes in the human nucleus, J. Cell Biol. 145 (1999) 1119-1131] and specific chromosomal regions [N.L. Mahy, P.E. Perry, S. Gilchrist, R.A. Baldock, W.A. Bickmore, Spatial organization of active and inactive genes and noncoding DNA within chromosome territories, J. Cell Biol. 157 (2002) 579-589] (Fig. 1A, A'). In prophase, when cyclin B activity reaches a high threshold, chromosome condensation occurs followed by Nuclear Envelope Breakdown (NEB) [1]. At this point vertebrate chromosomes appear as compact structures harboring an attachment point for the spindle microtubules physically recognizable as a primary constriction where the two sister chromatids are held together. The transition from an unshaped interphase chromosome to the highly structured mitotic chromosome (compare Figs. 1A and B) has fascinated researchers for several decades now; however a definite picture of how this process is achieved and regulated is not yet in our hands and it will require more investigation to comprehend the complete process. From a biochemical point of view a vertebrate mitotic chromosomes is composed of DNA, histone proteins (60%) and non-histone proteins (40%) [6]. I will discuss below what is known to date on the contribution of these two different classes

  17. Increased spontaneous mitotic segregation in MMS-sensitive mutants of Saccharomyces cerevisiae

    International Nuclear Information System (INIS)

    Prakash, S.; Prakash, L.

    1977-01-01

    Methyl methanesulfonate (MMS)-sensitive mutants of Saccharomyces cerevisiae belonging to four different complementation groups, when homozygous, increase the rate of spontaneous mitotic segregation to canavanine resistance from heterozygous sensitive (can/sup r//+) diploids by 13- to 170-fold. The mms8-1 mutant is MMS and x-ray sensitive and increases the rate of spontaneous mitotic segregation 170-fold. The mms9-1 and mms13-1 mutants are sensitive to x rays and uv, respectively, in addition to MMS, and increase the rate of spontaneous mitotic segregation by 13-fold and 85-fold, respectively. The mutant mms21-1 is sensitive to MMS, x rays and uv and increases the rate of spontaneous mitotic segregation 23-fold

  18. Generation time, net reproductive rate, and growth in stage-age-structured populations

    DEFF Research Database (Denmark)

    Steiner, Uli; Tuljapurkar, Shripad; Coulson, Tim

    2014-01-01

    examples to show how reproductive timing Tc and level R0 are shaped by stage dynamics (individual trait changes), selection on the trait, and parent-offspring phenotypic correlation. We also show how population structure can affect dispersion in reproduction among ages and stages. These macroscopic...... to age-structured populations. Here we generalize this result to populations structured by stage and age by providing a new, unique measure of reproductive timing (Tc) that, along with net reproductive rate (R0), has a direct mathematical relationship to and approximates growth rate (r). We use simple...

  19. High infection control rate and function after routine one-stage exchange for chronically infected TKA.

    Science.gov (United States)

    Jenny, Jean-Yves; Barbe, Bruno; Gaudias, Jeannot; Boeri, Cyril; Argenson, Jean-Noël

    2013-01-01

    Many surgeons consider two-stage exchange the gold standard for treating chronic infection after TKA. One-stage exchange is an alternative for infection control and might provide better knee function, but the rates of infection control and levels of function are unclear. We asked whether a one-stage exchange protocol would lead to infection control rates and knee function similar to those after two-stage exchange. We followed all 47 patients with chronically infected TKAs treated with one-stage exchange between July 2004 and February 2007. We monitored for recurrence of infection and obtained Knee Society Scores. We followed patients a minimum of 3 years or until death or infection recurrence. Three of the 47 patients (6%) experienced a persistence or recurrence of the index infection with the same pathogen isolated. Three patients (6%) had control of the index infection but between 6 and 17 months experienced an infection with another pathogen. The 3-year survival rates were 87% for being free of any infection and 91% for being healed of the index infection. Twenty-five of the 45 patients (56%) had a Knee Society Score of more than 150 points. While routine one-stage exchange was not associated with a higher rate of infection recurrence failure, knee function was not improved compared to that of historical patients having two-stage exchange. One stage-exchange may be a reasonable alternative in chronically infected TKA as a more convenient approach for patients without the risks of two operations and hospitalizations and for reducing costs. The ideal one stage-exchange candidate should be identified in future studies.

  20. Curative high dose rate vaginal apex brachytherapy in stage I papillary serous carcinoma of the endometrium

    International Nuclear Information System (INIS)

    Turner, B.C.; Kacinski, B.M.; Gumbs, A.; Peschel, R.E.; Haffty, B.G.; Wilson, L.D.

    1996-01-01

    Introduction: Uterine papillary serous carcinoma (UPSC) is a morphologically distinct variant of endometrial carcinoma that is associated with a poor prognosis, high recurrence rate, clinical understaging, and poor response to salvage treatment. We describe the presentation, local and distant control, survival, salvage rate, and complications for patients undergoing whole abdominal radiation therapy (WART), low dose rate (LDR) intracavitary brachytherapy, or high dose rate (HDR) vaginal brachytherapy in patients with stage I UPSC. Methods: Between 1976 and 1994 more than 1700 patients with endometrial carcinoma were treated with radiation therapy, 30 patients with stage I UPSC (1.8%) were treated with radiation before or following TAH/BSO. All patients underwent either preoperative Simon's packing or tandem and plaque which delivered 30-40 Gy to the serosa, WART, or HDR Ir-192 vaginal apex brachytherapy to a total dose of 21 Gy in 3 fractions at 0.5 cm from the vaginal mucosa. A total of 14 patients received HDR vaginal brachytherapy and (5(14)) patients received systemic chemotherapy. All patients presented with vaginal bleeding at a median age of 67 years (range 34-88). The group of 30 patients underwent TAH/BSO, 17 patients were completely staged pathologically (pelvic and para-aortic lymph nodes, omentectomy, and pelvic washings), and 2 patients underwent omental biopsy and pelvic washings only. All specimens revealed UPSC, nuclear grade 3, and lymphovascular invasion (23%). The pathologic stage was IA: 23% (7), IB: 67% (20), and IC: 10% (3). The median follow-up for all patients was 49 months (range 13-187 months). For the patients receiving postoperative HDR vaginal brachytherapy the median time from surgery to radiation was 42 days (range 29-91). Results: The 5-year actuarial disease free survival for Figo stage I UPSC patients treated with postoperative HDR vaginal brachytherapy and systemic chemotherapy was 100% compared to 74% for stage I UPSC patient

  1. Post-operative high dose rate vaginal apex brachytherapy in stage I endometrial adenocarcinoma

    International Nuclear Information System (INIS)

    Gumbs, A.A.; Turner, B.C.; Knisely, J.P.S.; Kacinski, B.M.; Roberts, K.B.; Peschel, R.E.; Haffty, B.G.; Rutherford, T.J.; Edraki, B.; Schwartz, P.E.; Wilson, L.D.

    1996-01-01

    Purpose/Objective: Patients with Stage I endometrial adenocarcinoma have traditionally been treated with total abdominal hysterectomy/bilateral salpingo-oophorectomy and radiation. The reported incidence of local recurrence in surgically treated patients with FIGO Stage IA or IB endometrial adenocarcinoma is 4-10% at 2 years. Combined surgery and radiation has resulted in a reduction of recurrence to 2-6%. We report the presentation, actuarial survival, actuarial rate of local failure, salvage rate, and complications for patients undergoing high dose rate (HDR) vaginal apex brachytherapy following surgery. Materials and Methods: Between 1985 and 1994 a total of 286 patients with FIGO Stage I endometrioid uterine adenocarcinoma were treated with HDR Ir-192 vaginal apex brachytherapy alone to a total dose of 21 Gy in 3 fractions at 0.5 cm from the vaginal mucosa. The pathologic stage by treatment group was IA: 31%, IB: 68%, and IC: 1%. The histologic grade of the patient's tumors was grade 1: 69%, 2: 29%, and 3: 2% of patients. The median time from surgery to radiation was 34 days (range 14-66 days). The median follow-up for 286 patients with Stage IA (92 patients), IB (190 patients), and IC (4 patients) was respectively, 37, 35 and 40 months (2 patients lost to follow-up prior to 6 months). Results: Patients presented with vaginal bleeding (94%) or abnormal pap smear (6%) at a median age for Stage IA and IB, of 54 and 63 years, respectively (range 32-88). The 5-year overall actuarial survival rate was 94.5%. The 5-year actuarial survival rate by histologic grade was 97.5% and 91.5% for FIGO grade 1 and 2, respectively (p=.011). The 5-year actuarial survival rate by depth of myometrial invasion was 99.0% and 92.5% for Stage IA and IB, respectively (p=.029). Median overall time to failure is 19.5 months (range 10-36 months). The 5-year actuarial rate of local failure was 4.5%. The overall failure rate in our study group was 2.8% (8 patients), local failure only 1

  2. Survival and Complication Rate of Radiation Therapy in Stage I and II Carcinoma of uterine Cervix

    International Nuclear Information System (INIS)

    Ma, Sun Young; Cho, Heung Lea; Sohn, Seung Chang

    1995-01-01

    Purpose : To analyze survival rate and late rectal and bladder complication for patients with stage with stage I and II carcinoma of uterine cervix treated by radiation alone or combined with chemotherapy. Materials and Methods : Between November 1984 and December 1993, 127 patients with stage I and II carcinoma of uterine cervix treated by radiation alone or combined therapy of radiation and chemotherapy. Retrospective analysis for survival rate was carried out on eligible 107 patients and review for complication was possible in 91 patients. The median follow-up was 47 months (range 3-118) and the median age of patients was 56 years (range 31-76). 26 patients were stage IB by FIGO classification. 40 were stage IIA and 41 were stage IIB. 86 cases were treated by radiation alone and 21 were treated by radiation and chemotherapy. 101 patients were treated with intracavitary radiation therapy (ICRT), of these, 80 were received low dose rate (LDR) ICRT and 21 were received high dose rate (HDR) ICRT. Of the patients who received LDR ICRT, 63 were treated by 1 intracavitary insertion and 17 were underwent 2 insertions. And we evaluated the external radiation dose and midline shield. Results : Acturial survival rate at 5 years was 92% for stage IB, 75% for stage IIA, 53% for stage IIB and 69% in all patients. Grade 1 rectal complications were developed in 20 cases(22%), grade 2 were in 22 cases (24%), 22 cases (24%) of grade 1 urinary complications and 17 cases (19%) of grade 2 urinary complications were observed But no patients had severe complications that needed surgical management or admission care. Maximum bladder dose for the group of patients with urinary complications was higher than that for the patients without urinary complications(7608cGy v 6960cGy, p<0.01). Maximum rectal dose for the group of patients with rectal complications was higher than that for the patients without urinary complications (7041cGy v 6269cGy, p<0.01). While there was no significant

  3. Sample size reassessment for a two-stage design controlling the false discovery rate.

    Science.gov (United States)

    Zehetmayer, Sonja; Graf, Alexandra C; Posch, Martin

    2015-11-01

    Sample size calculations for gene expression microarray and NGS-RNA-Seq experiments are challenging because the overall power depends on unknown quantities as the proportion of true null hypotheses and the distribution of the effect sizes under the alternative. We propose a two-stage design with an adaptive interim analysis where these quantities are estimated from the interim data. The second stage sample size is chosen based on these estimates to achieve a specific overall power. The proposed procedure controls the power in all considered scenarios except for very low first stage sample sizes. The false discovery rate (FDR) is controlled despite of the data dependent choice of sample size. The two-stage design can be a useful tool to determine the sample size of high-dimensional studies if in the planning phase there is high uncertainty regarding the expected effect sizes and variability.

  4. The CRO-1 gene of Saccharomyces cerevisiae controls mitotic crossing over, chromosomal stability and sporulation

    International Nuclear Information System (INIS)

    Esposito, M.S.; Maleas, D.T.; Bjornstad, K.A.; Holbrook, L.L.

    1987-01-01

    The properties of a novel temperature-sensitive recombination-defective mutant of Saccharomyces cerevisiae, cro1-1 is described. The cro1-1 mutant is the first instance of a rec mutation that reduces drastically the rates of spontaneous mitotic crossing-over events but not those of gene conversional events. The cro1-1 mutation thus provides evidence that mitotic crossing-over is dependent upon gene products that are not essential for gene conversional events. The cro1-1 mutation also results in enhanced mitotic-chromosomal instability and MATa/MATα cro1-1/cro1-1 mutants are sporulation deficient. These phenotypes indicate that the CRO1 gene modulates mitotic chromosomal integrity and is essential for normal meiosis. The cro1-1 mutant possesses Holliday junction resolvase activity, hence its recombinational defect does not involve failure to execute this putative final recombinational step. 7 refs., 1 fig., 5 tabs

  5. Mitotic Figure Recognition: Agreement among Pathologists and Computerized Detector

    Directory of Open Access Journals (Sweden)

    Christopher Malon

    2012-01-01

    Full Text Available Despite the prognostic importance of mitotic count as one of the components of the Bloom – Richardson grade [3], several studies ([2, 9, 10] have found that pathologists’ agreement on the mitotic grade is fairly modest. Collecting a set of more than 4,200 candidate mitotic figures, we evaluate pathologists' agreement on individual figures, and train a computerized system for mitosis detection, comparing its performance to the classifications of three pathologists. The system’s and the pathologists’ classifications are based on evaluation of digital micrographs of hematoxylin and eosin stained breast tissue. On figures where the majority of pathologists agree on a classification, we compare the performance of the trained system to that of the individual pathologists. We find that the level of agreement of the pathologists ranges from slight to moderate, with strong biases, and that the system performs competitively in rating the ground truth set. This study is a step towards automatic mitosis count to accelerate a pathologist's work and improve reproducibility.

  6. Postoperative high dose rate vaginal apex brachytherapy in stage I endometrial adenocarcinoma

    International Nuclear Information System (INIS)

    Turner, B.; Knisely, J.; Kacinski, B.; Roberts, K.; Peschel, R.; Gumbs, A.; Rutherford, T.; Edraki, B.; Schwartz, P.; Chambers, J.; Kohorn, E.; Wilson, L.

    1996-01-01

    Introduction: Patients with stage I endometrial adenocarcinoma have traditionally been treated with TAH/BSO and radiation. The reported incidence of local recurrence in surgically treated patients with Figo stage IA or IB endometrial adenocarcinoma is 4-10% at 2 years. Combined surgery and radiation has resulted in a reduction of recurrence to 2-6%. We report the presentation, local and distant control, salvage rate, survival and complications for patients undergoing high dose rate (HDR) vaginal apex brachytherapy following surgery. Methods: Between 1985 and 1994 a total of 302 patients with Figo stage I endometrial carcinoma were treated with HDR Ir-192 vaginal apex brachytherapy to a total dose of 21 Gy in 3 fractions at 0.5 cm from the vaginal mucosa. The pathologic stage by treatment group was IA: 31%, IB: 68%, and IC: 1%. The histologic grade of the patient's tumors was grade 1: 69%, 2: 27%, and 3: 4%. The median time from surgery to radiation was 33 days (range 14-66 days). The median follow-up for 300 patients with stage IA (91 patients), IB (205 patients), and IC (4 patients) was respectively 36, 34 and 40 months (2 patients lost to follow-up prior to 6 months). Results: Patients presented with vaginal bleeding (94%) or abnormal pap smear (6%) at a median age for stage IA and IB, of 55 and 64 years, respectively. The crude overall survival of the patient population at 2 years is 95%. Median overall time to failure is 19.5 months (range 10-36 months). The overall failure rate was 2.7% (8 patients), local failure only 1.0% (38% of failed group), distant failure only 0.3% (12% of failed group) and combined local/distant failure 1.3% (50% of failed group). The local failure rate for pathologic stage IA patients was 1.0% and no distant disease was observed. The local failure rate for pathologic stage IB patients was 3.4% 7/205 and distant failure was 2.4% 5/205. The majority of patients with recurrence had grade 2 histologic changes 5/8. The overall salvage rate

  7. New mitotic regulators released from chromatin

    Directory of Open Access Journals (Sweden)

    Hideki eYokoyama

    2013-12-01

    Full Text Available Faithful action of the mitotic spindle segregates duplicated chromosomes into daughter cells. Perturbations of this process result in chromosome mis-segregation, leading to chromosomal instability and cancer development. Chromosomes are not simply passengers segregated by spindle microtubules but rather play a major active role in spindle assembly. The GTP bound form of the Ran GTPase (RanGTP, produced around chromosomes, locally activates spindle assembly factors. Recent studies have uncovered that chromosomes organize mitosis beyond spindle formation. They distinctly regulate other mitotic events, such as spindle maintenance in anaphase, which is essential for chromosome segregation. Furthermore, the direct function of chromosomes is not only to produce RanGTP but, in addition, to release key mitotic regulators from chromatin. Chromatin-remodeling factors and nuclear pore complex proteins, which have established functions on chromatin in interphase, dissociate from mitotic chromatin and function in spindle assembly or maintenance. Thus, chromosomes actively organize their own segregation using chromatin-releasing mitotic regulators as well as RanGTP.

  8. Computerized analysis of fetal heart rate variability signal during the stages of labor.

    Science.gov (United States)

    Annunziata, Maria Laura; Tagliaferri, Salvatore; Esposito, Francesca Giovanna; Giuliano, Natascia; Mereghini, Flavia; Di Lieto, Andrea; Campanile, Marta

    2016-03-01

    To analyze computerized cardiotocographic (cCTG) parameters (baseline fetal heart rate, baseline FHR; short term variability, STV; approximate entropy, ApEn; low frequency, LF; movement frequency, MF; high frequency, HF) in physiological pregnancy in order to correlate them with the stages of labor. This could provide more information for understanding the mechanisms of nervous system control of FHR during labor progression. A total of 534 pregnant women were monitored on cCTG from the 37th week before the onset of spontaneous labor and during the first and the second stage of labor. Statistical analysis was performed using Kruskal-Wallis test and Wilcoxon rank-sum test with the Bonferroni adjusted α (labor, and the first and second stages of labor. Differences between some of the stages were found for ApEn, LF and for LF/(HF + MF), where the first and the third were reduced and the second was increased. cCTG modifications during labor may reflect the physiologic increased activation of the autonomous nervous system. Using computerized fetal heart rate analysis during labor it may be possible to obtain more information from the fetal cardiac signal, in comparison with the traditional tracing. © 2016 Japan Society of Obstetrics and Gynecology.

  9. Bayesian analysis of stage-fall-discharge rating curves and their uncertainties

    Science.gov (United States)

    Mansanarez, Valentin; Le Coz, Jérôme; Renard, Benjamin; Lang, Michel; Pierrefeu, Gilles; Le Boursicaud, Raphaël; Pobanz, Karine

    2016-04-01

    Stage-fall-discharge (SFD) rating curves are traditionally used to compute streamflow records at sites where the energy slope of the flow is variable due to variable backwater effects. Building on existing Bayesian approaches, we introduce an original hydraulics-based method for developing SFD rating curves used at twin gauge stations and estimating their uncertainties. Conventional power functions for channel and section controls are used, and transition to a backwater-affected channel control is computed based on a continuity condition, solved either analytically or numerically. The difference between the reference levels at the two stations is estimated as another uncertain parameter of the SFD model. The method proposed in this presentation incorporates information from both the hydraulic knowledge (equations of channel or section controls) and the information available in the stage-fall-discharge observations (gauging data). The obtained total uncertainty combines the parametric uncertainty and the remnant uncertainty related to the model of rating curve. This method provides a direct estimation of the physical inputs of the rating curve (roughness, width, slope bed, distance between twin gauges, etc.). The performance of the new method is tested using an application case affected by the variable backwater of a run-of-the-river dam: the Rhône river at Valence, France. In particular, a sensitivity analysis to the prior information and to the gauging dataset is performed. At that site, the stage-fall-discharge domain is well documented with gaugings conducted over a range of backwater affected and unaffected conditions. The performance of the new model was deemed to be satisfactory. Notably, transition to uniform flow when the overall range of the auxiliary stage is gauged is correctly simulated. The resulting curves are in good agreement with the observations (gaugings) and their uncertainty envelopes are acceptable for computing streamflow records. Similar

  10. False negative rate of syndesmotic injury in pronation-external rotation stage IV ankle fractures

    Directory of Open Access Journals (Sweden)

    Kwang-Soon Song

    2013-01-01

    Full Text Available Background: To investigate false negative rate in the diagnosis of diastasis on initial static anteroposterior radiograph and reliability of intraoperative external rotational stress test for detection of concealed disruption of syndesmosis in pronation external rotation (PER stage IV (Lauge-Hansen ankle fractures. Materials and Methods: We prospectively studied 34 PER stage IV ankle fractures between September 2001 and September 2008. Twenty (59% patients show syndesmotic injury on initial anteroposterior radiographs. We performed an intraoperative external rotation stress test in other 14 patients with suspicious PER stage IV ankle fractures, which showed no defined syndesmotic injury on anteroposterior radiographs inspite of a medial malleolar fracture, an oblique fibular fracture above the syndesmosis and fracture of the posterior tubercle of the tibia. Results: All 14 fractures showed different degrees of tibiofibular clear space (TFCS and tibiofibular overlapping (TFO on the external rotation stress test radiograph compared to the initial plain anteroposterior radiograph. It is important to understand the fracture pattern characterstic of PER stage IV ankle fractures even though it appears normal on anteroposterior radiographs, it is to be confirmed for the concealed syndesmotic injury through a routine intraoperative external rotational stress radiograph.

  11. Induced mitotic gynogenesis in common carp (Cyprinus carpio L.), optimizing irradiation dose of X- and gamma-ray

    International Nuclear Information System (INIS)

    Yousefian, M.; Amirinia, C.; Bercsenyi, M.; Horvath, L.

    1997-01-01

    Mitotic gynogenesis was induced in common carp, Cyprinus carpio L., in hatchery and laboratory conditions, using 60Co gamma-ray and X-ray for inactivation of sperm DNA and a subsequent heat shock for inducing endomitosis. The parameter examined was the dose of irradiation in the range of 70-140 Krad. Carp spermatozoa irradiated by 70-100 Krad doses showed higher motility and fertilization ability than the ones irradiated by 110-140 Krad. Sperm treated with doses of 70-90 Krad showed the same fertility rate, but lower survival rate at embryo stage compared with 100 Krad. The shock temperature and duration applied in these experiments for restoration of diploidy level were 40 degrees C plus/minus 0.1 and 2 min., respectively. The highest frequency of mitotic gynogenetic larvae was achieved by 100 Krad 60Co gamma ray at 34 min. after fertilization, - up to 12.2 percent (at 23 degrees C incubating temperature)

  12. Profiling DNA damage response following mitotic perturbations

    DEFF Research Database (Denmark)

    Pedersen, Ronni Sølvhøi; Karemore, Gopal; Gudjonsson, Thorkell

    2016-01-01

    that a broad spectrum of mitotic errors correlates with increased DNA breakage in daughter cells. Unexpectedly, we find that only a subset of these correlations are functionally linked. We identify the genuine mitosis-born DNA damage events and sub-classify them according to penetrance of the observed...

  13. Interlinked bistable mechanisms generate robust mitotic transitions.

    Science.gov (United States)

    Hutter, Lukas H; Rata, Scott; Hochegger, Helfrid; Novák, Béla

    2017-10-18

    The transitions between phases of the cell cycle have evolved to be robust and switch-like, which ensures temporal separation of DNA replication, sister chromatid separation, and cell division. Mathematical models describing the biochemical interaction networks of cell cycle regulators attribute these properties to underlying bistable switches, which inherently generate robust, switch-like, and irreversible transitions between states. We have recently presented new mathematical models for two control systems that regulate crucial transitions in the cell cycle: mitotic entry and exit, 1 and the mitotic checkpoint. 2 Each of the two control systems is characterized by two interlinked bistable switches. In the case of mitotic checkpoint control, these switches are mutually activating, whereas in the case of the mitotic entry/exit network, the switches are mutually inhibiting. In this Perspective we describe the qualitative features of these regulatory motifs and show that having two interlinked bistable mechanisms further enhances robustness and irreversibility. We speculate that these network motifs also underlie other cell cycle transitions and cellular transitions between distinct biochemical states.

  14. Dose rate distribution for products irradiated in a semi-industrial irradiation plant. 1st stage

    International Nuclear Information System (INIS)

    Mangussi, J.

    2005-01-01

    The model of the bulk product absorbed dose rate distribution in a semi industrial irradiation plant is presented. In this plant the products are subject to a dynamic irradiation process: single-plaque, single-direction, four-passes. The additional two passes, also one on each side of the plaque, serve to minimize the lateral dose variation as well as the depth-dose non-uniformity. The first stage of this model takes only into account the direct absorbed dose rate; the model outputs are the depth-dose distribution and the lateral-dose distribution. The calculated absorbed dose in the bulk product and its uniformity-ratio after the dynamic irradiation process for different products is compared. The model results are in good agreement with the experimental measurements in a bulk of irradiated product; and the air absorbed dose rate in the irradiation chamber behind the product subject to the dynamic irradiation process. (author) [es

  15. EGovernment Stage Model: Evaluating the Rate of Web Development Progress of Government Websites in Saudi Arabia

    OpenAIRE

    Osama Alfarraj; Steve Drew; Rayed Abdullah AlGhamdi

    2011-01-01

    This paper contributes to the issue of eGovernment implementation in Saudi Arabia by discussing the current situation of ministry websites. It evaluates the rate of web development progress of vital government websites in Saudi Arabia using the eGovernment stage model. In 2010, Saudi Arabia ranked 58th in the world and 4th in the Gulf region in eGovernment readiness according to United Nations reports. In particular, Saudi Arabia has ranked 75th worldwide for its online service index and its ...

  16. Thermal Death Kinetics of Conogethes Punctiferalis (Lepidoptera: Pyralidae) as Influenced by Heating Rate and Life Stage.

    Science.gov (United States)

    Hou, Lixia; Du, Yanli; Johnson, Judy A; Wang, Shaojin

    2015-10-01

    Thermal death kinetics of Conogethes punctiferalis (Guenée) (Lepidoptera: Pyralidae) at different life stages, heating rate, and temperature is essential for developing postharvest treatments to control pests in chestnuts. Using a heating block system (HBS), the most heat-tolerant life stage of C. punctiferalis and the effects of heating rate (0.1, 0.5, 1, 5, and 10°C/min) on insect mortality were determined. The thermal death kinetic data of fifth-instar C. punctiferalis were obtained at temperatures between 44 and 50°C at a heating rate of 5°C/min. The results showed that the relative heat tolerance of C. punctiferalis was found to be fifth instars>pupae> third instars> eggs. To avoid the enhanced thermal tolerance of C. punctiferalis at low heating rates (0.1 or 0.5°C/min), a high heating rate of 5°C/min was selected to simulate the fast radio frequency heating in chestnuts and further determine the thermal death kinetic data. Thermal death curves of C. punctiferalis followed a 0th-order kinetic reaction model. The minimum exposure time to achieve 100% mortality was 55, 12, 6, and 3 min at 44, 46, 48, and 50°C, respectively. The activation energy for controlling C. punctiferalis was 482.15 kJ/mol with the z value of 4.09°C obtained from the thermal death-time curve. The information provided by thermal death kinetics for C. punctiferalis is useful in developing effective postharvest thermal treatment protocols for disinfesting chestnuts. © The Authors 2015. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  17. Automating and estimating glomerular filtration rate for dosing medications and staging chronic kidney disease

    Directory of Open Access Journals (Sweden)

    Trinkley KE

    2014-05-01

    Full Text Available Katy E Trinkley,1 S Michelle Nikels,2 Robert L Page II,1 Melanie S Joy11Skaggs School of Pharmacy and Pharmaceutical Sciences, 2School of Medicine, University of Colorado, Aurora, CO, USA Objective: The purpose of this paper is to serve as a review for primary care providers on the bedside methods for estimating glomerular filtration rate (GFR for dosing and chronic kidney disease (CKD staging and to discuss how automated health information technologies (HIT can enhance clinical documentation of staging and reduce medication errors in patients with CKD.Methods: A nonsystematic search of PubMed (through March 2013 was conducted to determine the optimal approach to estimate GFR for dosing and CKD staging and to identify examples of how automated HITs can improve health outcomes in patients with CKD. Papers known to the authors were included, as were scientific statements. Articles were chosen based on the judgment of the authors.Results: Drug-dosing decisions should be based on the method used in the published studies and package labeling that have been determined to be safe, which is most often the Cockcroft–Gault formula unadjusted for body weight. Although Modification of Diet in Renal Disease is more commonly used in practice for staging, the CKD–Epidemiology Collaboration (CKD–EPI equation is the most accurate formula for estimating the CKD staging, especially at higher GFR values. Automated HITs offer a solution to the complexity of determining which equation to use for a given clinical scenario. HITs can educate providers on which formula to use and how to apply the formula in a given clinical situation, ultimately improving appropriate medication and medical management in CKD patients.Conclusion: Appropriate estimation of GFR is key to optimal health outcomes. HITs assist clinicians in both choosing the most appropriate GFR estimation formula and in applying the results of the GFR estimation in practice. Key limitations of the

  18. Decreased growth rate of P. falciparum blood stage parasitemia with age in a holoendemic population.

    Science.gov (United States)

    Pinkevych, Mykola; Petravic, Janka; Chelimo, Kiprotich; Vulule, John; Kazura, James W; Moormann, Ann M; Davenport, Miles P

    2014-04-01

    In malaria holoendemic settings, decreased parasitemia and clinical disease is associated with age and cumulative exposure. The relative contribution of acquired immunity against various stages of the parasite life cycle is not well understood. In particular, it is not known whether changes in infection dynamics can be best explained by decreasing rates of infection, or by decreased growth rates of parasites in blood. Here, we analyze the dynamics of Plasmodium falciparum infection after treatment in a cohort of 197 healthy study participants of different ages. We use both polymerase chain reaction (PCR) and microscopy detection of parasitemia in order to understand parasite growth rates and infection rates over time. The more sensitive PCR assay detects parasites earlier than microscopy, and demonstrates a higher overall prevalence of infection than microscopy alone. The delay between PCR and microscopy detection is significantly longer in adults compared with children, consistent with slower parasite growth with age. We estimated the parasite multiplication rate from delay to PCR and microscopy detections of parasitemia. We find that both the delay between PCR and microscopy infection as well as the differing reinfection dynamics in different age groups are best explained by a slowing of parasite growth with age.

  19. Thermal effect on heart rate and hemodynamics in vitelline arteries of stage 18 chicken embryos.

    Science.gov (United States)

    Lee, Jung Yeop; Lee, Sang Joon

    2010-12-01

    We investigated the thermal effects on heart rate, hemodynamics, and response of vitelline arteries of stage-18 chicken embryos. Heart rate was monitored by a high-speed imaging method, while hemodynamic quantities were evaluated using a particle image velocimetry (PIV) technique. Experiments were carried out at seven different temperatures (36-42 °C with 1 °C interval) after 1h of incubation to stabilize the heart rate. The heart rate increased in a linear manner (r = 0.992). Due to the increased cardiac output (or heart rate), the hemodynamic quantities such as mean velocity (U(mean)), velocity fluctuation (U(fluc)), and peak velocity (U(peak)) also increased with respect to the Womersley number (Ω) in the manner r = 0.599, 0.693, and 0.725, respectively. This indicates that the mechanical force exerting on the vessel walls increases. However, the active response (or regulation) of the vitelline arteries was not observed in this study. Copyright © 2010 Elsevier Ltd. All rights reserved.

  20. Two-stage revision of septic knee prosthesis with articulating knee spacers yields better infection eradication rate than one-stage or two-stage revision with static spacers.

    Science.gov (United States)

    Romanò, C L; Gala, L; Logoluso, N; Romanò, D; Drago, L

    2012-12-01

    The best method for treating chronic periprosthetic knee infection remains controversial. Randomized, comparative studies on treatment modalities are lacking. This systematic review of the literature compares the infection eradication rate after two-stage versus one-stage revision and static versus articulating spacers in two-stage procedures. We reviewed full-text papers and those with an abstract in English published from 1966 through 2011 that reported the success rate of infection eradication after one-stage or two-stage revision with two different types of spacers. In all, 6 original articles reporting the results after one-stage knee exchange arthoplasty (n = 204) and 38 papers reporting on two-stage revision (n = 1,421) were reviewed. The average success rate in the eradication of infection was 89.8% after a two-stage revision and 81.9% after a one-stage procedure at a mean follow-up of 44.7 and 40.7 months, respectively. The average infection eradication rate after a two-stage procedure was slightly, although significantly, higher when an articulating spacer rather than a static spacer was used (91.2 versus 87%). The methodological limitations of this study and the heterogeneous material in the studies reviewed notwithstanding, this systematic review shows that, on average, a two-stage procedure is associated with a higher rate of eradication of infection than one-stage revision for septic knee prosthesis and that articulating spacers are associated with a lower recurrence of infection than static spacers at a comparable mean duration of follow-up. IV.

  1. Assessment of Estimation Methods ForStage-Discharge Rating Curve in Rippled Bed Rivers

    Directory of Open Access Journals (Sweden)

    P. Maleki

    2016-02-01

    Full Text Available Introduction: Interactionbetweenwater flow characteristics andthe bed erodibilityplays an important role in sediment transport process. In order to reach stability, rivers with deposition or bottom erosion make a different bed form in the riverbed. One way to identify thebehavior of therivers is to study the structure and formation of bed forms within them. Ripples are the smallest of the bed forms. The longitudinal cross section of ripples are usually not symmetrical. The upstream face is long and has a gentle slope, and the downstream face is short and steep. The height of ripples is usually between 0.5 cm and 2 cm; the height ripple is not more than 5 cm. The wave lengths normally do not exceed 30cm, and they are usually within the range of 1 cm to 15 cm. Their occurrence is the result of the unstable viscous layer near the boundary. They can form in both shallow and deep water.With an increase of the flow velocity, the plan form of the ripples gradually develops form straight line to curves and then to a pattern like fish scales, symmetrical or unsymmetrical, as shown in Fig 1. Figure1-The patterndevelopment oftheripple Raudkivi (1966 was the first person that, the flow structure over ripples was investigated experimentally.Hethenestablishseveraldifferent conditionsonthemovingsandbedinanlaboratorychannelconsisted of a rectangular cross-section with base width of 70cm, wasable toform arow ofripples , he wassucceed toform arow ofripples.JafariMianaei and Keshavarzi(2008,studied the turbulentflow betweentwoartificialripples for investigate the change of kinetic energyandshearstress on overripples. The stage- discharge rating curve is one of the most important tools in the hydraulic studies. In alluvial rivers,bed rippled are formed and significantly affect the stage- discharge rating curve. In this research, the effects of two different type of ripples (parallel and flakeshape onthe hydraulic characteristicsof flow were experimentally studied

  2. The hydrolytic stage in high solids temperature phased anaerobic digestion improves the downstream methane production rate.

    Science.gov (United States)

    Buffière, P; Dooms, M; Hattou, S; Benbelkacem, H

    2018-07-01

    The role of the hydrolytic stage in high solids temperature phased anaerobic digestion was investigated with a mixture of cattle slurry and maize silage with variable ratios (100, 70 and 30% volatile solids coming from cattle slurry). It was incubated for 48 h at 37, 55, 65 and 72 °C. Soluble chemical oxygen demand and biochemical methane potential were measured at 0, 24 and 48 h. Higher temperatures improved the amount of solubilized COD, which confirmed previously reported results. Nevertheless, solubilization mostly took place during the first 24 h. The rate of methane production in post-hydrolysis BMPs increased after 48 h hydrolysis time, but not after 24 h. The first order kinetic constant rose by 40% on average. No correlation was observed between soluble COD and downstream methane production rate, indicating a possible modification of the physical structure of the particulate solids during the hydrolytic stage. Copyright © 2018 Elsevier Ltd. All rights reserved.

  3. Very low dose and dose-rate X-ray induced adaptive response in human lymphocytes at various cell cycle stages against bleomycin induced chromatid aberrations

    International Nuclear Information System (INIS)

    Hossein Mozdarani; Moghadam, R.N.

    2007-01-01

    Complete text of publication follows. Objective: To study the adaptive response induced by very low doses of X-rays at very low dose rate in human lymphocytes at different cell cycle stages followed by a challenge dose of bleomycin sulphate at G2 phase. Materials and Methods: Human peripheral blood lymphocytes before (G0) and after PHA stimulation (G1 and G2) were exposed to 1 and 5 cGy X-rays generated by a fluoroscopy unit with a dose rate of 5.56 mGy/min and challenged with 5 μg/ml bleomycin sulphate (BLM) 48 hours after culture initiation. Mitotic cells were arrested at metaphase by addition of colcemid in cultures 1.5 h before harvesting. Harvesting and slide preparation was performed using standard method. 100 well spread metaphases were analyzed for the presence of chromatid type aberrations for each sample. Results: Results obtained indicate that there is a linear relationship between the dose of BLM and chromatid aberrations below 5 μg/ml (R=0.93, p<0.0001). The results also show that pretreatment of lymphocytes with low dose X-rays at G0, G1 and G2 phases of the cell cycle significantly reduced the sensitivity of lymphocytes to the clastogenic effects of BLM in G2. Much lower frequencies of chromatid aberrations were observed in X-ray irradiated lymphocytes following BLM treatment (p<0.05). The magnitudes of adaptation induced at different phases of the cell cycle were not significantly different. Furthermore, there was no a significant difference in the magnitude of adaptive response induced by either 1 or 5 cGy X-rays. Conclusion: These observations might indicate that resistance of pre-exposure of lymphocytes to very low doses of X-rays protects them from clastogenic effects of BLM. This effect might be due to initial DNA damage induced in these cells leading to provocation of an active DNA repair mechanism independent of cell cycle stage.

  4. Adjuvant high dose rate vaginal cuff brachytherapy for early stage endometrial cancer

    International Nuclear Information System (INIS)

    Tannehill, S.P.; Petereit, D.G.; Schink, J.C.; Grosen, E.A.; Hartenbach, E.M.; Thomadsen, B.R.; Buchler, D.A.

    1997-01-01

    Objective: To determine the efficacy and complications of adjuvant high dose rate (HDR) vaginal cuff brachytherapy (VCB) in patients (pts) with low risk endometrial carcinoma. Materials and Methods: Since 1989, 154 patients were treated with outpatient adjuvant VCB for low risk endometrial cancer (Stage IA-14%, Stage IB-82%). Four percent of patients with stage IC disease were treated with VCB only because of medical contraindications to pelvic radiation. Patients had the following histologic grades: 53% grade 1, 40% grade 2, 5% grade 3 and 3% unknown (99%-adenocarcinoma, <1% papillary serous histology). Seventy-three percent of patients had their surgery (TAH-BSO) performed at an outside institution with minimal surgical assessment of the lymph nodes. At a median of 6 weeks after surgery, patients were treated with 2 HDR VCB insertions delivered 1 week apart. Ovoids were placed at the vaginal apex to deliver 16.2 Gy per fraction to the vaginal surface (LDR equivalent of 60 Gy at 100 cGy/h) under conscious outpatient sedation. All clinical endpoints were calculated using the Kaplan Meier method. Complications were scored using the RTOG 5-tiered system. Results: The median time in the brachytherapy suite was 60 minutes with no acute complications observed. With a median follow-up of 33 months (3-79 months), the 4-year overall and disease-free survival were 93% and 96% respectively. Five patients (3%) recurred: 2 intra-abdominally, 1 with lung metastases, and 2 in the pelvic lymph nodes. There were no vaginal cuff recurrences. The single patient with an isolated pelvic sidewall recurrence was salvaged with pelvic RT. Six patients developed a small area of asymptomatic necrosis at the vaginal cuff, which spontaneously healed at a median time of 4 months. There were no grade 3 or greater late tissue toxicities. No patient experienced significant vaginal stenosis, with 20% of the patients experiencing mild fibrosis of the vaginal apex. Conclusions: Adjuvant HDR VCB in 2

  5. Predicted Rates of Secondary Malignancies From Proton Versus Photon Radiation Therapy for Stage I Seminoma

    Energy Technology Data Exchange (ETDEWEB)

    Simone, Charles B., E-mail: csimone@alumni.upenn.edu [Department of Radiation Oncology, Hospital of University of Pennsylvania, Philadelphia, Pennsylvania (United States); Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (United States); Kramer, Kevin [Henry M. Jackson Foundation for the Advancement of Military Medicine, Rockville, Maryland (United States); O' Meara, William P. [Division of Radiation Oncology, National Naval Medical Center, Bethesda, Maryland (United States); Bekelman, Justin E. [Department of Radiation Oncology, Hospital of University of Pennsylvania, Philadelphia, Pennsylvania (United States); Belard, Arnaud [Henry M. Jackson Foundation for the Advancement of Military Medicine, Rockville, Maryland (United States); McDonough, James [Department of Radiation Oncology, Hospital of University of Pennsylvania, Philadelphia, Pennsylvania (United States); O' Connell, John [Radiation Oncology Service, Walter Reed Army Medical Center, Washington, DC (United States)

    2012-01-01

    Purpose: Photon radiotherapy has been the standard adjuvant treatment for stage I seminoma. Single-dose carboplatin therapy and observation have emerged as alternative options due to concerns for acute toxicities and secondary malignancies from radiation. In this institutional review board-approved study, we compared photon and proton radiotherapy for stage I seminoma and the predicted rates of excess secondary malignancies for both treatment modalities. Methods and Material: Computed tomography images from 10 consecutive patients with stage I seminoma were used to quantify dosimetric differences between photon and proton therapies. Structures reported to be at increased risk for secondary malignancies and in-field critical structures were contoured. Reported models of organ-specific radiation-induced cancer incidence rates based on organ equivalent dose were used to determine the excess absolute risk of secondary malignancies. Calculated values were compared with tumor registry reports of excess secondary malignancies among testicular cancer survivors. Results: Photon and proton plans provided comparable target volume coverage. Proton plans delivered significantly lower mean doses to all examined normal tissues, except for the kidneys. The greatest absolute reduction in mean dose was observed for the stomach (119 cGy for proton plans vs. 768 cGy for photon plans; p < 0.0001). Significantly more excess secondary cancers per 10,000 patients/year were predicted for photon radiation than for proton radiation to the stomach (4.11; 95% confidence interval [CI], 3.22-5.01), large bowel (0.81; 95% CI, 0.39-1.01), and bladder (0.03; 95% CI, 0.01-0.58), while no difference was demonstrated for radiation to the pancreas (0.02; 95% CI, -0.01-0.06). Conclusions: For patients with stage I seminoma, proton radiation therapy reduced the predicted secondary cancer risk compared with photon therapy. We predict a reduction of one additional secondary cancer for every 50 patients

  6. Measuring mitotic spindle dynamics in budding yeast

    Science.gov (United States)

    Plumb, Kemp

    In order to carry out its life cycle and produce viable progeny through cell division, a cell must successfully coordinate and execute a number of complex processes with high fidelity, in an environment dominated by thermal noise. One important example of such a process is the assembly and positioning of the mitotic spindle prior to chromosome segregation. The mitotic spindle is a modular structure composed of two spindle pole bodies, separated in space and spanned by filamentous proteins called microtubules, along which the genetic material of the cell is held. The spindle is responsible for alignment and subsequent segregation of chromosomes into two equal parts; proper spindle positioning and timing ensure that genetic material is appropriately divided amongst mother and daughter cells. In this thesis, I describe fluorescence confocal microscopy and automated image analysis algorithms, which I have used to observe and analyze the real space dynamics of the mitotic spindle in budding yeast. The software can locate structures in three spatial dimensions and track their movement in time. By selecting fluorescent proteins which specifically label the spindle poles and cell periphery, mitotic spindle dynamics have been measured in a coordinate system relevant to the cell division. I describe how I have characterised the accuracy and precision of the algorithms by simulating fluorescence data for both spindle poles and the budding yeast cell surface. In this thesis I also describe the construction of a microfluidic apparatus that allows for the measurement of long time-scale dynamics of individual cells and the development of a cell population. The tools developed in this thesis work will facilitate in-depth quantitative analysis of the non-equilibrium processes in living cells.

  7. Effects of solvents on the early stage stiffening rate of demineralized dentin matrix.

    Science.gov (United States)

    Garcia, Fernanda C P; Otsuki, Masayuki; Pashley, David H; Tay, Franklin R; Carvalho, Ricardo M

    2005-05-01

    To monitor the stiffening rate of demineralized dentin matrix at the early stages after exposure to different neat solvents. Dentin beams approximately 0.8x0.7x8.0 mm were obtained from human third molars. After covering their ends with resin composite, the middle exposed length of 4.0mm (gauge-length) was demineralized in 0.5 M EDTA (pH 7.0) for 7 days. The specimens were gripped by a testing machine, pre-loaded to 10 g and cyclically stressed in tension to 5% strain, for 30 repeated cycles (total 20 min) at 0.6 mm/min while immersed in water (control). Then, water was replaced by either 100% acetone, methanol, ethanol, propanol, HEMA or air and the specimens subjected to the same cyclic protocol. The maximum apparent modulus of elasticity (E(Max)) was calculated for every cycle, plotted as a function of time and subjected to regression analysis. Stiffening rate was calculated as changes in E (min). Regression analysis examined the relationship between E and time for each solvent. Data were analyzed by one-way ANOVA and Student-Newman-Keuls test at alpha=0.05. Regression analysis showed that E increased significantly with time in all water-free solvents (R2=0.8-0.99). Stiffening rate was higher for acetone (0.9 MPa/min) and ethanol (0.8 MPa/min), intermediate for air (0.7 MPa/min), methanol (0.6 MPa/min) and propanol (0.5 MPa/min), lower for HEMA (0.2 MPa/min) and practically none for water (0.07 MPa/min) with prate of demineralized dentin matrix is both time and solvent-dependent. The ability of solvents to promptly stiffen the demineralized dentin matrix may be important in maintaining the resin-infiltrated matrix expanded during the solvent evaporation stage of resin bonding.

  8. Postoperative vaginal irradiation by a high dose-rate afterloading technique in endometrial carcinoma stage I

    International Nuclear Information System (INIS)

    Sorbe, B.; Smeds, A.C.

    1989-01-01

    A high dose-rate (cobalt-60) afterloading technique was used for postoperative vaginal irradiation in a series of 404 women with endometrial carcinoma stage I. The total recurrence rate was 3.7% with 0.7% vaginal lesions. The crude 5-year survival rate for the complete series was 91.8% compared to 13.3% for those with recurrences. Depth of myometrical infiltration (>1/3 of the uterine wall) and nuclear grade were the most important prognostic factors. Clinically significant late radiation reactions (bladder and/or rectum) were recorded in 6.9%. The absorbed dose per fraction and the size of the treatment volume were significantly related to the occurrence of both early and late radiation reactions. Vaginal shortening was closely related to the dose per fraction, length of the referce isodose and the applicator diameter. The shape of the vaginal applicator versus the isodose contours and the importance of the source train geometry and relative activity for absorbed dose inhomogeneitis within the treatment volume are discussed. Cumulative radiation effect (CRE) and linear-quadratic (LQ) calculations have been performed and related to tissue reactions within the target volume and in the risk organs. An alpha-beta quotient of 8.8 Gy for vaginal shrinkage effect and 2.0 Gy for late rectal complications are suggested on the basis of calculations using a maximum likelihood method for quantal radiation data. (orig.)

  9. Postoperative vaginal irradiation with high dose rate afterloading technique in endometrial carcinoma stage I

    International Nuclear Information System (INIS)

    Sorbe, B.G.; Smeds, A.C.

    1990-01-01

    A high dose rate ( 60 Co) afterloading technique was used for postoperative prophylactic vaginal irradiation in a series of 404 women with endometrial carcinoma Stage I. The total recurrence rate was 3.7% with 0.7% vaginal deposits. The crude 5-year survival rate for the complete series was 91.8% compared to 13.3% for those with recurrences. Depth of myometrial infiltration (greater than 1/3 of the uterine wall) and nuclear grade were the most important prognostic factors. Clinically significant late radiation reactions (bladder and/or rectum) were recorded in 6.9%. Dose per fraction and the size of the target volume were highly significantly related to the occurrence of both early and late radiation reactions. Vaginal shortening is closely related to the dose per fraction, length of the reference isodose, and the applicator diameter. The shape of the vaginal applicator versus the isodoses and the importance of the source train geometry and relative activity for dose gradient inhomogeneities within the target volume are discussed. Cumulative radiation effect (CRE) and linear-quadratic (LQ) calculations have been performed and related to tissue reactions within the target volume and in the risk organs. An alpha-beta quotient of 8.8 for vaginal shrinkage effect and 2.0 for late rectal complications are suggested on the basis of calculations using a maximum likelihood method for quantal radiation data

  10. Treatment outcome with low-dose-rate interstitial brachytherapy in early-stage oral tongue cancers

    Directory of Open Access Journals (Sweden)

    Bhalavat Rajendra

    2009-01-01

    Full Text Available Purpose : Although radical radiotherapy is known to be equally effective for early-stage oral tongue cancers (T1-2 N0 with the added advantage of organ and function preservation, surgery remains the preferred treatment. We present outcome of patients treated with brachytherapy (BT either radical or boost. Materials and Methods : Fifty-seven patients (T1/T2 31/26 were studied. Seventeen patients (30% were treated with radical BT (50-67 Gy while 40 (70% with external beam radiation therapy (EBRT + BT (36-56 Gy + 15-38 Gy]. Low-dose-rate (LDR BT was delivered with 192 Ir wires, using plastic bead technique with varied dose rates (< 60 cGy/h in 29 patients, 60-90 cGy/h in 17, and> 90 cGy/h in 11. Results : The overall local control (LCR was achieved in 59.7% (34/57 patients. LCR for T1 and T2 was 67.8% and 50%, respectively. A total of 23 patients had failures [local: 20 (T1: 8; T2: 12 patients, node: 5 (T1:2; T2: 3, and local + nodal: 3]. Overall 5-year disease-free survival and overall survival (OAS were 51% and 67%, respectively and those for T1 and T2 was 64.5/77.4% and 38.5/54% respectively (P = 0.002. All 16 patients were salvaged. Median survival after salvage treatment was 13.5 months (6-100 months. Soft tissue necrosis was observed in 12.3% (7/57 and osteoradionecrosis in two patients. Conclusion : BT, as an integral part of radical radiation therapy in early-stage tongue cancers, appears to be an effective alternative treatment modality with preservation of the organ and function without jeopardizing the outcome.

  11. High dose rate brachytherapy for medically inoperable stage I endometrial cancer

    Energy Technology Data Exchange (ETDEWEB)

    Petereit, Daniel G; Sarkaria, Jann N; Schink, Julian; Springman, Scott R; Kinsella, Timothy J; Buchler, Dolores A

    1995-07-01

    Purpose/Objective: To determine the efficacy of high dose rate (HDR) brachytherapy in patients with medically inoperable endometrial cancer clinically confined to the corpus. Materials and Methods: Forty-two patients with endometrial cancer and an intact uterus have been treated since 1989 with HDR brachytherapy. Twenty-six patients with medically inoperable Stage I disease were treated with radiation alone and form the basis of this study. Obesity was assessed using the body mass index (BMI kg/m{sup 2}) scale. Patients with a BMI above 28 were considered obese and those above 35 morbidly obese, per standard anesthesia guidelines. Brachytherapy was delivered in 5 HDR insertions, 1 week apart, without any external beam radiation. The following doses were delivered per insertion: 5.7 Gy to point S, 7.0 Gy to point W, 8.2 Gy to the vaginal surface and 9.2 Gy to point M. Point M represents the conventional point A dose, while points S and W are myometrial points. A single tandem with either ovoids or cylinders was placed, unless the uterine cavity would accommodate 2 tandems. All treatments were outpatient using intravenous fentanyl and midazolam for sedation. Pelvic ultrasound was commonly used at the time of brachytherapy to verify tandem placement. Three year clinical endpoints were calculated using the Kaplan Meier method. Results: The median follow-up for the study cohort was 21 months with follow-up greater than 36 months in 11 patients. Seventeen of the 26 patients were inoperable due to morbid obesity (median weight and BMI; 316 lbs and 55 kg/m{sup 2}, respectively); the other patients had poor cardiopulmonary reserve {+-} obesity. The median age, KPS (Karnofsky Performance Status), weight, ASA (American Society of Anesthesiologists' Physical Class System) and BMI were 63 yrs, 80%, 285 lbs, 3 and 49 kg/m{sup 2}, respectively. Two patients with an ASA of 3 and 4 died from acute cardio-pulmonary events within 30 days of the last insertion, emphasizing the need

  12. High dose rate brachytherapy for medically inoperable stage I endometrial cancer

    International Nuclear Information System (INIS)

    Petereit, Daniel G.; Sarkaria, Jann N.; Schink, Julian; Springman, Scott R.; Kinsella, Timothy J.; Buchler, Dolores A.

    1995-01-01

    Purpose/Objective: To determine the efficacy of high dose rate (HDR) brachytherapy in patients with medically inoperable endometrial cancer clinically confined to the corpus. Materials and Methods: Forty-two patients with endometrial cancer and an intact uterus have been treated since 1989 with HDR brachytherapy. Twenty-six patients with medically inoperable Stage I disease were treated with radiation alone and form the basis of this study. Obesity was assessed using the body mass index (BMI kg/m 2 ) scale. Patients with a BMI above 28 were considered obese and those above 35 morbidly obese, per standard anesthesia guidelines. Brachytherapy was delivered in 5 HDR insertions, 1 week apart, without any external beam radiation. The following doses were delivered per insertion: 5.7 Gy to point S, 7.0 Gy to point W, 8.2 Gy to the vaginal surface and 9.2 Gy to point M. Point M represents the conventional point A dose, while points S and W are myometrial points. A single tandem with either ovoids or cylinders was placed, unless the uterine cavity would accommodate 2 tandems. All treatments were outpatient using intravenous fentanyl and midazolam for sedation. Pelvic ultrasound was commonly used at the time of brachytherapy to verify tandem placement. Three year clinical endpoints were calculated using the Kaplan Meier method. Results: The median follow-up for the study cohort was 21 months with follow-up greater than 36 months in 11 patients. Seventeen of the 26 patients were inoperable due to morbid obesity (median weight and BMI; 316 lbs and 55 kg/m 2 , respectively); the other patients had poor cardiopulmonary reserve ± obesity. The median age, KPS (Karnofsky Performance Status), weight, ASA (American Society of Anesthesiologists' Physical Class System) and BMI were 63 yrs, 80%, 285 lbs, 3 and 49 kg/m 2 , respectively. Two patients with an ASA of 3 and 4 died from acute cardio-pulmonary events within 30 days of the last insertion, emphasizing the need for accurate pre

  13. Suspension of Mitotic Activity in Dentate Gyrus of the Hibernating Ground Squirrel

    Directory of Open Access Journals (Sweden)

    Victor I. Popov

    2011-01-01

    Full Text Available Neurogenesis occurs in the adult mammalian hippocampus, a region of the brain important for learning and memory. Hibernation in Siberian ground squirrels provides a natural model to study mitosis as the rapid fall in body temperature in 24 h (from 35-36°C to +4–6°C permits accumulation of mitotic cells at different stages of the cell cycle. Histological methods used to study adult neurogenesis are limited largely to fixed tissue, and the mitotic state elucidated depends on the specific phase of mitosis at the time of day. However, using an immunohistochemical study of doublecortin (DCX and BrdU-labelled neurons, we demonstrate that the dentate gyrus of the ground squirrel hippocampus contains a population of immature cells which appear to possess mitotic activity. Our data suggest that doublecortin-labelled immature cells exist in a mitotic state and may represent a renewable pool for generation of new neurons within the dentate gyrus.

  14. The oxygen consumption rates of different life stages of the endoparasitic nematode

    Directory of Open Access Journals (Sweden)

    Willie van Aardt

    2010-01-01

    Full Text Available The oxygen consumption rates of different life stages of the endoparasitic nematode, Pratylenchus zeae (Nematoda: Tylenchida during non- and post-anhydrobiosisPratylenchus zeae, widely distributed in tropical and subtropical regions, is an endoparasite in roots of maize and other crop plants. The nematode is attracted to plant roots by CO2 and root exudates and feeds primarily on cells of the root cortex, making channels and openings where the eggs are deposited, with the result that secondary infection occurs due to bacteria and fungi. Nothing is known about the respiration physiology of this nematode and how it manages to survive during dry seasons. To measure the oxygen consumption rate (VO2 of individual P. zeae (less than half a millimeter long, a special measuring technique namely Cartesian diver micro-respirometry was applied. The Cartesian divers were machined from Perspex, and proved to be more accurate to measure VO2 compared with heavier glass divers used in similar experiments on free living nematodes. An accuracy of better than one nanoliter of oxygen consumed per hour was achieved with a single P. zeae inside the diver. Cartesian diver micro-respirometry measurements are based in principle on the manometric changes that occur in a fl otation tube in a manometer set-up when oxygen is consumed by P. zeae and CO2 from the animal is chemically absorbed. VO2 was measured for eggs (length: < 0.05 mm, larvae (length: 0.36 mm and adults (length: 0.47 mm before induction to anhydrobiosis. P. zeae from infected maize roots were extracted and exposed aseptically to in vitro maize root cultures in a grow cabinet at 50 % to 60% relative humidity at 28 ºC using eggs, larvae and adults. VO2 was also measured for post-anhydrobiotic eggs, larvae and adults by taking 50 individuals, eggs and larvae from the culture and placing them in Petri-dishes with 1% agar/water to dry out for 11 days at 28 ºC and 50% relative humidity. The VO2 was measured

  15. Developmental rate and behavior of early life stages of bighead carp and silver carp

    Science.gov (United States)

    Chapman, Duane C.; George, Amy E.

    2011-01-01

    The early life stages of Asian carp are well described by Yi and others (1988), but since these descriptions are represented by line drawings based only on live individuals and lacked temperature controls, further information on developmental time and stages is of use to expand understanding of early life stages of these species. Bighead carp and silver carp were cultured under two different temperature treatments to the one-chamber gas bladder stage, and a photographic guide is provided for bighead carp and silver carp embryonic and larval development, including notes about egg morphology and larval swimming behavior. Preliminary information on developmental time and hourly thermal units for each stage is also provided. Both carp species developed faster under warmer conditions. Developmental stages and behaviors are generally consistent with earlier works with the exception that strong vertical swimming immediately after hatching was documented in this report.

  16. The detection rates and tumor clinical/pathological stages of whole-body FDG-PET cancer screening

    International Nuclear Information System (INIS)

    Ono, Ken; Omagari, Junichi; Ochiai, Reiji; Yoshida, Tsuyoshi; Kitagawa, Mami; Kobayashi, Hisashi; Yamashita, Yasuyuki

    2007-01-01

    Fluorodeoxyglucose (FDG)-positron emission tomography (PET) has been used for cancer screening, mainly in East-Asia, and cancers are found not infrequently. However, their stages have not been clarified. We examined the detection rates of various cancers using whole-body PET for the screening of cancers in asymptomatic individuals, focusing on their clinical and pathological stages. Whole-body PET was obtained as a part of our cancer screening program among 3,426 healthy subjects. All subjects participated in a course of PET examination in conjunction with conventional examinations including a medical questionnaire, tumor markers, immunological fecal occult blood test, neck and abdominal ultrasonography and whole body computed tomography. A diagnosis and staging was obtained by an analysis of the pathological findings or by an analysis of the clinical follow-up data. Malignant tumors were discovered in 65 lesions found in 3,426 participants (1.90%). The PET findings were true-positive in 46 of the 65 cancer cases. The cancers were found in the following organs: the colon 14; thyroid gland 10; stomach 7; lung 5; liver 3; breast 2; and one each in the kidney, gallbladder, esophagus, pancreas and retroperitoneum. The stages were as follows: stage 0 5, stage I 17, stage II 10, stage III 7, and stage IV 6. One was an unknown primary. There were 19 false-negative findings (0.6%) on PET. Six cancers (0.18%) were missed in our screening program. PET imaging has the potential to detect a wide variety of cancers at potentially curative stages. Most PET-negative cancers are early stage cancers, and thus can be detected using other conventional examinations such as endoscopy. (author)

  17. Revertant mosaicism in epidermolysis bullosa caused by mitotic gene conversion

    NARCIS (Netherlands)

    Jonkman, MF; Scheffer, H; Stulp, R; Pas, HH; Nijenhuis, Albertine; Heeres, K; Owaribe, K; Pulkkinen, L; Uitto, J

    1997-01-01

    Mitotic gene conversion acting as reverse mutation has not been previously demonstrated in human. We report here that the revertant mosaicism of a compound heterozygous proband with an autosomal recessive genodermatosis, generalized atrophic benign epidermolysis bullosa, is caused by mitotic gene

  18. Mitotic spindle proteomics in Chinese hamster ovary cells.

    Directory of Open Access Journals (Sweden)

    Mary Kate Bonner

    Full Text Available Mitosis is a fundamental process in the development of all organisms. The mitotic spindle guides the cell through mitosis as it mediates the segregation of chromosomes, the orientation of the cleavage furrow, and the progression of cell division. Birth defects and tissue-specific cancers often result from abnormalities in mitotic events. Here, we report a proteomic study of the mitotic spindle from Chinese Hamster Ovary (CHO cells. Four different isolations of metaphase spindles were subjected to Multi-dimensional Protein Identification Technology (MudPIT analysis and tandem mass spectrometry. We identified 1155 proteins and used Gene Ontology (GO analysis to categorize proteins into cellular component groups. We then compared our data to the previously published CHO midbody proteome and identified proteins that are unique to the CHO spindle. Our data represent the first mitotic spindle proteome in CHO cells, which augments the list of mitotic spindle components from mammalian cells.

  19. Oxygen consumption rate and Na+/K+-ATPase activity in early developmental stages of the sea urchin Paracentrotus lividus Lam.

    Science.gov (United States)

    Tomšić, Sanja; Stanković, Suzana; Lucu, Čedomil

    2011-09-01

    Changes in oxygen consumption rate and Na+/K+-ATPase activity during early development were studied in the sea urchin Paracentrotus lividus Lam. The oxygen consumption rate increased from 0.12 μmol O2 mg protein-1 h-1 in unfertilized eggs to 0.38 μmol O2 mg protein-1 h-1 25 min after fertilization. Specific activity of the Na+/K+-ATPase was significantly stimulated after fertilization, ranging up to 1.07 μmol Pi h-1 mg protein-1 in the late blastula stage and slightly lower values in the early and late pluteus stages.

  20. The impact of HIV infection and disease stage on the rate of weight ...

    African Journals Online (AJOL)

    The differential effect of the World Health Organization (WHO) clinical stages of. HIV on nutrition recovery has not been sufficiently, if at all, explored; .... syndromic classifications based on the Wellcome classification system,[14] having records ...

  1. Comparison of Survival Rates, Tumor Stages, and Localization in between Obese and Nonobese Patients with Gastric Cancer

    Directory of Open Access Journals (Sweden)

    Hakan Kocoglu

    2016-01-01

    Full Text Available Purpose. In this study we tried to determine the association between body-mass index (BMI, survival rate, and the stage of tumor at the time of diagnosis in patients with gastric cancer. Methods. A total of 270 gastric cancer patients’ hospital records were retrospectively evaluated. Patients were grouped according to their BMI at the time of tumor diagnosis. Tumor stages at admission were compared according to their BMI values. Results. There were no differences in OS among BMI subgroups (p=0.230. The percent of patients with stage III tumor was significantly higher in nonobese while the percent of stage IV tumor was surprisingly higher in obese patients (p was 0.011 and 0.004, resp.. Percent of patients who did not have any surgical intervention was significantly lower in overweight and obese patients than normal and/or underweight patients. Conclusions. At the time of diagnosis, obese patients had significantly higher percent of stage IV tumor than nonobese patients. Despite of that, there were no differences in survival rates among BMI subgroups. Our study results are consistent with “obesity paradox” in gastric cancer patients. We also did not find any relationship between BMI and localization of gastric tumor.

  2. Gamma ray heating rates due to chromium isotopes in stellar core during late stages of high mass stars (>10M⊙

    Directory of Open Access Journals (Sweden)

    Nabi Jameel-Un

    2017-01-01

    Full Text Available Gamma ray heating rates are thought to play a crucial role during the pre-supernova stage of high mass stars. Gamma ray heating rates, due to β±-decay and electron (positron capture on chromium isotopes, are calculated using proton-neutron quasiparticle random phase approximation theory. The electron capture significantly affects the lepton fraction (Ye and accelerates the core contraction. The gamma rays emitted as a result of weak processes heat the core and tend to hinder the cooling and contraction due to electron capture and neutrino emission. The emitted gamma rays tend to produce enormous entropy and set the convection to play its role at this stage. The gamma heating rates, on 50-60Cr, are calculated for the density range 10 < ρ (g.cm-3 < 1011 and temperature range 107 < T (K < 3.0×1010.

  3. Estimating the incidence reporting rates of new influenza pandemics at an early stage using travel data from the source country.

    Science.gov (United States)

    Chong, K C; Fong, H F; Zee, C Y

    2014-05-01

    During the surveillance of influenza pandemics, underreported data are a public health challenge that complicates the understanding of pandemic threats and can undermine mitigation efforts. We propose a method to estimate incidence reporting rates at early stages of new influenza pandemics using 2009 pandemic H1N1 as an example. Routine surveillance data and statistics of travellers arriving from Mexico were used. Our method incorporates changes in reporting rates such as linearly increasing trends due to the enhanced surveillance. From our results, the reporting rate was estimated at 0·46% during early stages of the pandemic in Mexico. We estimated cumulative incidence in the Mexican population to be 0·7% compared to 0·003% reported by officials in Mexico at the end of April. This method could be useful in estimation of actual cases during new influenza pandemics for policy makers to better determine appropriate control measures.

  4. Maintaining Genome Stability in Defiance of Mitotic DNA Damage

    Science.gov (United States)

    Ferrari, Stefano; Gentili, Christian

    2016-01-01

    The implementation of decisions affecting cell viability and proliferation is based on prompt detection of the issue to be addressed, formulation and transmission of a correct set of instructions and fidelity in the execution of orders. While the first and the last are purely mechanical processes relying on the faithful functioning of single proteins or macromolecular complexes (sensors and effectors), information is the real cue, with signal amplitude, duration, and frequency ultimately determining the type of response. The cellular response to DNA damage is no exception to the rule. In this review article we focus on DNA damage responses in G2 and Mitosis. First, we set the stage describing mitosis and the machineries in charge of assembling the apparatus responsible for chromosome alignment and segregation as well as the inputs that control its function (checkpoints). Next, we examine the type of issues that a cell approaching mitosis might face, presenting the impact of post-translational modifications (PTMs) on the correct and timely functioning of pathways correcting errors or damage before chromosome segregation. We conclude this essay with a perspective on the current status of mitotic signaling pathway inhibitors and their potential use in cancer therapy. PMID:27493659

  5. Stage-specific incidence rates and trends of prostate cancer by age, race, and ethnicity, United States, 2004-2014.

    Science.gov (United States)

    Li, Jun; Siegel, David A; King, Jessica B

    2018-05-01

    Current literature shows different findings on the contemporary trends of distant-stage prostate cancer incidence, in part, due to low study population coverage and wide age groupings. This study aimed to examine the stage-specific incidence rates and trends of prostate cancer by age (5-year grouping), race, and ethnicity using nationwide cancer registry data. Data on prostate cancer cases came from the 2004-2014 United States Cancer Statistics data set. We calculated stage-specific incidence and 95% confidence intervals by age (5-year age grouping), race, and ethnicity. To measure the changes in rates over time, we calculated annual percentage change (APC). We identified 2,137,054 incident prostate cancers diagnosed during 2004-2014, with an age-adjusted incidence rate of 453.8 per 100,000. Distant-stage prostate cancer incidence significantly decreased during 2004-2010 (APC = -1.2) and increased during 2010-2014 (APC = 3.3). Significant increases in distant prostate cancer incidence also occurred in men aged older than or equal to 50 years except men aged 65-74 and older than or equal to 85 years, in men with white race (APC = 3.9), and non-Hispanic ethnicity (APC = 3.5). Using data representing over 99% of U.S. population, we found that incidence rates of distant-stage prostate cancer significantly increased during 2010-2014 among men in certain ages, in white, and with non-Hispanic ethnicity. Published by Elsevier Inc.

  6. ATP depletion during mitotic arrest induces mitotic slippage and APC/CCdh1-dependent cyclin B1 degradation.

    Science.gov (United States)

    Park, Yun Yeon; Ahn, Ju-Hyun; Cho, Min-Guk; Lee, Jae-Ho

    2018-04-27

    ATP depletion inhibits cell cycle progression, especially during the G1 phase and the G2 to M transition. However, the effect of ATP depletion on mitotic progression remains unclear. We observed that the reduction of ATP after prometaphase by simultaneous treatment with 2-deoxyglucose and NaN 3 did not arrest mitotic progression. Interestingly, ATP depletion during nocodazole-induced prometaphase arrest resulted in mitotic slippage, as indicated by a reduction in mitotic cells, APC/C-dependent degradation of cyclin B1, increased cell attachment, and increased nuclear membrane reassembly. Additionally, cells successfully progressed through the cell cycle after mitotic slippage, as indicated by EdU incorporation and time-lapse imaging. Although degradation of cyclin B during normal mitotic progression is primarily regulated by APC/C Cdc20 , we observed an unexpected decrease in Cdc20 prior to degradation of cyclin B during mitotic slippage. This decrease in Cdc20 was followed by a change in the binding partner preference of APC/C from Cdc20 to Cdh1; consequently, APC/C Cdh1 , but not APC/C Cdc20 , facilitated cyclin B degradation following ATP depletion. Pulse-chase analysis revealed that ATP depletion significantly abrogated global translation, including the translation of Cdc20 and Cdh1. Additionally, the half-life of Cdh1 was much longer than that of Cdc20. These data suggest that ATP depletion during mitotic arrest induces mitotic slippage facilitated by APC/C Cdh1 -dependent cyclin B degradation, which follows a decrease in Cdc20 resulting from reduced global translation and the differences in the half-lives of the Cdc20 and Cdh1 proteins.

  7. Changes in Ect2 Localization Couple Actomyosin-Dependent Cell Shape Changes to Mitotic Progression

    Science.gov (United States)

    Matthews, Helen K.; Delabre, Ulysse; Rohn, Jennifer L.; Guck, Jochen; Kunda, Patricia; Baum, Buzz

    2012-01-01

    Summary As they enter mitosis, animal cells undergo profound actin-dependent changes in shape to become round. Here we identify the Cdk1 substrate, Ect2, as a central regulator of mitotic rounding, thus uncovering a link between the cell-cycle machinery that drives mitotic entry and its accompanying actin remodeling. Ect2 is a RhoGEF that plays a well-established role in formation of the actomyosin contractile ring at mitotic exit, through the local activation of RhoA. We find that Ect2 first becomes active in prophase, when it is exported from the nucleus into the cytoplasm, activating RhoA to induce the formation of a mechanically stiff and rounded metaphase cortex. Then, at anaphase, binding to RacGAP1 at the spindle midzone repositions Ect2 to induce local actomyosin ring formation. Ect2 localization therefore defines the stage-specific changes in actin cortex organization critical for accurate cell division. PMID:22898780

  8. Rates of oxygen uptake increase independently of changes in heart rate in late stages of development and at hatching in the green iguana, Iguana iguana.

    Science.gov (United States)

    Sartori, Marina R; Abe, Augusto S; Crossley, Dane A; Taylor, Edwin W

    2017-03-01

    Oxygen consumption (VO 2 ), heart rate (f H ), heart mass (M h ) and body mass (M b ) were measured during embryonic incubation and in hatchlings of green iguana (Iguana iguana). Mean f H and VO 2 were unvarying in early stage embryos. VO 2 increased exponentially during the later stages of embryonic development, doubling by the end of incubation, while f H was constant, resulting in a 2.7-fold increase in oxygen pulse. Compared to late stage embryos, the mean inactive level of VO 2 in hatchlings was 1.7 fold higher, while f H was reduced by half resulting in a further 3.6 fold increase in oxygen pulse. There was an overall negative correlation between mean f H and VO 2 when data from hatchlings was included. Thus, predicting metabolic rate as VO 2 from measurements of f H is not possible in embryonic reptiles. Convective transport of oxygen to supply metabolism during embryonic incubation was more reliably indicated as an index of cardiac output (CO i ) derived from the product of f H and M h . However, a thorough analysis of factors determining rates of oxygen supply during development and eclosion in reptiles will require cannulation of blood vessels that proved impossible in the present study, to determine oxygen carrying capacity by the blood and arteriovenous oxygen content difference (A-V diff), plus patterns of blood flow. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. In vitro autoradiographic studies for determination of mitotic index and labelling index in biopsies of the human oral mucosa

    International Nuclear Information System (INIS)

    Etzbach, T.

    1980-01-01

    In order to find the most favourable method of incubation for in-vitro autoradiographies of biopsies of human oral mucosa, tissue biopsies were taken from oral mucosa transplants of 10 patients (7 females, 3 males) and either fixed or incubated at once. The author then investigated the mitotic index of the non-incubated tissue specimens, the mitotic index of the tissue specimens incubated in atmospheric conditions (A), and the mitotic index of the tissue specimens incubated under pressure (B). Simultaneously, autoradiographs of the incubated tissue specimens were prepared in order to determine their labelling indices. The mitotic indices of the non-incubated tissue specimen were found to differ significantly from those of the A-incubated tissue specimens. A similar difference was found between the mitotic indices of the A- and B-incubated tissue biopsies. Further, the labelling indices of A autoradiographs differed significantly from the labelling indices of B autoradiographs. The findings suggest that incubation with an excess oxygen pressure of 2 bar is the method of choice for in-vitro studies of human oral mucosa as the cells retain their specific activity and cell processes will continue unhindered. Further, the findings can be transferred to in-vivo conditions with a reasonable error rate. (orig./MG) [de

  10. Magic with moulds: Meiotic and mitotic crossing over in Neurospora ...

    Indian Academy of Sciences (India)

    2006-02-16

    Feb 16, 2006 ... Home; Journals; Journal of Biosciences; Volume 31; Issue 1. Commentary: Magic with moulds: Meiotic and mitotic crossing over in Neurospora inversions and duplications. Durgadas P Kasbekar. Volume 31 Issue 1 March 2006 pp 3-4 ...

  11. Effect of colchicine on mitotic polyploidization and morphological ...

    African Journals Online (AJOL)

    Ajai

    2012-05-15

    May 15, 2012 ... to diseases and insects and reduction in fertility of flowering plants ..... soaking duration was noticed to cause the treated seeds to give low height .... Addison-. Wesley, London. Stadler J, Phillips RL, Leonard M (1989).Mitotic ...

  12. A Three-Stage Optimization Algorithm for the Stochastic Parallel Machine Scheduling Problem with Adjustable Production Rates

    Directory of Open Access Journals (Sweden)

    Rui Zhang

    2013-01-01

    Full Text Available We consider a parallel machine scheduling problem with random processing/setup times and adjustable production rates. The objective functions to be minimized consist of two parts; the first part is related with the due date performance (i.e., the tardiness of the jobs, while the second part is related with the setting of machine speeds. Therefore, the decision variables include both the production schedule (sequences of jobs and the production rate of each machine. The optimization process, however, is significantly complicated by the stochastic factors in the manufacturing system. To address the difficulty, a simulation-based three-stage optimization framework is presented in this paper for high-quality robust solutions to the integrated scheduling problem. The first stage (crude optimization is featured by the ordinal optimization theory, the second stage (finer optimization is implemented with a metaheuristic called differential evolution, and the third stage (fine-tuning is characterized by a perturbation-based local search. Finally, computational experiments are conducted to verify the effectiveness of the proposed approach. Sensitivity analysis and practical implications are also discussed.

  13. Mechanical control of mitotic progression in single animal cells

    OpenAIRE

    Cattin, Cedric J.; Düggelin, Marcel; Martinez-Martin, David; Gerber, Christoph; Müller, Daniel J.; Stewart, Martin P.

    2015-01-01

    Despite the importance of mitotic cell rounding in tissue development and cell proliferation, there remains a paucity of approaches to investigate the mechanical robustness of cell rounding. Here we introduce ion beam-sculpted microcantilevers that enable precise force-feedback-controlled confinement of single cells while characterizing their progression through mitosis. We identify three force regimes according to the cell response: small forces (∼5 nN) that accelerate mitotic progression, i...

  14. The effect of mitotic inhibitors on DNA strand size and radiation-associated break repair in Down syndrome fibroblasts

    International Nuclear Information System (INIS)

    Woods, W.G.; Steiner, M.E.; Kalvonjian, S.L.

    1985-01-01

    The effect of mitotic inhibitors on formation and repair of DNA breaks was studied in cultured fibroblasts from patients with Down syndrome in order to investigate the hypothesis that the karyotyping procedure itself may play a role in the increased chromosome breakage seen in these cells after gamma radiation exposure. Using the nondenaturing elution and alkaline elution techniques to examine fibroblasts from Down syndrome patients and from controls, no specific abnormalities in Down syndrome cells could be detected after exposure to mitotic inhibitors, including rate and extent of elution of DNA from filters as well as repair of radiation-induced DNA breaks. In both normal and Down syndrome cell strains, however, exposure to mitotic inhibitors was associated with a decrease in cellular DNA strand size, suggesting the presence of drug-induced DNA strand breaks. The mechanism of increased chromosome sensitivity of Down syndrome cells to gamma radiation remains unknown. (orig.)

  15. Timeless links replication termination to mitotic kinase activation.

    Directory of Open Access Journals (Sweden)

    Jayaraju Dheekollu

    2011-05-01

    Full Text Available The mechanisms that coordinate the termination of DNA replication with progression through mitosis are not completely understood. The human Timeless protein (Tim associates with S phase replication checkpoint proteins Claspin and Tipin, and plays an important role in maintaining replication fork stability at physical barriers, like centromeres, telomeres and ribosomal DNA repeats, as well as at termination sites. We show here that human Tim can be isolated in a complex with mitotic entry kinases CDK1, Auroras A and B, and Polo-like kinase (Plk1. Plk1 bound Tim directly and colocalized with Tim at a subset of mitotic structures in M phase. Tim depletion caused multiple mitotic defects, including the loss of sister-chromatid cohesion, loss of mitotic spindle architecture, and a failure to exit mitosis. Tim depletion caused a delay in mitotic kinase activity in vivo and in vitro, as well as a reduction in global histone H3 S10 phosphorylation during G2/M phase. Tim was also required for the recruitment of Plk1 to centromeric DNA and formation of catenated DNA structures at human centromere alpha satellite repeats. Taken together, these findings suggest that Tim coordinates mitotic kinase activation with termination of DNA replication.

  16. Cell-cycle variation in the induction of lethality and mitotic recombination after treatment with UV and nitrous acid in the yeast, Saccharomyces cerevisiae

    International Nuclear Information System (INIS)

    Davies, P.J.; Tippins, R.S.; Parry, J.M.

    1978-01-01

    Exponentially growing yeast cultures separated into discrete periods of the cell cycle by zonal rotor centrifugation show cyclic variation in both UV and nitrous acid induced cell lethality, mitotic gene conversion and mitotic crossing-over. Maximum cell survival after UV treatment was observed in the S and G2 phases of the cell cycle at a time when UV induction of both types of mitotic recombination was at a minumum. In contrast, cell inactivation by the chemical mutagen nitrous acid showed a single discrete period of sensitivity which occurred in S phase cells which are undergoing DNA synthesis. Mitotic gene conversion ahd mitotic crossing-over were induced by nitrous acid in cells at all stages of the cell cycle with a peak of induction of both events occurring at the time of maximum cell lethality. The lack of correlation observed between maximum cell survival and the maximum induction of mitotic intragenic recombination suggest that other DNA-repair mechanisms besides DNA-recombination repair are involved in the recovery of inactivated yeast cells during the cell cycle. (Auth.)

  17. Continuous production of biohythane from hydrothermal liquefied cornstalk biomass via two-stage high-rate anaerobic reactors.

    Science.gov (United States)

    Si, Bu-Chun; Li, Jia-Ming; Zhu, Zhang-Bing; Zhang, Yuan-Hui; Lu, Jian-Wen; Shen, Rui-Xia; Zhang, Chong; Xing, Xin-Hui; Liu, Zhidan

    2016-01-01

    Biohythane production via two-stage fermentation is a promising direction for sustainable energy recovery from lignocellulosic biomass. However, the utilization of lignocellulosic biomass suffers from specific natural recalcitrance. Hydrothermal liquefaction (HTL) is an emerging technology for the liquefaction of biomass, but there are still several challenges for the coupling of HTL and two-stage fermentation. One particular challenge is the limited efficiency of fermentation reactors at a high solid content of the treated feedstock. Another is the conversion of potential inhibitors during fermentation. Here, we report a novel strategy for the continuous production of biohythane from cornstalk through the integration of HTL and two-stage fermentation. Cornstalk was converted to solid and liquid via HTL, and the resulting liquid could be subsequently fed into the two-stage fermentation systems. The systems consisted of two typical high-rate reactors: an upflow anaerobic sludge blanket (UASB) and a packed bed reactor (PBR). The liquid could be efficiently converted into biohythane via the UASB and PBR with a high density of microbes at a high organic loading rate. Biohydrogen production decreased from 2.34 L/L/day in UASB (1.01 L/L/day in PBR) to 0 L/L/day as the organic loading rate (OLR) of the HTL liquid products increased to 16 g/L/day. The methane production rate achieved a value of 2.53 (UASB) and 2.54 L/L/day (PBR), respectively. The energy and carbon recovery of the integrated HTL and biohythane fermentation system reached up to 79.0 and 67.7%, respectively. The fermentation inhibitors, i.e., 5-hydroxymethyl furfural (41.4-41.9% of the initial quantity detected) and furfural (74.7-85.0% of the initial quantity detected), were degraded during hydrogen fermentation. Compared with single-stage fermentation, the methane process during two-stage fermentation had a more efficient methane production rate, acetogenesis, and COD removal. The microbial distribution

  18. Effect of recirculation rate on methane production and SEBAR system performance using active stage digester.

    Science.gov (United States)

    Tubtong, Cheevanuch; Towprayoon, Sirintornthep; Connor, Michael Anthony; Chaiprasert, Pawinee; Nopharatana, Annop

    2010-09-01

    A project was undertaken to examine the feasibility of treating organic wastes from Thai fruit and vegetable markets using the sequential batch anaerobic digester (SEBAR) approach. A key feature of the SEBAR system is the regular interchanging, or recirculation, of portions of leachate between each freshly filled digester and a support digester to which it is coupled until it is ready to operate independently. Leachate transfer from this support digester to the fresh waste digester provides additional alkalinity to help counteract the effects of early high acid release rates; it also helps build a balanced microbial population in the fresh waste digester. To optimize the leachate recirculation process, the effect of varying the quantities of leachate interchanged between freshly filled waste digesters and the still highly active support digesters to which they were coupled was studied. It was found that increasing the recirculation rate accelerated the onset of both waste degradation and methane production. The increasing of recirculation rate from 10% to 20% and 10% to 30% could reduce the SEBAR cycle period by approximately 7% and 22% without significant reduction in the amount of methane obtained from the systems. The methane yields were 0.0063, 0.0068 and 0.0077 l g(-1) VS added in the NEW digester per day using leachate recirculation rates of 10%, 20% and 30%, respectively. This finding has potentially important practical and economic implications for those using the SEBAR system to add value to market waste.

  19. Quantitative comparison of entropy analysis of fetal heart rate variability related to the different stages of labor.

    Science.gov (United States)

    Lim, Jongil; Kwon, Ji Young; Song, Juhee; Choi, Hosoon; Shin, Jong Chul; Park, In Yang

    2014-02-01

    The interpretation of the fetal heart rate (FHR) signal considering labor progression may improve perinatal morbidity and mortality. However, there have been few studies that evaluate the fetus in each labor stage quantitatively. To evaluate whether the entropy indices of FHR are different according to labor progression. A retrospective comparative study of FHR recordings in three groups: 280 recordings in the second stage of labor before vaginal delivery, 31 recordings in the first stage of labor before emergency cesarean delivery, and 23 recordings in the pre-labor before elective cesarean delivery. The stored FHR recordings of external cardiotocography during labor. Approximate entropy (ApEn) and sample entropy (SampEn) for the final 2000 RR intervals. The median ApEn and SampEn for the 2000 RR intervals showed the lowest values in the second stage of labor, followed by the emergency cesarean group and the elective cesarean group for all time segments (all PEntropy indices of FHR were significantly different according to labor progression. This result supports the necessity of considering labor progression when developing intrapartum fetal monitoring using the entropy indices of FHR. Copyright © 2013 Elsevier Ltd. All rights reserved.

  20. Three stage supply chain model with two warehouse, imperfect production, variable demand rate and inflation

    Directory of Open Access Journals (Sweden)

    Preety Gupta

    2013-01-01

    Full Text Available This study develops an integrated production inventory model from the perspectives of vendor, supplier and buyer. The demand rate is time dependent for the vendor and supplier and buyer assumes the stock dependent demand rate. As per the demand, supplier uses two warehouses (rented and owned for the storage of excess quantities. Shortages are allowed at the buyer’s part only and the unfulfilled demand is partially backlogged. The effect of imperfect production processes on lot sizing is also considered. This complete model is studied under the effect of inflation. The objective is to minimize the total cost for the system. A solution procedure is developed to find a near optimal solution for the model. A numerical example along with sensitivity analysis is given to illustrate the model.

  1. Stage-discharge rating curves based on satellite altimetry and modeled discharge in the Amazon basin

    OpenAIRE

    Paris, Adrien; Dias de Paiva, Rodrigo; Santos da Silva, Joecila; Medeiros Moreira, Daniel; Calmant, Stephane; Garambois, Pierre-André; Collischonn, Walter; Bonnet, Marie-Paule; Seyler, Frederique

    2016-01-01

    In this study, rating curves (RCs) were determined by applying satellite altimetry to a poorly gauged basin. This study demonstrates the synergistic application of remote sensing and watershed modeling to capture the dynamics and quantity of flow in the Amazon River Basin, respectively. Three major advancements for estimating basin-scale patterns in river discharge are described. The first advancement is the preservation of the hydrological meanings of the parameters expressed by ...

  2. Stage discharge curve for Guillemard Bridge streamflow sation based on rating curve method using historical flood event data

    International Nuclear Information System (INIS)

    Ros, F C; Sidek, L M; Desa, M N; Arifin, K; Tosaka, H

    2013-01-01

    The purpose of the stage-discharge curves varies from water quality study, flood modelling study, can be used to project climate change scenarios and so on. As the bed of the river often changes due to the annual monsoon seasons that sometimes cause by massive floods, the capacity of the river will changed causing shifting controlled to happen. This study proposes to use the historical flood event data from 1960 to 2009 in calculating the stage-discharge curve of Guillemard Bridge located in Sg. Kelantan. Regression analysis was done to check the quality of the data and examine the correlation between the two variables, Q and H. The mean values of the two variables then were adopted to find the value of difference between zero gauge height and the level of zero flow, 'a', K and 'n' to fit into rating curve equation and finally plotting the stage-discharge rating curve. Regression analysis of the historical flood data indicate that 91 percent of the original uncertainty has been explained by the analysis with the standard error of 0.085.

  3. Mcl-1 dynamics influence mitotic slippage and death in mitosis.

    Science.gov (United States)

    Sloss, Olivia; Topham, Caroline; Diez, Maria; Taylor, Stephen

    2016-02-02

    Microtubule-binding drugs such as taxol are frontline treatments for a variety of cancers but exactly how they yield patient benefit is unclear. In cell culture, inhibiting microtubule dynamics prevents spindle assembly, leading to mitotic arrest followed by either apoptosis in mitosis or slippage, whereby a cell returns to interphase without dividing. Myeloid cell leukaemia-1 (Mcl-1), a pro-survival member of the Bcl-2 family central to the intrinsic apoptosis pathway, is degraded during a prolonged mitotic arrest and may therefore act as a mitotic death timer. Consistently, we show that blocking proteasome-mediated degradation inhibits taxol-induced mitotic apoptosis in a Mcl-1-dependent manner. However, this degradation does not require the activity of either APC/C-Cdc20, FBW7 or MULE, three separate E3 ubiquitin ligases implicated in targeting Mcl-1 for degradation. This therefore challenges the notion that Mcl-1 undergoes regulated degradation during mitosis. We also show that Mcl-1 is continuously synthesized during mitosis and that blocking protein synthesis accelerates taxol induced death-in-mitosis. Modulating Mcl-1 levels also influences slippage; overexpressing Mcl-1 extends the time from mitotic entry to mitotic exit in the presence of taxol, while inhibiting Mcl-1 accelerates it. We suggest that Mcl-1 competes with Cyclin B1 for binding to components of the proteolysis machinery, thereby slowing down the slow degradation of Cyclin B1 responsible for slippage. Thus, modulating Mcl-1 dynamics influences both death-in-mitosis and slippage. However, because mitotic degradation of Mcl-1 appears not to be under the control of an E3 ligase, we suggest that the notion of network crosstalk is used with caution.

  4. Stage-discharge rating curves based on satellite altimetry and modeled discharge in the Amazon basin

    Science.gov (United States)

    Paris, Adrien; Dias de Paiva, Rodrigo; Santos da Silva, Joecila; Medeiros Moreira, Daniel; Calmant, Stephane; Garambois, Pierre-André; Collischonn, Walter; Bonnet, Marie-Paule; Seyler, Frederique

    2016-05-01

    In this study, rating curves (RCs) were determined by applying satellite altimetry to a poorly gauged basin. This study demonstrates the synergistic application of remote sensing and watershed modeling to capture the dynamics and quantity of flow in the Amazon River Basin, respectively. Three major advancements for estimating basin-scale patterns in river discharge are described. The first advancement is the preservation of the hydrological meanings of the parameters expressed by Manning's equation to obtain a data set containing the elevations of the river beds throughout the basin. The second advancement is the provision of parameter uncertainties and, therefore, the uncertainties in the rated discharge. The third advancement concerns estimating the discharge while considering backwater effects. We analyzed the Amazon Basin using nearly one thousand series that were obtained from ENVISAT and Jason-2 altimetry for more than 100 tributaries. Discharge values and related uncertainties were obtained from the rain-discharge MGB-IPH model. We used a global optimization algorithm based on the Monte Carlo Markov Chain and Bayesian framework to determine the rating curves. The data were randomly allocated into 80% calibration and 20% validation subsets. A comparison with the validation samples produced a Nash-Sutcliffe efficiency (Ens) of 0.68. When the MGB discharge uncertainties were less than 5%, the Ens value increased to 0.81 (mean). A comparison with the in situ discharge resulted in an Ens value of 0.71 for the validation samples (and 0.77 for calibration). The Ens values at the mouths of the rivers that experienced backwater effects significantly improved when the mean monthly slope was included in the RC. Our RCs were not mission-dependent, and the Ens value was preserved when applying ENVISAT rating curves to Jason-2 altimetry at crossovers. The cease-to-flow parameter of our RCs provided a good proxy for determining river bed elevation. This proxy was validated

  5. In-target rare nuclei production rates with EURISOL single-stage configuration

    CERN Document Server

    Chabod, S P; Ene, D; Doré, D; Blideanu, V; David, J.-Ch; Ridikas, D

    2010-01-01

    We conducted calculations of exotic nuclei production rates for 320 configurations of EURISOL (European Isotope Separation On-Line Radioactive Ion Beam Facility) direct spallation targets. The nuclei yields were evaluated using neutron generation-transport codes, completed with evolution calculations to account for nuclei decays and low energy neutron interactions. The yields were optimized for 11 selected elements (Li, Be, Ne, Mg, Ar, Ni, Ga, Kr, Sn, Hg, Fr) and 23 of their isotopes, as function of the target compositions and geometries as well as the incident proton beam energies. For the considered elements, we evaluated the yield distributions as functions of the charge and mass numbers using two different spallation models.

  6. Prediction of basal metabolic rate in obese children and adolescents considering pubertal stages and anthropometric characteristics or body composition.

    Science.gov (United States)

    Lazzer, S; Patrizi, A; De Col, A; Saezza, A; Sartorio, A

    2014-06-01

    To develop and crossvalidate new equations for predicting basal metabolic rate (BMR) in obese children and adolescents in relation to pubertal stages, anthropometric characteristics or body composition. A total of 1696 obese Caucasian children and adolescents (mean body mass index z-score: 3.5±0.8) participated in this study. BMR was determined by indirect calorimetry and fat-free mass (FFM) and fat mass (FM) by bioelectrical impedance analysis. Equations were derived by stepwise multiple regression analysis using a calibration cohort of 848 subjects, and the equations were crossvalidated with a Bland and Altman method in the remaining 848 subjects. Two new specific equations based on gender (1: males; 0: females), pubertal stages (from 1 to 5, assessed according Marshall & Tanner methods) and body weight (BW, kg), stature (m) or body composition (kg) were generated as follows: (1) BMR=(BW × 0.044)+(stature × 2.836)-(pubertal stage × 0.148)+(gender × 0.781)-0.551 (adjusted coefficient of determination (R(2)adj)= 0.69 and root mean squared error (RMSE)=0.954 MJ); (2) BMR=(FFM × 0.082)+(FM × 0.037)-(pubertal stage × 0.125)+(gender × 0.706)+2.528 (R(2)adj= 0.70 and RMSE=0.943 MJ). In the crossvalidation group, mean-predicted BMR was not significantly different from the mean-measured BMR (MBMR) for all children and adolescents, as well as for boys and girls (differenceBMR was predicted accurately (90-110% of MBMR) in 67% of subjects. The new prediction equations considering the pubertal stages allow an accurate and more appropriate (vs equations using chronological age) estimation of BMR in obese children and adolescents.

  7. Effect of Non-linear Velocity Loss Changes in Pumping Stage of Hydraulic Ram Pumps on Pumping Discharge Rate

    Directory of Open Access Journals (Sweden)

    Reza Fatahialkouhi

    2018-03-01

    the previous researchers. Comparing the results indicates that in the proposed model, noticing that the recommended equations of pumping stage are presented based on nonlinear closing theory of the impulse valve, the model accuracy for predicting relative pumping rate has been increased up to 3% compared with linear closure theory (Lansford and Dugan, 1941 and has been increased up to 5% compared with rapid closure theory (Tacke, 1988.

  8. Disparities in treatment rates of paediatric end-stage renal disease across Europe

    DEFF Research Database (Denmark)

    Chesnaye, Nicholas C; Schaefer, Franz; Groothoff, Jaap W

    2015-01-01

    /1321 km, P rates were found in wealthier countries (2.47 pmc/€10 378 GDP per capita, P among those...... and physical access to treatment were collected through an online survey and from the World Bank database. The estimated effect is presented per 1SD increase for each indicator. RESULTS: The incidence of paediatric RRT in Europe was 5.4 cases pmc. Incidence decreased from Western to Eastern Europe (-1.91 pmc...... that tend to spend more on healthcare (1.45 pmc/1.7% public health expenditure, P among countries where patients pay less out-of-pocket for healthcare (-1.29 pmc/11.7% out-of-pocket health expenditure, P

  9. Robust mitotic entry is ensured by a latching switch

    Directory of Open Access Journals (Sweden)

    Chloe Tuck

    2013-07-01

    Cell cycle events are driven by Cyclin dependent kinases (CDKs and by their counter-acting phosphatases. Activation of the Cdk1:Cyclin B complex during mitotic entry is controlled by the Wee1/Myt1 inhibitory kinases and by Cdc25 activatory phosphatase, which are themselves regulated by Cdk1:Cyclin B within two positive circuits. Impairing these two feedbacks with chemical inhibitors induces a transient entry into M phase referred to as mitotic collapse. The pathology of mitotic collapse reveals that the positive circuits play a significant role in maintaining the M phase state. To better understand the function of these feedback loops during G2/M transition, we propose a simple model for mitotic entry in mammalian cells including spatial control over Greatwall kinase phosphorylation. After parameter calibration, the model is able to recapture the complex and non-intuitive molecular dynamics reported by Potapova et al. (Potapova et al., 2011. Moreover, it predicts the temporal patterns of other mitotic regulators which have not yet been experimentally tested and suggests a general design principle of cell cycle control: latching switches buffer the cellular stresses which accompany cell cycle processes to ensure that the transitions are smooth and robust.

  10. Robust mitotic entry is ensured by a latching switch.

    Science.gov (United States)

    Tuck, Chloe; Zhang, Tongli; Potapova, Tamara; Malumbres, Marcos; Novák, Béla

    2013-01-01

    Cell cycle events are driven by Cyclin dependent kinases (CDKs) and by their counter-acting phosphatases. Activation of the Cdk1:Cyclin B complex during mitotic entry is controlled by the Wee1/Myt1 inhibitory kinases and by Cdc25 activatory phosphatase, which are themselves regulated by Cdk1:Cyclin B within two positive circuits. Impairing these two feedbacks with chemical inhibitors induces a transient entry into M phase referred to as mitotic collapse. The pathology of mitotic collapse reveals that the positive circuits play a significant role in maintaining the M phase state. To better understand the function of these feedback loops during G2/M transition, we propose a simple model for mitotic entry in mammalian cells including spatial control over Greatwall kinase phosphorylation. After parameter calibration, the model is able to recapture the complex and non-intuitive molecular dynamics reported by Potapova et al. (Potapova et al., 2011). Moreover, it predicts the temporal patterns of other mitotic regulators which have not yet been experimentally tested and suggests a general design principle of cell cycle control: latching switches buffer the cellular stresses which accompany cell cycle processes to ensure that the transitions are smooth and robust.

  11. A Brief History of Research on Mitotic Mechanisms

    Directory of Open Access Journals (Sweden)

    J. Richard McIntosh

    2016-12-01

    Full Text Available This chapter describes in summary form some of the most important research on chromosome segregation, from the discovery and naming of mitosis in the nineteenth century until around 1990. It gives both historical and scientific background for the nine chapters that follow, each of which provides an up-to-date review of a specific aspect of mitotic mechanism. Here, we trace the fruits of each new technology that allowed a deeper understanding of mitosis and its underlying mechanisms. We describe how light microscopy, including phase, polarization, and fluorescence optics, provided descriptive information about mitotic events and also enabled important experimentation on mitotic functions, such as the dynamics of spindle fibers and the forces generated for chromosome movement. We describe studies by electron microscopy, including quantitative work with serial section reconstructions. We review early results from spindle biochemistry and genetics, coupled to molecular biology, as these methods allowed scholars to identify key molecular components of mitotic mechanisms. We also review hypotheses about mitotic mechanisms whose testing led to a deeper understanding of this fundamental biological event. Our goal is to provide modern scientists with an appreciation of the work that has laid the foundations for their current work and interests.

  12. A case of central type early stage lung cancer receiving 60Co high dose-rate postoperative endobronchial radiation

    International Nuclear Information System (INIS)

    Nakamori, Syouji; Kodama, Ken; Kurokawa, Eiji; Doi, Osamu; Terasawa, Toshio; Chatani, Masashi; Inoue, Toshihiko; Tateishi, Ryuhei

    1985-01-01

    Right middle-lower lobectomy and mediastinal lymph node dissection were performed for a case of central type early stage lung cancer. Tumor extended very closely to the line of incision margin of the resected specimen, appearing as carcinoma in situ. To inprove curativity, postoperative radiation therapy was performed with 60 Co high dose-rate endobronchial radiation by a remote afterloading system. A total dose of 40Gy was administered to the target area without any severe side effects. The patient is healthy and has no evidence of metastasis. This procedure is considered to be an effective treatment for postoperative lung cancer with possible residual malignancy. (author)

  13. Decomposition rate of peat-forming plants in the oligotrophic peatland at the first stages of destruction

    Science.gov (United States)

    Nikonova, L. G.; Golovatskaya, E. A.; Terechshenko, N. N.

    2018-03-01

    The research presents quantitative estimates of the decomposition rate of plant residues at the initial stages of the decay of two plant species (Eriophorum vaginatum and Sphagnum fuscum) in a peat deposit of the oligotrophic bog in the southern taiga subzone of Western Siberia. We also studied a change in the content of total carbon and nitrogen in plant residues and the activity of microflora in the initial stages of decomposition. At the initial stage of the transformation process of peat-forming plants the losses of mass of Sph. fuscum is 2.5 times lower then E. vaginatum. The most active mass losses, as well as a decrease in the total carbon content, is observed after four months of the experiment. The most active carbon removal is characteristic for E. vaginatum. During the decomposition of plant residues, the nitrogen content decreases, and the most intense nitrogen losses were characteristic for Sph. fuscum. The microorganisms assimilating organic and mineral nitrogen are more active in August, the oligotrophic and cellulolytic microorganisms – in July.

  14. Effectiveness of music therapy in state-trait anxiety rate of addicts in drug-free rehabilitation stage

    Directory of Open Access Journals (Sweden)

    E Soleimani

    2016-02-01

    Full Text Available Objective: This study was an attempt to investigate the effect of music therapy on addicts’ state-trait anxiety rate in the stage of drug-free rehabilitation. Method: A quasi-experimental research design, along with pretest-posttest and control group was employed for the conduct of this study. The statistical population of the study included the addicts in the rehabilitation stage who had referred to the clean collaborators rehabilitation camp in Ardebil province in November 2014. From this population, the number of 32 addicts in 16-50-year-old age range was selected as the participants of the study by convenience sampling method. State-Trait Anxiety Inventory was used for data collection. Results: The results of multivariate covariant analysis showed that there is a significant difference between control and experimental groups in state and trait anxiety. In other words, the state and trait anxiety of addicts in the experimental group had been reduced after music therapy. Conclusion: Considering the obtained results, it can be concluded that music therapy alone or along other psychological interventions can be an effective method for reducing addicts’ anxiety in drug-free rehabilitation stage.

  15. Mechanisms and Regulation of Mitotic Recombination in Saccharomyces cerevisiae

    Science.gov (United States)

    Symington, Lorraine S.; Rothstein, Rodney; Lisby, Michael

    2014-01-01

    Homology-dependent exchange of genetic information between DNA molecules has a profound impact on the maintenance of genome integrity by facilitating error-free DNA repair, replication, and chromosome segregation during cell division as well as programmed cell developmental events. This chapter will focus on homologous mitotic recombination in budding yeast Saccharomyces cerevisiae. However, there is an important link between mitotic and meiotic recombination (covered in the forthcoming chapter by Hunter et al. 2015) and many of the functions are evolutionarily conserved. Here we will discuss several models that have been proposed to explain the mechanism of mitotic recombination, the genes and proteins involved in various pathways, the genetic and physical assays used to discover and study these genes, and the roles of many of these proteins inside the cell. PMID:25381364

  16. Disappearance of nucleosome positioning in mitotic chromatin in vivo.

    Science.gov (United States)

    Komura, Jun-ichiro; Ono, Tetsuya

    2005-04-15

    During mitosis, transcription is silenced and most transcription factors are displaced from their recognition sequences. By in vivo footprinting analysis, we have confirmed and extended previous studies showing loss of transcription factors from an RNA polymerase II promoter (c-FOS) and, for the first time, an RNA polymerase III promoter (U6) in HeLa cells. Because little was known about nucleosomal organization in mitotic chromosomes, we performed footprinting analysis for nucleosomes on these promoters in interphase and mitotic cells. During interphase, each of the promoters had a positioned nucleosome in the region intervening between proximal promoter elements and distal enhancer elements, but the strong nucleosome positioning disappeared during mitosis. Thus, the nucleosomal organization that appears to facilitate transcription in interphase cells may be lost in mitotic cells, and nucleosome positioning during mitosis does not seem to be a major component of the epigenetic mechanisms to mark genes for rapid reactivation after this phase.

  17. Self-rated appetite as a predictor of mortality in patients with stage 5 chronic kidney disease.

    Science.gov (United States)

    Gama-Axelsson, Thiane; Lindholm, Bengt; Bárány, Peter; Heimbürger, Olof; Stenvinkel, Peter; Qureshi, Abdul Rashid

    2013-03-01

    To investigate the level of anorexia and its correlation with mortality in chronic kidney disease stage 5 patients not yet on dialysis (CKD5-ND) and in those with stage 5 chronic kidney disease undergoing dialysis (CKD5-D). In an observational study, self-rated appetite (as part of a subjective global assessment of nutritional status), along with anthropometrics and biochemical markers of nutritional status, was analyzed in relation to survival. In a subgroup of patients, appetite change after start of dialysis was studied prospectively. Two hundred eighty CKD5-ND (40% female; age 54 ± 12 years; glomerular filtration rate 7 ± 2 mL/minute) and 243 CKD5-D patients (116 hemodialysis and 127 peritoneal dialysis [PD]; 44% female; age 54 ± 12 years; dialysis vintage time 12 ± 2 months) who had been on dialysis for about 1 year were studied. CKD5-ND patients with poor appetite (50%) had a higher prevalence of cardiovascular disease, lower body weight and serum creatinine level, and higher C-reactive protein. CKD5-D patients with poor appetite (33%) had impaired subjective global assessment of nutritional status and lower body weight, fat body mass, handgrip strength, hemoglobin, and serum albumin level. In a Kaplan-Meier analysis, appetite was not associated with survival difference, whereas in the Cox proportional hazards model with competing risk analysis, poor appetite increased mortality risk in PD patients but not in hemodialysis and CKD5-ND patients. In CKD5-ND patients, self-rated appetite was not an independent predictor of 48-months survival, whereas there was a significant increase in mortality risk in PD patients with poor appetite. Copyright © 2013 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

  18. Adherence rates to ferric citrate as compared to active control in patients with end stage kidney disease on dialysis.

    Science.gov (United States)

    Jalal, Diana; McFadden, Molly; Dwyer, Jamie P; Umanath, Kausik; Aguilar, Erwin; Yagil, Yoram; Greco, Barbara; Sika, Mohammed; Lewis, Julia B; Greene, Tom; Goral, Simin

    2017-04-01

    Oral phosphate binders are the main stay of treatment of hyperphosphatemia. Adherence rates to ferric citrate, a recently approved phosphate binder, are unknown. We conducted a post-hoc analysis to evaluate whether adherence rates were different for ferric citrate vs. active control in 412 subjects with end stage kidney disease (ESKD) who were randomized to ferric citrate vs. active control (sevelamer carbonate and/or calcium acetate). Adherence was defined as percent of actual number of pills taken to total number of pills prescribed. There were no significant differences in baseline characteristics including gender, race/ethnicity, and age between the ferric citrate and active control groups. Baseline phosphorus, calcium, and parathyroid hormone levels were similar. Mean (SD) adherence was 81.4% (17.4) and 81.7% (15.9) in the ferric citrate and active control groups, respectively (P = 0.88). Adherence remained similar between both groups after adjusting for gender, race/ethnicity, age, cardiovascular disease (CVD), and diabetic nephropathy (mean [95% CI]: 81.4% [78.2, 84.6] and 81.5% [77.7, 85.2] for ferric citrate and active control, respectively). Gender, race/ethnicity, age, and diagnosis of diabetic nephropathy did not influence adherence to the prescribed phosphate binder. Subjects with CVD had lower adherence rates to phosphate binder; this was significant only in the active control group. Adherence rates to the phosphate binder, ferric citrate, were similar to adherence rates to active control. Similar adherence rates to ferric citrate are notable since tolerance to active control was an entry criteria and the study was open label. Gender, race/ethnicity, nor age influenced adherence. © 2016 International Society for Hemodialysis.

  19. Comparison of high dose rate (HDR) and low dose rate (LDR) brachytherapy in the treatment of stage IIIB cervix cancer with radiation therapy alone. The preliminary results

    International Nuclear Information System (INIS)

    Trippe, Nivaldo; Novaes, P.E.; Ferrigno, R.; Pellizzon, A.C.; Salvajoli, J.V.; Fogaroli, R.C.; Maia, M.A.C.; Baraldi, H.E.

    1996-01-01

    Purpose/Objective: To compare the results between HDR and LDR brachytherapy in the treatment of stage IIIB cervix cancer with radiation therapy alone through a prospective and randomized trial. Materials and Methods: From September 1992 to December 1993, 65 patients with stage IIIB cervical cancer were randomized to one of the following treatment schedule according to the brachytherapy used to complement the dose of external beam radiotherapy (EBRT): 1 - High dose rate (HDR) - 36 patients - 4 weekly insertions of 6,0 Gy at point A 2 - Low dose rate (LDR) - 29 patients - 2 insertions two weeks apart of 17,5 Gy at point A The External Beam radiotherapy was performed through a Linac 4MV, in box arrangement for whole pelvis and in AP-PA fields for parametrial complementation of dose. The dose at the whole pelvis was 45 Gy in 25 fractions of 1,8 Gy and the parametrial dose was 16 Gy. The brachytherapy was realized with Fletcher colpostats and intrauterine tandem, in both arms. The HDR brachytherapy was realized through a Micro-Selectron device, working with Iridium-192 with initial activity of 10 Ci and started ten days after the beginning of EBRT. The total treatment time was shortened in two weeks for this group. The LDR brachytherapy started only after the end of EBRT. Results: With the minimum follow up of 24 months and medium of 31 months, the disease free survival was 50% among the 36 patients in HDR group and 47,8% among the 29 patients in LDR group. Local failures occurred in 50% and 52,8% respectively. Grade I and II complications were restricted to rectites and cistites and the incidence of them was 8,3% for HDR group and 13% for LDR group. Until the time of evaluation there were no grade III complications in any group. Conclusions: Although the number of patients is small and the time of follow up still short, these preliminary results suggest that the HDR brachytherapy has an equivalent efficiency in local control as the LDR in the treatment of stage IIIB

  20. Identification of Pathways Required for the Coordination of Late Mitotic Events in Animal Cells

    National Research Council Canada - National Science Library

    Baumgartner, Bridget L; Harper, J. W

    2005-01-01

    ... in genomic instability, a hallmark of cancer. In yeast, a signaling pathway has been identified, called the Mitotic Exit Network, which coordinates mitotic exit and cytokinesis with the end of anaphase...

  1. Identification of Pathways Required for the Coordination of Late Mitotic Events in Animal Cells

    National Research Council Canada - National Science Library

    Baumgartner, Bridget

    2004-01-01

    ... in genomic instability, a hallmark of cancer. In yeast, a signaling pathway has been identified, called the Mitotic Exit Network, which coordinates mitotic exit and cytokinesis with the end of anaphase...

  2. Mitotic Stress in Cancer: Tipping the Fine Balance

    Indian Academy of Sciences (India)

    Acer

    of these molecules do not fit into the classical definition of oncogenes or tumor suppressor genes. In some cases, both over-expression and decreased expression of these genes result in mitotic arrest. Moreover, some .... The Clinical Collaborators: Dr. Arunabha Sengupta. Dr. Arun Roy. Dr. Jayanta Chakrabarty, CNCI. Prof.

  3. Cdc20 control of cell fate during prolonged mitotic arrest

    DEFF Research Database (Denmark)

    Nilsson, Jakob

    2011-01-01

    The fate of cells arrested in mitosis by antimitotic compounds is complex but is influenced by competition between pathways promoting cell death and pathways promoting mitotic exit. As components of both of these pathways are regulated by Cdc20-dependent degradation, I hypothesize that variations...

  4. Radiation-induced mitotic catastrophe in PARG-deficient cells

    Energy Technology Data Exchange (ETDEWEB)

    Ame, J.Ch.; Fouquerel, E.; Dantzer, F.; De Murcia, G.; Schreiber, V. [IREBS-FRE3211 du CNRS, Universite de Strasbourg, ESBS, Bd Sebastien Brant, BP 10413, 67412 Illkirch Cedex (France); Gauthier, L.R.; Boussin, F.D. [Laboratoire de Radiopathologie/INSERM U967, CEA-DSV-IRCM, 92265 Fontenay aux Roses, Cedex 6 (France); Biard, D. [CEA-DSV-IRCM/INSERM U935, Institut A. Lwoff-CNRS, BP 8, 94801 Villejuif cedex (France)

    2009-07-01

    Poly(ADP-ribosyl)ation is a post-translational modification of proteins involved in the regulation of chromatin structure, DNA metabolism, cell division and cell death. Through the hydrolysis of poly(ADP-ribose) (PAR), Poly(ADP-ribose) glyco-hydrolase (PARG) has a crucial role in the control of life-and-death balance following DNA insult. Comprehension of PARG function has been hindered by the existence of many PARG isoforms encoded by a single gene and displaying various subcellular localizations. To gain insight into the function of PARG in response to irradiation, we constitutively and stably knocked down expression of PARG isoforms in HeLa cells. PARG depletion leading to PAR accumulation was not deleterious to undamaged cells and was in fact rather beneficial, because it protected cells from spontaneous single-strand breaks and telomeric abnormalities. By contrast, PARG-deficient cells showed increased radiosensitivity, caused by defects in the repair of single- and double-strand breaks and in mitotic spindle checkpoint, leading to alteration of progression of mitosis. Irradiated PARG-deficient cells displayed centrosome amplification leading to mitotic supernumerary spindle poles, and accumulated aberrant mitotic figures, which induced either polyploidy or cell death by mitotic catastrophe. Our results suggest that PARG could be a novel potential therapeutic target for radiotherapy. (authors)

  5. Detection of mitotic nuclei in breast histopathology images using localized ACM and Random Kitchen Sink based classifier.

    Science.gov (United States)

    Beevi, K Sabeena; Nair, Madhu S; Bindu, G R

    2016-08-01

    The exact measure of mitotic nuclei is a crucial parameter in breast cancer grading and prognosis. This can be achieved by improving the mitotic detection accuracy by careful design of segmentation and classification techniques. In this paper, segmentation of nuclei from breast histopathology images are carried out by Localized Active Contour Model (LACM) utilizing bio-inspired optimization techniques in the detection stage, in order to handle diffused intensities present along object boundaries. Further, the application of a new optimal machine learning algorithm capable of classifying strong non-linear data such as Random Kitchen Sink (RKS), shows improved classification performance. The proposed method has been tested on Mitosis detection in breast cancer histological images (MITOS) dataset provided for MITOS-ATYPIA CONTEST 2014. The proposed framework achieved 95% recall, 98% precision and 96% F-score.

  6. Radiation-induced mitotic and meiotic aneuploidy in the yeast Saccharomyces cerevisiae.

    Science.gov (United States)

    Parry, J M; Sharp, D; Tippins, R S; Parry, E M

    1979-06-01

    A number of genetic systems are described which in yeast may be used to monitor the induction of chromosome aneuploidy during both mitotic and meiotic cell division. Using these systems we have been able to demonstrate the induction of both monosomic and trisomic cells in mitotically dividing cells and disomic spores in meiotically dividing cells after both UV light and X-ray exposure. The frequency of UV-light-induced monosomic colonies were reduced by post-treatment with photoreactivity light and both UV-light- and X-ray-induced monosomic colonies were reduced by liquid holding post-treatment under non-nutrient conditions. Both responses indicate an involvement of DNA-repair mechanisms in the removal of lesions which may lead to monosomy in yeast. This was further confirmed by the response of an excision-defective yeast strain which showed considerably increased sensitivity to the induction of monosomic colonies by UV-light treatment at low doses. Yeast cultures irradiated at different stages of growth showed variation in their responses to both UV-light and X-rays, cells at the exponential phase of growth show maximum sensitivity to the induction of monosomic colonies at low doses whereas stationary phase cultures showed maximum induction of monosomic colonies at high does. The frequencies of X-ray-induced chromosome aneuploidy during meiosis leading to the production of disomic spores was shown to be dependent upon the stage of meiosis at which the yeast cells were exposed to radiation. Cells which had proceeded beyond the DNA synthetic stage of meiosis were shown to produce disomic spores at considerably lower radiation doses than those cells which had only recently been inoculated into sporulation medium. The results obtained suggest that the yeast sustem may be suitable for the study of sensitivities of the various stages of meiotic cell division to the induction of chromosome aneuploidy after radiation exposure.

  7. Success rates for initial eradication of peri-prosthetic knee infection treated with a two-stage procedure.

    Science.gov (United States)

    Kaminski, Andrzej; Citak, Mustafa; Schildhauer, Thomas Armin; Fehmer, Tobias

    2014-01-01

    In Germany, rates of primary total knee arthroplasty procedures and exchange arthroplasty procedures continue to rise. Late-onset peri-prosthetic infection constitutes a serious complication whose management may be dependent upon the spectrum of micro-organisms involved. The aim of this study was to provide a retrospective analysis of the effectiveness of initial eradication measures performed as part of a two-stage procedure. Between 2002 and 2008, a total of 328 patients who had received a first-time diagnosis of chronic peri-prosthetic knee infection following total knee arthroplasty (TKA) subsequently underwent surgery at our clinic. The surgical approach consisted of a two-stage procedure, with the initial procedure consisting of the removal of the prosthesis and radical debridement, followed by insertion of an antibiotic-loaded static spacer. The effectiveness of the procedure was assessed after six weeks, with each patient undergoing a number of clinical and laboratory-based tests, including knee joint aspiration. Staphylococcus aureus strains were responsible for 68% (n=223) of the total number of cases of peri-prosthetic knee infection. 19% of cases (n=62) showed evidence of gram-negative bacteria, while MRSA accounted for 15% (n=49) of cases. Six weeks after completion of the above-named treatment regimen, eradication of infection was considered successful in 289 patients (88.1%). Eradication was unsuccessful in 22% of MRSA infections (n=11) and 7% of MSSA infections (n=23). The treatment regimen outlined in this report is capable of achieving satisfactory results in the management of late-onset peri-prosthetic knee infection, with one exception: patients with infections caused by MRSA showed high failure rates.

  8. High dose rate versus low dose rate brachytherapy in the treatment of stage IIIB cervical cancer, and the importance of brachytherapy timing

    International Nuclear Information System (INIS)

    Petereit, Daniel G.; Sarkaria, Jann N.; Czyzewski, Ann; Buchler, Dolores A.

    1996-01-01

    Purpose/Objective: To determine the efficacy of HDR versus LDR brachytherapy for Stage IIIB cervical cancer patients. Material and Methods: Forty-four HDR patients were retrospectively compared to 51 LDR patients treated at the same institution from 1977 to 1988 (LDR) and from 1989 to 1995 (HDR). A tumor burden score (TBS) of 2-9 was calculated for both groups of patients to assess volume of disease (2-4 low tumor burden, 5-9 high tumor burden). LDR and HDR patients received 60 Gy to the whole pelvis at 1.7 Gy/Fx. The majority of LDR patients were treated after completion of external beam radiation (EBR) with one 25 Gy implant to Point A (55 cGy/h). The HDR patients were treated with 4-5 HDR fractions of 3.7 Gy to 5.8 Gy/Fx for an LDR equivalence of 20-25 Gy (median dose/Fx 4.3 Gy, median insertion number 5). Clinical endpoints were calculated actuarially with significance determined by the log rank test and the relative risk (RR). Results: The median follow-up for the HDR and LDR groups was 1.8 and 5 years, respectively. Pelvic control and survival was better in the LDR group than the HDR group, 51%, 73%, 32%, 44% (p = 0.004, RR = 0.4), with grade III and above RTOG complications of 19% and 15%, respectively. The median age and performance status were similar between the two groups; however, a TBS score ≥7 was present in 23% of the HDR patients and in 9% of the LDR patients. Pelvic control in the HDR group was 58% with a TBS ≤4, and 17% with a TBS >4 (p = 0.01, RR = 0.4). The median EBR dose at the first HDR insertion was 31 Gy while all the LDR patients received 60 Gy before the insertion. Pelvic control rates in Table 1 indicate a trend towards improved outcome within the HDR group and same TBS if more external beam radiation was given prior to the first HDR insertion. Pelvic control was also higher within the HDR group when Point A received a BED Gy 10≥100 versus <100: 62%, 40%, respectively (RR 0.6). Conclusion: These retrospective results of HDR versus

  9. Mechanism of APC/CCDC20 activation by mitotic phosphorylation.

    Science.gov (United States)

    Qiao, Renping; Weissmann, Florian; Yamaguchi, Masaya; Brown, Nicholas G; VanderLinden, Ryan; Imre, Richard; Jarvis, Marc A; Brunner, Michael R; Davidson, Iain F; Litos, Gabriele; Haselbach, David; Mechtler, Karl; Stark, Holger; Schulman, Brenda A; Peters, Jan-Michael

    2016-05-10

    Chromosome segregation and mitotic exit are initiated by the 1.2-MDa ubiquitin ligase APC/C (anaphase-promoting complex/cyclosome) and its coactivator CDC20 (cell division cycle 20). To avoid chromosome missegregation, APC/C(CDC20) activation is tightly controlled. CDC20 only associates with APC/C in mitosis when APC/C has become phosphorylated and is further inhibited by a mitotic checkpoint complex until all chromosomes are bioriented on the spindle. APC/C contains 14 different types of subunits, most of which are phosphorylated in mitosis on multiple sites. However, it is unknown which of these phospho-sites enable APC/C(CDC20) activation and by which mechanism. Here we have identified 68 evolutionarily conserved mitotic phospho-sites on human APC/C bound to CDC20 and have used the biGBac technique to generate 47 APC/C mutants in which either all 68 sites or subsets of them were replaced by nonphosphorylatable or phospho-mimicking residues. The characterization of these complexes in substrate ubiquitination and degradation assays indicates that phosphorylation of an N-terminal loop region in APC1 is sufficient for binding and activation of APC/C by CDC20. Deletion of the N-terminal APC1 loop enables APC/C(CDC20) activation in the absence of mitotic phosphorylation or phospho-mimicking mutations. These results indicate that binding of CDC20 to APC/C is normally prevented by an autoinhibitory loop in APC1 and that its mitotic phosphorylation relieves this inhibition. The predicted location of the N-terminal APC1 loop implies that this loop controls interactions between the N-terminal domain of CDC20 and APC1 and APC8. These results reveal how APC/C phosphorylation enables CDC20 to bind and activate the APC/C in mitosis.

  10. THE INFLUENCE OF CAFFEINE ON MITOTIC DIVISION AT CAPSICUM ANNUUM L.

    Directory of Open Access Journals (Sweden)

    Elena Rosu

    2006-08-01

    Full Text Available The paper presents, the caffeine effects in mitotic division at Capsicum annuum L.. The treatment has determined the lessening of the mitotic index (comparative with the control variant, until mitotic division total inhibition, as well as an growth frequency of division aberation in anaphase and telophase.

  11. File list: ALL.Emb.10.AllAg.Mitotic_cycle_13 [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  12. File list: Oth.Emb.20.AllAg.Mitotic_cycle_13 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Emb.20.AllAg.Mitotic_cycle_13 dm3 TFs and others Embryo Mitotic cycle 13 SRX750...072,SRX750083 http://dbarchive.biosciencedbc.jp/kyushu-u/dm3/assembled/Oth.Emb.20.AllAg.Mitotic_cycle_13.bed ...

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  17. File list: ALL.Emb.05.AllAg.Mitotic_cycle_13 [Chip-atlas[Archive

    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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  1. File list: ALL.Emb.50.AllAg.Mitotic_cycle_14 [Chip-atlas[Archive

    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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  3. File list: ALL.Emb.10.AllAg.Mitotic_cycle_14 [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  4. Dysregulation of mitotic machinery genes precedes genome instability during spontaneous pre-malignant transformation of mouse ovarian surface epithelial cells

    Directory of Open Access Journals (Sweden)

    Ulises Urzúa

    2016-10-01

    Full Text Available Abstract Background Based in epidemiological evidence, repetitive ovulation has been proposed to play a role in the origin of ovarian cancer by inducing an aberrant wound rupture-repair process of the ovarian surface epithelium (OSE. Accordingly, long term cultures of isolated OSE cells undergo in vitro spontaneous transformation thus developing tumorigenic capacity upon extensive subcultivation. In this work, C57BL/6 mouse OSE (MOSE cells were cultured up to passage 28 and their RNA and DNA copy number profiles obtained at passages 2, 5, 7, 10, 14, 18, 23, 25 and 28 by means of DNA microarrays. Gene ontology, pathway and network analyses were focused in passages earlier than 20, which is a hallmark of malignancy in this model. Results At passage 14, 101 genes were up-regulated in absence of significant DNA copy number changes. Among these, the top-3 enriched functions (>30 fold, adj p < 0.05 comprised 7 genes coding for centralspindlin, chromosome passenger and minichromosome maintenance protein complexes. The genes Ccnb1 (Cyclin B1, Birc5 (Survivin, Nusap1 and Kif23 were the most recurrent in over a dozen GO terms related to the mitotic process. On the other hand, Pten plus the large non-coding RNAs Malat1 and Neat1 were among the 80 down-regulated genes with mRNA processing, nuclear bodies, ER-stress response and tumor suppression as relevant terms. Interestingly, the earliest discrete segmental aneuploidies arose by passage 18 in chromosomes 7, 10, 11, 13, 15, 17 and 19. By passage 23, when MOSE cells express the malignant phenotype, the dysregulated gene expression repertoire expanded, DNA imbalances enlarged in size and covered additional loci. Conclusion Prior to early aneuploidies, overexpression of genes coding for the mitotic apparatus in passage-14 pre-malignant MOSE cells indicate an increased proliferation rate suggestive of replicative stress. Concomitant down-regulation of nuclear bodies and RNA processing related genes

  5. The moyamoya disease susceptibility variant RNF213 R4810K (rs112735431) induces genomic instability by mitotic abnormality

    Energy Technology Data Exchange (ETDEWEB)

    Hitomi, Toshiaki [Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University, Kyoto (Japan); Habu, Toshiyuki [Radiation Biology Center, Kyoto University, Kyoto (Japan); Kobayashi, Hatasu; Okuda, Hiroko; Harada, Kouji H. [Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University, Kyoto (Japan); Osafune, Kenji [Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto (Japan); Taura, Daisuke; Sone, Masakatsu [Department of Medicine and Clinical Science, Graduate School of Medicine, Kyoto University, Kyoto (Japan); Asaka, Isao; Ameku, Tomonaga; Watanabe, Akira; Kasahara, Tomoko; Sudo, Tomomi; Shiota, Fumihiko [Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto (Japan); Hashikata, Hirokuni; Takagi, Yasushi [Department of Neurosurgery, Graduate School of Medicine, Kyoto University, Kyoto (Japan); Morito, Daisuke [Faculty of Life Sciences, Kyoto Sangyo University, Kyoto (Japan); Miyamoto, Susumu [Department of Neurosurgery, Graduate School of Medicine, Kyoto University, Kyoto (Japan); Nakao, Kazuwa [Department of Medicine and Clinical Science, Graduate School of Medicine, Kyoto University, Kyoto (Japan); Koizumi, Akio, E-mail: koizumi.akio.5v@kyoto-u.ac.jp [Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University, Kyoto (Japan)

    2013-10-04

    Highlights: •Overexpression of RNF213 R4810K inhibited cell proliferation. •Overexpression of RNF213 R4810K had the time of mitosis 4-fold and mitotic failure. •R4810K formed a complex with MAD2 more readily than wild-type. •iPSECs from the MMD patients had elevated mitotic failure compared from the control. •RNF213 R4810K induced mitotic abnormality and increased risk of aneuploidy. -- Abstract: Moyamoya disease (MMD) is a cerebrovascular disease characterized by occlusive lesions in the Circle of Willis. The RNF213 R4810K polymorphism increases susceptibility to MMD. In the present study, we characterized phenotypes caused by overexpression of RNF213 wild type and R4810K variant in the cell cycle to investigate the mechanism of proliferation inhibition. Overexpression of RNF213 R4810K in HeLa cells inhibited cell proliferation and extended the time of mitosis 4-fold. Ablation of spindle checkpoint by depletion of mitotic arrest deficiency 2 (MAD2) did not shorten the time of mitosis. Mitotic morphology in HeLa cells revealed that MAD2 colocalized with RNF213 R4810K. Immunoprecipitation revealed an RNF213/MAD2 complex: R4810K formed a complex with MAD2 more readily than RNF213 wild-type. Desynchronized localization of MAD2 was observed more frequently during mitosis in fibroblasts from patients (n = 3, 61.0 ± 8.2%) compared with wild-type subjects (n = 6, 13.1 ± 7.7%; p < 0.01). Aneuploidy was observed more frequently in fibroblasts (p < 0.01) and induced pluripotent stem cells (iPSCs) (p < 0.03) from patients than from wild-type subjects. Vascular endothelial cells differentiated from iPSCs (iPSECs) of patients and an unaffected carrier had a longer time from prometaphase to metaphase than those from controls (p < 0.05). iPSECs from the patients and unaffected carrier had significantly increased mitotic failure rates compared with controls (p < 0.05). Thus, RNF213 R4810K induced mitotic abnormalities and increased risk of genomic instability.

  6. The moyamoya disease susceptibility variant RNF213 R4810K (rs112735431) induces genomic instability by mitotic abnormality

    International Nuclear Information System (INIS)

    Hitomi, Toshiaki; Habu, Toshiyuki; Kobayashi, Hatasu; Okuda, Hiroko; Harada, Kouji H.; Osafune, Kenji; Taura, Daisuke; Sone, Masakatsu; Asaka, Isao; Ameku, Tomonaga; Watanabe, Akira; Kasahara, Tomoko; Sudo, Tomomi; Shiota, Fumihiko; Hashikata, Hirokuni; Takagi, Yasushi; Morito, Daisuke; Miyamoto, Susumu; Nakao, Kazuwa; Koizumi, Akio

    2013-01-01

    Highlights: •Overexpression of RNF213 R4810K inhibited cell proliferation. •Overexpression of RNF213 R4810K had the time of mitosis 4-fold and mitotic failure. •R4810K formed a complex with MAD2 more readily than wild-type. •iPSECs from the MMD patients had elevated mitotic failure compared from the control. •RNF213 R4810K induced mitotic abnormality and increased risk of aneuploidy. -- Abstract: Moyamoya disease (MMD) is a cerebrovascular disease characterized by occlusive lesions in the Circle of Willis. The RNF213 R4810K polymorphism increases susceptibility to MMD. In the present study, we characterized phenotypes caused by overexpression of RNF213 wild type and R4810K variant in the cell cycle to investigate the mechanism of proliferation inhibition. Overexpression of RNF213 R4810K in HeLa cells inhibited cell proliferation and extended the time of mitosis 4-fold. Ablation of spindle checkpoint by depletion of mitotic arrest deficiency 2 (MAD2) did not shorten the time of mitosis. Mitotic morphology in HeLa cells revealed that MAD2 colocalized with RNF213 R4810K. Immunoprecipitation revealed an RNF213/MAD2 complex: R4810K formed a complex with MAD2 more readily than RNF213 wild-type. Desynchronized localization of MAD2 was observed more frequently during mitosis in fibroblasts from patients (n = 3, 61.0 ± 8.2%) compared with wild-type subjects (n = 6, 13.1 ± 7.7%; p < 0.01). Aneuploidy was observed more frequently in fibroblasts (p < 0.01) and induced pluripotent stem cells (iPSCs) (p < 0.03) from patients than from wild-type subjects. Vascular endothelial cells differentiated from iPSCs (iPSECs) of patients and an unaffected carrier had a longer time from prometaphase to metaphase than those from controls (p < 0.05). iPSECs from the patients and unaffected carrier had significantly increased mitotic failure rates compared with controls (p < 0.05). Thus, RNF213 R4810K induced mitotic abnormalities and increased risk of genomic instability

  7. Significance and outcome of nuclear anaplasia and mitotic index in prostatic adenocarcinomas.

    Science.gov (United States)

    Kır, Gozde; Sarbay, Billur Cosan; Gumus, Eyup

    2016-10-01

    The Gleason grading system measures architectural differentiation and disregards nuclear atypia and the cell proliferation index. Several studies have reported that nuclear grade and mitotic index (MI) are prognostically useful. This study included 232 radical prostatectomy specimens. Nuclear anaplasia (NA) was determined on the basis of nucleomegali (at least 20µm); vesicular chromatin; eosinophilic macronucleoli, nuclear lobulation, and irregular thickened nuclear membranei. The proportion of area of NA was recorded in each tumor in 10% increments. The MI was defined as the number of mitotic figures in 10 consecutive high-power fields (HPF). In univariate analysis, significant differences included associations between biochemical prostate-specific antigen recurrence (BCR) and Gleason score, extraprostatic extension, positive surgical margin, the presence of high-pathologic stage, NA≥10% of tumor area, MI≥3/10 HPF, and preoperative prostate-specific antigen. In a stepwise Cox regression model, a positive surgical margin, the presence of a NA≥10% of tumor area, and a MI of≥3/10 HPF were independent predictors of BCR after radical prostatectomy. NA≥10% of tumor area appeared to have a stronger association with outcome than MI≥3/10 HPF, as still associated with BCR when Gleason score was in the model. The results of our study showed that, in addition to the conventional Gleason grading system, NA, and MI are useful prognostic parameters while evaluating long-term prognosis in prostatic adenocarcinoma. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. DNA lesions induced by replication stress trigger mitotic aberration and tetraploidy development.

    Directory of Open Access Journals (Sweden)

    Yosuke Ichijima

    Full Text Available During tumorigenesis, cells acquire immortality in association with the development of genomic instability. However, it is still elusive how genomic instability spontaneously generates during the process of tumorigenesis. Here, we show that precancerous DNA lesions induced by oncogene acceleration, which induce situations identical to the initial stages of cancer development, trigger tetraploidy/aneuploidy generation in association with mitotic aberration. Although oncogene acceleration primarily induces DNA replication stress and the resulting lesions in the S phase, these lesions are carried over into the M phase and cause cytokinesis failure and genomic instability. Unlike directly induced DNA double-strand breaks, DNA replication stress-associated lesions are cryptogenic and pass through cell-cycle checkpoints due to limited and ineffective activation of checkpoint factors. Furthermore, since damaged M-phase cells still progress in mitotic steps, these cells result in chromosomal mis-segregation, cytokinesis failure and the resulting tetraploidy generation. Thus, our results reveal a process of genomic instability generation triggered by precancerous DNA replication stress.

  9. Local Recurrence in Women With Stage I Breast Cancer: Declining Rates Over Time in a Large, Population-Based Cohort

    Energy Technology Data Exchange (ETDEWEB)

    Canavan, Joycelin, E-mail: canavanjoycelin@gmail.com [Radiation Therapy Program and Breast Cancer Outcomes Unit, British Columbia Cancer Agency, Vancouver Island Centre, University of British Columbia, Victoria, British Columbia (Canada); Truong, Pauline T.; Smith, Sally L. [Radiation Therapy Program and Breast Cancer Outcomes Unit, British Columbia Cancer Agency, Vancouver Island Centre, University of British Columbia, Victoria, British Columbia (Canada); Lu, Linghong; Lesperance, Mary [Department of Mathematics and Statistics, University of Victoria, British Columbia (Canada); Olivotto, Ivo A. [Department of Radiation Oncology, Tom Baker Cancer Centre, University of Calgary (Canada)

    2014-01-01

    Purpose: To evaluate whether local recurrence (LR) risk has changed over time among women with stage I breast cancer treated with breast-conserving therapy. Methods and Materials: Subjects were 5974 women aged ≥50 years diagnosis with pT1N0 breast cancer from 1989 to 2006, treated with breast-conserving surgery and radiation therapy. Clinicopathologic characteristics, treatment, and LR outcomes were compared among 4 cohorts stratified by year of diagnosis: 1989 to 1993 (n=1077), 1994 to 1998 (n=1633), 1999 to 2002 (n=1622), and 2003 to 2006 (n=1642). Multivariable analysis was performed, with year of diagnosis as a continuous variable. Results: Median follow-up time was 8.6 years. Among patients diagnosed in 1989 to 1993, 1994 to 1998, 1999 to 2002, and 2003 to 2006, the proportions of grade 1 tumors increased (16% vs 29% vs 40% vs 39%, respectively, P<.001). Surgical margin clearance rates increased from 82% to 93% to 95% and 88%, respectively (P<.001). Over time, the proportions of unknown estrogen receptor (ER) status decreased (29% vs 10% vs 1.2% vs 0.5%, respectively, P<.001), whereas ER-positive tumors increased (56% vs 77% vs 86% vs 86%, respectively, P<.001). Hormone therapy use increased (23% vs 23% vs 62% vs 73%, respectively, P<.001), and chemotherapy use increased (2% vs 5% vs 10% vs 13%, respectively, P<.001). The 5-year cumulative incidence rates of LR over the 4 time periods were 2.8% vs 1.7% vs 0.9% vs 0.8%, respectively (Gray's test, P<.001). On competing risk multivariable analysis, year of diagnosis was significantly associated with decreased LR (hazard ratio, 0.92 per year, P=.0003). Relative to grade 1 histology, grades 2, 3, and unknown were associated with increased LR. Hormone therapy use was associated with reduced LR. Conclusion: Significant changes in the multimodality management of stage I breast cancer have occurred over the past 2 decades. More favorable-risk tumors were diagnosed, and margin clearance and systemic therapy use

  10. Local Recurrence in Women With Stage I Breast Cancer: Declining Rates Over Time in a Large, Population-Based Cohort

    International Nuclear Information System (INIS)

    Canavan, Joycelin; Truong, Pauline T.; Smith, Sally L.; Lu, Linghong; Lesperance, Mary; Olivotto, Ivo A.

    2014-01-01

    Purpose: To evaluate whether local recurrence (LR) risk has changed over time among women with stage I breast cancer treated with breast-conserving therapy. Methods and Materials: Subjects were 5974 women aged ≥50 years diagnosis with pT1N0 breast cancer from 1989 to 2006, treated with breast-conserving surgery and radiation therapy. Clinicopathologic characteristics, treatment, and LR outcomes were compared among 4 cohorts stratified by year of diagnosis: 1989 to 1993 (n=1077), 1994 to 1998 (n=1633), 1999 to 2002 (n=1622), and 2003 to 2006 (n=1642). Multivariable analysis was performed, with year of diagnosis as a continuous variable. Results: Median follow-up time was 8.6 years. Among patients diagnosed in 1989 to 1993, 1994 to 1998, 1999 to 2002, and 2003 to 2006, the proportions of grade 1 tumors increased (16% vs 29% vs 40% vs 39%, respectively, P<.001). Surgical margin clearance rates increased from 82% to 93% to 95% and 88%, respectively (P<.001). Over time, the proportions of unknown estrogen receptor (ER) status decreased (29% vs 10% vs 1.2% vs 0.5%, respectively, P<.001), whereas ER-positive tumors increased (56% vs 77% vs 86% vs 86%, respectively, P<.001). Hormone therapy use increased (23% vs 23% vs 62% vs 73%, respectively, P<.001), and chemotherapy use increased (2% vs 5% vs 10% vs 13%, respectively, P<.001). The 5-year cumulative incidence rates of LR over the 4 time periods were 2.8% vs 1.7% vs 0.9% vs 0.8%, respectively (Gray's test, P<.001). On competing risk multivariable analysis, year of diagnosis was significantly associated with decreased LR (hazard ratio, 0.92 per year, P=.0003). Relative to grade 1 histology, grades 2, 3, and unknown were associated with increased LR. Hormone therapy use was associated with reduced LR. Conclusion: Significant changes in the multimodality management of stage I breast cancer have occurred over the past 2 decades. More favorable-risk tumors were diagnosed, and margin clearance and systemic therapy use

  11. Impact of Pretreatment Tumor Growth Rate on Outcome of Early-Stage Lung Cancer Treated With Stereotactic Body Radiation Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Atallah, Soha; Cho, B.C. John; Allibhai, Zishan; Taremi, Mojgan; Giuliani, Meredith [Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Ontario (Canada); Department of Radiation Oncology, University of Toronto, Toronto, Ontario (Canada); Le, Lisa W. [Department of Biostatistics, Princess Margaret Cancer Centre, Toronto, Ontario (Canada); Brade, Anthony; Sun, Alexander; Bezjak, Andrea [Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Ontario (Canada); Department of Radiation Oncology, University of Toronto, Toronto, Ontario (Canada); Hope, Andrew J., E-mail: andrew.hope@rmp.uhn.on.ca [Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Ontario (Canada); Department of Radiation Oncology, University of Toronto, Toronto, Ontario (Canada)

    2014-07-01

    Purpose: To determine the influence of pretreatment tumor growth rate on outcomes in patients with early-stage non-small cell lung cancer (NSCLC) treated with stereotactic body radiation therapy (SBRT). Methods and Materials: A review was conducted on 160 patients with T1-T2N0M0 NSCLC treated with SBRT at single institution. The patient's demographic and clinical data, time interval (t) between diagnostic and planning computed tomography (CT), vital status, disease status, and cause of death were extracted from a prospectively kept database. Differences in gross tumor volume between diagnostic CT (GTV1) and planning CT (GTV2) were recorded, and growth rate was calculated by use of specific growth rate (SGR). Kaplan-Meier curves were constructed for overall survival (OS). Differences between groups were compared with a log-rank test. Multivariate analyses were performed by use of the Cox proportional hazard model with SGR and other relevant clinical factors. Cumulative incidence was calculated for local, regional, and distant failures by use of the competing risk approach and was compared with Gray's test. Results: The median time interval between diagnostic and planning CT was 82 days. The patients were divided into 2 groups, and the median SGR was used as a cut-off. The median survival times were 38.6 and 27.7 months for the low and high SGR groups, respectively (P=.03). Eastern Cooperative Oncology Group performance status (P=.01), sex (P=.04), SGR (P=.03), and GTV2 (P=.002) were predictive for OS in multivariable Cox regression analysis and, except sex, were similarly predictive for failure-free survival (FFS). The 3-year cumulative incidences of regional failure were 19.2% and 6.0% for the high and low SGR groups, respectively (P=.047). Conclusion: High SGR was correlated with both poorer OS and FFS in patients with early-stage NSCLC treated with SBRT. If validated, this measurement may be useful in identifying patients most likely to benefit from

  12. Net CO2 exchange rates in three different successional stages of the 'Dark Taiga' of central Siberia

    International Nuclear Information System (INIS)

    Roeser, C.; Schulze, E.D.; Montagnani, L.

    2002-01-01

    The net ecosystem exchange (NEE) of successional stages of the Abies-dominated dark taiga was measured in central Siberia (61 deg N, 90 deg E) during the growing season of the year 2000 using the eddy covariance technique. Measurements started before snow melt and canopy activity in spring on day of year (DOY) 99 and lasted until a permanent snow cover had developed and respiration had ceased in autumn DOY 299. Three stands growing in close vicinity were investigated: 50 yr-old Betula pubescens ('Betula stand', an early successional stage after fire), 250 yr-old mixed boreal forest, representing the transition from Betula-dominated to Abies-dominated canopies, and 200-yr-old Abies sibirica ('Abies stand', representing a late successional stage following the mixed boreal forest). The mixed boreal forest had a multi-layered canopy with dense under story and trees of variable height and age below the main canopy, which was dominated by Abies sibirica, Picea obovata and few old Betula pubescens and Populus tremula trees. The Abies stand had a uniform canopy dominated by Abies sibirica. This stand appears to have established not after fire but after wind break or insect damage in a later successional stage. The stands differed with respect to the number of days with net CO 2 uptake (Betula stand 89 days, mixed boreal forest 109 days, and Abies stand 135 days), maximum measured LAI (Betula 2.6 m 2 /m 2 , mixed boreal forest 3.5 m 2 /m 2 and Abies stand 4.1 m 2 /m 2 ) and basal area (Betula stand 30.2 m 2 /ha, mixed boreal forest 35.7 m 2 /ha, and Abies stand 46.5 m 2 /ha). In the mixed boreal forest, many days with net daytime CO 2 release were observed in summer. Both other sites were almost permanent sinks in summer. Mean daytime CO 2 exchange rates in July were 8.45 mol/m 2 /s in the Betula stand, 4.65 mol/m 2 /s in the mixed boreal forest and 6.31 mol/m 2 /s in the Abies stand. Measured uptake for the growing season was 247.2 g C/m 2 in the Betula stand, 99.7 g C/m 2

  13. Single-walled carbon nanotube-induced mitotic disruption⋆

    OpenAIRE

    Sargent, L.M.; Hubbs, A.F.; Young, S.-H.; Kashon, M.L.; Dinu, C.Z.; Salisbury, J.L.; Benkovic, S.A.; Lowry, D.T.; Murray, A.R.; Kisin, E.R.; Siegrist, K.J.; Battelli, L.; Mastovich, J.; Sturgeon, J.L.; Bunker, K.L.

    2011-01-01

    Carbon nanotubes were among the earliest products of nanotechnology and have many potential applications in medicine, electronics, and manufacturing. The low density, small size, and biological persistence of carbon nanotubes create challenges for exposure control and monitoring and make respiratory exposures to workers likely. We have previously shown mitotic spindle aberrations in cultured primary and immortalized human airway epithelial cells exposed to 24, 48 and 96 μg/cm2 single-walled c...

  14. Carbamazepine induces mitotic arrest in mammalian Vero cells

    International Nuclear Information System (INIS)

    Perez Martin, J.M.; Fernandez Freire, P.; Labrador, V.; Hazen, M.J.

    2008-01-01

    We reported recently that the anticonvulsant drug carbamazepine, at supratherapeutic concentrations, exerts antiproliferative effects in mammalian Vero cells, but the underlying mechanism has not been elucidated. This motivates us to examine rigorously whether growth arrest was associated with structural changes in cellular organization during mitosis. In the present work, we found that exposure of the cells to carbamazepine led to an increase in mitotic index, mainly due to the sustained block at the metaphase/anaphase boundary, with the consequent inhibition of cell proliferation. Indirect immunofluorescence, using antibodies directed against spindle apparatus proteins, revealed that mitotic arrest was associated with formation of monopolar spindles, caused by impairment of centrosome separation. The final consequence of the spindle defects induced by carbamazepine, depended on the duration of cell cycle arrest. Following the time course of accumulation of metaphase and apoptotic cells during carbamazepine treatments, we observed a causative relationship between mitotic arrest and induction of cell death. Conversely, cells released from the block of metaphase by removal of the drug, continued to progress through mitosis and resume normal proliferation. Our results show that carbamazepine shares a common antiproliferative mechanism with spindle-targeted drugs and contribute to a better understanding of the cytostatic activity previously described in Vero cells. Additional studies are in progress to extend these initial findings that define a novel mode of action of carbamazepine in cultured mammalian cells

  15. Carbamazepine induces mitotic arrest in mammalian Vero cells

    Energy Technology Data Exchange (ETDEWEB)

    Perez Martin, J.M.; Fernandez Freire, P.; Labrador, V. [Departamento de Biologia, Facultad de Ciencias, Universidad Autonoma de Madrid, Cantoblanco, 28049 Madrid (Spain); Hazen, M.J. [Departamento de Biologia, Facultad de Ciencias, Universidad Autonoma de Madrid, Cantoblanco, 28049 Madrid (Spain)], E-mail: mariajose.hazen@uam.es

    2008-01-01

    We reported recently that the anticonvulsant drug carbamazepine, at supratherapeutic concentrations, exerts antiproliferative effects in mammalian Vero cells, but the underlying mechanism has not been elucidated. This motivates us to examine rigorously whether growth arrest was associated with structural changes in cellular organization during mitosis. In the present work, we found that exposure of the cells to carbamazepine led to an increase in mitotic index, mainly due to the sustained block at the metaphase/anaphase boundary, with the consequent inhibition of cell proliferation. Indirect immunofluorescence, using antibodies directed against spindle apparatus proteins, revealed that mitotic arrest was associated with formation of monopolar spindles, caused by impairment of centrosome separation. The final consequence of the spindle defects induced by carbamazepine, depended on the duration of cell cycle arrest. Following the time course of accumulation of metaphase and apoptotic cells during carbamazepine treatments, we observed a causative relationship between mitotic arrest and induction of cell death. Conversely, cells released from the block of metaphase by removal of the drug, continued to progress through mitosis and resume normal proliferation. Our results show that carbamazepine shares a common antiproliferative mechanism with spindle-targeted drugs and contribute to a better understanding of the cytostatic activity previously described in Vero cells. Additional studies are in progress to extend these initial findings that define a novel mode of action of carbamazepine in cultured mammalian cells.

  16. Unconventional functions of mitotic kinases in kidney tumourigenesis

    Directory of Open Access Journals (Sweden)

    Pauline eHascoet

    2015-10-01

    Full Text Available Human tumours exhibit a variety of genetic alterations, including point mutations, translocations, gene amplifications and deletions, as well as aneuploid chromosome numbers. For carcinomas, aneuploidy is associated with poor patient outcome for a large variety of tumour types, including breast, colon and renal cell carcinoma. The Renal cell cancer (RCC is a heterogeneous carcinoma consisting of different histologic types. The clear renal cell carcinoma (ccRCC is the most common subtype and represents 85 % of the RCC. Central to the biology of the ccRCC is the loss of function of the Von Hippel Lindau gene but is also associated with genetic instability that could be caused by abrogation of the cell cycle mitotic spindle checkpoint and may involve the Aurora kinases, which regulate centrosome maturation. Aneuploidy can also result from the loss of cell-cell adhesion and apical-basal cell polarity that also may be regulated by the mitotic kinases (Plk1, CK2, DLCK1 and Aurora kinases. In this review, we describe the non mitotic unconventional functions of these kinases in renal tumourigenesis.

  17. Upregulation of meiosis-specific genes in lymphoma cell lines following genotoxic insult and induction of mitotic catastrophe

    International Nuclear Information System (INIS)

    Kalejs, Martins; Ivanov, Andrey; Plakhins, Gregory; Cragg, Mark S; Emzinsh, Dzintars; Illidge, Timothy M; Erenpreisa, Jekaterina

    2006-01-01

    We have previously reported that p53 mutated radioresistant lymphoma cell lines undergo mitotic catastrophe after irradiation, resulting in metaphase arrest and the generation of endopolyploid cells. A proportion of these endopolyploid cells then undergo a process of de-polyploidisation, stages of which are partially reminiscent of meiotic prophase. Furthermore, expression of meiosis-specific proteins of the cancer/testis antigens group of genes has previously been reported in tumours. We therefore investigated whether expression of meiosis-specific genes was associated with the polyploidy response in our tumour model. Three lymphoma cell lines, Namalwa, WI-L2-NS and TK6, of varying p53 status were exposed to a single 10 Gy dose of gamma radiation and their responses assessed over an extended time course. DNA flow cytometry and mitotic counts were used to assess the kinetics and extent of polyploidisation and mitotic progression. Expression of meiotic genes was analysed using RT-PCR and western blotting. In addition, localisation of the meiotic cohesin REC8 and its relation to centromeres was analysed by immunofluorescence. The principal meiotic regulator MOS was found to be significantly post-transcriptionally up-regulated after irradiation in p53 mutated but not p53 wild-type lymphoma cells. The maximum expression of MOS coincided with the maximal fraction of metaphase arrested cells and was directly proportional to both the extent of the arrest and the number of endopolyploid cells that subsequently emerged. The meiotic cohesin REC8 was also found to be up-regulated after irradiation, linking sister chromatid centromeres in the metaphase-arrested and subsequent giant cells. Finally, RT-PCR revealed expression of the meiosis-prophase genes, DMC1, STAG3, SYCP3 and SYCP1. We conclude that multiple meiotic genes are aberrantly activated during mitotic catastrophe in p53 mutated lymphoma cells after irradiation. Furthermore, we suggest that the coordinated expression

  18. Interaction of low-dose irradiation with subsequent mutagenic treatment. Role of mitotic delay

    International Nuclear Information System (INIS)

    Salone, B.; Pretazzoli, V.; Bosi, A.; Olivieri, G.

    1996-01-01

    Experiments were carried out with human lymphocytes to test whether there was any relation between the changes that conditioning treatment can produce in cell progression or in mitotic delay induced by the challenge dose and the presence of an 'adaptive response' (AR). In experiments in which the cells were successively fixed after the challenge dose, the interaction between conditioning treatment and challenge was of the same sign for all the fixation times: therefore it is likely that modifications of the cytogenetic damage in primed cells is not a mere reflection of stage sensitivity. In experiments in which using 1 Gy as conditioning treatment we induced a drastic extension of G 2 , we did not observe any AR; therefore, even if conditioning treatment can induce modifications in the cell-cycle phases before and/or after challenge, there is probably no link between these modifications and the presence of an AR

  19. Physical Limits on the Precision of Mitotic Spindle Positioning by Microtubule Pushing forces: Mechanics of mitotic spindle positioning.

    Science.gov (United States)

    Howard, Jonathon; Garzon-Coral, Carlos

    2017-11-01

    Tissues are shaped and patterned by mechanical and chemical processes. A key mechanical process is the positioning of the mitotic spindle, which determines the size and location of the daughter cells within the tissue. Recent force and position-fluctuation measurements indicate that pushing forces, mediated by the polymerization of astral microtubules against- the cell cortex, maintain the mitotic spindle at the cell center in Caenorhabditis elegans embryos. The magnitude of the centering forces suggests that the physical limit on the accuracy and precision of this centering mechanism is determined by the number of pushing microtubules rather than by thermally driven fluctuations. In cells that divide asymmetrically, anti-centering, pulling forces generated by cortically located dyneins, in conjunction with microtubule depolymerization, oppose the pushing forces to drive spindle displacements away from the center. Thus, a balance of centering pushing forces and anti-centering pulling forces localize the mitotic spindles within dividing C. elegans cells. © 2017 The Authors. BioEssays published by Wiley Periodicals, Inc.

  20. Studies on the induction of mitotic gene conversion by ultraviolet irradiation

    International Nuclear Information System (INIS)

    Ito, T.; Kobayashi, K.

    1975-01-01

    The UV (270-nm) dose-frequency relationship for the induction of intragenic mitotic recombination at trp 5 locus in Saccharomyces cerevisiae was non-linear. Two parameters, α and a, in the proposed equation for the non-linear relationship f = (at)α were determined so as to fit the experimental data by the method of least squares. The analysis was extended over 5 cell stages during synchronous growth. It was found that (1) parameter α changed from 2.02 for unbudded small cells to 1.09 for the stage where the cell had finished the division of the nucleus, and (2) parameter a changed correspondingly from 7.25.10 -4 to 0.180.10- 4 sec -1 during the same period. One interesting outcome in this analysis was the deduction of a dose-dependent nature of relative sensitivity with respect to the stage. The determination of these two parameters enabled us to calculate dose-effect relationships beyond the limits of experimental restrictions. Such an ''imaginary'' relationship, calculated at an extremely low dose, revealed the existence of maximal sensitivity around the DNA synthesis period. It was further shown that this maximum would easily be masked even in the moderate dose range. Thus, we conclude that the validity of single dose comparisons is diminished unless α is constant regardless of the cell stage. Some considerations on the proposed parameters have been made in relation to the mechanisms of the induction of gene conversion by UV

  1. Evaluation of the recombination in somatic cells induced by radiation in different stages of Drosophila larval development

    International Nuclear Information System (INIS)

    Cruces, M.P.; Morales R, P.

    1997-01-01

    The mitotic recombination can happen spontaneously and its frequency is very low, however the recombination rate of a cell can be increased by the exposure to agents which cause damage to DNA. This type of agents are knew commonly as recombinogens. The ionizing radiation and a numerous chemical agents can be mentioned (Vogel, 1992). The objective of this work is to determine if the mutation/recombination rate induced by gamma rays varies with the development stage. In order to realize this investigation it was used the mutation and somatic recombination test of Drosophila wing (Graf and col. 1984). The mwh/ mwh and flr 3 /TM3, Ser stocks were used. (Author)

  2. Clinically evident fat necrosis in women treated with high-dose-rate brachytherapy alone for early-stage breast cancer

    International Nuclear Information System (INIS)

    Wazer, David E.; Lowther, David; Boyle, Teresa; Ulin, Kenneth; Neuschatz, Andrew; Ruthazer, Robin; DiPetrillo, Thomas A.

    2001-01-01

    Purpose: To investigate the incidence of and variables associated with clinically evident fat necrosis in women treated on a protocol of high-dose-rate (HDR) brachytherapy alone without external-beam whole-breast irradiation for early-stage breast carcinoma. Methods and Materials: From 6/1997 until 8/1999, 30 women diagnosed with Stage I or II breast carcinoma underwent surgical excision and postoperative irradiation via HDR brachytherapy implant as part of a multi-institutional clinical Phase I/II protocol. Patients eligible included those with T1, T2, N0, N1 (≤3 nodes positive), M0 tumors of nonlobular histology with negative surgical margins, no extracapsular lymph-node extension, and a negative postexcision mammogram. Brachytherapy catheters were placed at the initial excision, re-excision, or at the time of axillary sampling. Direct visualization, surgical clips, ultrasound, or CT scans assisted in delineating the target volume defined as the excision cavity plus 2-cm margin. High activity 192 Ir (3-10 Ci) was used to deliver 340 cGy per fraction, 2 fractions per day, for 5 consecutive days to a total dose of 34 Gy to the target volume. Source position and dwell times were calculated using standard volume optimization techniques. Dosimetric analyses were performed with three-dimensional postimplant dose and volume reconstructions. The median follow-up of all patients was 24 months (range, 12-36 months). Results: Eight patients (crude incidence of 27%) developed clinically evident fat necrosis postimplant in the treated breast. Fat necrosis was determined by clinical presentation including pain and swelling in the treated volume, computed tomography, and/or biopsy. All symptomatic patients (7 of 8 cases) were successfully treated with 3 to 12 months of conservative management. Continuous variables that were found to be associated significantly with fat necrosis included the number of source dwell positions (p=0.04), and the volume of tissue which received

  3. Xanthium strumarium extract inhibits mammalian cell proliferation through mitotic spindle disruption mediated by xanthatin.

    Science.gov (United States)

    Sánchez-Lamar, Angel; Piloto-Ferrer, Janet; Fiore, Mario; Stano, Pasquale; Cozzi, Renata; Tofani, Daniela; Cundari, Enrico; Francisco, Marbelis; Romero, Aylema; González, Maria L; Degrassi, Francesca

    2016-12-24

    Xanthium strumarium L. is a member of the Asteraceae family popularly used with multiple therapeutic purposes. Whole extracts of this plant have shown anti-mitotic activity in vitro suggesting that some components could induce mitotic arrest in proliferating cells. Aim of the present work was to characterize the anti-mitotic properties of the X. strumarium whole extract and to isolate and purify active molecule(s). The capacity of the whole extract to inhibit mitotic progression in mammalian cultured cells was investigated to identify its anti-mitotic activity. Isolation of active component(s) was performed using a bioassay-guided multistep separation procedure in which whole extract was submitted to a progressive process of fractionation and fractions were challenged for their anti-mitotic activity. Our results show for the first time that X. strumarium whole extract inhibits assembly of the mitotic spindle and spindle-pole separation, thereby heavily affecting mitosis, impairing the metaphase to anaphase transition and inducing apoptosis. The purification procedure led to a fraction with an anti-mitotic activity comparable to that of the whole extract. Chemical analysis of this fraction showed that its major component was xanthatin. The present work shows a new activity of X. strumarium extract, i.e. the alteration of the mitotic apparatus in cultured cells that may be responsible for the anti-proliferative activity of the extract. Anti-mitotic activity is shown to be mainly exerted by xanthatin. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  4. APC/C-Cdh1-dependent anaphase and telophase progression during mitotic slippage

    Directory of Open Access Journals (Sweden)

    Toda Kazuhiro

    2012-02-01

    Full Text Available Abstract Background The spindle assembly checkpoint (SAC inhibits anaphase progression in the presence of insufficient kinetochore-microtubule attachments, but cells can eventually override mitotic arrest by a process known as mitotic slippage or adaptation. This is a problem for cancer chemotherapy using microtubule poisons. Results Here we describe mitotic slippage in yeast bub2Δ mutant cells that are defective in the repression of precocious telophase onset (mitotic exit. Precocious activation of anaphase promoting complex/cyclosome (APC/C-Cdh1 caused mitotic slippage in the presence of nocodazole, while the SAC was still active. APC/C-Cdh1, but not APC/C-Cdc20, triggered anaphase progression (securin degradation, separase-mediated cohesin cleavage, sister-chromatid separation and chromosome missegregation, in addition to telophase onset (mitotic exit, during mitotic slippage. This demonstrates that an inhibitory system not only of APC/C-Cdc20 but also of APC/C-Cdh1 is critical for accurate chromosome segregation in the presence of insufficient kinetochore-microtubule attachments. Conclusions The sequential activation of APC/C-Cdc20 to APC/C-Cdh1 during mitosis is central to accurate mitosis. Precocious activation of APC/C-Cdh1 in metaphase (pre-anaphase causes mitotic slippage in SAC-activated cells. For the prevention of mitotic slippage, concomitant inhibition of APC/C-Cdh1 may be effective for tumor therapy with mitotic spindle poisons in humans.

  5. Relative cataractogenic effects of X rays, fission-spectrum neutrons, and 56Fe particles: A comparison with mitotic effects

    International Nuclear Information System (INIS)

    Riley, E.F.; Lindgren, A.L.; Andersen, A.L.; Miller, R.C.; Ainsworth, E.J.

    1991-01-01

    The eyes of Sprague-Dawley rats were irradiated with doses of 2.5-10 Gy 250-kVp X rays, 1.25-2.25 Gy fission-spectrum neutrons (approximately 0.85 MeV), or 0.1-2.0 Gy 600-MeV/A 56Fe particles. Lens opacifications were evaluated for 51-61 weeks following X and neutron irradiations and for 87 weeks following X and 56Fe-particle irradiations. Average stage of opacification was determined relative to time after irradiation, and the time required for 50% of the irradiated lenses to achieve various stages (T50) was determined as a function of radiation dose. Data from two experiments were combined in dose-effect curves as T50 experimental values taken as percentages of the respective T50 control values (T50-% control). Simple exponential curves best describe dose responsiveness for both high-LET radiations. For X rays, a shallow dose-effect relationship (shoulder) up to 4.5 Gy was followed at higher doses by a steeper exponential dose-effect relationship. As a consequence, RBE values for the high-LET radiations are dose dependent. Dose-effect curves for cataracts were compared to those for mitotic abnormalities observed when quiescent lens epithelial cells were stimulated mechanically to proliferate at various intervals after irradiation. Neutrons were about 1.6-1.8 times more effective than 56Fe particles for inducing both cataracts and mitotic abnormalities. For stage 1 and 2 cataracts, the X-ray Dq was 10-fold greater and the D0 was similar to those for mitotic abnormalities initially expressed after irradiation

  6. Effective treatment of Stage I uterine papillary serous carcinoma with high dose-rate vaginal apex radiation (192Ir) and chemotherapy

    International Nuclear Information System (INIS)

    Turner, Bruce C.; Knisely, Jonathan P. S.; Kacinski, Barry M.; Haffty, Bruce G.; Gumbs, Andrew A.; Roberts, Kenneth B.; Frank, Alex H.; Peschel, Richard E.; Rutherford, Thomas J.; Edraki, Babak; Kohorn, Ernest I.; Chambers, Setsuko K.; Schwartz, Peter E.; Wilson, Lynn D.

    1998-01-01

    Purpose: Uterine papillary serous carcinoma (UPSC) is a morphologically distinct variant of endometrial carcinoma that is associated with a poor prognosis, high recurrence rate, frequent clinical understaging, and poor response to salvage treatment. We retrospectively analyzed local control, actuarial overall survival (OS), actuarial disease-free survival (DFS), salvage rate, and complications for patients with Federation International of Gynecology and Obstetrics (FIGO) (1988) Stage I UPSC. Methods and Materials: This retrospective analysis describes 38 patients with FIGO Stage I UPSC who were treated with the combinations of radiation therapy, chemotherapy, total abdominal hysterectomy, and bilateral salpingo-oophorectomy (TAH/BSO), with or without a surgical staging procedure. Twenty of 38 patients were treated with a combination of low dose-rate (LDR) uterine/vaginal brachytherapy using 226 Ra or 137 Cs and conventional whole-abdomen radiation therapy (WART) or whole-pelvic radiation therapy (WPRT). Of 20 patients (10%) in this treatment group, 2 received cisplatin chemotherapy. Eighteen patients were treated with high dose-rate (HDR) vaginal apex brachytherapy using 192 Ir with an afterloading device and cisplatin, doxorubicin, and cyclophosphamide (CAP) chemotherapy (5 of 18 patients). Only 6 of 20 UPSC patients treated with combination LDR uterine/vaginal brachytherapy and conventional external beam radiotherapy underwent complete surgical staging, consisting of TAH/BSO, pelvic/para-aortic lymph node sampling, omentectomy, and peritoneal fluid analysis, compared to 15 of 18 patients treated with HDR vaginal apex brachytherapy. Results: The 5-year actuarial OS for patients with complete surgical staging and adjuvant radiation/chemotherapy treatment was 100% vs. 61% for patients without complete staging (p = 0.002). The 5-year actuarial OS for all Stage I UPSC patients treated with postoperative HDR vaginal apex brachytherapy and systemic chemotherapy was 94

  7. Decline in estimated glomerular filtration rate and subsequent risk of end-stage renal disease and mortality.

    Science.gov (United States)

    Coresh, Josef; Turin, Tanvir Chowdhury; Matsushita, Kunihiro; Sang, Yingying; Ballew, Shoshana H; Appel, Lawrence J; Arima, Hisatomi; Chadban, Steven J; Cirillo, Massimo; Djurdjev, Ognjenka; Green, Jamie A; Heine, Gunnar H; Inker, Lesley A; Irie, Fujiko; Ishani, Areef; Ix, Joachim H; Kovesdy, Csaba P; Marks, Angharad; Ohkubo, Takayoshi; Shalev, Varda; Shankar, Anoop; Wen, Chi Pang; de Jong, Paul E; Iseki, Kunitoshi; Stengel, Benedicte; Gansevoort, Ron T; Levey, Andrew S

    2014-06-25

    The established chronic kidney disease (CKD) progression end point of end-stage renal disease (ESRD) or a doubling of serum creatinine concentration (corresponding to a change in estimated glomerular filtration rate [GFR] of −57% or greater) is a late event. To characterize the association of decline in estimated GFR with subsequent progression to ESRD with implications for using lesser declines in estimated GFR as potential alternative end points for CKD progression. Because most people with CKD die before reaching ESRD, mortality risk also was investigated. Individual meta-analysis of 1.7 million participants with 12,344 ESRD events and 223,944 deaths from 35 cohorts in the CKD Prognosis Consortium with a repeated measure of serum creatinine concentration over 1 to 3 years and outcome data. Transfer of individual participant data or standardized analysis of outputs for random-effects meta-analysis conducted between July 2012 and September 2013, with baseline estimated GFR values collected from 1975 through 2012. End-stage renal disease (initiation of dialysis or transplantation) or all-cause mortality risk related to percentage change in estimated GFR over 2 years, adjusted for potential confounders and first estimated GFR. The adjusted hazard ratios (HRs) of ESRD and mortality were higher with larger estimated GFR decline. Among participants with baseline estimated GFR of less than 60 mL/min/1.73 m2, the adjusted HRs for ESRD were 32.1 (95% CI, 22.3-46.3) for changes of −57% in estimated GFR and 5.4 (95% CI, 4.5-6.4) for changes of −30%. However, changes of −30% or greater (6.9% [95% CI, 6.4%-7.4%] of the entire consortium) were more common than changes of −57% (0.79% [95% CI, 0.52%-1.06%]). This association was strong and consistent across the length of the baseline period (1 to 3 years), baseline estimated GFR, age, diabetes status, or albuminuria. Average adjusted 10-year risk of ESRD (in patients with a baseline estimated GFR of 35 mL/min/1.73 m2

  8. KSHV cell attachment sites revealed by ultra sensitive tyramide signal amplification (TSA) localize to membrane microdomains that are up-regulated on mitotic cells.

    Science.gov (United States)

    Garrigues, H Jacques; Rubinchikova, Yelena E; Rose, Timothy M

    2014-03-01

    Cell surface structures initiating attachment of Kaposi's sarcoma-associated herpesvirus (KSHV) were characterized using purified hapten-labeled virions visualized by confocal microscopy with a sensitive fluorescent enhancement using tyramide signal amplification (TSA). KSHV attachment sites were present in specific cellular domains, including actin-based filopodia, lamellipodia, ruffled membranes, microvilli and intercellular junctions. Isolated microdomains were identified on the dorsal surface, which were heterogeneous in size with a variable distribution that depended on cellular confluence and cell cycle stage. KSHV binding domains ranged from scarce on interphase cells to dense and continuous on mitotic cells, and quantitation of bound virus revealed a significant increase on mitotic compared to interphase cells. KSHV also bound to a supranuclear domain that was distinct from microdomains in confluent and interphase cells. These results suggest that rearrangement of the cellular membrane during mitosis induces changes in cell surface receptors implicated in the initial attachment stage of KSHV entry. Copyright © 2014 Elsevier Inc. All rights reserved.

  9. Effect of SKT-b Vibrio probiotic bacteria addition at different developmental stages on tiger shrimp Penaeus monodon larvae survival rate

    Directory of Open Access Journals (Sweden)

    . Widanarni

    2009-07-01

    Full Text Available This experiment was conducted to study the effect of probiotic bacteria SKT-b Vibrio addition at different developmental stages on survival rates of tiger shrimp Penaeus monodon larva.  Main activity of this experiment consisted of tiger shrimp rearing started from nauplius stage until Pl10 and addition of 106 CFU/ml SKT-b Vibrio probiotic bacteria at various developmental stages namely at early nauplius stage, early zoea zoea stage, early mysis stage, early postlarva (Pl stage, every developmental stage changes, everyday, and control (without probiotic bacteria addition. Results showed that survival rates of shrimp larva ranged at 24,17%-35,83% with the higest value in the treatment of probiotic bacteria addition at every developmental stage changes namely 35,83%, whereas the lowest was found at control (without probiotic bacteria addition namely 24,17%.  No significantly different was found in term of shrimp growth rate among control and treatment. Growth rate in length of tiger shrimp larva ranged 18,64%-19,09% for SKT-b Vibrio addition and 18,47% for control. Key word: Probiotic bacteria, SKT-b Vibrio, Penaeus monodon, shrimp larvae stages   ABSTRAK Penelitian ini dilakukan untuk mempelajari pengaruh pemberian bakteri probiotik Vibrio SKT-b pada stadia yang berbeda terhadap kelangsungan hidup larva udang windu Penaeus monodon. Kegiatan utama dari penelitian ini adalah pemeliharaan udang windu yang dimulai dari stadia nauplius sampai Pl10 dan diberi bakteri probiotik Vibrio SKT-b dengan dosis 106 CFU/ml pada waktu yang berbeda yaitu pada awal stadia nauplius, awal stadia zoea, awal stadia mysis, awal stadia postlarva (Pl, setiap pergantian stadia, setiap hari, dan kontrol (tanpa pemberian bakteri probiotik. Hasil penelitian yang diperoleh menunjukkan bahwa tingkat kelangsungan hidup larva udang berkisar antara 24,17%-35,83% dengan nilai tertinggi terdapat pada perlakuan pemberian bakteri probiotik pada setiap pergantian stadia yaitu

  10. Sequential phosphorylation of GRASP65 during mitotic Golgi disassembly

    Directory of Open Access Journals (Sweden)

    Danming Tang

    2012-09-01

    GRASP65 phosphorylation during mitosis and dephosphorylation after mitosis are required for Golgi disassembly and reassembly during the cell cycle. At least eight phosphorylation sites on GRASP65 have been identified, but whether they are modified in a coordinated fashion during mitosis is so far unknown. In this study, we raised phospho-specific antibodies that recognize phosphorylated T220/T224, S277 and S376 residues of GRASP65, respectively. Biochemical analysis showed that cdc2 phosphorylates all three sites, while plk1 enhances the phosphorylation. Microscopic studies using these antibodies for double and triple labeling demonstrate sequential phosphorylation and dephosphorylation during the cell cycle. S277 and S376 are phosphorylated from late G2 phase through metaphase until telophase when the new Golgi is reassembled. T220/224 is not modified until prophase, but is highly modified from prometaphase to anaphase. In metaphase, phospho-T220/224 signal localizes on both Golgi haze and mitotic Golgi clusters that represent dispersed Golgi vesicles and Golgi remnants, respectively, while phospho-S277 and S376 labeling is more concentrated on mitotic Golgi clusters. Expression of a phosphorylation-resistant GRASP65 mutant T220A/T224A inhibited mitotic Golgi fragmentation to a much larger extent than the expression of the S277A and S376A mutants. In cytokinesis, T220/224 dephosphorylation occurs prior to that of S277, but after S376. This study provides evidence that GRASP65 is sequentially phosphorylated and dephosphorylated during mitosis at different sites to orchestrate Golgi disassembly and reassembly during cell division, with phosphorylation of the T220/224 site being most critical in the process.

  11. Mitotic delay of irradiated cells and its connection with quantity of radiation injuries

    International Nuclear Information System (INIS)

    Lobachevskij, P.N.; Fominykh, E.V.

    1989-01-01

    The study is dedicated to development of mathematical approach to interpret radiation-induced mitosic delay. An assumption is made that mitotic delay is conditioned by discrete injuries distributed in cells according to stochasticity of interaction of radiation and target substance. It is supposed to consider the problem on injuries nature causing mitotic delay and to use the developed method for accounting the effect of radiation-induced mitotic delay on registered chromosomal aberration yield. 10 refs.; 2 figs.; 3 tabs

  12. Mitotic defects lead to pervasive aneuploidy and accompany loss of RB1 activity in mouse LmnaDhe dermal fibroblasts.

    Directory of Open Access Journals (Sweden)

    C Herbert Pratt

    2011-03-01

    Full Text Available Lamin A (LMNA is a component of the nuclear lamina and is mutated in several human diseases, including Emery-Dreifuss muscular dystrophy (EDMD; OMIM ID# 181350 and the premature aging syndrome Hutchinson-Gilford progeria syndrome (HGPS; OMIM ID# 176670. Cells from progeria patients exhibit cell cycle defects in both interphase and mitosis. Mouse models with loss of LMNA function have reduced Retinoblastoma protein (RB1 activity, leading to aberrant cell cycle control in interphase, but how mitosis is affected by LMNA is not well understood.We examined the cell cycle and structural phenotypes of cells from mice with the Lmna allele, Disheveled hair and ears (Lmna(Dhe. We found that dermal fibroblasts from heterozygous Lmna(Dhe (Lmna(Dhe/+ mice exhibit many phenotypes of human laminopathy cells. These include severe perturbations to the nuclear shape and lamina, increased DNA damage, and slow growth rates due to mitotic delay. Interestingly, Lmna(Dhe/+ fibroblasts also had reduced levels of hypophosphorylated RB1 and the non-SMC condensin II-subunit D3 (NCAP-D3, a mitosis specific centromere condensin subunit that depends on RB1 activity. Mitotic check point control by mitotic arrest deficient-like 1 (MAD2L1 also was perturbed in Lmna(Dhe/+ cells. Lmna(Dhe/+ fibroblasts were consistently aneuploid and had higher levels of micronuclei and anaphase bridges than normal fibroblasts, consistent with chromosome segregation defects.These data indicate that RB1 may be a key regulator of cellular phenotype in laminopathy-related cells, and suggest that the effects of LMNA on RB1 include both interphase and mitotic cell cycle control.

  13. Mitotic Defects Lead to Pervasive Aneuploidy and Accompany Loss of RB1 Activity in Mouse LmnaDhe Dermal Fibroblasts

    Science.gov (United States)

    Pratt, C. Herbert; Curtain, Michelle; Donahue, Leah Rae; Shopland, Lindsay S.

    2011-01-01

    Background Lamin A (LMNA) is a component of the nuclear lamina and is mutated in several human diseases, including Emery-Dreifuss muscular dystrophy (EDMD; OMIM ID# 181350) and the premature aging syndrome Hutchinson-Gilford progeria syndrome (HGPS; OMIM ID# 176670). Cells from progeria patients exhibit cell cycle defects in both interphase and mitosis. Mouse models with loss of LMNA function have reduced Retinoblastoma protein (RB1) activity, leading to aberrant cell cycle control in interphase, but how mitosis is affected by LMNA is not well understood. Results We examined the cell cycle and structural phenotypes of cells from mice with the Lmna allele, Disheveled hair and ears (LmnaDhe). We found that dermal fibroblasts from heterozygous LmnaDhe (LmnaDhe/+) mice exhibit many phenotypes of human laminopathy cells. These include severe perturbations to the nuclear shape and lamina, increased DNA damage, and slow growth rates due to mitotic delay. Interestingly, LmnaDhe/+ fibroblasts also had reduced levels of hypophosphorylated RB1 and the non-SMC condensin II-subunit D3 (NCAP-D3), a mitosis specific centromere condensin subunit that depends on RB1 activity. Mitotic check point control by mitotic arrest deficient-like 1 (MAD2L1) also was perturbed in LmnaDhe /+ cells. LmnaDhe /+ fibroblasts were consistently aneuploid and had higher levels of micronuclei and anaphase bridges than normal fibroblasts, consistent with chromosome segregation defects. Conclusions These data indicate that RB1 may be a key regulator of cellular phenotype in laminopathy-related cells, and suggest that the effects of LMNA on RB1 include both interphase and mitotic cell cycle control. PMID:21464947

  14. Radiation induced mitotic delay and stimulation of growth

    International Nuclear Information System (INIS)

    Feldmann, A.

    1974-01-01

    The mechanisms responsible for the radiation induced mitotic delay and stimulation of growth are discussed in connection with the results of studies in Lemna minor and Lepidium sativum. The action of temperature seems to be of major importance. As many authors suggest that various chemical agents and slight intoxications also affect mitosis in a way similar to that induced by ionizing radiation, the radiation induced stimulation has lost its specific character and approaches might be found for further investigations of this phenomenon. (MG) [de

  15. Studies on the induction of mitotic gene conversion by ultraviolet irradiation

    International Nuclear Information System (INIS)

    Ito, T.; Kobayashi, K.

    1975-01-01

    Action spectra for the induction of intragenic mitotic recombination (gene conversion) at the trp 5 locus by UV are presented for three cell stages (T 0 , T 9 and T 16 ) taken from synchronously growing cultures of Saccharomyces cerevisiae. The spectra over the range from 230 to 300 nm were taken mostly in 5-nm steps. The peak in the action spectra was significantly shifted, regardless of the stage, towards the longer wavelengths as compared with that of the absorption spectrum of DNA (258nm) or even that of thymine (265nm). In one extreme case ( 16 ), the peak was shifted 17nm from the absorption peak of DNA. Further, the spectrum changed its shape as the cell stage advanced from the non-dividing (unbudded) (T 0 ) to a dividing phase (T 16 ). Furthermore, the induction cross section decreased by a large factor (about 40), regardless of the wavelength, in going from the non-dividing to a dividing phase. From observations of the high photoreversibility of induced conversions, the major primary damage was thought to be pyrimidine dimers in the DNA

  16. Trading stages

    DEFF Research Database (Denmark)

    Steiner, Uli; Tuljapurkar, Shripad; Coulson, Tim

    2012-01-01

    Interest in stage-and age structured models has recently increased because they can describe quantitative traits such as size that are left out of age-only demography. Available methods for the analysis of effects of vital rates on lifespan in stage-structured models have not been widely applied ...... examples. Much of our approach relies on trading of time and mortality risk in one stage for time and risk in others. Our approach contributes to the new framework of the study of age- and stage-structured biodemography....

  17. Rumen degradation characteristics of ryegrass herbage and ryegrass silage are affected by interactions between stage of maturity and nitrogen fertilisation rate

    NARCIS (Netherlands)

    Heeren, J.A.H.; Podesta, S.C.; Hatew, B.; Klop, G.; Laar, van H.; Bannink, A.; Warner, D.; Jonge, de L.H.; Dijkstra, J.

    2014-01-01

    The objective of this experiment was to evaluate interaction effects between stage of maturity and N fertilization rate on rumen degradation characteristics determined with nylon bag incubations of ryegrass herbages and ryegrass silage. Grass herbage (n = 4) was cut after 3 or 5 weeks of regrowth

  18. Lower estimated glomerular filtration rate and higher albuminuria are associated with mortality and end-stage renal disease. A collaborative meta-analysis of kidney disease population cohorts

    DEFF Research Database (Denmark)

    Astor, Brad C; Matsushita, Kunihiro; Gansevoort, Ron T

    2011-01-01

    We studied here the independent associations of estimated glomerular filtration rate (eGFR) and albuminuria with mortality and end-stage renal disease (ESRD) in individuals with chronic kidney disease (CKD). We performed a collaborative meta-analysis of 13 studies totaling 21,688 patients selected...

  19. Automated high-throughput quantification of mitotic spindle positioning from DIC movies of Caenorhabditis embryos.

    Directory of Open Access Journals (Sweden)

    David Cluet

    Full Text Available The mitotic spindle is a microtubule-based structure that elongates to accurately segregate chromosomes during anaphase. Its position within the cell also dictates the future cell cleavage plan, thereby determining daughter cell orientation within a tissue or cell fate adoption for polarized cells. Therefore, the mitotic spindle ensures at the same time proper cell division and developmental precision. Consequently, spindle dynamics is the matter of intensive research. Among the different cellular models that have been explored, the one-cell stage C. elegans embryo has been an essential and powerful system to dissect the molecular and biophysical basis of spindle elongation and positioning. Indeed, in this large and transparent cell, spindle poles (or centrosomes can be easily detected from simple DIC microscopy by human eyes. To perform quantitative and high-throughput analysis of spindle motion, we developed a computer program ACT for Automated-Centrosome-Tracking from DIC movies of C. elegans embryos. We therefore offer an alternative to the image acquisition and processing of transgenic lines expressing fluorescent spindle markers. Consequently, experiments on large sets of cells can be performed with a simple setup using inexpensive microscopes. Moreover, analysis of any mutant or wild-type backgrounds is accessible because laborious rounds of crosses with transgenic lines become unnecessary. Last, our program allows spindle detection in other nematode species, offering the same quality of DIC images but for which techniques of transgenesis are not accessible. Thus, our program also opens the way towards a quantitative evolutionary approach of spindle dynamics. Overall, our computer program is a unique macro for the image- and movie-processing platform ImageJ. It is user-friendly and freely available under an open-source licence. ACT allows batch-wise analysis of large sets of mitosis events. Within 2 minutes, a single movie is processed

  20. A molecular mechanism of mitotic centrosome assembly in Drosophila

    Science.gov (United States)

    Conduit, Paul T; Richens, Jennifer H; Wainman, Alan; Holder, James; Vicente, Catarina C; Pratt, Metta B; Dix, Carly I; Novak, Zsofia A; Dobbie, Ian M; Schermelleh, Lothar; Raff, Jordan W

    2014-01-01

    Centrosomes comprise a pair of centrioles surrounded by pericentriolar material (PCM). The PCM expands dramatically as cells enter mitosis, but it is unclear how this occurs. In this study, we show that the centriole protein Asl initiates the recruitment of DSpd-2 and Cnn to mother centrioles; both proteins then assemble into co-dependent scaffold-like structures that spread outwards from the mother centriole and recruit most, if not all, other PCM components. In the absence of either DSpd-2 or Cnn, mitotic PCM assembly is diminished; in the absence of both proteins, it appears to be abolished. We show that DSpd-2 helps incorporate Cnn into the PCM and that Cnn then helps maintain DSpd-2 within the PCM, creating a positive feedback loop that promotes robust PCM expansion around the mother centriole during mitosis. These observations suggest a surprisingly simple mechanism of mitotic PCM assembly in flies. DOI: http://dx.doi.org/10.7554/eLife.03399.001 PMID:25149451

  1. Parameters of mitotic recombination in minute mutants of Drosophila melanogaster

    International Nuclear Information System (INIS)

    Ferrus, A.

    1975-01-01

    A sample of 16 Minutes, representing 12 loci distributed over all the chromosome arms and including 3 pairs of alleles and 4 deficiencies, has been studied with respect to several developmental and recombinational parameters. Cell marker mutants located in most of the chromosome arms were used to assess (1) spontaneous and x-ray-induced mitotic recombination frequencies of each Minute, and (2) clone sizes of the different cell marker clones. These parameters were analyzed both in the wing disc and in the abdominal histoblasts. Whereas spontaneous frequencies are not affected by the presence of the Minutes studied, the different Minutes characteristically increase the frequency of recombination clones arising after x irradiation. The recombinant clones which are M + /M + are significantly larger than clones in the same fly which retain the M + /M condition. This is particularly striking in clones in the wing disc, slightly so in clones in the tergites. The occurrence of mitotic recombination in the fourth chromosome is reported for the first time. Chaeta length and developmental delay correlates with the recombinational parameters in different ways. Possible causal interrelationships of the different traits of the Minute syndrome are discussed. (U.S.)

  2. Inhibition of mitotic-specific histone phophorylation by sodium arsenite

    Energy Technology Data Exchange (ETDEWEB)

    Cobo, J.M. [Universidad de Alcala de Henares, Madrid (Spain); Valdez, J.G.; Gurley, L.R. [Los Alamos National Lab., NM (United States)

    1994-10-01

    Synchronized cultures of Chinese hamster cells (line CHO) were used to measure the effects of 10{mu}M sodium arsenite on histone phosphorylation. This treatment caused cell proliferation to be temporarily arrested, after which the cells spontaneously resumed cell proliferation in a radiomimetric manner. Immediately following treatment, it was found that sodium arsenite affected only mitotic-specific HI and H3 phosphorylations. Neither interphase, nor mitotic, H2A and H4 phosphorylations were affected, nor was interphase HI Phosphorylation affected. The phosphorylation of HI was inhibited only in mitosis, reducing HI phosphorylation to 38.1% of control levels, which was the level of interphase HI phosphorylation. The phosphorylation of both H3 variants was inhibited in mitosis, the less hydrophobic H3 to 19% and the more hydrophobic H3 to 24% of control levels. These results suggest that sodium arsenite may inhibite cell proliferation by interfering with the cyclin B/p34{sup cdc2} histone kinase activity which is thought to play a key role in regulating the cell cycle. It has been proposed by our laboratory that HI and H3 phosphorylations play a role in restructuring interphase chromatin into metaphase chromosomes. Interference of this process by sodium arsenite may lead to structurally damaged chromosomes resulting in the increased cancer risks known to be produced by arsenic exposure from the environment.

  3. Effects of growth rate, size, and light availability on tree survival across life stages: a demographic analysis accounting for missing values and small sample sizes.

    Science.gov (United States)

    Moustakas, Aristides; Evans, Matthew R

    2015-02-28

    Plant survival is a key factor in forest dynamics and survival probabilities often vary across life stages. Studies specifically aimed at assessing tree survival are unusual and so data initially designed for other purposes often need to be used; such data are more likely to contain errors than data collected for this specific purpose. We investigate the survival rates of ten tree species in a dataset designed to monitor growth rates. As some individuals were not included in the census at some time points we use capture-mark-recapture methods both to allow us to account for missing individuals, and to estimate relocation probabilities. Growth rates, size, and light availability were included as covariates in the model predicting survival rates. The study demonstrates that tree mortality is best described as constant between years and size-dependent at early life stages and size independent at later life stages for most species of UK hardwood. We have demonstrated that even with a twenty-year dataset it is possible to discern variability both between individuals and between species. Our work illustrates the potential utility of the method applied here for calculating plant population dynamics parameters in time replicated datasets with small sample sizes and missing individuals without any loss of sample size, and including explanatory covariates.

  4. B microchromosomes in the family Curimatidae (Characiformes): mitotic and meiotic behavior.

    Science.gov (United States)

    Sampaio, Tatiane Ramos; Gravena, Waleska; Gouveia, Juceli Gonzalez; Giuliano-Caetano, Lucia; Dias, Ana Lúcia

    2011-01-01

    Cyphocharax voga (Hensel, 1870), Cyphocharax spilotus (Vari, 1987), Cyphocharax saladensis (Meinken, 1933), Cyphocharax modestus (Fernández-Yépez, 1948), Steindachnerina biornata (Braga & Azpelicueta, 1987) and Steindachnerina insculpta (Fernández-Yépez, 1948) collected from two hydrographic basins. All samples presented 2n=54 meta-submetacentric (m-sm) chromosomes and FN equal to 108, and 1 or 2 B microchromosomes in the mitotic and meiotic cells of the six sampled populations showing inter-and intraindividual variation. The analysis of the meiotic cells in Cyphocharax saladensis, Cyphocharax spilotus, and Cyphocharax voga showed a modal number of 54 chromosomes in the spermatogonial metaphases and 27 bivalents in the pachytene, diplotene, diakinesis and in metaphase I stages, and 27 chromosomes in metaphase II; in Cyphocharax modestus, Steindachnerina biornata, and Steindachnerina insculpta, spermatogonial metaphases with 54 chromosomes and pachytene and metaphase I with 27 bivalents were observed. The B microchromosome was observed as univalent in the spermatogonial metaphase of Cyphocharax spilotus, in the pachytene stage in the other species, with the exception of Cyphocharax saladensis, and Steindachnerina biornata in metaphase I. New occurrences of the B microchromosome in Cyphocharax voga, Cyphocharax saladensis and Steindachnerina biornata were observed, confirming that the presence of this type of chromosome is a striking characteristic of this group of fish.

  5. CYTOGENETICS EFFECTS INDUCED BY NITRATE OF LEAD ON MITOTIC DIVISION AT ALLIUM CEPA L.

    OpenAIRE

    Silvica Padureanu

    2005-01-01

    The paper presents the influence of nitrate of lead upon the mitotic division of Allium cepa L. The treatment with nitrate of lead has determined the lessening of the mitotic index and the chromosomial mutations. Also nitrate of lead determined in little proportion cells autopoliploid. The experiment prowed that nitrate of lead, known as a polluting agent has a mutagenic potential on the plants.

  6. Mitotically Active Leiomyoma of the Uterus in a Postmenopausal Breast Cancer Patient Receiving Tamoxifen

    Directory of Open Access Journals (Sweden)

    I-Feng Liu

    2006-06-01

    Conclusion: Endometrial cancer is rarely noted in breast cancer patients taking tamoxifen. Further, none have reported mitotically active leiomyoma of the uterus. From this case, endometrial proliferation and mitotically active leiomyoma of the uterus may be related to tamoxifen therapy, and should not be neglected in breast cancer patients.

  7. Timely Endocytosis of Cytokinetic Enzymes Prevents Premature Spindle Breakage during Mitotic Exit.

    Directory of Open Access Journals (Sweden)

    Cheen Fei Chin

    2016-07-01

    Full Text Available Cytokinesis requires the spatio-temporal coordination of membrane deposition and primary septum (PS formation at the division site to drive acto-myosin ring (AMR constriction. It has been demonstrated that AMR constriction invariably occurs only after the mitotic spindle disassembly. It has also been established that Chitin Synthase II (Chs2p neck localization precedes mitotic spindle disassembly during mitotic exit. As AMR constriction depends upon PS formation, the question arises as to how chitin deposition is regulated so as to prevent premature AMR constriction and mitotic spindle breakage. In this study, we propose that cells regulate the coordination between spindle disassembly and AMR constriction via timely endocytosis of cytokinetic enzymes, Chs2p, Chs3p, and Fks1p. Inhibition of endocytosis leads to over accumulation of cytokinetic enzymes during mitotic exit, which accelerates the constriction of the AMR, and causes spindle breakage that eventually could contribute to monopolar spindle formation in the subsequent round of cell division. Intriguingly, the mitotic spindle breakage observed in endocytosis mutants can be rescued either by deleting or inhibiting the activities of, CHS2, CHS3 and FKS1, which are involved in septum formation. The findings from our study highlight the importance of timely endocytosis of cytokinetic enzymes at the division site in safeguarding mitotic spindle integrity during mitotic exit.

  8. Rate dependent direct inverse hysteresis compensation of piezoelectric micro-actuator used in dual-stage hard disk drive head positioning system.

    Science.gov (United States)

    Rahman, Md Arifur; Al Mamun, Abdullah; Yao, Kui

    2015-08-01

    The head positioning servo system in hard disk drive is implemented nowadays using a dual-stage actuator—the primary stage consisting of a voice coil motor actuator providing long range motion and the secondary stage controlling the position of the read/write head with fine resolution. Piezoelectric micro-actuator made of lead zirconate titanate (PZT) has been a popular choice for the secondary stage. However, PZT micro-actuator exhibits hysteresis—an inherent nonlinear characteristic of piezoelectric material. The advantage expected from using the secondary micro-actuator is somewhat lost by the hysteresis of the micro-actuator that contributes to tracking error. Hysteresis nonlinearity adversely affects the performance and, if not compensated, may cause inaccuracy and oscillation in the response. Compensation of hysteresis is therefore an important aspect for designing head-positioning servo system. This paper presents a new rate dependent model of hysteresis along with rigorous analysis and identification of the model. Parameters of the model are found using particle swarm optimization. Direct inverse of the proposed rate-dependent generalized Prandtl-Ishlinskii model is used as the hysteresis compensator. Effectiveness of the overall solution is underscored through experimental results.

  9. [Stability in association of the peripheral material with mitotic chromosomes].

    Science.gov (United States)

    Kosykh, M I; Chentsov, Iu S

    2002-01-01

    The localization of nucleolar proteins (fibrillarin and B-23), and of the protein of interphase nuclear matrix (NMP-65) was studied in the perichromosomal material (CM) after of short hypotonic treatment (15% solution of Henks medium) on cultured pig embryonic kidney cells, followed by restoration of isotonic conditions. It is shown that during hypotonic shock the mitotic chromosomes demonstrate reversible swelling, but their periphery is bounded with a rim of PCM, containing antibodies to fibrillarin and NMP-65, but not to B-23. After returning the cells to the initial isotonic medium, all the three proteins can be detected again on the periphery of chromosomes. It suggests the existence of different stability in the association of free proteins with chromosome bodies. Besides, B-23 and fibrillarin could be visualized in residual nucleoli after a complete extraction of histones and DNA from nuclei.

  10. Aurora A's functions during mitotic exit: the Guess Who game

    Directory of Open Access Journals (Sweden)

    David eReboutier

    2015-12-01

    Full Text Available Until recently, the knowledge of Aurora A kinase functions during mitosis was limited to pre-metaphase events, particularly centrosome maturation, G2/M transition, and mitotic spindle assembly. However, an involvement of Aurora A in post-metaphase events was also suspected, but not clearly demonstrated due to the technical difficulty to perform the appropriate experiments. Recent developments of both an analog specific version of Aurora A, and of small molecule inhibitors have led to the first demonstration that Aurora A is required for the early steps of cytokinesis. As in pre-metaphase, Aurora A plays diverse functions during anaphase, essentially participating in astral microtubules dynamics and central spindle assembly and functioning. The present review describes the experimental systems used to decipher new functions of Aurora A during late mitosis and situate these functions into the context of cytokinesis mechanisms.

  11. Smurf2 as a novel mitotic regulator: From the spindle assembly checkpoint to tumorigenesis

    Directory of Open Access Journals (Sweden)

    Moore Finola E

    2009-07-01

    Full Text Available Abstract The execution of the mitotic program with high fidelity is dependent upon precise spatiotemporal regulation of posttranslational protein modifications. For example, the timely polyubiquitination of critical mitotic regulators by Anaphase Promoting Complex/Cyclosome (APC/C is essential for the metaphase to anaphase transition and mitotic exit. The spindle assembly checkpoint prevents unscheduled activity of APC/C-Cdc20 in early mitosis, allowing bipolar attachment of kinetochores to mitotic spindle and facilitating equal segregation of sister chromatids. The critical effector of the spindle checkpoint, Mitotic arrest deficient 2 (Mad2, is recruited to unattached kinetochores forming a complex with other regulatory proteins to efficiently and cooperatively inhibit APC/C-Cdc20. A weakened and/or dysfunctional spindle checkpoint has been linked to the development of genomic instability in both cell culture and animal models, and evidence suggests that aberrant regulation of the spindle checkpoint plays a critical role in human carcinogenesis. Recent studies have illuminated a network of both degradative and non-degradative ubiquitination events that regulate the metaphase to anaphase transition and mitotic exit. Within this context, our recent work showed that the HECT (Homologous to E6-AP C-terminus-family E3 ligase Smurf2 (Smad specific ubiquitin regulatory factor 2, known as a negative regulator of transforming growth factor-beta (TGF-β signaling, is required for a functional spindle checkpoint by promoting the functional localization and stability of Mad2. Here we discuss putative models explaining the role of Smurf2 as a new regulator in the spindle checkpoint. The dynamic mitotic localization of Smurf2 to the centrosome and other critical mitotic structures provides implications about mitotic checkpoint control dependent on various ubiquitination events. Finally, deregulated Smurf2 activity may contribute to carcinogenesis by

  12. Binding, internalization and fate of Huntingtin Exon1 fibrillar assemblies in mitotic and nonmitotic neuroblastoma cells.

    Science.gov (United States)

    Ruiz-Arlandis, G; Pieri, L; Bousset, L; Melki, R

    2016-02-01

    The aggregation of Huntingtin (HTT) protein and of its moiety encoded by its Exon1 (HTTExon1) into fibrillar structures inside neurons is the molecular hallmark of Huntington's disease. Prion-like transmission of these aggregates between cells has been demonstrated. The cell-to-cell transmission mechanisms of these protein aggregates and the susceptibility of different kinds of neuronal cells to these toxic assemblies still need assessment. Here, we documented the binding to and internalization by differentiated and undifferentiated neuroblastoma cells of exogenous fibrillar HTTExon1 and polyglutamine (polyQ) polypeptides containing the same number of glutamines. We assessed the contribution of endocytosis to fibrillar HTTExon1 uptake, their intracellular localization and fate. We observed that undifferentiated neuroblastoma cells were more susceptible to fibrillar HTTExon1 and polyQ than their differentiated counterparts. Furthermore, we demonstrated that exogenous HTTExon1 aggregates are mainly taken up by endocytosis and directed to lysosomal compartments in both mitotic and quiescent cells. These data suggest that the rates of endocytic processes that differ in mitotic and quiescent cells strongly impact the uptake of exogenous HTTExon1 and polyQ fibrils. This may be either the consequence of distinct metabolisms or distributions of specific protein partners for amyloid-like assemblies at the surface of highly dividing versus quiescent cells. Our results highlight the importance of endocytic processes in the internalization of exogenous HTTExon1 fibrils and suggest that a proportion of those assemblies reach the cytosol where they can amplify by recruiting the endogenous protein after escaping, by yet an unknown process, from the endo-lysosomal compartments. © 2015 British Neuropathological Society.

  13. Different effects of dose rate on radiation-induced mutation frequency in various germ-cell stages of the mouse, and their implications for the analysis of tumorigenesis

    International Nuclear Information System (INIS)

    Russell, W.L.

    1979-01-01

    The following factors affecting mutation induction by radiation in mice are discussed: dose rate, cell stage, and sex. It is suggested that for cancers of presumed mutational origin, the risk from chronic radiation exposure may be only one-third the risk from acute exposure. This is based only on responses of spermatogonia; other cell types behave quite differently. Specific and general applications are discussed

  14. In-silico modeling of the mitotic spindle assembly checkpoint.

    Directory of Open Access Journals (Sweden)

    Bashar Ibrahim

    2008-02-01

    Full Text Available The Mitotic Spindle Assembly Checkpoint ((MSAC is an evolutionary conserved mechanism that ensures the correct segregation of chromosomes by restraining cell cycle progression from entering anaphase until all chromosomes have made proper bipolar attachments to the mitotic spindle. Its malfunction can lead to cancer.We have constructed and validated for the human (MSAC mechanism an in silico dynamical model, integrating 11 proteins and complexes. The model incorporates the perspectives of three central control pathways, namely Mad1/Mad2 induced Cdc20 sequestering based on the Template Model, MCC formation, and APC inhibition. Originating from the biochemical reactions for the underlying molecular processes, non-linear ordinary differential equations for the concentrations of 11 proteins and complexes of the (MSAC are derived. Most of the kinetic constants are taken from literature, the remaining four unknown parameters are derived by an evolutionary optimization procedure for an objective function describing the dynamics of the APC:Cdc20 complex. MCC:APC dissociation is described by two alternatives, namely the "Dissociation" and the "Convey" model variants. The attachment of the kinetochore to microtubuli is simulated by a switching parameter silencing those reactions which are stopped by the attachment. For both, the Dissociation and the Convey variants, we compare two different scenarios concerning the microtubule attachment dependent control of the dissociation reaction. Our model is validated by simulation of ten perturbation experiments.Only in the controlled case, our models show (MSAC behaviour at meta- to anaphase transition in agreement with experimental observations. Our simulations revealed that for (MSAC activation, Cdc20 is not fully sequestered; instead APC is inhibited by MCC binding.

  15. The role of estrogen and progesterone receptors in response rate to megestrol acetate: conservative treatment of stage Ia endometrial adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Yarandi F

    2010-12-01

    Full Text Available "nBackground: Surgery is the most effective treatment of well-differentiated endometrial cancer. But using systemic progestins, have been evaluated to treat the young patients with well-differentiated endometrial cancer who wish to preserve their fertility. The aim of this study was the evaluation of megestrol acetate on endometrial adenocarcino-ma with regard to the receptors."n "nMethods: This was a quasi-experimental study. In 16 infertile patients with stage Ia well-differentiated endometrial adenocarcinoma. The treatment initiated with 160mg/d of megestrol acetate and continued with 320mg/d for non-responsive cases. All of the patients followed with FD&C and hysteroscopy. The responsive patients were referred to IVF group and they were followed for three years."n "nResults: Of nine patient in the first step of the study, 4 (25% became pregnant. Eight patients underwent Total Abdominal Hysterectomy (TAH, and one was retreated conservatively. Of seven patient of second step of the study, five are under treatment at the time of closing the paper (three cases candidate for IVF and two are under 320 mg/d megestrol acetate, one patient is a candidate for hysterectomy, and one exited of study because of male infertility. All of the patients were progesterone receptor positive, and only one was estrogen receptor negative."n "nConclusion: Conservative treatment of early stage well-differentiated endometrial adenocarcinoma with progestins may be used in highly selected young patients who have not completed their family. Close long- term follow up in this special group of patients is necessary. The evaluation of estrogen and progesterone receptors assay may be useful in predicting response to the treatment.

  16. File list: His.Emb.50.AllAg.Mitotic_cycle_7-9 [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  17. File list: NoD.Emb.05.AllAg.Mitotic_cycle_12-14 [Chip-atlas[Archive

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  18. File list: Pol.Emb.10.AllAg.Mitotic_cycle_8-9 [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  19. File list: ALL.Emb.05.AllAg.Mitotic_cycle_8-9 [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  20. File list: InP.Emb.20.AllAg.Mitotic_cycle_8-9 [Chip-atlas[Archive

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  1. File list: Pol.Emb.05.AllAg.Mitotic_cycle_13-14 [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  2. File list: Oth.Emb.50.AllAg.Mitotic_cycle_13-14 [Chip-atlas[Archive

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  3. File list: Pol.Emb.10.AllAg.Mitotic_cycle_11-13 [Chip-atlas[Archive

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  4. File list: His.Emb.20.AllAg.Mitotic_cycle_11-13 [Chip-atlas[Archive

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  5. File list: NoD.Emb.10.AllAg.Mitotic_cycle_7-9 [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  6. File list: InP.Emb.50.AllAg.Mitotic_cycle_14 [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  7. File list: InP.Emb.50.AllAg.Mitotic_cycle_7-9 [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  8. File list: Pol.Emb.20.AllAg.Mitotic_cycle_12-14 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Pol.Emb.20.AllAg.Mitotic_cycle_12-14 dm3 RNA polymerase Embryo Mitotic cycle 12-14 ...http://dbarchive.biosciencedbc.jp/kyushu-u/dm3/assembled/Pol.Emb.20.AllAg.Mitotic_cycle_12-14.bed ...

  9. File list: Oth.Emb.20.AllAg.Mitotic_cycle_7-9 [Chip-atlas[Archive

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  10. File list: InP.Emb.50.AllAg.Mitotic_cycle_8-9 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available InP.Emb.50.AllAg.Mitotic_cycle_8-9 dm3 Input control Embryo Mitotic cycle 8-9 http:...//dbarchive.biosciencedbc.jp/kyushu-u/dm3/assembled/InP.Emb.50.AllAg.Mitotic_cycle_8-9.bed ...

  11. File list: DNS.Emb.20.AllAg.Mitotic_cycle_12-14 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available DNS.Emb.20.AllAg.Mitotic_cycle_12-14 dm3 DNase-seq Embryo Mitotic cycle 12-14 http:...//dbarchive.biosciencedbc.jp/kyushu-u/dm3/assembled/DNS.Emb.20.AllAg.Mitotic_cycle_12-14.bed ...

  12. File list: His.Emb.50.AllAg.Mitotic_cycle_13-14 [Chip-atlas[Archive

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  13. File list: DNS.Emb.10.AllAg.Mitotic_cycle_12-14 [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  14. File list: ALL.Emb.20.AllAg.Mitotic_cycle_8-9 [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  15. File list: Pol.Emb.20.AllAg.Mitotic_cycle_11-13 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Pol.Emb.20.AllAg.Mitotic_cycle_11-13 dm3 RNA polymerase Embryo Mitotic cycle 11-13 ...http://dbarchive.biosciencedbc.jp/kyushu-u/dm3/assembled/Pol.Emb.20.AllAg.Mitotic_cycle_11-13.bed ...

  16. File list: NoD.Emb.20.AllAg.Mitotic_cycle_7-9 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available NoD.Emb.20.AllAg.Mitotic_cycle_7-9 dm3 No description Embryo Mitotic cycle 7-9 http...://dbarchive.biosciencedbc.jp/kyushu-u/dm3/assembled/NoD.Emb.20.AllAg.Mitotic_cycle_7-9.bed ...

  17. File list: Unc.Emb.50.AllAg.Mitotic_cycle_11-13 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Unc.Emb.50.AllAg.Mitotic_cycle_11-13 dm3 Unclassified Embryo Mitotic cycle 11-13 ht...tp://dbarchive.biosciencedbc.jp/kyushu-u/dm3/assembled/Unc.Emb.50.AllAg.Mitotic_cycle_11-13.bed ...

  18. File list: NoD.Emb.05.AllAg.Mitotic_cycle_11-13 [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  19. File list: Unc.Emb.05.AllAg.Mitotic_cycle_11-13 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Unc.Emb.05.AllAg.Mitotic_cycle_11-13 dm3 Unclassified Embryo Mitotic cycle 11-13 ht...tp://dbarchive.biosciencedbc.jp/kyushu-u/dm3/assembled/Unc.Emb.05.AllAg.Mitotic_cycle_11-13.bed ...

  20. File list: InP.Emb.05.AllAg.Mitotic_cycle_13-14 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available InP.Emb.05.AllAg.Mitotic_cycle_13-14 dm3 Input control Embryo Mitotic cycle 13-14 h...ttp://dbarchive.biosciencedbc.jp/kyushu-u/dm3/assembled/InP.Emb.05.AllAg.Mitotic_cycle_13-14.bed ...

  1. File list: Pol.Emb.50.AllAg.Mitotic_cycle_7-9 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Pol.Emb.50.AllAg.Mitotic_cycle_7-9 dm3 RNA polymerase Embryo Mitotic cycle 7-9 http...://dbarchive.biosciencedbc.jp/kyushu-u/dm3/assembled/Pol.Emb.50.AllAg.Mitotic_cycle_7-9.bed ...

  2. File list: Pol.Emb.20.AllAg.Mitotic_cycle_8-9 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Pol.Emb.20.AllAg.Mitotic_cycle_8-9 dm3 RNA polymerase Embryo Mitotic cycle 8-9 http...://dbarchive.biosciencedbc.jp/kyushu-u/dm3/assembled/Pol.Emb.20.AllAg.Mitotic_cycle_8-9.bed ...

  3. File list: DNS.Emb.50.AllAg.Mitotic_cycle_11-13 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available DNS.Emb.50.AllAg.Mitotic_cycle_11-13 dm3 DNase-seq Embryo Mitotic cycle 11-13 http:...//dbarchive.biosciencedbc.jp/kyushu-u/dm3/assembled/DNS.Emb.50.AllAg.Mitotic_cycle_11-13.bed ...

  4. File list: Pol.Emb.50.AllAg.Mitotic_cycle_12-14 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Pol.Emb.50.AllAg.Mitotic_cycle_12-14 dm3 RNA polymerase Embryo Mitotic cycle 12-14 ...http://dbarchive.biosciencedbc.jp/kyushu-u/dm3/assembled/Pol.Emb.50.AllAg.Mitotic_cycle_12-14.bed ...

  5. File list: Pol.Emb.50.AllAg.Mitotic_cycle_11-13 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Pol.Emb.50.AllAg.Mitotic_cycle_11-13 dm3 RNA polymerase Embryo Mitotic cycle 11-13 ...http://dbarchive.biosciencedbc.jp/kyushu-u/dm3/assembled/Pol.Emb.50.AllAg.Mitotic_cycle_11-13.bed ...

  6. File list: Oth.Emb.10.AllAg.Mitotic_cycle_11-13 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Emb.10.AllAg.Mitotic_cycle_11-13 dm3 TFs and others Embryo Mitotic cycle 11-13 ...http://dbarchive.biosciencedbc.jp/kyushu-u/dm3/assembled/Oth.Emb.10.AllAg.Mitotic_cycle_11-13.bed ...

  7. File list: ALL.Emb.50.AllAg.Mitotic_cycle_13-14 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ALL.Emb.50.AllAg.Mitotic_cycle_13-14 dm3 All antigens Embryo Mitotic cycle 13-14 SR...X084384 http://dbarchive.biosciencedbc.jp/kyushu-u/dm3/assembled/ALL.Emb.50.AllAg.Mitotic_cycle_13-14.bed ...

  8. File list: Oth.Emb.50.AllAg.Mitotic_cycle_11-13 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Emb.50.AllAg.Mitotic_cycle_11-13 dm3 TFs and others Embryo Mitotic cycle 11-13 ...http://dbarchive.biosciencedbc.jp/kyushu-u/dm3/assembled/Oth.Emb.50.AllAg.Mitotic_cycle_11-13.bed ...

  9. File list: ALL.Emb.20.AllAg.Mitotic_cycle_13-14 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ALL.Emb.20.AllAg.Mitotic_cycle_13-14 dm3 All antigens Embryo Mitotic cycle 13-14 SR...X084384 http://dbarchive.biosciencedbc.jp/kyushu-u/dm3/assembled/ALL.Emb.20.AllAg.Mitotic_cycle_13-14.bed ...

  10. File list: His.Emb.20.AllAg.Mitotic_cycle_13-14 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available His.Emb.20.AllAg.Mitotic_cycle_13-14 dm3 Histone Embryo Mitotic cycle 13-14 http://...dbarchive.biosciencedbc.jp/kyushu-u/dm3/assembled/His.Emb.20.AllAg.Mitotic_cycle_13-14.bed ...

  11. File list: InP.Emb.20.AllAg.Mitotic_cycle_11-13 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available InP.Emb.20.AllAg.Mitotic_cycle_11-13 dm3 Input control Embryo Mitotic cycle 11-13 S...RX645138 http://dbarchive.biosciencedbc.jp/kyushu-u/dm3/assembled/InP.Emb.20.AllAg.Mitotic_cycle_11-13.bed ...

  12. File list: InP.Emb.20.AllAg.Mitotic_cycle_12-14 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available InP.Emb.20.AllAg.Mitotic_cycle_12-14 dm3 Input control Embryo Mitotic cycle 12-14 h...ttp://dbarchive.biosciencedbc.jp/kyushu-u/dm3/assembled/InP.Emb.20.AllAg.Mitotic_cycle_12-14.bed ...

  13. File list: NoD.Emb.05.AllAg.Mitotic_cycle_7-9 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available NoD.Emb.05.AllAg.Mitotic_cycle_7-9 dm3 No description Embryo Mitotic cycle 7-9 http...://dbarchive.biosciencedbc.jp/kyushu-u/dm3/assembled/NoD.Emb.05.AllAg.Mitotic_cycle_7-9.bed ...

  14. File list: DNS.Emb.05.AllAg.Mitotic_cycle_11-13 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available DNS.Emb.05.AllAg.Mitotic_cycle_11-13 dm3 DNase-seq Embryo Mitotic cycle 11-13 http:...//dbarchive.biosciencedbc.jp/kyushu-u/dm3/assembled/DNS.Emb.05.AllAg.Mitotic_cycle_11-13.bed ...

  15. File list: Unc.Emb.10.AllAg.Mitotic_cycle_11-13 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Unc.Emb.10.AllAg.Mitotic_cycle_11-13 dm3 Unclassified Embryo Mitotic cycle 11-13 ht...tp://dbarchive.biosciencedbc.jp/kyushu-u/dm3/assembled/Unc.Emb.10.AllAg.Mitotic_cycle_11-13.bed ...

  16. File list: His.Emb.05.AllAg.Mitotic_cycle_12-14 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available His.Emb.05.AllAg.Mitotic_cycle_12-14 dm3 Histone Embryo Mitotic cycle 12-14 SRX6474...41,SRX647443,SRX647442,SRX647440 http://dbarchive.biosciencedbc.jp/kyushu-u/dm3/assembled/His.Emb.05.AllAg.Mitotic_cycle_12-14.bed ...

  17. File list: NoD.Emb.10.AllAg.Mitotic_cycle_11-13 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available NoD.Emb.10.AllAg.Mitotic_cycle_11-13 dm3 No description Embryo Mitotic cycle 11-13 ...http://dbarchive.biosciencedbc.jp/kyushu-u/dm3/assembled/NoD.Emb.10.AllAg.Mitotic_cycle_11-13.bed ...

  18. File list: Pol.Emb.50.AllAg.Mitotic_cycle_8-9 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Pol.Emb.50.AllAg.Mitotic_cycle_8-9 dm3 RNA polymerase Embryo Mitotic cycle 8-9 http...://dbarchive.biosciencedbc.jp/kyushu-u/dm3/assembled/Pol.Emb.50.AllAg.Mitotic_cycle_8-9.bed ...

  19. File list: InP.Emb.05.AllAg.Mitotic_cycle_12 [Chip-atlas[Archive

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    Full Text Available InP.Emb.05.AllAg.Mitotic_cycle_12 dm3 Input control Embryo Mitotic cycle 12 SRX7500...69 http://dbarchive.biosciencedbc.jp/kyushu-u/dm3/assembled/InP.Emb.05.AllAg.Mitotic_cycle_12.bed ...

  20. File list: Oth.Emb.10.AllAg.Mitotic_cycle_8-9 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Emb.10.AllAg.Mitotic_cycle_8-9 dm3 TFs and others Embryo Mitotic cycle 8-9 SRX0...84383 http://dbarchive.biosciencedbc.jp/kyushu-u/dm3/assembled/Oth.Emb.10.AllAg.Mitotic_cycle_8-9.bed ...

  1. File list: InP.Emb.10.AllAg.Mitotic_cycle_12 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available InP.Emb.10.AllAg.Mitotic_cycle_12 dm3 Input control Embryo Mitotic cycle 12 SRX7500...69 http://dbarchive.biosciencedbc.jp/kyushu-u/dm3/assembled/InP.Emb.10.AllAg.Mitotic_cycle_12.bed ...

  2. File list: Unc.Emb.50.AllAg.Mitotic_cycle_12-14 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Unc.Emb.50.AllAg.Mitotic_cycle_12-14 dm3 Unclassified Embryo Mitotic cycle 12-14 ht...tp://dbarchive.biosciencedbc.jp/kyushu-u/dm3/assembled/Unc.Emb.50.AllAg.Mitotic_cycle_12-14.bed ...

  3. File list: His.Emb.50.AllAg.Mitotic_cycle_11-13 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available His.Emb.50.AllAg.Mitotic_cycle_11-13 dm3 Histone Embryo Mitotic cycle 11-13 SRX6451...30,SRX645124,SRX645116,SRX645108,SRX645127,SRX645112,SRX645120 http://dbarchive.biosciencedbc.jp/kyushu-u/dm3/assembled/His.Emb.50.AllAg.Mitotic_cycle_11-13.bed ...

  4. File list: InP.Emb.10.AllAg.Mitotic_cycle_12-14 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available InP.Emb.10.AllAg.Mitotic_cycle_12-14 dm3 Input control Embryo Mitotic cycle 12-14 h...ttp://dbarchive.biosciencedbc.jp/kyushu-u/dm3/assembled/InP.Emb.10.AllAg.Mitotic_cycle_12-14.bed ...

  5. File list: Pol.Emb.10.AllAg.Mitotic_cycle_7-9 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Pol.Emb.10.AllAg.Mitotic_cycle_7-9 dm3 RNA polymerase Embryo Mitotic cycle 7-9 http...://dbarchive.biosciencedbc.jp/kyushu-u/dm3/assembled/Pol.Emb.10.AllAg.Mitotic_cycle_7-9.bed ...

  6. File list: Unc.Emb.05.AllAg.Mitotic_cycle_13-14 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Unc.Emb.05.AllAg.Mitotic_cycle_13-14 dm3 Unclassified Embryo Mitotic cycle 13-14 ht...tp://dbarchive.biosciencedbc.jp/kyushu-u/dm3/assembled/Unc.Emb.05.AllAg.Mitotic_cycle_13-14.bed ...

  7. File list: InP.Emb.05.AllAg.Mitotic_cycle_13 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available InP.Emb.05.AllAg.Mitotic_cycle_13 dm3 Input control Embryo Mitotic cycle 13 SRX7500...81,SRX750070 http://dbarchive.biosciencedbc.jp/kyushu-u/dm3/assembled/InP.Emb.05.AllAg.Mitotic_cycle_13.bed ...

  8. File list: DNS.Emb.05.AllAg.Mitotic_cycle_12-14 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available DNS.Emb.05.AllAg.Mitotic_cycle_12-14 dm3 DNase-seq Embryo Mitotic cycle 12-14 http:...//dbarchive.biosciencedbc.jp/kyushu-u/dm3/assembled/DNS.Emb.05.AllAg.Mitotic_cycle_12-14.bed ...

  9. File list: InP.Emb.50.AllAg.Mitotic_cycle_12-14 [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  10. File list: NoD.Emb.50.AllAg.Mitotic_cycle_13-14 [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  11. File list: Oth.Emb.10.AllAg.Mitotic_cycle_13-14 [Chip-atlas[Archive

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  12. File list: InP.Emb.10.AllAg.Mitotic_cycle_13-14 [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  13. File list: NoD.Emb.50.AllAg.Mitotic_cycle_7-9 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available NoD.Emb.50.AllAg.Mitotic_cycle_7-9 dm3 No description Embryo Mitotic cycle 7-9 http...://dbarchive.biosciencedbc.jp/kyushu-u/dm3/assembled/NoD.Emb.50.AllAg.Mitotic_cycle_7-9.bed ...

  14. The Effects of Audible Sound for Enhancing the Growth Rate of Microalgae Haematococcus pluvialis in Vegetative Stage

    Directory of Open Access Journals (Sweden)

    Marcelinus Christwardana

    2017-07-01

    Full Text Available Physico-stimulant like audible sound is one of the new promising methods for enhancing microalgae growth rate. Here, microalgae Haematococcus pluvialis was cultivated with the addition of audible sound with titles “Blues for Elle” and “Far and Wide.” The objective of this research was to evaluate the effect of audible sound to the growth and productivity of microalgae. The experiment has been conducted by exposing the audible sound for 8 h in 22 days to microalgae cultivation. The result showed that microalgae H. pluvialis treated by the music “Blues for Elle” shows the highest growth rate (0.03 per day, and 58% higher than the one without audible sound. The average number of cells in stationary phase is 0.76 × 104 cells/mL culture and the productivity is 3.467 × 102 cells/mL/day. The pH of microalgae medium slightly decreases because of proton production during photosynthesis process. The kinetic rate constant (kapp is 0.078 per day, reaction half-life (t1/2 is 8.89 days, and catalytic surface (Ksurf is 1.66 × 10−5/day/cm2. In conclusion, this audible sound is very useful to stimulate microalgae growth rate, especially H. pluvialis.

  15. Mapping water exchange rates in rat tumor xenografts using the late-stage uptake following bolus injections of contrast agent.

    Science.gov (United States)

    Bailey, Colleen; Moosvi, Firas; Stanisz, Greg J

    2014-05-01

    To map the intra-to-extracellular water exchange rate constant in rat xenografts using a two-compartment model of relaxation with water exchange and a range of contrast agent concentrations and compare with histology. MDA-MB-231 cells were xenografted into six nude rats. Three bolus injections of gadodiamide were administered. When uptake in the tumor demonstrated a steady-state, T1 data were acquired by spoiled gradient recalled acquisitions at four flip angles. A global fit of data to a two-compartment model incorporating exchange was performed, assuming a distribution volume of 20% of the rat. Voxels that did not reach steady-state and were excluded from parametric maps tended to be in large necrotic areas. TUNEL-negative (nonapoptotic) regions tended to have well-defined error bounds, with an average intra-to-extracellular exchange rate constant of 0.6 s(-1) . Apoptotic regions had higher exchange, but poorly determined upper bounds, with goodness of fit similar to that for a model assuming infinitely fast exchange. A lower bound of >3 s(-1) was used to establish voxels where the exchange rate constant was fast despite a large upper bound. Water exchange rates were higher in apoptotic regions, but examination of statistical errors was an important step in the mapping process. Copyright © 2013 Wiley Periodicals, Inc.

  16. Modeling winter moth Operophtera brumata egg phenology: nonlinear effects of temperature and developmental stage on developmental rate

    NARCIS (Netherlands)

    Salis, Lucia; Lof, Marjolein; Van Asch, M.; Visser, Marcel E.

    2016-01-01

    Understanding the relationship between an insect's developmental rate and temperature is crucial to forecast insect phenology under climate change. In the winter moth Operophtera brumata timing of egg-hatching has severe fitness consequences on growth and reproduction as egg-hatching has to match

  17. 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.

  18. Counterbalancing angiogenic regulatory factors control the rate of cancer progression and survival in a stage-specific manner.

    Science.gov (United States)

    Xie, Liang; Duncan, Michael B; Pahler, Jessica; Sugimoto, Hikaru; Martino, Margot; Lively, Julie; Mundel, Thomas; Soubasakos, Mary; Rubin, Kristofer; Takeda, Takaaki; Inoue, Masahiro; Lawler, Jack; Hynes, Richard O; Hanahan, Douglas; Kalluri, Raghu

    2011-06-14

    Whereas the roles of proangiogenic factors in carcinogenesis are well established, those of endogenous angiogenesis inhibitors (EAIs) remain to be fully elaborated. We investigated the roles of three EAIs during de novo tumorigenesis to further test the angiogenic balance hypothesis, which suggests that blood vessel development in the tumor microenvironment can be governed by a net loss of negative regulators of angiogenesis in addition to the well-established principle of up-regulated angiogenesis inducers. In a mouse model of pancreatic neuroendocrine cancer, administration of endostatin, thrombospondin-1, and tumstatin peptides, as well as deletion of their genes, reveal neoplastic stage-specific effects on angiogenesis, tumor progression, and survival, correlating with endothelial expression of their receptors. Deletion of tumstatin and thrombospondin-1 in mice lacking the p53 tumor suppressor gene leads to increased incidence and reduced latency of angiogenic lymphomas associated with diminished overall survival. The results demonstrate that EAIs are part of a balance mechanism regulating tumor angiogenesis, serving as intrinsic microenvironmental barriers to tumorigenesis.

  19. Counterbalancing angiogenic regulatory factors control the rate of cancer progression and survival in a stage-specific manner

    Science.gov (United States)

    Xie, Liang; Duncan, Michael B.; Pahler, Jessica; Sugimoto, Hikaru; Martino, Margot; Lively, Julie; Mundel, Thomas; Soubasakos, Mary; Rubin, Kristofer; Takeda, Takaaki; Inoue, Masahiro; Lawler, Jack; Hynes, Richard O.; Hanahan, Douglas; Kalluri, Raghu

    2011-01-01

    Whereas the roles of proangiogenic factors in carcinogenesis are well established, those of endogenous angiogenesis inhibitors (EAIs) remain to be fully elaborated. We investigated the roles of three EAIs during de novo tumorigenesis to further test the angiogenic balance hypothesis, which suggests that blood vessel development in the tumor microenvironment can be governed by a net loss of negative regulators of angiogenesis in addition to the well-established principle of up-regulated angiogenesis inducers. In a mouse model of pancreatic neuroendocrine cancer, administration of endostatin, thrombospondin-1, and tumstatin peptides, as well as deletion of their genes, reveal neoplastic stage-specific effects on angiogenesis, tumor progression, and survival, correlating with endothelial expression of their receptors. Deletion of tumstatin and thrombospondin-1 in mice lacking the p53 tumor suppressor gene leads to increased incidence and reduced latency of angiogenic lymphomas associated with diminished overall survival. The results demonstrate that EAIs are part of a balance mechanism regulating tumor angiogenesis, serving as intrinsic microenvironmental barriers to tumorigenesis. PMID:21622854

  20. Effect of a Shortened Duration of FOLFOX Chemotherapy on the Survival Rate of Patients with Stage II and III Colon Cancer.

    Science.gov (United States)

    Ji, Woong Bae; Hong, Kwang Dae; Kim, Jung-Sik; Joung, Sung-Yup; Um, Jun Won; Min, Byung-Wook

    2018-01-01

    FOLFOX chemotherapy is widely used as an adjuvant treatment for advanced colon cancer. The duration of adjuvant chemotherapy is usually set to 6 months, which is based on a former study of 5-fluorouracil/leucovorin chemotherapy. However, the FOLFOX regimen is known to have complications, such as peripheral neuropathy. The aim of this study was to compare the survival rates and complications experienced by patients receiving either 4 or 6 months of FOLFOX chemotherapy. Retrospective data analysis was performed for stage II and III patients who underwent radical resection of colon cancer. We compared the 5-year survival rates and the occurrence of complications in patients who completed only 8 cycles of FOLFOX chemotherapy with patients who completed 12 cycles of chemotherapy. Among 188 patients who underwent adjuvant FOLFOX chemotherapy for stage II or III colon cancer, 83 (44.1%) completed 6 months of FOLFOX chemotherapy and 64 (34.0%) patients discontinued after 4 months of chemotherapy. The 5-year overall survival and disease-free survival rates did not show a significant difference. Patients in the 6-month group had peripheral neuropathy more frequently (p = 0.028). Five-year overall and disease-free survival were not significantly different between the 2 groups. Large-scale prospective studies are necessary for the analysis of complications and survival rates. © 2017 S. Karger AG, Basel.

  1. The use of high-dose-rate brachytherapy alone after lumpectomy in patients with early-stage breast cancer treated with breast-conserving therapy

    International Nuclear Information System (INIS)

    Baglan, Kathy L.; Martinez, Alvaro A.; Frazier, Robert C.; Kini, Vijay R.; Kestin, Larry L.; Chen, Peter Y.; Edmundson, Greg; Mele, Elizabeth; Jaffray, David; Vicini, Frank A.

    2001-01-01

    Purpose: We present the preliminary results of our in-house protocol using outpatient high-dose-rate (HDR) brachytherapy as the sole radiation modality following lumpectomy in patients with early-stage breast cancer. Methods and Materials: Thirty-seven patients with 38 Stage I-II breast cancers received radiation to the lumpectomy cavity alone using an HDR interstitial implant with 192 Ir. A minimum dose of 32 Gy was delivered on an outpatient basis in 8 fractions of 4 Gy to the lumpectomy cavity plus a 1- to 2-cm margin over consecutive 4 days. Results: Median follow-up is 31 months. There has been one ipsilateral breast recurrence for a crude failure rate of 2.6% and no regional or distant failures. Wound healing was not impaired in patients undergoing an open-cavity implant. Three minor breast infections occurred, and all resolved with oral antibiotics. The cosmetic outcome was good to excellent in all patients. Conclusion: In selected patients with early-stage breast cancer, treatment of the lumpectomy cavity alone with outpatient HDR brachytherapy is both technically feasible and well tolerated. Early results are encouraging, however, longer follow-up is necessary before equivalence to standard whole-breast irradiation can be established and to determine the most optimal radiation therapy technique to be employed

  2. DSP30 and interleukin-2 as a mitotic stimulant in B-cell disorders including those with a low disease burden.

    Science.gov (United States)

    Dun, Karen A; Riley, Louise A; Diano, Giuseppe; Adams, Leanne B; Chiu, Eleanor; Sharma, Archna

    2018-05-01

    Chromosome abnormalities detected during cytogenetic investigations for B-cell malignancy offer prognostic information that can have wide ranging clinical impacts on patients. These impacts may include monitoring frequency, treatment type, and disease staging level. The use of the synthetic oligonucleotide DSP30 combined with interleukin 2 (IL2) has been described as an effective mitotic stimulant in B-cell disorders, not only in chronic lymphocytic leukemia (CLL) but also in a range of other B-cell malignancies. Here, we describe the comparison of two B-cell mitogens, lipopolysaccharide (LPS), and DSP30 combined with IL2 as mitogens in a range of common B-cell disorders excluding CLL. The results showed that DSP30/IL2 was an effective mitogen in mature B-cell disorders, revealing abnormal cytogenetic results in a range of B-cell malignancies. The abnormality rate increased when compared to the use of LPS to 64% (DSP30/IL2) from 14% (LPS). In a number of cases the disease burden was proportionally very low, less than 10% of white cells. In 37% of these cases, the DSP30 culture revealed abnormal results. Importantly, we also obtained abnormal conventional cytogenetics results in 3 bone marrow cases in which immunophenotyping showed an absence of an abnormal B-cell clone. In these cases, the cytogenetics results correlated with the provisional diagnosis and altered their staging level. The use of DSP30 and IL2 is recommended for use in many B-cell malignancies as an effective mitogen and their use has been shown to enable successful culture of the malignant clone, even at very low levels of disease. © 2018 Wiley Periodicals, Inc.

  3. Associations of Census-Tract Poverty with Subsite-Specific Colorectal Cancer Incidence Rates and Stage of Disease at Diagnosis in the United States

    Directory of Open Access Journals (Sweden)

    Kevin A. Henry

    2014-01-01

    Full Text Available Background. It remains unclear whether neighborhood poverty contributes to differences in subsite-specific colorectal cancer (CRC incidence. We examined associations between census-tract poverty and CRC incidence and stage by anatomic subsite and race/ethnicity. Methods. CRC cases diagnosed between 2005 and 2009 from 15 states and Los Angeles County (N=278,097 were assigned to 1 of 4 groups based on census-tract poverty. Age-adjusted and stage-specific CRC incidence rates (IRs and incidence rate ratios (IRRs were calculated. Analyses were stratified by subsite (proximal, distal, and rectum, sex, race/ethnicity, and poverty. Results. Compared to the lowest poverty areas, CRC IRs were significantly higher in the most impoverished areas for men (IRR = 1.14 95% CI 1.12–1.17 and women (IRR = 1.06 95% CI 1.05–1.08. Rate differences between high and low poverty were strongest for distal colon (male IRR = 1.24 95% CI 1.20–1.28; female IRR = 1.14 95% CI 1.10–1.18 and weakest for proximal colon. These rate differences were significant for non-Hispanic whites and blacks and for Asian/Pacific Islander men. Inverse associations between poverty and IRs of all CRC and proximal colon were found for Hispanics. Late-to-early stage CRC IRRs increased monotonically with increasing poverty for all race/ethnicity groups. Conclusion. There are differences in subsite-specific CRC incidence by poverty, but associations were moderated by race/ethnicity.

  4. Cosmetic Analysis Following Breast-Conserving Surgery and Adjuvant High-Dose-Rate Interstitial Brachytherapy for Early-Stage Breast Cancer: A Prospective Clinical Study

    International Nuclear Information System (INIS)

    Garsa, Adam A.; Ferraro, Daniel J.; DeWees, Todd; Margenthaler, Julie A.; Naughton, Michael; Aft, Rebecca; Gillanders, William E.; Eberlein, Timothy; Matesa, Melissa A.; Zoberi, Imran

    2013-01-01

    Purpose: To prospectively evaluate cosmetic outcomes in women treated with accelerated partial breast irradiation using high-dose-rate interstitial brachytherapy for early-stage breast cancer. Methods and Materials: Between 2004 and 2008, 151 patients with early-stage breast cancer were enrolled in a phase 2 prospective clinical trial. Eligible patients had stage Tis-T2 tumors of ≤3 cm that were excised with negative margins and with no nodal involvement. Patients received 3.4 Gy twice daily to a total dose of 34 Gy. Both the patients and the treating radiation oncologist qualitatively rated cosmesis as excellent, good, fair, or poor over time and ascribed a cause for changes in cosmesis. Cosmetic outcome was evaluated quantitatively by percentage of breast retraction assessment (pBRA). Patients also reported their satisfaction with treatment over time. Results: Median follow-up was 55 months. The rates of excellent-to-good cosmesis reported by patients and the treating radiation oncologist were 92% and 97% pretreatment, 91% and 97% at 3 to 4 months' follow-up, 87% and 94% at 2 years, and 92% and 94% at 3 years, respectively. Breast infection and adjuvant chemotherapy were independent predictors of a fair-to-poor cosmetic outcome at 3 years. Compared to pretreatment pBRA (7.35), there was no significant change in pBRA over time. The volume receiving more than 150 Gy (V150) was the only significant predictor of pBRA. The majority of patients (86.6%) were completely satisfied with their treatment. Conclusions: Patients and the treating physician reported a high rate of excellent-to-good cosmetic outcomes at all follow-up time points. Acute breast infection and chemotherapy were associated with worse cosmetic outcomes. Multicatheter interstitial brachytherapy does not significantly change breast size as measured by pBRA

  5. The relation of Complementary-Alternative Medicine use with glomerular filtration rate and depression in patients with chronic kidney disease at predialysis stage.

    Science.gov (United States)

    Esen, Bennur; Atay, Ahmet Engin; Gokmen, Emel Saglam; Karakoc, Ayten; Sari, Hakan; Sarisakal, Samprie; Kahvecioglu, Serdar; Kayabasi, Hasan; Sit, Dede

    2015-05-08

    Complementary and alternative medicine is a broad field of health including all health care practices and methods; and their accompanying theories and beliefs. In the present study, we aimed to examine the frequency of complementary-alternative medicine use, and its relation with glomerular filtration rate and depression in patients with chronic kidney disease at predialysis stage. A total of 1053 predialysis patients; 518 female and 535 male, that were followed up with chronic kidney disease for at least 3 months were enrolled into the study. Demographic features, biochemical parameters and findings of physical examination were recorded. Their compliance to diet, and knowledge about disease were questioned. Beck depression inventory and questionnaire regarding to complementary-alternative medicine use were performed. The overall frequency of complementary-alternative medicine use was 40.3% . Total ratio of herbal products was 46%. Complementary-alternative medicine use was significantly more frequent in female or single patients, and patients that informed about chronic kidney disease or under strict diet (p:0.007, p:0.016, p:0.02, p:0.016; respectively). When glomerular filtration rate of participants were considered, complementary-alternative medicine use was similar in different stages of kidney disease. Depression was observed in 41.9% of patients and significantly frequent in patients with alternative method use (p:0.002). Depression score was higher as creatinine increases and glomerular filtration rate decreases (p:0.002; r: 0,093). We determined that complementary-alternative medicine use gradually increases at predialysis stage as glomerular filtration rate decreases and there is a strict relation between complementary-alternative medicine use and depression or female gender. Disorder related stressors may lead to seeking of alternative methods. This article is protected by copyright. All rights reserved.

  6. Cosmetic Analysis Following Breast-Conserving Surgery and Adjuvant High-Dose-Rate Interstitial Brachytherapy for Early-Stage Breast Cancer: A Prospective Clinical Study

    Energy Technology Data Exchange (ETDEWEB)

    Garsa, Adam A.; Ferraro, Daniel J.; DeWees, Todd [Department of Radiation Oncology, Siteman Cancer Center, Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, Missouri (United States); Margenthaler, Julie A. [Department of Surgery, Siteman Cancer Center, Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, Missouri (United States); Naughton, Michael [Department of Medicine, Siteman Cancer Center, Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, Missouri (United States); Aft, Rebecca [Department of Surgery, Siteman Cancer Center, Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, Missouri (United States); Department of Surgery, John Cochran Veterans Hospital, St. Louis, Missouri (United States); Gillanders, William E.; Eberlein, Timothy [Department of Surgery, Siteman Cancer Center, Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, Missouri (United States); Matesa, Melissa A. [Department of Radiation Oncology, Siteman Cancer Center, Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, Missouri (United States); Zoberi, Imran, E-mail: izoberi@radonc.wustl.edu [Department of Radiation Oncology, Siteman Cancer Center, Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, Missouri (United States)

    2013-03-15

    Purpose: To prospectively evaluate cosmetic outcomes in women treated with accelerated partial breast irradiation using high-dose-rate interstitial brachytherapy for early-stage breast cancer. Methods and Materials: Between 2004 and 2008, 151 patients with early-stage breast cancer were enrolled in a phase 2 prospective clinical trial. Eligible patients had stage Tis-T2 tumors of ≤3 cm that were excised with negative margins and with no nodal involvement. Patients received 3.4 Gy twice daily to a total dose of 34 Gy. Both the patients and the treating radiation oncologist qualitatively rated cosmesis as excellent, good, fair, or poor over time and ascribed a cause for changes in cosmesis. Cosmetic outcome was evaluated quantitatively by percentage of breast retraction assessment (pBRA). Patients also reported their satisfaction with treatment over time. Results: Median follow-up was 55 months. The rates of excellent-to-good cosmesis reported by patients and the treating radiation oncologist were 92% and 97% pretreatment, 91% and 97% at 3 to 4 months' follow-up, 87% and 94% at 2 years, and 92% and 94% at 3 years, respectively. Breast infection and adjuvant chemotherapy were independent predictors of a fair-to-poor cosmetic outcome at 3 years. Compared to pretreatment pBRA (7.35), there was no significant change in pBRA over time. The volume receiving more than 150 Gy (V150) was the only significant predictor of pBRA. The majority of patients (86.6%) were completely satisfied with their treatment. Conclusions: Patients and the treating physician reported a high rate of excellent-to-good cosmetic outcomes at all follow-up time points. Acute breast infection and chemotherapy were associated with worse cosmetic outcomes. Multicatheter interstitial brachytherapy does not significantly change breast size as measured by pBRA.

  7. Associations of Census-Tract Poverty with Sub site-Specific Colorectal Cancer Incidence Rates and Stage of Disease at Diagnosis in the United States

    International Nuclear Information System (INIS)

    Henry, K. A.; Stroup, A. M.; Sherman, R. L.

    2014-01-01

    It remains unclear whether neighborhood poverty contributes to differences in subsite-specific colorectal cancer (CRC) incidence. We examined associations between census-tract poverty and CRC incidence and stage by anatomic sub site and race/ethnicity. Methods. CRC cases diagnosed between 2005 and 2009 from 15 states and Los Angeles County (N = 278,097) were assigned to 1 of 4 groups based on census-tract poverty. Age-adjusted and stage-specific CRC incidence rates (IRs) and incidence rate ratios (IRRs) were calculated. Analyses were stratified by sub site (proximal, distal, and rectum), sex, race/ethnicity, and poverty. Results. Compared to the lowest poverty areas, CRC IRs were significantly higher in the most impoverished areas for men (IRR = 1.14 95% CI 1.12-1.17) and women (IRR = 1.06 95% CI 1.05-1.08). Rate differences between high and low poverty were strongest for distal colon (male IRR = 1.24 95% CI 1.20-1.28; female IRR = 1.14 95% CI 1.10-1.18) and weakest for proximal colon. These rate differences were significant for non-Hispanic whites and blacks and for Asian/Pacific Islander men. Inverse associations between poverty and IRs of all CRC and proximal colon were found for Hispanics. Late-to-early stage CRC IRRs increased monotonically with increasing poverty for all race/ethnicity groups. Conclusion. There are differences in sub site-specific CRC incidence by poverty, but associations were moderated by race/ethnicity.

  8. Changes in Ect2 Localization Couple Actomyosin-Dependent Cell Shape Changes to Mitotic Progression

    OpenAIRE

    Matthews, Helen K.; Delabre, Ulysse; Rohn, Jennifer L.; Guck, Jochen; Kunda, Patricia; Baum, Buzz

    2012-01-01

    Summary As they enter mitosis, animal cells undergo profound actin-dependent changes in shape to become round. Here we identify the Cdk1 substrate, Ect2, as a central regulator of mitotic rounding, thus uncovering a link between the cell-cycle machinery that drives mitotic entry and its accompanying actin remodeling. Ect2 is a RhoGEF that plays a well-established role in formation of the actomyosin contractile ring at mitotic exit, through the local activation of RhoA. We find that Ect2 first...

  9. Effect of insulin on the mitotic activity of bone marrow cells after irradiation. [Gamma radiation, rats

    Energy Technology Data Exchange (ETDEWEB)

    Barkalaya, A I

    1976-02-01

    A total of 236 white rats were given a whole-body gamma dose of 750 R. Part of the rats were given a subcutaneous insulin injection of 0.2 units/kg. After 10, 20, 30 min, 1, 2, 3, 5, 8, 10 and 12 hours the mitotic index was determined in both groups of rats in the bone marrow of the femur. The content of glucose and insulin in the blood was determined. The mitotic index was found to be higher on administering insulin. The use of insulin in radiation sickness intensifies the mitotic activity of bone marrow cells and stimulates the recovery of bone marrow hematopoiesis. 5 references.

  10. A Cost-Effective Power Ramp-Rate Control Strategy for Single-Phase Two-Stage Grid-Connected Photovoltaic Systems

    DEFF Research Database (Denmark)

    Sangwongwanich, Ariya; Yang, Yongheng; Blaabjerg, Frede

    2016-01-01

    In the case of a wide-scale adoption of grid-connected Photovoltaic (PV) systems, more fluctuated power will be injected into the grid due to the intermittency of solar PV energy. A sudden change in the PV power can potentially induce grid voltage fluctuations, and thus challenge the stability......-point. Experiments conducted on a 3-kW single-phase two-stage grid-connected PV system have verified that the proposed solution can accomplish fast dynamics, high accuracy, and high robustness in the power ramp-rate control for PV systems....

  11. Recurrence of squamous cell carcinoma of the oesophagus after curative surgery: rates and patterns on imaging studies correlated with tumour location and pathological stage

    International Nuclear Information System (INIS)

    Lee, S.J.; Lee, K.S.; Yim, Y.J.; Kim, T.S.; Shim, Y.M.; Kim, K.

    2005-01-01

    Many factors have been related to recurrence after resection of squamous cell carcinoma of the oesophagus. These include age, gender, location and local stage of tumours, cell differentiation, lymph node metastasis and vascular involvement. The recurrence rates of squamous cell carcinoma after curative surgery are high (34-79%). Tumour recurrence is categorized as locoregional or distant. Lymph node recurrence and haematogenous metastasis to solid organs (commonly to the lung) are the usual patterns of recurrence. Awareness of recurrence patterns, particularly on imaging studies, is essential for the diagnosis of recurrent tumours on follow-up examinations

  12. Accumulation of senescent cells in mitotic tissue of aging primates.

    Science.gov (United States)

    Jeyapalan, Jessie C; Ferreira, Mark; Sedivy, John M; Herbig, Utz

    2007-01-01

    Cellular senescence, a stress induced growth arrest of somatic cells, was first documented in cell cultures over 40 years ago, however its physiological significance has only recently been demonstrated. Using novel biomarkers of cellular senescence we examined whether senescent cells accumulate in tissues from baboons of ages encompassing the entire lifespan of this species. We show that dermal fibroblasts, displaying markers of senescence such as telomere damage, active checkpoint kinase ATM, high levels of heterochromatin proteins and elevated levels of p16, accumulate in skin biopsies from baboons with advancing age. The number of dermal fibroblasts containing damaged telomeres reaches a value of over 15% of total fibroblasts, whereas 80% of cells contain high levels of the heterochromatin protein HIRA. In skeletal muscle, a postmitotic tissue, only a small percentage of myonuclei containing damaged telomeres were detected regardless of animal age. The presence of senescent cells in mitotic tissues might therefore be a contributing factor to aging and age related pathology and provides further evidence that cellular senescence is a physiological event.

  13. Control of the mitotic exit network during meiosis

    Science.gov (United States)

    Attner, Michelle A.; Amon, Angelika

    2012-01-01

    The mitotic exit network (MEN) is an essential GTPase signaling pathway that triggers exit from mitosis in budding yeast. We show here that during meiosis, the MEN is dispensable for exit from meiosis I but contributes to the timely exit from meiosis II. Consistent with a role for the MEN during meiosis II, we find that the signaling pathway is active only during meiosis II. Our analysis further shows that MEN signaling is modulated during meiosis in several key ways. Whereas binding of MEN components to spindle pole bodies (SPBs) is necessary for MEN signaling during mitosis, during meiosis MEN signaling occurs off SPBs and does not require the SPB recruitment factor Nud1. Furthermore, unlike during mitosis, MEN signaling is controlled through the regulated interaction between the MEN kinase Dbf20 and its activating subunit Mob1. Our data lead to the conclusion that a pathway essential for vegetative growth is largely dispensable for the specialized meiotic divisions and provide insights into how cell cycle regulatory pathways are modulated to accommodate different modes of cell division. PMID:22718910

  14. Phosphorylation and disassembly of intermediate filaments in mitotic cells

    International Nuclear Information System (INIS)

    Chou, Yinghao; Rosevear, E.; Goldman, R.D.

    1989-01-01

    As baby hamster kidney (BHK-21) cells enter mitosis, networks of intermediate filaments (IFs) are transformed into cytoplasmic aggregates of protofilaments. Coincident with this morphological change, the phosphate content of vimentin increases from 0.3 mol of P i per mol of protein in interphase to 1.9 mol of P i per mol of protein in mitosis. A similar increase in phosphate content is observed with desmin, from 0.5 mol of P i per mol of protein to 1.5 mol of P i per mol of protein. Fractionation of mitotic cell lysates by hydroxylapatite column chromatography reveals the presence of two IF protein kinase activities, designated as IF protein kinase I and IF protein kinase II. Comparison of two-dimensional 32 P-labeled phosphopeptide maps of vimentin and desmin phosphorylated in vivo in mitosis, and in vitro using partially purified kinase fractions, reveals extensive similarity in the two sets of phosphorylation sites. Phosphorylation of in vitro polymerized IFs by IF protein kinase II induces complete disassembly as determined by negative-stain electron microscopy. The results support the idea that the disassembly of IFs in mitosis is regulated by the phosphorylation of its subunit proteins

  15. X-ray induction of mitotic and meiotic chromosome aberrations

    International Nuclear Information System (INIS)

    Yao, K.T.S.

    1980-01-01

    In 1964 six pairs of rat kangaroo (Potorous tridactylis) were obtained from Australia. The tissues of these animals were used to initiate cell lines. Since this species has a low chromosome number of six pairs, each pair with its own distinctive morphology, it is particularly favorable for cytogenetic research. In cell cultures derived from the corneal endothelial tissues of one animal there emerged a number of haploid cells. The number of haploid cells in the cultures reached as high as 20% of the total mitotic configurations. The in vitro diploid and haploid mixture cell cultures could be a resemblance or a coincidence to the mixture existence of the diploid primary spermatocytes and the haploid secondary spermatocytes (gametes) in the in vivo testicular tissues of the male animals. It would be interesting to compare reactions of the haploid and diploid cell mixture, either in the cultures or in the testes, to x-ray exposure. Two other studies involving x-ray effects on Chinese hamster oocyte maturation and meiotic chromosomes and the x-ray induction of Chinese hamster spermatocyte meiotic chromosome aberrations have been done in this laboratory. A review of these three studies involving diploid and haploid chromosomes may lead to further research in the x-ray induction of chromosome aberrations

  16. Genetical control of mitotic crossing over in yeast

    International Nuclear Information System (INIS)

    Fedorova, I.V.; Marfin, A.B.

    1982-01-01

    Lethal effect of 8 methoxypsoralen (8-MOP) and long-wave ultraviolet radiation (LUR) on diploid and haploid radiosensitive strains of yeast LSaccharomyces cerevisiae has been studied. It is shown that wild type diploids and homozygous with respect to locus rad 2 is considerably more stable than corresponding haploids, while diploid homozygous with respect to rad 54 locus is more sensitive than haploid. Use of the method of repeated irradiation permitted to study capability of radiosensitive diploids to remove 8 MOP-induced DNA photodamages-monoadducts. This process proceeds effectively in the wild type strain and rad 54 rad 54 diploid and was absent in rad 2 rad 2 diploid. Very strong recombinogenous effect of 8-MOP and LUR was discovered when studying mitotic segregation and crossing-over. It is also shown that rad 2 mutation increases slightly and rad 54 mutation decreases sharply frequency of recombination events in yeast cells. It is established by means of the repeated irradiation method that the main contribution to the 8 MOP and LUR recombinogenous effect is made with DNA sutures induced with these agents. Possible participation of different repair systems in the recombination processes induced with 8 MOP and LUR in yeast cells is discussed

  17. Mitotic chromosome transmission fidelity mutants in Saccharomyces cerevisiae

    International Nuclear Information System (INIS)

    Spencer, F.; Gerring, S.L.; Connelly, C.; Hieter, P.

    1990-01-01

    The authors have isolated 136 independent EMS-induced mutations in haploid yeast strains that exhibit decreased chromosome transmission fidelity in mitosis. Eight-five percent of the mutations are recessive and 15% are partially dominant. Complementation analysis between MATa and MATα isolates identifies 11 chromosome transmission fidelity (CTF) complementation groups, the largest of which is identical to CHL1. For 49 independent mutations, no corresponding allele has been recovered in the opposite mating type. The initial screen monitored the stability of a centromere-linked color marker on a nonessential yeast chromosome fragment; the mitotic inheritance of natural yeast chromosome III is also affected by the ctf mutations. Of the 136 isolates identified, seven were inviable at 37 degree and five were inviable at 11 degree. In all cases tested, these temperature conditional lethalities cosegregated with the chromosome instability phenotype. Five additional complementation groups (ctf12 through ctf16) have been defined by complementation analysis of the mutations causing inviability at 37 degree. All of the mutant strains showed normal sensitivity to ultraviolet and γ-irradiation

  18. Effects of 5-fluorouracil on the mitotic activity of onion root tips apical meristem

    Directory of Open Access Journals (Sweden)

    Waldemar Lechowicz

    2015-01-01

    Full Text Available The effects of various concentrations of 5-FU on the mitotic activity of onion root tips apical meristem were investigated during 24-hour incubation in 5-FU and postincubation in water. The incubation in 5-FU caused a reversible inhibition of mitotic activity, and waves of the partially synchronised mitoses were observed during the period of postincubation. The most pronounced synchronisation of mitoses was obtained after incubation in 100 mg/l. 5-FU but the mitotic index of the resumed mitotic activity amounted to only one half of the control value. 5-FU was found to cause some cytological changes in meristematic cells such as enlargement of the nucleoli, change in the interphasic nuclei structure, appearance of subchromatid and chromatid aberrations and micronuclei. The effects of 5-FU on nucleic acids and the cell division cycle ace discussed and compared with the effects of 5-FUdR.

  19. Mapping genes by meiotic and UV-induced mitotic recombination in Coprinus cinereus

    International Nuclear Information System (INIS)

    Amirkhanian, J.D.; Cowan, J.W.

    1985-01-01

    Three morphological mutants in Coprinus cinereus—one spontaneous (den-2) and two chemically induced (zigand sta)—were assigned to linkage groups and utilized in meiotic and mitotic mapping. Mutants den-2 and zig belong to linkage group III, den-2 being close to the centromere and about 20 map units (mu) from zig. The mutant sta in linkage group ‘G’ is at a distance of about 37 mu from ade-3. Mitotic mapping confirmed the gene order in linkage group III and provided evidence that trp-2 in linkage group ‘G’ was between the centromere and ade-3. These morphological mutants are compact in colony growth and therefore suited to high-density plating. The rarity of spontaneously occurring mitotic segregants suggests that diploids of Coprinus cinereus, heterozygous for morphoiogical markers in repuision, could serve as useful test systems for rapid screening of chemical mutagen/carcinogens via mitotic recombination studies

  20. Effect of head-irradiation upon epidermal mitotic activity during wound healing in the adrenalectomized mice

    International Nuclear Information System (INIS)

    Kobayashi, Koshi

    1977-01-01

    Epidermal mitotic activity during wound healing was estimated both in the adrenalectomized, head-irradiated mice and in the adrenalectomized, non-irradiated mice, and was compared with those obtained previously from the unoperated, head-irradiated mice. It was found that head-irradiation caused a mitotic depression to a much smaller extent in the adrenalectomized mice than it did in the unoperated mice, though adrenalectomy itself had exerted a great inhibitory effect upon the mitosis induced by an injury. Whether this abscopal effect of head-irradiation upon the mitotic activity was mediated via the adrenals, and whether in the adrenalectomized mice the head-irradiation acted to increase epidermal response to injury, making the mitotic pattern of adrenalectomized mice to come near that of control mice were discussed. (auth.)

  1. The FEAR protein Slk19 restricts Cdc14 phosphatase to the nucleus until the end of anaphase, regulating its participation in mitotic exit in Saccharomyces cerevisiae.

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    Ann Marie E Faust

    Full Text Available In Saccharomyces cerevisiae mitosis, the protein Slk19 plays an important role in the initial release of Cdc14 phosphatase from the nucleolus to the nucleus in early anaphase, an event that is critical for proper anaphase progression. A role for Slk19 in later mitotic stages of Cdc14 regulation, however, has not been demonstrated. While investigating the role of Slk19 post-translational modification on Cdc14 regulation, we found that a triple point mutant of SLK19, slk19(3R (three lysine-to-arginine mutations, strongly affects Cdc14 localization during late anaphase and mitotic exit. Using fluorescence live-cell microscopy, we found that, similar to slk19Δ cells, slk19(3R cells exhibit no defect in spindle stability and only a mild defect in spindle elongation dynamics. Unlike slk19Δcells, however, slk19(3R cells exhibit no defect in Cdc14 release from the nucleolus to the nucleus. Instead, slk19(3R cells are defective in the timing of Cdc14 movement from the nucleus to the cytoplasm at the end of anaphase. This mutant has a novel phenotype: slk19(3R causes premature Cdc14 movement to the cytoplasm prior to, rather than concomitant with, spindle disassembly. One consequence of this premature Cdc14 movement is the inappropriate activation of the mitotic exit network, made evident by the fact that slk19(3R partially rescues a mutant of the mitotic exit network kinase Cdc15. In conclusion, in addition to its role in regulating Cdc14 release from the nucleolus to the nucleus, we found that Slk19 is also important for regulating Cdc14 movement from the nucleus to the cytoplasm at the end of anaphase.

  2. Automatic sleep staging using empirical mode decomposition, discrete wavelet transform, time-domain, and nonlinear dynamics features of heart rate variability signals.

    Science.gov (United States)

    Ebrahimi, Farideh; Setarehdan, Seyed-Kamaledin; Ayala-Moyeda, Jose; Nazeran, Homer

    2013-10-01

    The conventional method for sleep staging is to analyze polysomnograms (PSGs) recorded in a sleep lab. The electroencephalogram (EEG) is one of the most important signals in PSGs but recording and analysis of this signal presents a number of technical challenges, especially at home. Instead, electrocardiograms (ECGs) are much easier to record and may offer an attractive alternative for home sleep monitoring. The heart rate variability (HRV) signal proves suitable for automatic sleep staging. Thirty PSGs from the Sleep Heart Health Study (SHHS) database were used. Three feature sets were extracted from 5- and 0.5-min HRV segments: time-domain features, nonlinear-dynamics features and time-frequency features. The latter was achieved by using empirical mode decomposition (EMD) and discrete wavelet transform (DWT) methods. Normalized energies in important frequency bands of HRV signals were computed using time-frequency methods. ANOVA and t-test were used for statistical evaluations. Automatic sleep staging was based on HRV signal features. The ANOVA followed by a post hoc Bonferroni was used for individual feature assessment. Most features were beneficial for sleep staging. A t-test was used to compare the means of extracted features in 5- and 0.5-min HRV segments. The results showed that the extracted features means were statistically similar for a small number of features. A separability measure showed that time-frequency features, especially EMD features, had larger separation than others. There was not a sizable difference in separability of linear features between 5- and 0.5-min HRV segments but separability of nonlinear features, especially EMD features, decreased in 0.5-min HRV segments. HRV signal features were classified by linear discriminant (LD) and quadratic discriminant (QD) methods. Classification results based on features from 5-min segments surpassed those obtained from 0.5-min segments. The best result was obtained from features using 5-min HRV

  3. Effects of polyamines and polyamine biosynthetic inhibitors on mitotic activity of Allium cepa root tips.

    Science.gov (United States)

    Unal, Meral; Palavan-Unsal, Narcin; Tufekci, M A

    2008-03-01

    The genotoxic and cytotoxic effects of exogenous polyamines (PAs), putrescine (Put), spermidine (Spd), spermine (Spm) and PA biosynthetic inhibitors, alpha-difluoromethylornithine (DFMO), cyclohexilamine (CHA), methylglioxal bis-(guanylhydrazone) (MGBG) were investigated in the root meristems of Allium cepa L. The reduction of mitotic index and the induction of chromosomal aberrations such as bridges, stickiness, c-mitotic anaphases, micronuclei, endoredupliction by PAs and PA biosynthetic inhibitors were observed and these were used as evidence of genotoxicity and cytotoxicity.

  4. Radiation-induced mitotic and meiotic aneuploidy in the yeast Saccharomyces cerevisiae

    International Nuclear Information System (INIS)

    Parry, J.M.; Sharp, D.; Tippins, R.S.; Parry, E.M.

    1979-01-01

    A number of genetic systems are described which in yeast may be used to monitor the induction of chromosome aneuploidy during both mitotic and meiotic cell division. Using these systems the authors have been able to demonstrate the induction of both monosomic and trisomic cells in mitotically dividing cells and disomic spores in meiotically dividing cells after both UV light and X-ray exposure. (Auth.)

  5. The structure of the mitotic spindle and nucleolus during mitosis in the amebo-flagellate Naegleria.

    Science.gov (United States)

    Walsh, Charles J

    2012-01-01

    Mitosis in the amebo-flagellate Naegleria pringsheimi is acentrosomal and closed (the nuclear membrane does not break down). The large central nucleolus, which occupies about 20% of the nuclear volume, persists throughout the cell cycle. At mitosis, the nucleolus divides and moves to the poles in association with the chromosomes. The structure of the mitotic spindle and its relationship to the nucleolus are unknown. To identify the origin and structure of the mitotic spindle, its relationship to the nucleolus and to further understand the influence of persistent nucleoli on cellular division in acentriolar organisms like Naegleria, three-dimensional reconstructions of the mitotic spindle and nucleolus were carried out using confocal microscopy. Monoclonal antibodies against three different nucleolar regions and α-tubulin were used to image the nucleolus and mitotic spindle. Microtubules were restricted to the nucleolus beginning with the earliest prophase spindle microtubules. Early spindle microtubules were seen as short rods on the surface of the nucleolus. Elongation of the spindle microtubules resulted in a rough cage of microtubules surrounding the nucleolus. At metaphase, the mitotic spindle formed a broad band completely embedded within the nucleolus. The nucleolus separated into two discreet masses connected by a dense band of microtubules as the spindle elongated. At telophase, the distal ends of the mitotic spindle were still completely embedded within the daughter nucleoli. Pixel by pixel comparison of tubulin and nucleolar protein fluorescence showed 70% or more of tubulin co-localized with nucleolar proteins by early prophase. These observations suggest a model in which specific nucleolar binding sites for microtubules allow mitotic spindle formation and attachment. The fact that a significant mass of nucleolar material precedes the chromosomes as the mitotic spindle elongates suggests that spindle elongation drives nucleolar division.

  6. Factors associated with a poor prognosis for the IVF-ICSI live birth rate in women with rAFS stage III and IV endometriosis.

    Science.gov (United States)

    Roux, Pauline; Perrin, Jeanne; Mancini, Julien; Agostini, Aubert; Boubli, Léon; Courbiere, Blandine

    2017-07-01

    To assess the factors associated with a poor prognosis for a cumulative IVF live birth rate (LBR) in women with stage III and IV endometriosis according to the revised classification of the American Fertility Society (rAFS). A retrospective cohort study was conducted between January 1, 2010, and December 31, 2014, in our Reproductive Medicine Center. We analyzed different factors associated with a poor prognosis for a cumulative IVF LBR in women with rAFS stage III and IV endometriosis. A total of 101 patients were included, representing 232 IVF-ICSI cycles and 212 embryo transfers. The primary endpoint was the cumulative LBR per cycle and per patient. The cumulative LBR per cycle was 14.7% (n = 34) and that per patient was 31.7% (n = 32). The cumulative LBR was significantly decreased by active smoking [ adj OR = 3.4, 95% CI (1.12-10.60), p = 0.031], poor ovarian response (POR) according to the Bologna criteria [ adj OR = 11.5, 95% CI (1.37-96.83), p = 0.024], and rAFS stage IV [ adj OR = 3.2, 95% CI (1.13-8.95), p = 0.024]. The cumulative LBR per women was 59.4% without factors associated with a poor prognosis and 25.6% in the case of one factor, and it decreased to 7.7% in the case of two or three factors (p endometriosis had a negative impact on the IVF-ICSI cumulative LBR for women with rAFS stage III and IV endometriosis. Because smoking dramatically decreases the LBR with endometriosis, stopping smoking before IVF-ICSI should be strongly advised.

  7. The activity of ascorbic acid and catechol oxidase, the rate of photosynthesis and respiration as related to plant organs, stage of development and copper supply

    Directory of Open Access Journals (Sweden)

    St. Łyszcz

    2015-06-01

    Full Text Available Some experiments were performed to investigate the physiological role of copper in oat and sunflower and to recognize some effects of copper deficiency. Oat and sunflower plants were grown in pots on a peat soil under copper deficiency conditions (–Cu or with the optimal copper supply (+Cu. In plants the following measurements were carried out: 1 the activity of ascorbic acid oxidase (AAO and of catechol oxidase (PPO in different plant organs and at different stages of plant development, 2 the activity and the rate of photosynthesis, 3 the activity of RuDP-carboxylase, 4 the intensity of plant respiration. The activity of AAO and of PPO, and also the rate and the activity of photosynthesis were significantly lower under conditions of copper deficiency. The activity of both discussed oxidases depended on: 1 the plant species, 2 plant organs, 3 stage of plant development. Copper deficiency caused decrease of the respiration intensity of sunflower leaves but it increased to some extent the respiration of oat tops. Obtained results are consistent with the earlier suggestion of the authors that the PPO activity in sunflower leaves could be a sensitive indicator of copper supply of the plants, farther experiments are in progress.

  8. Effects of sludge recirculation rate and mixing time on performance of a prototype single-stage anaerobic digester for conversion of food wastes to biogas and energy recovery.

    Science.gov (United States)

    Ratanatamskul, Chavalit; Saleart, Tawinan

    2016-04-01

    Food wastes have been recognized as the largest waste stream and accounts for 39.25 % of total municipal solid waste in Thailand. Chulalongkorn University has participated in the program of in situ energy recovery from food wastes under the Ministry of Energy (MOE), Thailand. This research aims to develop a prototype single-stage anaerobic digestion system for biogas production and energy recovery from food wastes inside Chulalongkorn University. Here, the effects of sludge recirculation rate and mixing time were investigated as the main key parameters for the system design and operation. From the results obtained in this study, it was found that the sludge recirculation rate of 100 % and the mixing time of 60 min per day were the most suitable design parameters to achieve high efficiencies in terms of chemical oxygen demand (COD), total solids (TS), and total volatile solid (TVS) removal and also biogas production by this prototype anaerobic digester. The obtained biogas production was found to be 0.71 m(3)/kg COD and the composition of methane was 61.6 %. Moreover, the efficiencies of COD removal were as high as 82.9 % and TVS removal could reach 83.9 % at the optimal condition. Therefore, the developed prototype single-stage anaerobic digester can be highly promising for university canteen application to recover energy from food wastes via biogas production.

  9. The Effectiveness of Marlaat’s Cognitive Behavior Intervention and Group Treatment Based on Change Stages for Recovery and Relapse Prevention Rates in Male Heroin Crack Addicts

    Directory of Open Access Journals (Sweden)

    S Khodadust

    2014-11-01

    Full Text Available Objective: The aim of this study was the Study of effectiveness of Marlaat’s cognitive behavior intervention and group treatment based on change stages for recovery and relapse rates in male heroin crack addictions. Method: In a experimental research design, 45 men addictions, who were diagnosed as the dependence of the heroin crack on the basis of DSM-IV-TR criteria, were chosen after successfully detoxified. They were divided two experimental groups (30 participants and a control group (15 participants that have been selected by random sampling. The first experimental group was undergone group treatment based on change stages underwent 16 sessions of 1.5 hours, totally 24 hours and the second experimental groups who were undergone Marlaat’s cognitive behavior intervention has been held 15 sessions of 2 hours, totally 24 hours. The control group were just received MMT without any psychotherapy. All participants were assessed by structured interview, urine test, before treatment, after treatment and after 3 months follow up. Results: Results showed that both psychotherapy treatments were affected on recovery and relapse rates. Conclusion: It seems that psychological problems and conflicts before addiction and after addiction could be caused for individuals’ tendency to narcotics consumption. Therefore, applying of psychotherapy could be useful in relapse prevention.

  10. Trends in Breast Cancer Incidence Rates by Age and Stage at Diagnosis in Gharbiah, Egypt, over 10 Years (1999–2008

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    Kelly A. Hirko

    2013-01-01

    Full Text Available Background. This study was undertaken to evaluate trends in breast cancer incidence in Egypt from 1999 to 2008 and to make projections for breast cancer occurrence for the years 2009–2015. Patients and Methods. We utilized joinpoint regression and average annual percent change (AAPC measures with 95% confidence intervals (CI to describe the trends in breast cancer incidence rates from the Gharbiah Cancer Registry by age and stage at diagnosis and to estimate expected breast cancer caseloads for 2009–2015. Results. From 1999 to 2008, the AAPC in breast cancer incidence rates in Gharbiah significantly increased among women 50 years and older and among localized tumors (AAPC %, 95% CI, 3.1% to 8.0%. Our results predict a significant increase in breast cancer caseloads from 2009 to 2015 among women aged 30–39 (AAPC %, 95% CI, 0.9% to 1.1% and among women aged 40–49 years (AAPC %, 95% CI, 1.0% to 2.6%. Conclusion. These results have important implications for allocating limited resources, managing treatment needs, and exploring the consequences of prior interventions and/or changing risk factors in Egypt and other developing countries at the same stages of demographic and health transitions.

  11. Utilization during mitotic cell division of loci controlling meiotic recombination and disjunction in Drosophila melanogaster

    International Nuclear Information System (INIS)

    Baker, B.S.; Carpenter, A.T.C.; Ripoll, P.

    1978-01-01

    To inquire whether the loci identified by recombination-defective and disjunction-defective meiotic mutants in Drosophila are also utilized during mitotic cell division, the effects of 18 meiotic mutants (representing 13 loci) on mitotic chromosome stability have been examined genetically. To do this, meiotic-mutant-bearing flies heterozygous for recessive somatic cell markers were examined for the frequencies and types of spontaneous clones expressing the cell markers. In such flies, marked clones can arise via mitotic recombination, mutation, chromosome breakage, nondisjunction or chromosome loss, and clones from these different origins can be distinguished. In addition, meiotic mutants at nine loci have been examined for their effects on sensitivity to killing by uv and x rays. Mutants at six of the seven recombination-defective loci examined (mei-9, mei-41, c(3)G, mei-W68, mei-S282, mei-352, mei-218) cause mitotic chromosome instability in both sexes, whereas mutants at one locus (mei-218) do not affect mitotic chromosome stability. Thus many of the loci utilized during meiotic recombination also function in the chromosomal economy of mitotic cells

  12. Identification of Mitosis-Specific Phosphorylation in Mitotic Chromosome-Associated Proteins.

    Science.gov (United States)

    Ohta, Shinya; Kimura, Michiko; Takagi, Shunsuke; Toramoto, Iyo; Ishihama, Yasushi

    2016-09-02

    During mitosis, phosphorylation of chromosome-associated proteins is a key regulatory mechanism. Mass spectrometry has been successfully applied to determine the complete protein composition of mitotic chromosomes, but not to identify post-translational modifications. Here, we quantitatively compared the phosphoproteome of isolated mitotic chromosomes with that of chromosomes in nonsynchronized cells. We identified 4274 total phosphorylation sites and 350 mitosis-specific phosphorylation sites in mitotic chromosome-associated proteins. Significant mitosis-specific phosphorylation in centromere/kinetochore proteins was detected, although the chromosomal association of these proteins did not change throughout the cell cycle. This mitosis-specific phosphorylation might play a key role in regulation of mitosis. Further analysis revealed strong dependency of phosphorylation dynamics on kinase consensus patterns, thus linking the identified phosphorylation sites to known key mitotic kinases. Remarkably, chromosomal axial proteins such as non-SMC subunits of condensin, TopoIIα, and Kif4A, together with the chromosomal periphery protein Ki67 involved in the establishment of the mitotic chromosomal structure, demonstrated high phosphorylation during mitosis. These findings suggest a novel mechanism for regulation of chromosome restructuring in mitosis via protein phosphorylation. Our study generated a large quantitative database on protein phosphorylation in mitotic and nonmitotic chromosomes, thus providing insights into the dynamics of chromatin protein phosphorylation at mitosis onset.

  13. Co-delivery of paclitaxel and cetuximab by nanodiamond enhances mitotic catastrophe and tumor inhibition.

    Science.gov (United States)

    Lin, Yu-Wei; Raj, Emmanuel Naveen; Liao, Wei-Siang; Lin, Johnson; Liu, Kuang-Kai; Chen, Ting-Hua; Cheng, Hsiao-Chun; Wang, Chi-Ching; Li, Lily Yi; Chen, Chinpiao; Chao, Jui-I

    2017-08-29

    The poor intracellular uptake and non-specific binding of anticancer drugs into cancer cells are the bottlenecks in cancer therapy. Nanocarrier platforms provide the opportunities to improve the drug efficacy. Here we show a carbon-based nanomaterial nanodiamond (ND) that carried paclitaxel (PTX), a microtubule inhibitor, and cetuximab (Cet), a specific monoclonal antibody against epidermal growth factor receptor (EGFR), inducing mitotic catastrophe and tumor inhibition in human colorectal cancer (CRC). ND-PTX blocked the mitotic progression, chromosomal separation, and induced apoptosis in the CRC cells; however, NDs did not induce these effects. Conjugation of ND-PTX with Cet (ND-PTX-Cet) was specifically binding to the EGFR-positive CRC cells and enhanced the mitotic catastrophe and apoptosis induction. Besides, ND-PTX-Cet markedly decreased tumor size in the xenograft EGFR-expressed human CRC tumors of nude mice. Moreover, ND-PTX-Cet induced the mitotic marker protein phospho-histone 3 (Ser10) and apoptotic protein active-caspase 3 for mitotic catastrophe and apoptosis. Taken together, this study demonstrated that the co-delivery of PTX and Cet by ND enhanced the effects of mitotic catastrophe and apoptosis in vitro and in vivo, which may be applied in the human CRC therapy.

  14. Primary Tumor Thickness is a Prognostic Factor in Stage IV Melanoma: A Retrospective Study of Primary Tumor Characteristics.

    Science.gov (United States)

    Luen, Stephen; Wong, Siew Wei; Mar, Victoria; Kelly, John W; McLean, Catriona; McArthur, Grant A; Haydon, Andrew

    2018-01-01

    Stage IV melanoma exhibits a diverse range of tumor biology from indolent to aggressive disease. Many important prognostic factors have already been identified. Despite this, the behavior of metastatic melanoma remains difficult to predict. We sought to determine if any primary tumor characteristics affect survival following the diagnosis of stage IV melanoma. All patients diagnosed with stage IV melanoma between January 2003 and December 2012 were identified from the Victorian Melanoma Service database. Retrospective chart review was performed to collect data on primary tumor characteristics (thickness, ulceration, mitotic rate, melanoma subtype, or occult primary). Known and suspected prognostic factors were additionally collected (time to diagnosis of stage IV disease, age, sex, stage, receipt of chemotherapy, and era of recurrence). The effect of primary tumor characteristics on overall survival from the date of diagnosis of stage IV disease was assessed. A total of 227 patients with a median follow-up of 5 years from diagnosis of stage IV disease were identified. Median overall survival of the cohort was 250 days.Of the primary tumor characteristics assessed, only tumor thickness affected survival from diagnosis of stage IV disease, hazard ratio=1.09 (1.02 to 1.16), P=0.008. This remained significant in multivariate analysis, P=0.007. Other primary tumor characteristics did not significantly influence survival. Primary tumor thickness is a significant prognostic factor in stage IV melanoma. Our data suggest that the biology of the primary melanoma may persist to influence the behavior of metastatic disease.

  15. Clinicopathologic Comparison of High-Dose-Rate Endorectal Brachytherapy versus Conventional Chemoradiotherapy in the Neoadjuvant Setting for Resectable Stages II and III Low Rectal Cancer

    Directory of Open Access Journals (Sweden)

    Jessica A. Smith

    2012-01-01

    Full Text Available Purpose. To assess for differences in clinical, radiologic, and pathologic outcomes between patients with stage II-III rectal adenocarcinoma treated neoadjuvantly with conventional external beam radiotherapy (3D conformal radiotherapy (3DRT or intensity-modulated radiotherapy (IMRT versus high-dose-rate endorectal brachytherapy (EBT. Methods. Patients undergoing neoadjuvant EBT received 4 consecutive daily 6.5 Gy fractions without chemotherapy, while those undergoing 3DRT or IMRT received 28 daily 1.8 Gy fractions with concurrent 5-fluorouracil. Data was collected prospectively for 7 EBT patients and retrospectively for 25 historical 3DRT/IMRT controls. Results. Time to surgery was less for EBT compared to 3DRT and IMRT (P<0.001. There was a trend towards higher rate of pathologic CR for EBT (P=0.06. Rates of margin and lymph node positivity at resection were similar for all groups. Acute toxicity was less for EBT compared to 3DRT and IMRT (P=0.025. Overall and progression-free survival were noninferior for EBT. On MRI, EBT achieved similar complete response rate and reduction in tumor volume as 3DRT and IMRT. Histopathologic comparison showed that EBT resulted in more localized treatment effects and fewer serosal adhesions. Conclusions. EBT offers several practical benefits over conventional radiotherapy techniques and appears to be at least as effective against low rectal cancer as measured by short-term outcomes.

  16. Frequency and mitotic heritability of epimutations in Schistosoma mansoni.

    Science.gov (United States)

    Roquis, David; Rognon, Anne; Chaparro, Cristian; Boissier, Jerome; Arancibia, Nathalie; Cosseau, Celine; Parrinello, Hugues; Grunau, Christoph

    2016-04-01

    Schistosoma mansoni is a parasitic platyhelminth responsible for intestinal bilharzia. It has a complex life cycle, infecting a freshwater snail of the Biomphalaria genus, and then a mammalian host. Schistosoma mansoni adapts rapidly to new (allopatric) strains of its intermediate host. To study the importance of epimutations in this process, we infected sympatric and allopatric mollusc strains with parasite clones. ChIP-Seq was carried out on four histone modifications (H3K4me3, H3K27me3, H3K27ac and H4K20me1) in parallel with genomewide DNA resequencing (i) on parasite larvae shed by the infected snails and (ii) on adult worms that had developed from the larvae. No change in single nucleotide polymorphisms and no mobilization of transposable elements were observed, but 58-105 copy number variations (CNVs) within the parasite clones in different molluscs were detected. We also observed that the allopatric environment induces three types of chromatin structure changes: (i) host-induced changes on larvae epigenomes in 51 regions of the genome that are independent of the parasites' genetic background, (ii) spontaneous changes (not related to experimental condition or genotype of the parasite) at 64 locations and (iii) 64 chromatin structure differences dependent on the parasite genotype. Up to 45% of the spontaneous, but none of the host-induced chromatin structure changes were transmitted to adults. In our model, the environment induces epigenetic changes at specific loci but only spontaneous epimutations are mitotically heritable and have therefore the potential to contribute to transgenerational inheritance. We also show that CNVs are the only source of genetic variation and occur at the same order of magnitude as epimutations. © 2016 John Wiley & Sons Ltd.

  17. Change of mitotic behavior and ultra structure of 'Fuju' (Citrus reticulata Blanco) stem-apex clones after space flight

    International Nuclear Information System (INIS)

    Wu Rujian; Huang Jinghao; Wen Shouxing; Cai Zijian; Luo Tuyan; Chen Liangfeng; Wang Zhouwen

    2011-01-01

    By using conventional squash stain technique and ultrathin sectioning technique, the effects of space flight on mitotic behavior and ultrastructure were studied in the shoot apical meristem of 'Fuju' (Citrus reticulata Blanco), which had been carried by China's seed-breeding satellite, Shijian-8. The results showed that space flight had effect on the mutagenesis of stem-apical meristem. Abnormal mitosis with various degrees had been detected in 13 mutant clones, of which mitotic aberrations in clone '08004' were significantly higher than the others. The aberration rate of numerical abnormalities of chromosomes at metaphase, lagging chromosome, micronucleus, C-spindle, S-spindle and polyarch spindle in the clone '08004' was 0.34%, 0.669%, 0.86%, 0.17%, 1.20% and 1.03%, respectively. The ultrastructure of mesophyll cell in most clones was unchanged, but nucleus chromatin agglutination, chloroplast thylakoid disintegrated, autophagosome appeared, cell vacuolated, plasmolysis and the formation of apoptotic body were found in the clone '08004', suggesting that programmed cell death (PCD) Nevertheless, no change in the mitochondrial structure was observed until terminal phase of PCD. (authors)

  18. Impact of axillary nodal metastases on lymphatic mapping and sentinel lymph node identification rate in patients with early stage breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Pelosi, Ettore [Ospedale S. Giovanni Battista, S.C.D.U. Medicina Nucleare 2, Turin (Italy); Universita Torino, Dottorato di Ricerca Radioimmunolocalizzazione dei Tumori Umani, Turin (Italy); Ala, Ada; Bussone, Riccardo [Ospedale S. Giovanni Battista, Reparto di Chirurgia Oncologica 10, Turin (Italy); Bello, Marilena; Douroukas, Anastasios; Varetto, Teresio [Ospedale S. Giovanni Battista, S.C.D.U. Medicina Nucleare 2, Turin (Italy); Migliaretti, Giuseppe [Universita di Torino, Dipartimento di Sanita Pubblica e Microbiologia, Turin (Italy); Berardengo, Ester [Ospedale S. Giovanni Battista, Servizio di Anatomia Patologica 4, Turin (Italy); Bisi, Gianni [Ospedale S. Giovanni Battista, S.C.D.U. Medicina Nucleare 2, Turin (Italy); Universita di Torino, Dipartimento di Medicina Interna, SCDU Medicina Nucleare 2, Turin (Italy)

    2005-08-01

    The aim of this study was to define the impact of the presence of axillary nodal metastases on lymphatic mapping and sentinel lymph node (SLN) identification rate in patients with early breast cancer. Two hundred and forty-six lymphatic mapping procedures were performed with both labelled nanocolloid and blue dye, followed by SLN biopsy and/or complete axillary dissection. The following parameters were recorded: patient's age, tumour laterality and location, tumour size, tumour histology, tumour stage, tumour grade, lymphovascular invasion, radiotracer injection site (subdermal-peritumoural/peri-areolar), SLN visualisation at lymphoscintigraphy, SLN metastases (presence/absence, size) and other axillary metastases (presence/absence, number). Discriminant analysis was used to analyse the data. SLNs were identified by labelled nanocolloid alone in 94.7% of tumours, by blue dye alone in 93.5% and by the combined technique in 99.2%. Discriminant analysis showed the gamma probe SLN identification rate to be significantly limited by the presence of axillary nodal metastases. In particular, the size of SLN metastases and the number of other axillary metastases were the most important variables in reducing the gamma probe SLN identification rate (p=0.004 and p=0.002, respectively). On the other hand, high tumour grade was the only parameter limiting the blue dye SLN identification rate. The accuracy of lymphatic mapping with labelled nanocolloid is limited by the presence of axillary nodal metastases, and particularly by the degree of SLN tumoural invasion and the presence and number of other axillary nodal metastases. Neither of these elements seems to interfere with the blue dye identification rate. The combination of the two tracers maximises the SLN identification rate. (orig.)

  19. Impact of axillary nodal metastases on lymphatic mapping and sentinel lymph node identification rate in patients with early stage breast cancer

    International Nuclear Information System (INIS)

    Pelosi, Ettore; Ala, Ada; Bussone, Riccardo; Bello, Marilena; Douroukas, Anastasios; Varetto, Teresio; Migliaretti, Giuseppe; Berardengo, Ester; Bisi, Gianni

    2005-01-01

    The aim of this study was to define the impact of the presence of axillary nodal metastases on lymphatic mapping and sentinel lymph node (SLN) identification rate in patients with early breast cancer. Two hundred and forty-six lymphatic mapping procedures were performed with both labelled nanocolloid and blue dye, followed by SLN biopsy and/or complete axillary dissection. The following parameters were recorded: patient's age, tumour laterality and location, tumour size, tumour histology, tumour stage, tumour grade, lymphovascular invasion, radiotracer injection site (subdermal-peritumoural/peri-areolar), SLN visualisation at lymphoscintigraphy, SLN metastases (presence/absence, size) and other axillary metastases (presence/absence, number). Discriminant analysis was used to analyse the data. SLNs were identified by labelled nanocolloid alone in 94.7% of tumours, by blue dye alone in 93.5% and by the combined technique in 99.2%. Discriminant analysis showed the gamma probe SLN identification rate to be significantly limited by the presence of axillary nodal metastases. In particular, the size of SLN metastases and the number of other axillary metastases were the most important variables in reducing the gamma probe SLN identification rate (p=0.004 and p=0.002, respectively). On the other hand, high tumour grade was the only parameter limiting the blue dye SLN identification rate. The accuracy of lymphatic mapping with labelled nanocolloid is limited by the presence of axillary nodal metastases, and particularly by the degree of SLN tumoural invasion and the presence and number of other axillary nodal metastases. Neither of these elements seems to interfere with the blue dye identification rate. The combination of the two tracers maximises the SLN identification rate. (orig.)

  20. Chromosome segregation regulation in human zygotes: altered mitotic histone phosphorylation dynamics underlying centromeric targeting of the chromosomal passenger complex.

    Science.gov (United States)

    van de Werken, C; Avo Santos, M; Laven, J S E; Eleveld, C; Fauser, B C J M; Lens, S M A; Baart, E B

    2015-10-01

    Are the kinase feedback loops that regulate activation and centromeric targeting of the chromosomal passenger complex (CPC), functional during mitosis in human embryos? Investigation of the regulatory kinase pathways involved in centromeric CPC targeting revealed normal phosphorylation dynamics of histone H2A at T120 (H2ApT120) by Bub1 kinase and subsequent recruitment of Shugoshin, but phosphorylation of histone H3 at threonine 3 (H3pT3) by Haspin failed to show the expected centromeric enrichment on metaphase chromosomes in the zygote. Human cleavage stage embryos show high levels of chromosomal instability. What causes this high error rate is unknown, as mechanisms used to ensure proper chromosome segregation in mammalian embryos are poorly described. In this study, we investigated the pathways regulating CPC targeting to the inner centromere in human embryos. We characterized the distribution of the CPC in relation to activity of its two main centromeric targeting pathways: the Bub1-H2ApT120-Sgo-CPC and Haspin-H3pT3-CPC pathways. The study was conducted between May 2012 and March 2014 on human surplus embryos resulting from in vitro fertilization treatment and donated for research. In zygotes, nuclear envelope breakdown was monitored by time-lapse imaging to allow timed incubations with specific inhibitors to arrest at prometaphase and metaphase, and to interfere with Haspin and Aurora B/C kinase activity. Functionality of the targeting pathways was assessed through characterization of histone phosphorylation dynamics by immunofluorescent analysis, combined with gene expression by RT-qPCR and immunofluorescent localization of key pathway proteins. Immunofluorescent analysis of the CPC subunit Inner Centromere Protein revealed the pool of stably bound CPC proteins was not strictly confined to the inner centromere of prometaphase chromosomes in human zygotes, as observed in later stages of preimplantation development and somatic cells. Investigation of the

  1. Evidence of activity-specific, radial organization of mitotic chromosomes in Drosophila.

    Directory of Open Access Journals (Sweden)

    Yuri G Strukov

    2011-01-01

    Full Text Available The organization and the mechanisms of condensation of mitotic chromosomes remain unsolved despite many decades of efforts. The lack of resolution, tight compaction, and the absence of function-specific chromatin labels have been the key technical obstacles. The correlation between DNA sequence composition and its contribution to the chromosome-scale structure has been suggested before; it is unclear though if all DNA sequences equally participate in intra- or inter-chromatin or DNA-protein interactions that lead to formation of mitotic chromosomes and if their mitotic positions are reproduced radially. Using high-resolution fluorescence microscopy of live or minimally perturbed, fixed chromosomes in Drosophila embryonic cultures or tissues expressing MSL3-GFP fusion protein, we studied positioning of specific MSL3-binding sites. Actively transcribed, dosage compensated Drosophila genes are distributed along the euchromatic arm of the male X chromosome. Several novel features of mitotic chromosomes have been observed. MSL3-GFP is always found at the periphery of mitotic chromosomes, suggesting that active, dosage compensated genes are also found at the periphery of mitotic chromosomes. Furthermore, radial distribution of chromatin loci on mitotic chromosomes was found to be correlated with their functional activity as judged by core histone modifications. Histone modifications specific to active chromatin were found peripheral with respect to silent chromatin. MSL3-GFP-labeled chromatin loci become peripheral starting in late prophase. In early prophase, dosage compensated chromatin regions traverse the entire width of chromosomes. These findings suggest large-scale internal rearrangements within chromosomes during the prophase condensation step, arguing against consecutive coiling models. Our results suggest that the organization of mitotic chromosomes is reproducible not only longitudinally, as demonstrated by chromosome-specific banding

  2. Correlation of glomerular filtration rate measurement using Tc-99m DTPA with cystatin-C levels and creatinine clearance for staging of chronic kidney disease

    International Nuclear Information System (INIS)

    Elliyanti, A.; Iskandar, Azmi S.

    2007-01-01

    Full text: The presence of Chronic Kidney Disease (CKD) was established based on kidney damage presence and the level of kidney function through Glomerular filtration rate (GFR). It was also recognized that renal scintigraphy (renogram) using TC-99m DTPA (diethylenetriamine pentacetic acid) has advantages in the measurement of GFR. Recently, serum Cystatin-C is proposed as the new marker of GFR. The aim of this study is to find out the correlation of GFR, derived from renogram, with Cystatin- C levels and Creatinine Clearance (CC) in CKD. Material and Methods: A total of 30 subjects (age mean is 60.8 years, 21 males and 9 females) were enrolled in this study with diagnosis stage 2 of CKD. CKD staging was determined by Cockroft-Gault (CG) equation, taking into account the serum creatinine. Renogram was performed using a single head camera with IV administration of 5 mCi DTPA. Cystatin-C and creatinine clearance (24-hours urine samples) were include in this study. Results: The mean GFR of renogram, Cystatin-C, CC and CG are 64.96 ml/min/1.73m2 (SD 28.047), 53.37 ml/min/1.73m2 (SD 21.29), 58.09 ml/min/1.73m2 (SD 35.45), 46.00 ml/min/1.73m2 (SD 12.06) respectively. There is better correlation between renogram and Cystatin-C (r=0.585, p0.0007) compared renogram and CC (r=0.388, p=0.03) or renogram and CG (r=-0.029, p=0.87). Conclusion: Cystatin-C shows better indicator of GFR than CC and CG. Serum creatinine concentration alone should not be used to assess the level of kidney function in the staging of CKD. (author)

  3. Molecular mechanism of APC/C activation by mitotic phosphorylation.

    Science.gov (United States)

    Zhang, Suyang; Chang, Leifu; Alfieri, Claudio; Zhang, Ziguo; Yang, Jing; Maslen, Sarah; Skehel, Mark; Barford, David

    2016-05-12

    results reveal the mechanism for the regulation of mitotic APC/C by phosphorylation and provide a rationale for the development of selective inhibitors of this state.

  4. Trophic Relationships between the Parasitic Plant Species Phelipanche ramosa (L.) and Different Hosts Depending on Host Phenological Stage and Host Growth Rate

    Science.gov (United States)

    Moreau, Delphine; Gibot-Leclerc, Stéphanie; Girardin, Annette; Pointurier, Olivia; Reibel, Carole; Strbik, Florence; Fernández-Aparicio, Mónica; Colbach, Nathalie

    2016-01-01

    Phelipanche ramosa (L.) Pomel (branched broomrape) is a holoparasitic plant that reproduces on crops and also on weeds, which contributes to increase the parasite seed bank in fields. This parasite extracts all its nutrients at the host’s expense so that host–parasite trophic relationships are crucial to determine host and parasite growth. This study quantified the intensity with which P. ramosa draws assimilates from its host and analyzed whether it varied with host species, host phenological stage and host growth rate. A greenhouse experiment was conducted on three host species: the crop species Brassica napus (L.) (oilseed rape) and two weed species, Capsella bursa-pastoris (L.) Medik. and Geranium dissectum (L.). Plants were grown with or without P. ramosa and under three light levels to modulate host growth rate. The proportion of host biomass loss due to parasitism by P. ramosa differed between host species (at host fructification, biomass loss ranged from 34 to 84%). B. napus and C. bursa-pastoris displayed a similar response to P. ramosa, probably because they belong to the same botanical family. The sensitivity to P. ramosa in each host species could be related to the precocity of P. ramosa development on them. Host compartments could be ranked as a function of their sensitivity to parasitism, with the reproductive compartment being the most severely affected, followed by stems and roots. The proportion of biomass allocated to leaves was not reduced by parasitism. The proportion of pathosystem biomass allocated to the parasite depended on host species. It generally increased with host stage progression but was constant across light induced-host growth rate, showing that P. ramosa adapts its growth to host biomass production. The rank order of host species in terms of sink strength differed from that in terms of host sensitivity. Finally, for B. napus, the biomass of individual parasite shoots decreased with increasing their number per host plant

  5. Trophic relationships between the parasitic plant species Phelipanche ramosa (L. and different hosts depending on host phenological stage and host growth rate

    Directory of Open Access Journals (Sweden)

    Delphine Moreau

    2016-07-01

    Full Text Available Phelipanche ramosa (L. Pomel (branched broomrape is a holoparasitic plant that reproduces on crops and also on weeds, which contributes to increase the parasite seed bank in fields. This parasite extracts all its nutrients at the host's expense so that host-parasite trophic relationships are crucial to determine host and parasite growth. This study quantified the intensity with which P. ramosa draws assimilates from its host and analyzed whether it varied with host species, host phenological stage and host growth rate. A greenhouse experiment was conducted on three host species: the crop species Brassica napus (L. (oilseed rape and two weed species, Capsella bursa-pastoris (L. Medik. and Geranium dissectum (L.. Plants were grown with or without P. ramosa and under three light levels to modulate host growth rate. The proportion of host biomass loss due to parasitism by P. ramosa differed between host species (at host fructification, biomass loss ranged from 34% to 84%. Brassica napus and C. bursa-pastoris displayed a similar response to P. ramosa, probably because they belong to the same botanical family. The sensitivity to P. ramosa in each host species could be related to the precocity of P. ramosa development on them. Host compartments could be ranked as a function of their sensitivity to parasitism, with the reproductive compartment being the most severely affected, followed by stems and roots. The proportion of biomass allocated to leaves was not reduced by parasitism. The proportion of pathosystem biomass allocated to the parasite depended on host species. It generally increased with host stage progression but was constant across light induced-host growth rate, showing that P. ramosa adapts its growth to host biomass production. The rank order of host species in terms of sink strength differed from that in terms of host sensitivity. Finally, for B. napus, the biomass of individual parasite shoots decreased with increasing their number per

  6. File list: ALL.Emb.20.AllAg.Mitotic_cycle_7-9 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ALL.Emb.20.AllAg.Mitotic_cycle_7-9 dm3 All antigens Embryo Mitotic cycle 7-9 SRX645...111,SRX645115,SRX645103,SRX645123,SRX645107,SRX645137,SRX645099,SRX645119 http://dbarchive.biosciencedbc.jp/kyushu-u/dm3/assembled/ALL.Emb.20.AllAg.Mitotic_cycle_7-9.bed ...

  7. File list: ALL.Emb.20.AllAg.Mitotic_cycle_11-13 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ALL.Emb.20.AllAg.Mitotic_cycle_11-13 dm3 All antigens Embryo Mitotic cycle 11-13 SR...X645130,SRX645124,SRX645116,SRX645108,SRX645127,SRX645112,SRX645138,SRX645120 http://dbarchive.biosciencedbc.jp/kyushu-u/dm3/assembled/ALL.Emb.20.AllAg.Mitotic_cycle_11-13.bed ...

  8. File list: ALL.Emb.05.AllAg.Mitotic_cycle_11-13 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ALL.Emb.05.AllAg.Mitotic_cycle_11-13 dm3 All antigens Embryo Mitotic cycle 11-13 SR...X645108,SRX645116,SRX645127,SRX645124,SRX645130,SRX645112,SRX645120,SRX645138 http://dbarchive.biosciencedbc.jp/kyushu-u/dm3/assembled/ALL.Emb.05.AllAg.Mitotic_cycle_11-13.bed ...

  9. Mitotic and meiotic irregularities in somatic hybrids of Lycopersicon esculentum and Solanum tuberosum.

    Science.gov (United States)

    Wolters, A M; Schoenmakers, H C; Kamstra, S; Eden, J; Koornneef, M; Jong, J H

    1994-10-01

    Chromosome numbers were determined in metaphase complements of root-tip meristems of 107 tomato (+) potato somatic hybrids, obtained from five different combinations of parental genotypes. Of these hybrids 79% were aneuploid, lacking one or two chromosomes in most cases. All four hybrids that were studied at mitotic anaphase of root tips showed laggards and bridges, the three aneuploids in a higher frequency than the single euploid. Hybrid K2H2-1C, which showed the highest percentage of aberrant anaphases, possessed 46 chromosomes. Fluorescence in situ hybridization with total genomic DNA showed that this hybrid contained 23 tomato, 22 potato, and 1 recombinant chromosome consisting of a tomato chromosome arm and a potato chromosome arm. The potato parent of K2H2-1C was aneusomatic in its root tips with a high frequency of monosomic and trisomic cells and a relatively high frequency of cells with one fragment or telosome. Meiotic analyses of three tomato (+) potato somatic hybrids revealed laggards, which occurred most frequently in the triploid hybrids, and bridges, which were frequently present in pollen mother cells (PMCs) at anaphase I of hypotetraploid K2H2-1C. We observed putative trivalents in PMCs at diakinesis and metaphase I of eutriploid A7-82A and quadrivalents in part of the PMCs of hypotetraploid K2H2-1C, suggesting that homoeologous recombination between tomato and potato chromosomes occurred in these hybrids. All three hybrids showed a high percentage of first division restitution, giving rise to unreduced gametes. However, shortly after the tetrad stage all microspores completely degenerated, resulting in exclusively sterile pollen.

  10. Induction of chromosome aberrations and mitotic arrest by cytomegalovirus in human cells

    International Nuclear Information System (INIS)

    AbuBakar, S.; Au, W.W.; Legator, M.S.; Albrecht, T.

    1988-01-01

    Human cytomegalovirus (CMV) is potentially an effective but often overlooked genotoxic agent in humans. We report here evidence that indicates that infection by CMV can induce chromosome alterations and mitotic inhibition. The frequency of chromosome aberrations induced was dependent on the input multiplicity of infection (m.o.i.) for human lung fibroblasts (LU), but not for human peripheral blood lymphocytes (PBLs) when both cell types were infected at the GO phase of the cell cycle. The aberrations induced by CMV were mostly chromatid breaks and chromosome pulverizations that resembled prematurely condensed S-phase chromatin. Pulverized chromosomes were not observed in LU cells infected with virus stocks that had been rendered nonlytic by UV-irradiation at 24,000 ergs/mm2 or from infection of human lymphocytes. In LU cells infected with UV-irradiated CMV, the frequency of aberrations induced was inversely dependent on the extent of the exposure of the CMV stock to the UV-light. In permissive CMV infection of proliferating LU cells at 24 hr after subculture, a high percentage (greater than 40%) of the metaphase cells were arrested at their first metaphase and displayed severely condensed chromosomes when harvested 48 hr later. A significant increase (p less than 0.05) in the chromosome aberration frequency was also observed. Our study shows that CMV infection is genotoxic to host cells. The types and extent of damage are dependent on the viral genome expression and on the cell cycle stage of the cells at the time of infection. The possible mechanisms for induction of chromosome damage by CMV are discussed

  11. Mitotic evolution of Plasmodium falciparum shows a stable core genome but recombination in antigen families.

    Directory of Open Access Journals (Sweden)

    Selina E R Bopp

    Full Text Available Malaria parasites elude eradication attempts both within the human host and across nations. At the individual level, parasites evade the host immune responses through antigenic variation. At the global level, parasites escape drug pressure through single nucleotide variants and gene copy amplification events conferring drug resistance. Despite their importance to global health, the rates at which these genomic alterations emerge have not been determined. We studied the complete genomes of different Plasmodium falciparum clones that had been propagated asexually over one year in the presence and absence of drug pressure. A combination of whole-genome microarray analysis and next-generation deep resequencing (totaling 14 terabases revealed a stable core genome with only 38 novel single nucleotide variants appearing in seventeen evolved clones (avg. 5.4 per clone. In clones exposed to atovaquone, we found cytochrome b mutations as well as an amplification event encompassing the P. falciparum multidrug resistance associated protein (mrp1 on chromosome 1. We observed 18 large-scale (>1 kb on average deletions of telomere-proximal regions encoding multigene families, involved in immune evasion (9.5×10(-6 structural variants per base pair per generation. Six of these deletions were associated with chromosomal crossovers generated during mitosis. We found only minor differences in rates between genetically distinct strains and between parasites cultured in the presence or absence of drug. Using these derived mutation rates for P. falciparum (1.0-9.7×10(-9 mutations per base pair per generation, we can now model the frequency at which drug or immune resistance alleles will emerge under a well-defined set of assumptions. Further, the detection of mitotic recombination events in var gene families illustrates how multigene families can arise and change over time in P. falciparum. These results will help improve our understanding of how P. falciparum

  12. Determination of Uranium Concentration in Soil of Baghdad Governorate and its Effect on Mitotic Index Assay

    International Nuclear Information System (INIS)

    Mryoush, A.Q.; Salim, H.M.

    2015-01-01

    The aim of this work is to determine the uranium concentration in soil samples taken from the north, south, east, west and center of the city of Baghdad and measure its impact on the rate of cell division for non-smokers peoples and living in those areas and that between the ages 25-30 year.The uranium concentration in the samples determined by using CR-39 track detector.As calculated for the ten samples of each site when irradiated by thermal neutrons from the (Am - Be) source with flux (5x 10 3 n S -1 cm -2 ), the concentration values were calculated by a comparison with standard geological samples. The results indicate that the extent of the concentration of uranium in the soil north and east of Baghdad was 12.9 ± 0.7 in Al- Taji north of Baghdad and 12.4 ± 0.23ppm in the Diyala- Bridge area east of Baghdad and the results were recorded lower concentration of uranium in the western, central and southern Baghdad, which stood at 0.60 ± 0.21 in the Abu Ghraib area west of Baghdad, and 4.6 ± 0.7ppm in the Bab-Al-Sharqee of central Baghdad and 0.87 ± 0.7ppm in Al-Mhmodya area south of Baghdad.The mitotic index assay MI in the north and east of Baghdad was 2.3 ± 0.059 in the north and 2.43 ± 0.059 in eastern Baghdad, while the lowest rate in West and Central and South compared with the threshold level of 0.6 . Which indicates contamination north and east of Baghdad as a result of uranium wars on Iraq passed in 2003 which negatively affects the behavior of lymphocytes and on the rate of division

  13. Mitotic Evolution of Plasmodium falciparum Shows a Stable Core Genome but Recombination in Antigen Families

    Science.gov (United States)

    Bopp, Selina E. R.; Manary, Micah J.; Bright, A. Taylor; Johnston, Geoffrey L.; Dharia, Neekesh V.; Luna, Fabio L.; McCormack, Susan; Plouffe, David; McNamara, Case W.; Walker, John R.; Fidock, David A.; Denchi, Eros Lazzerini; Winzeler, Elizabeth A.

    2013-01-01

    Malaria parasites elude eradication attempts both within the human host and across nations. At the individual level, parasites evade the host immune responses through antigenic variation. At the global level, parasites escape drug pressure through single nucleotide variants and gene copy amplification events conferring drug resistance. Despite their importance to global health, the rates at which these genomic alterations emerge have not been determined. We studied the complete genomes of different Plasmodium falciparum clones that had been propagated asexually over one year in the presence and absence of drug pressure. A combination of whole-genome microarray analysis and next-generation deep resequencing (totaling 14 terabases) revealed a stable core genome with only 38 novel single nucleotide variants appearing in seventeen evolved clones (avg. 5.4 per clone). In clones exposed to atovaquone, we found cytochrome b mutations as well as an amplification event encompassing the P. falciparum multidrug resistance associated protein (mrp1) on chromosome 1. We observed 18 large-scale (>1 kb on average) deletions of telomere-proximal regions encoding multigene families, involved in immune evasion (9.5×10−6 structural variants per base pair per generation). Six of these deletions were associated with chromosomal crossovers generated during mitosis. We found only minor differences in rates between genetically distinct strains and between parasites cultured in the presence or absence of drug. Using these derived mutation rates for P. falciparum (1.0–9.7×10−9 mutations per base pair per generation), we can now model the frequency at which drug or immune resistance alleles will emerge under a well-defined set of assumptions. Further, the detection of mitotic recombination events in var gene families illustrates how multigene families can arise and change over time in P. falciparum. These results will help improve our understanding of how P. falciparum evolves to

  14. Sign and magnitude scaling properties of heart rate variability in patients with end-stage renal failure: Are these properties useful to identify pathophysiological adaptations?

    Science.gov (United States)

    Lerma, Claudia; Echeverría, Juan C.; Infante, Oscar; Pérez-Grovas, Héctor; González-Gómez, Hortensia

    2017-09-01

    The scaling properties of heart rate variability data are reliable dynamical features to predict mortality and for the assessment of cardiovascular risk. The aim of this manuscript was to determine if the scaling properties, as provided by the sign and magnitude analysis, can be used to differentiate between pathological changes and those adaptations basically introduced by modifications of the mean heart rate in distinct manoeuvres (active standing or hemodialysis treatment, HD), as well as clinical conditions (end stage renal disease, ESRD). We found that in response to active standing, the short-term scaling index (α1) increased in healthy subjects and in ESRD patients only after HD. The sign short-term scaling exponent (α1sign) increased in healthy subjects and ESRD patients, showing a less anticorrelated behavior in active standing. Both α1 and α1sign did show covariance with the mean heart rate in healthy subjects, while in ESRD patients, this covariance was observed only after HD. A reliable estimation of the magnitude short-term scaling exponent (α1magn) required the analysis of time series with a large number of samples (>3000 data points). This exponent was similar for both groups and conditions and did not show covariance with the mean heart rate. A surrogate analysis confirmed the presence of multifractal properties (α1magn > 0.5) in the time series of healthy subjects and ESDR patients. In conclusion, α1 and α1sign provided insights into the physiological adaptations during active standing, which revealed a transitory impairment before HD in ESRD patients. The presence of multifractal properties indicated that a reduced short-term variability does not necessarily imply a declined regulatory complexity in these patients.

  15. Tuberous Roots Yield, Transpiration Rate, Stomatal Conductance and Water Use Efficiency of Divergent Cassava Clones as Influenced by Climate and Growth Stage

    International Nuclear Information System (INIS)

    Githunguri, C.M; Chewa, J.A; Ekanayake, I.J

    1999-01-01

    Cassava roots provide a cheap source of dietary energy to millions of people in the tropics. Variations in yield, stomatal conductance, transpiration rate and water use efficiency occur due to various factors. This makes selection of clones with wide ecological adaptation and high yield difficult. The influence of crop age and agroecozones (AEZ) in Nigeria on above parametres were studied. The tested AEZs were Sudan savanna (Minjibir), Southern Guinea savanna (Mokwa) and forest-savanna transition (Ibadan) AEZ. The environment plays a significant role in determining root yield with plant age playing a bigger role at the early stages. Results suggest root development was restricted by low moisture stress. Cassava ought to be harvested at eight months after planting (MAP) rather than at 12 MAP in order to obtain maximum yields. Yields at Mokwa were significantly higher than both Minjibir and Ibadan suggesting that cassava is not a crop for either forest or semi arid zones. During both seasons Minjbir had the highest stomatal conductance trend while Ibadan had the lowest. Stomatal conductance at Minjibir becomes critical at 12 MAP. The highest transpiration rate was recorded at Minijibir at 4 and 12 MAP. The lowest transpiration rate ws observed at Ibadan. The lowest transpiration rate was also observed during drought. There was a close positive close relationship between tuberous roots yield and transpiration. The lowest and highest water use efficiency (WUE) was recorded at 4 and 8 MAP during rains. The lowest and the highest WUE was recorded at Ibadan and Mokwa respectively. The two seasons trends were similar. Clone TMS 50395 had the highest WUE. Tere was close positive relationship between WUE and tuberous roots yield

  16. Localization of latency-associated nuclear antigen (LANA) on mitotic chromosomes

    International Nuclear Information System (INIS)

    Rahayu, Retno; Ohsaki, Eriko; Omori, Hiroko; Ueda, Keiji

    2016-01-01

    In latent infection of Kaposi's sarcoma-associated herpesvirus (KSHV), viral gene expression is extremely limited and copy numbers of viral genomes remain constant. Latency-associated nuclear antigen (LANA) is known to have a role in maintaining viral genome copy numbers in growing cells. Several studies have shown that LANA is localized in particular regions on mitotic chromosomes, such as centromeres/pericentromeres. We independently examined the distinct localization of LANA on mitotic chromosomes during mitosis, using super-resolution laser confocal microscopy and correlative fluorescence microscopy–electron microscopy (FM-EM) analyses. We found that the majority of LANA were not localized at particular regions such as telomeres/peritelomeres, centromeres/pericentromeres, and cohesion sites, but at the bodies of condensed chromosomes. Thus, LANA may undergo various interactions with the host factors on the condensed chromosomes in order to tether the viral genome to mitotic chromosomes and realize faithful viral genome segregation during cell division. - Highlights: • This is the first report showing LANA dots on mitotic chromosomes by fluorescent microscopy followed by electron microscopy. • LANA dots localized randomly on condensed chromosomes other than centromere/pericentromere and telomere/peritelomre. • Cellular mitotic checkpoint should not be always involved in the segregation of KSHV genomes in the latency.

  17. High frequency induction of mitotic recombination by ionizing radiation in Mlh1 null mouse cells

    International Nuclear Information System (INIS)

    Wang Qi; Ponomareva, Olga N.; Lasarev, Michael; Turker, Mitchell S.

    2006-01-01

    Mitotic recombination in somatic cells involves crossover events between homologous autosomal chromosomes. This process can convert a cell with a heterozygous deficiency to one with a homozygous deficiency if a mutant allele is present on one of the two homologous autosomes. Thus mitotic recombination often represents the second mutational step in tumor suppressor gene inactivation. In this study we examined the frequency and spectrum of ionizing radiation (IR)-induced autosomal mutations affecting Aprt expression in a mouse kidney cell line null for the Mlh1 mismatch repair (MMR) gene. The mutant frequency results demonstrated high frequency induction of mutations by IR exposure and the spectral analysis revealed that most of this response was due to the induction of mitotic recombinational events. High frequency induction of mitotic recombination was not observed in a DNA repair-proficient cell line or in a cell line with an MMR-independent mutator phenotype. These results demonstrate that IR exposure can initiate a process leading to mitotic recombinational events and that MMR function suppresses these events from occurring

  18. Centrosome Amplification Increases Single-Cell Branching in Post-mitotic Cells.

    Science.gov (United States)

    Ricolo, Delia; Deligiannaki, Myrto; Casanova, Jordi; Araújo, Sofia J

    2016-10-24

    Centrosome amplification is a hallmark of cancer, although we are still far from understanding how this process affects tumorigenesis [1, 2]. Besides the contribution of supernumerary centrosomes to mitotic defects, their biological effects in the post-mitotic cell are not well known. Here, we exploit the effects of centrosome amplification in post-mitotic cells during single-cell branching. We show that Drosophila tracheal cells with extra centrosomes branch more than wild-type cells. We found that mutations in Rca1 and CycA affect subcellular branching, causing tracheal tip cells to form more than one subcellular lumen. We show that Rca1 and CycA post-mitotic cells have supernumerary centrosomes and that other mutant conditions that increase centrosome number also show excess of subcellular lumen branching. Furthermore, we show that de novo lumen formation is impaired in mutant embryos with fewer centrioles. The data presented here define a requirement for the centrosome as a microtubule-organizing center (MTOC) for the initiation of subcellular lumen formation. We propose that centrosomes are necessary to drive subcellular lumen formation. In addition, centrosome amplification increases single-cell branching, a process parallel to capillary sprouting in blood vessels [3]. These results shed new light on how centrosomes can contribute to pathology independently of mitotic defects. Copyright © 2016 Elsevier Ltd. All rights reserved.

  19. Localization of latency-associated nuclear antigen (LANA) on mitotic chromosomes

    Energy Technology Data Exchange (ETDEWEB)

    Rahayu, Retno; Ohsaki, Eriko [Division of Virology, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871 (Japan); Omori, Hiroko [Central Instrumentation Laboratory Research Institute for Microbial Diseases (BIKEN), Osaka University, Osaka 565-0871 (Japan); Ueda, Keiji, E-mail: kueda@virus.med.osaka-u.ac.jp [Division of Virology, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871 (Japan)

    2016-09-15

    In latent infection of Kaposi's sarcoma-associated herpesvirus (KSHV), viral gene expression is extremely limited and copy numbers of viral genomes remain constant. Latency-associated nuclear antigen (LANA) is known to have a role in maintaining viral genome copy numbers in growing cells. Several studies have shown that LANA is localized in particular regions on mitotic chromosomes, such as centromeres/pericentromeres. We independently examined the distinct localization of LANA on mitotic chromosomes during mitosis, using super-resolution laser confocal microscopy and correlative fluorescence microscopy–electron microscopy (FM-EM) analyses. We found that the majority of LANA were not localized at particular regions such as telomeres/peritelomeres, centromeres/pericentromeres, and cohesion sites, but at the bodies of condensed chromosomes. Thus, LANA may undergo various interactions with the host factors on the condensed chromosomes in order to tether the viral genome to mitotic chromosomes and realize faithful viral genome segregation during cell division. - Highlights: • This is the first report showing LANA dots on mitotic chromosomes by fluorescent microscopy followed by electron microscopy. • LANA dots localized randomly on condensed chromosomes other than centromere/pericentromere and telomere/peritelomre. • Cellular mitotic checkpoint should not be always involved in the segregation of KSHV genomes in the latency.

  20. Dietary flavonoid fisetin induces a forced exit from mitosis by targeting the mitotic spindle checkpoint

    Science.gov (United States)

    Salmela, Anna-Leena; Pouwels, Jeroen; Varis, Asta; Kukkonen, Anu M.; Toivonen, Pauliina; Halonen, Pasi K.; Perälä, Merja; Kallioniemi, Olli; Gorbsky, Gary J.; Kallio, Marko J.

    2009-01-01

    Fisetin is a natural flavonol present in edible vegetables, fruits and wine at 2–160 μg/g concentrations and an ingredient in nutritional supplements with much higher concentrations. The compound has been reported to exert anticarcinogenic effects as well as antioxidant and anti-inflammatory activity via its ability to act as an inhibitor of cell proliferation and free radical scavenger, respectively. Our cell-based high-throughput screen for small molecules that override chemically induced mitotic arrest identified fisetin as an antimitotic compound. Fisetin rapidly compromised microtubule drug-induced mitotic block in a proteasome-dependent manner in several human cell lines. Moreover, in unperturbed human cancer cells fisetin caused premature initiation of chromosome segregation and exit from mitosis without normal cytokinesis. To understand the molecular mechanism behind these mitotic errors, we analyzed the consequences of fisetin treatment on the localization and phoshorylation of several mitotic proteins. Aurora B, Bub1, BubR1 and Cenp-F rapidly lost their kinetochore/centromere localization and others became dephosphorylated upon addition of fisetin to the culture medium. Finally, we identified Aurora B kinase as a novel direct target of fisetin. The activity of Aurora B was significantly reduced by fisetin in vitro and in cells, an effect that can explain the observed forced mitotic exit, failure of cytokinesis and decreased cell viability. In conclusion, our data propose that fisetin perturbs spindle checkpoint signaling, which may contribute to the antiproliferative effects of the compound. PMID:19395653

  1. Effect of tumor promoters on ultraviolet light-induced mutation and mitotic recombination in Saccharomyces cerevisiae

    International Nuclear Information System (INIS)

    Kunz, B.A.; Hannan, M.A.; Haynes, R.H.

    1980-01-01

    Recently, it has been suggested that mitotic recombination is involved in tumor promotion. On this basis, one might expect tumor promoters to be recombinagenic. D7 is a diploid strain of yeast in which both mutation and mitotic recombination can be measured. We have used this strain to assay the known tumor promoters, iodacetate, anthralin, and 12-0-tetradecanoylphorbol-13-acetate, and the cocarcinogen, catechol, for mutagenicity, recombinagenicity, and the ability to enhance ultraviolet light (UV)-induced genetic events. In the absence of preirradiation with UV, iodoacetate was found to be recombinagenic whereas catechol was mutagenic; however, in both cases, the effects were small. Iodoacetate, anthralin, and catechol potentiated UV-induced mitotic crossing-over, aberrant colony formation, and mutation, while catechol also increased UV-induced gene conversion. We were unable to detect any mutagenic or recombinagenic effect of 12-0-tetradecanoyl-phorbol-13-acetate in either whole cells or spheroplasts. Our results do not indicate any consistent correlation between tumor-promoting activity and the ability of an agent to induce mitotic recombination in yeast. However, the ability to potentiate UV-induced mutation and mitotic recombination may reflect the cocarcinogenic activity of certain promoters

  2. Wnt activation followed by Notch inhibition promotes mitotic hair cell regeneration in the postnatal mouse cochlea

    Science.gov (United States)

    Li, Wenyan; Chen, Yan; Zhang, Shasha; Tang, Mingliang; Sun, Shan; Chai, Renjie; Li, Huawei

    2016-01-01

    Hair cell (HC) loss is the main cause of permanent hearing loss in mammals. Previous studies have reported that in neonatal mice cochleae, Wnt activation promotes supporting cell (SC) proliferation and Notch inhibition promotes the trans-differentiation of SCs into HCs. However, Wnt activation alone fails to regenerate significant amounts of new HCs, Notch inhibition alone regenerates the HCs at the cost of exhausting the SC population, which leads to the death of the newly regenerated HCs. Mitotic HC regeneration might preserve the SC number while regenerating the HCs, which could be a better approach for long-term HC regeneration. We present a two-step gene manipulation, Wnt activation followed by Notch inhibition, to accomplish mitotic regeneration of HCs while partially preserving the SC number. We show that Wnt activation followed by Notch inhibition strongly promotes the mitotic regeneration of new HCs in both normal and neomycin-damaged cochleae while partially preserving the SC number. Lineage tracing shows that the majority of the mitotically regenerated HCs are derived specifically from the Lgr5+ progenitors with or without HC damage. Our findings suggest that the co-regulation of Wnt and Notch signaling might provide a better approach to mitotically regenerate HCs from Lgr5+ progenitor cells. PMID:27564256

  3. A deep learning based strategy for identifying and associating mitotic activity with gene expression derived risk categories in estrogen receptor positive breast cancers.

    Science.gov (United States)

    Romo-Bucheli, David; Janowczyk, Andrew; Gilmore, Hannah; Romero, Eduardo; Madabhushi, Anant

    2017-06-01

    The treatment and management of early stage estrogen receptor positive (ER+) breast cancer is hindered by the difficulty in identifying patients who require adjuvant chemotherapy in contrast to those that will respond to hormonal therapy. To distinguish between the more and less aggressive breast tumors, which is a fundamental criterion for the selection of an appropriate treatment plan, Oncotype DX (ODX) and other gene expression tests are typically employed. While informative, these gene expression tests are expensive, tissue destructive, and require specialized facilities. Bloom-Richardson (BR) grade, the common scheme employed in breast cancer grading, has been shown to be correlated with the Oncotype DX risk score. Unfortunately, studies have also shown that the BR grade determined experiences notable inter-observer variability. One of the constituent categories in BR grading is the mitotic index. The goal of this study was to develop a deep learning (DL) classifier to identify mitotic figures from whole slides images of ER+ breast cancer, the hypothesis being that the number of mitoses identified by the DL classifier would correlate with the corresponding Oncotype DX risk categories. The mitosis detector yielded an average F-score of 0.556 in the AMIDA mitosis dataset using a 6-fold validation setup. For a cohort of 174 whole slide images with early stage ER+ breast cancer for which the corresponding Oncotype DX score was available, the distributions of the number of mitoses identified by the DL classifier was found to be significantly different between the high vs low Oncotype DX risk groups (P machine classifier trained to separate low/high Oncotype DX risk categories using the mitotic count determined by the DL classifier yielded a 83.19% classification accuracy. © 2017 International Society for Advancement of Cytometry. © 2017 International Society for Advancement of Cytometry.

  4. Theoretical effect of concentration, circulation rate, stages, pressure and temperature of single amine and amine mixture solvents on gas sweetening performance

    Directory of Open Access Journals (Sweden)

    Nilay Kumar Sarker

    2016-09-01

    Full Text Available This simulation experiment performed by Aspen Hysys is about theoretical investigation of gas sweetening performance of single amine solvents MEA1, MDEA2, DEA3, DGA4, DIPA5 and mixed amine solvents DGA–MEA, DEA–MDEA and SULFOLANE6–MDEA. Sweet gas having very high percentage of methane is produced by MEA (95.36%, DGA–MEA (95.37%, DEA–MDEA (95.51% and SULFOLANE–MDEA (95.10% and DGA (93.76% shows lowest performance. DGA, SULFOLANE–MDEA, MDEA remove H2S at a lower circulation rate and DEA, DIPA need higher but satisfactory circulation rate. Increasing stage number shows positive effect on DEA, DIPA and SULFOLANE–MDEA. Pressure change has no significant effect. Temperature increase and methane percentage are negatively correlated for all solvents (except low circulating DIPA. With temperature increase H2S composition increases for DEA–MDEA, DGA–MEA; CO2 increases for DEA–MDEA, DGA–MEA and high circulating SULFOLANE–MDEA.

  5. Standard metabolic rates of early life stages of the diamondback terrapin (Malaclemys terrapin), an estuarine turtle, suggest correlates between life history changes and the metabolic economy of hatchlings.

    Science.gov (United States)

    Rowe, Christopher L

    2018-04-01

    I estimated standard metabolic rates (SMR) using measurements of oxygen consumption rates of embryos and unfed, resting hatchlings of the diamondback terrapin (Malaclemys terrapin) three times during embryonic development and twice during the early post-hatching period. The highest observed SMRs occurred during mid to late embryonic development and the early post-hatching period when hatchlings were still reliant on yolk reserves provided by the mother. Hatchlings that were reliant on yolk displayed per capita SMR 135 % higher than when measured 25 calendar days later after they became reliant on exogenous resources. The magnitude of the difference in hatchling SMR between yolk-reliant and exogenously feeding stages was much greater than that attributed to costs of digestion (specific dynamic action) observed in another emydid turtle, suggesting that processing of the yolk was not solely responsible for the observed difference. The pre-feeding period of yolk reliance of hatchlings corresponds with the period of dispersal from the nesting site, suggesting that elevated SMR during this period could facilitate dispersal activities. Thus, I hypothesize that the reduction in SMR after the development of feeding behaviors may reflect an energy optimization strategy in which a high metabolic expenditure in support of development and growth of the embryo and dispersal of the hatchling is followed by a substantial reduction in metabolic expenditure coincident with the individual becoming reliant on exogenous resources following yolk depletion. Copyright © 2018 Elsevier GmbH. All rights reserved.

  6. Stage, tumor growth rate and optimal dose fractionation schedules in the treatment of squamous cell carcinoma of the head and neck

    International Nuclear Information System (INIS)

    Sugawara, Tadashi; Morita, Mamoru; Aihara, Toshinori; Tanaka, Osamu

    1983-01-01

    In 77 patients with cancer of the head and neck, 45 patients received radiotherapy alone, while 32 patients with T 1 or T 2 glottic cancer received combined therapy with laryngomicrosurgery performed prior to or during the course of irradiation. These T 1 and T 2 groups were separately analyzed from other T 1 and T 2 groups as T sub(LMS). Local recurrence rates were compared concerning overall time and fraction size in following three subgroups, i.e., T sub(LMS), Tsub(1+2), and Tsub(3+4). No significant correlation was detected between total dose converted to partial tolerance (PT) and local control in all subgroups except for Tsub(3+4), in which local recurrence rate was rather higher in high PT range. Local control was significantly dependent on overall treatment time and fraction size, differently by tumor stage. Favorable fractionation schedules considered as optimal for T sub(LMS) were those in which treatment was given 5 times weekly with a daily dose rate more than 196 rad in a shorter overall time of less than 42 days. In contrast to T sub(LMS), effective schedules for Tsub(3+4) consisted of longer overall time of more than 60 days and a lower daily dose rate of less than 153 rad. In Tsub(1+2), the optimal schedule was needed to be altered according to rapidness of progression of disease characterised by duration of the complaints, which was statistically proved to be significantly shorter in Tsub(1+2) than Tsub(3+4). Rapidity-adjusted schedule consisted of a shorter over-all time of less than 49 days with a daily dose rate of more than 175 rad 5 fractions a week for a case having a duration of complaints of less than 2.9 months, and a longer overall time of more than 50 days with a daily dose rate of less than 174 rad for a case having a duration of more than 3 months. (J.P.N.)

  7. A Prospective Longitudinal Clinical Trial Evaluating Quality of Life After Breast-Conserving Surgery and High-Dose-Rate Interstitial Brachytherapy for Early-Stage Breast Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Garsa, Adam A.; Ferraro, Daniel J.; DeWees, Todd A. [Department of Radiation Oncology, Siteman Cancer Center, Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, Missouri (United States); Deshields, Teresa L. [Department of Medicine, Siteman Cancer Center, Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, Missouri (United States); Margenthaler, Julie A.; Cyr, Amy E. [Department of Surgery, Siteman Cancer Center, Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, Missouri (United States); Naughton, Michael [Department of Medicine, Siteman Cancer Center, Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, Missouri (United States); Aft, Rebecca [Department of Surgery, Siteman Cancer Center, Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, Missouri (United States); Department of Surgery, John Cochran Veterans Hospital, St. Louis, Missouri (United States); Gillanders, William E.; Eberlein, Timothy [Department of Surgery, Siteman Cancer Center, Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, Missouri (United States); Matesa, Melissa A.; Ochoa, Laura L. [Department of Radiation Oncology, Siteman Cancer Center, Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, Missouri (United States); Zoberi, Imran, E-mail: izoberi@radonc.wustl.edu [Department of Radiation Oncology, Siteman Cancer Center, Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, Missouri (United States)

    2013-12-01

    Purpose: To prospectively examine quality of life (QOL) of patients with early stage breast cancer treated with accelerated partial breast irradiation (APBI) using high-dose-rate (HDR) interstitial brachytherapy. Methods and Materials: Between March 2004 and December 2008, 151 patients with early stage breast cancer were enrolled in a phase 2 prospective clinical trial. Eligible patients included those with Tis-T2 tumors measuring ≤3 cm excised with negative surgical margins and with no nodal involvement. Patients received 3.4 Gy twice daily to a total dose of 34 Gy. QOL was measured using European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, version 3.0, and QLQ-BR23 questionnaires. The QLQ-C30 and QLQ-BR23 questionnaires were evaluated during pretreatment and then at 6 to 8 weeks, 3 to 4 months, 6 to 8 months, and 1 and 2 years after treatment. Results: The median follow-up was 55 months. Breast symptom scores remained stable in the months after treatment, and they significantly improved 6 to 8 months after treatment. Scores for emotional functioning, social functioning, and future perspective showed significant improvement 2 years after treatment. Symptomatic fat necrosis was associated with several changes in QOL, including increased pain, breast symptoms, systemic treatment side effects, dyspnea, and fatigue, as well as decreased role functioning, emotional functioning, and social functioning. Conclusions: HDR multicatheter interstitial brachytherapy was well tolerated, with no significant detrimental effect on measured QOL scales/items through 2 years of follow-up. Compared to pretreatment scores, there was improvement in breast symptoms, emotional functioning, social functioning, and future perspective 2 years after treatment.

  8. A Prospective Longitudinal Clinical Trial Evaluating Quality of Life After Breast-Conserving Surgery and High-Dose-Rate Interstitial Brachytherapy for Early-Stage Breast Cancer

    International Nuclear Information System (INIS)

    Garsa, Adam A.; Ferraro, Daniel J.; DeWees, Todd A.; Deshields, Teresa L.; Margenthaler, Julie A.; Cyr, Amy E.; Naughton, Michael; Aft, Rebecca; Gillanders, William E.; Eberlein, Timothy; Matesa, Melissa A.; Ochoa, Laura L.; Zoberi, Imran

    2013-01-01

    Purpose: To prospectively examine quality of life (QOL) of patients with early stage breast cancer treated with accelerated partial breast irradiation (APBI) using high-dose-rate (HDR) interstitial brachytherapy. Methods and Materials: Between March 2004 and December 2008, 151 patients with early stage breast cancer were enrolled in a phase 2 prospective clinical trial. Eligible patients included those with Tis-T2 tumors measuring ≤3 cm excised with negative surgical margins and with no nodal involvement. Patients received 3.4 Gy twice daily to a total dose of 34 Gy. QOL was measured using European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, version 3.0, and QLQ-BR23 questionnaires. The QLQ-C30 and QLQ-BR23 questionnaires were evaluated during pretreatment and then at 6 to 8 weeks, 3 to 4 months, 6 to 8 months, and 1 and 2 years after treatment. Results: The median follow-up was 55 months. Breast symptom scores remained stable in the months after treatment, and they significantly improved 6 to 8 months after treatment. Scores for emotional functioning, social functioning, and future perspective showed significant improvement 2 years after treatment. Symptomatic fat necrosis was associated with several changes in QOL, including increased pain, breast symptoms, systemic treatment side effects, dyspnea, and fatigue, as well as decreased role functioning, emotional functioning, and social functioning. Conclusions: HDR multicatheter interstitial brachytherapy was well tolerated, with no significant detrimental effect on measured QOL scales/items through 2 years of follow-up. Compared to pretreatment scores, there was improvement in breast symptoms, emotional functioning, social functioning, and future perspective 2 years after treatment

  9. Enzymatic creatinine assays allow estimation of glomerular filtration rate in stages 1 and 2 chronic kidney disease using CKD-EPI equation.

    Science.gov (United States)

    Kuster, Nils; Cristol, Jean-Paul; Cavalier, Etienne; Bargnoux, Anne-Sophie; Halimi, Jean-Michel; Froissart, Marc; Piéroni, Laurence; Delanaye, Pierre

    2014-01-20

    The National Kidney Disease Education Program group demonstrated that MDRD equation is sensitive to creatinine measurement error, particularly at higher glomerular filtration rates. Thus, MDRD-based eGFR above 60 mL/min/1.73 m² should not be reported numerically. However, little is known about the impact of analytical error on CKD-EPI-based estimates. This study aimed at assessing the impact of analytical characteristics (bias and imprecision) of 12 enzymatic and 4 compensated Jaffe previously characterized creatinine assays on MDRD and CKD-EPI eGFR. In a simulation study, the impact of analytical error was assessed on a hospital population of 24084 patients. Ability using each assay to correctly classify patients according to chronic kidney disease (CKD) stages was evaluated. For eGFR between 60 and 90 mL/min/1.73 m², both equations were sensitive to analytical error. Compensated Jaffe assays displayed high bias in this range and led to poorer sensitivity/specificity for classification according to CKD stages than enzymatic assays. As compared to MDRD equation, CKD-EPI equation decreases impact of analytical error in creatinine measurement above 90 mL/min/1.73 m². Compensated Jaffe creatinine assays lead to important errors in eGFR and should be avoided. Accurate enzymatic assays allow estimation of eGFR until 90 mL/min/1.73 m² with MDRD and 120 mL/min/1.73 m² with CKD-EPI equation. Copyright © 2013 Elsevier B.V. All rights reserved.

  10. Pilot Randomized Study of a Gratitude Journaling Intervention on Heart Rate Variability and Inflammatory Biomarkers in Patients With Stage B Heart Failure.

    Science.gov (United States)

    Redwine, Laura S; Henry, Brook L; Pung, Meredith A; Wilson, Kathleen; Chinh, Kelly; Knight, Brian; Jain, Shamini; Rutledge, Thomas; Greenberg, Barry; Maisel, Alan; Mills, Paul J

    2016-01-01

    Stage B, asymptomatic heart failure (HF) presents a therapeutic window for attenuating disease progression and development of HF symptoms, and improving quality of life. Gratitude, the practice of appreciating positive life features, is highly related to quality of life, leading to development of promising clinical interventions. However, few gratitude studies have investigated objective measures of physical health; most relied on self-report measures. We conducted a pilot study in Stage B HF patients to examine whether gratitude journaling improved biomarkers related to HF prognosis. Patients (n = 70; mean [standard deviation] age = 66.2 [7.6] years) were randomized to an 8-week gratitude journaling intervention or treatment as usual. Baseline (T1) assessments included the six-item Gratitude Questionnaire, resting heart rate variability (HRV), and an inflammatory biomarker index. At T2 (midintervention), the six-item Gratitude Questionnaire was measured. At T3 (postintervention), T1 measures were repeated but also included a gratitude journaling task. The gratitude intervention was associated with improved trait gratitude scores (F = 6.0, p = .017, η = 0.10), reduced inflammatory biomarker index score over time (F = 9.7, p = .004, η = 0.21), and increased parasympathetic HRV responses during the gratitude journaling task (F = 4.2, p = .036, η = 0.15), compared with treatment as usual. However, there were no resting preintervention to postintervention group differences in HRV (p values > .10). Gratitude journaling may improve biomarkers related to HF morbidity, such as reduced inflammation; large-scale studies with active control conditions are needed to confirm these findings. Clinicaltrials.govidentifier:NCT01615094.

  11. Mitotic recombination induced by chemical and physical agents in the yeast Saccharomyces cerevisiae

    International Nuclear Information System (INIS)

    Davies, P.J.; Evans, W.E.; Parry, J.M.

    1975-01-01

    The treatment of diploid cultures of yeast with ultraviolet light (uv), γ-rays, nitrous acid (na) and ethyl methane sulphonate (ems) results in increases in cell death, mitotic gene conversion and crossing-over. Acridine orange (ao) treatment, in contrast, was effective only in increasing the frequency of gene conversion. The individual mutagens were effective in the order uv>na>γ-rays>ao>ems. Prior treatment of yeast cultures in starvation medium produced a significant reduction in the yield of induced gene conversion. The results have been interpreted on the basis of a general model of mitotic gene conversion which involves the post-replication repair of induced lesions involving de novo DNA synthesis without genetic exchange. In contrast mitotic crossing-over appears to involve the action of a repair system independent from excision or post-replication repair which involves genetic exchange between homologous chromosomes

  12. A nontranscriptional role for Oct4 in the regulation of mitotic entry

    Science.gov (United States)

    Zhao, Rui; Deibler, Richard W.; Lerou, Paul H.; Ballabeni, Andrea; Heffner, Garrett C.; Cahan, Patrick; Unternaehrer, Juli J.; Kirschner, Marc W.; Daley, George Q.

    2014-01-01

    Rapid progression through the cell cycle and a very short G1 phase are defining characteristics of embryonic stem cells. This distinct cell cycle is driven by a positive feedback loop involving Rb inactivation and reduced oscillations of cyclins and cyclin-dependent kinase (Cdk) activity. In this setting, we inquired how ES cells avoid the potentially deleterious consequences of premature mitotic entry. We found that the pluripotency transcription factor Oct4 (octamer-binding transcription factor 4) plays an unappreciated role in the ES cell cycle by forming a complex with cyclin–Cdk1 and inhibiting Cdk1 activation. Ectopic expression of Oct4 or a mutant lacking transcriptional activity recapitulated delayed mitotic entry in HeLa cells. Reduction of Oct4 levels in ES cells accelerated G2 progression, which led to increased chromosomal missegregation and apoptosis. Our data demonstrate an unexpected nontranscriptional function of Oct4 in the regulation of mitotic entry. PMID:25324523

  13. The Effect Of PHA And SEA On Mitotic Index Of Lymphocyte Cell Of Macaca Fasciulare

    International Nuclear Information System (INIS)

    Lubis, Masnelli; Iwiq-Indrawati

    2003-01-01

    The observation of influences of PHA (phytohemagglutinin) and SEA (staphilucoccal enterotoxin A) on mitotic index of lymphocyte of Macaca Fascicularis had been done. Half milliliters of lymphocyte cells stimulated with PHA or SEA were cultured in 10 ml RPMI + 1.0 ml Fetal Bouvine Serum (FBS ) + 0.1 ml L-glutamine + 0.15 ml PHA or 0.1 ml SEA ( 0.5 μg/ml ) + 0.1 ml Colchisin on 37 degree C for 96 hours. The result demonstrated that the frequency of mitotic index stimulated with PHA was higher than that of SEA. The average of mitotic index with PHA was 18.56 %, and with SEA was 8.3 %. (author)

  14. Mitotic Transcriptional Activation: Clearance of Actively Engaged Pol II via Transcriptional Elongation Control in Mitosis.

    Science.gov (United States)

    Liang, Kaiwei; Woodfin, Ashley R; Slaughter, Brian D; Unruh, Jay R; Box, Andrew C; Rickels, Ryan A; Gao, Xin; Haug, Jeffrey S; Jaspersen, Sue L; Shilatifard, Ali

    2015-11-05

    Although it is established that some general transcription factors are inactivated at mitosis, many details of mitotic transcription inhibition (MTI) and its underlying mechanisms are largely unknown. We have identified mitotic transcriptional activation (MTA) as a key regulatory step to control transcription in mitosis for genes with transcriptionally engaged RNA polymerase II (Pol II) to activate and transcribe until the end of the gene to clear Pol II from mitotic chromatin, followed by global impairment of transcription reinitiation through MTI. Global nascent RNA sequencing and RNA fluorescence in situ hybridization demonstrate the existence of transcriptionally engaged Pol II in early mitosis. Both genetic and chemical inhibition of P-TEFb in mitosis lead to delays in the progression of cell division. Together, our study reveals a mechanism for MTA and MTI whereby transcriptionally engaged Pol II can progress into productive elongation and finish transcription to allow proper cellular division. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. Semaphorin-Plexin Signaling Controls Mitotic Spindle Orientation during Epithelial Morphogenesis and Repair

    DEFF Research Database (Denmark)

    Xia, Jingjing; Swiercz, Jakub M.; Bañón-Rodríguez, Inmaculada

    2015-01-01

    Morphogenesis, homeostasis, and regeneration of epithelial tissues rely on the accurate orientation of cell divisions, which is specified by the mitotic spindle axis. To remain in the epithelial plane, symmetrically dividing epithelial cells align their mitotic spindle axis with the plane. Here, we...... show that this alignment depends on epithelial cell-cell communication via semaphorin-plexin signaling. During kidney morphogenesis and repair, renal tubular epithelial cells lacking the transmembrane receptor Plexin-B2 or its semaphorin ligands fail to correctly orient the mitotic spindle, leading...... to severe defects in epithelial architecture and function. Analyses of a series of transgenic and knockout mice indicate that Plexin-B2 controls the cell division axis by signaling through its GTPase-activating protein (GAP) domain and Cdc42. Our data uncover semaphorin-plexin signaling as a central...

  16. Comparison of one and two low dose rate brachytherapy insertions in the treatment of stage IIB cervix cancer with radiation therapy alone

    International Nuclear Information System (INIS)

    Ferrigno, Robson; Faria, S.L.C.O.

    1996-01-01

    Purpose/Objective: To compare one and two intracavitary brachytherapy with low dose rate in the management of stage IIB cervix cancer through a prospective and randomized trial. Materials and Methods: From September 1989 to December 1992, 81 patients with stage IIB cervix cancer were randomized in two arms according to the number of intracavitary brachytherapy insertion to be realized. Of these, 34 were treated by two intracavitary insertions (group A) and 47 by one insertion (group B). The external beam radiotherapy (EBRT) was realized through a Cobalt unit at whole pelvis with total dose of 40Gy in 20 fractions of 2,0Gy, in box arrangement, followed by parametrial complementation of 10Gy. The brachytherapy was realized right after the end of EBRT. The patients from group A were underwent to two insertions of 25Gy, calculated at point A, defined by the Manchester system. The interval between each insertions was 2 weeks. The patients from group B were underwent to one insertion of 40 Gy at point A. The average dose rate was 60cGy per hour at point A. Results: With the follow up ranging from 36 to 75 months and medium of 55 months, the disease free survival of the patients from group A was not statistically different of those from group B, 70,6% and 72,3% respectively (p=0,711). Local recurrence occurred in four patients from group A (11,7%) and in eight from group B (17%). Distant metastasis occurred in one patient from group A (2,9%) and in two from group B (4,2%). Three patients from group A (8,8%) and three from group B (6,4%) were lost to follow up and considered as dead. The causes of death among patients from group A were progression of local disease in four, distant metastasis in one, complicated diabetes mellitus in one and actinic intestinal complications in other one. The cause of deaths among patients from group B were progression of local disease in eight and distant metastasis in two. The grade I and II rectal complications rate was 5,9% and 6,3% at

  17. Preoperative radiotherapy with high dose rate brachytherapy in the treatment of stage IIB cervix cancer. A retrospective analysis of histological specimens

    International Nuclear Information System (INIS)

    Ferrigno, Robson; Trippe, N; Novaes, P.E.; Brandani, I.B.; Hanriot, R.; Souza, L.M.; Pellizzon, A.C.; Salvajoli, J.V.; Baraldi, H.E.; Maia, M.A.; Fogaroli, R.C.

    1996-01-01

    Purpose/Objective: To evaluate the histological specimens of the stage IIB cervix cancer patients who were treated by preoperative radiotherapy with external beam radiotherapy (EBRT) and high dose rate (HDR) brachytherapy. Materials and Methods: From August 1992 to August 1995, 32 patients with stage IIB cervix cancer were underwent to preoperative radiotherapy. All patients received EBRT at the whole pelvis with total dose of 45Gy in 25 fractions of 1,8Gy through a 4 MV linear accelerator. The HDR brachytherapy was realized through a Micro-Selectron device, working with Iridium-192 with initial activity of 10 Ci. The prescribed dose was 6,0Gy at point A, defined by the Manchester, system in 2 weekly insertions during the course of EBRT. The insertions were done by the Fletcher colpostats in association with intrauterine tandem. Four to six weeks after the end of radiotherapy, the patients were underwent to Total Hysterectomy and Salpingoforectomy through Piver second level technique. The uterine specimens were histologically analysed with attention to residual disease at the cervix and lymph nodes status. Results: The histological analysis showed that 19 (59,4%) patients had no residual tumor at the cervix while 13 (40,6%) had microscopic residual tumor. The lymph nodes were negative in 30 (93,8%) patients and positive in 2 (6,3%). All positive lymph nodes patients also had microscopic residual tumor at the cervix. With the follow up ranging from six to 42 months and medium of 21 months, 29 (90,6%) patients are alive with no evidence of disease, one (5,6%) is alive with local recurrence and two (6,2%) have died due to the progression of local disease. Of the 19 patients with negative specimens, 18 (94,7%) are alive with no evidence of disease and of the 13 patients with positive specimens, 11 (84,6%) are alive with no evidence of disease. Local recurrence occurred in two patients with positive specimens and in one with negative. These differences are not

  18. Cell fate after mitotic arrest in different tumor cells is determined by the balance between slippage and apoptotic threshold

    Energy Technology Data Exchange (ETDEWEB)

    Galán-Malo, Patricia; Vela, Laura; Gonzalo, Oscar; Calvo-Sanjuán, Rubén; Gracia-Fleta, Lucía; Naval, Javier; Marzo, Isabel, E-mail: imarzo@unizar.es

    2012-02-01

    Microtubule poisons and other anti-mitotic drugs induce tumor death but the molecular events linking mitotic arrest to cell death are still not fully understood. We have analyzed cell fate after mitotic arrest produced by the microtubule-destabilizing drug vincristine in a panel of human tumor cell lines showing different response to vincristine. In Jurkat, RPMI 8226 and HeLa cells, apoptosis was triggered shortly after vincristine-induced mitotic arrest. However, A549 cells, which express a great amount of Bcl-x{sub L} and undetectable amounts of Bak, underwent mitotic slippage prior to cell death. However, when Bcl-x{sub L} gene was silenced in A549 cells, vincristine induced apoptosis during mitotic arrest. Another different behavior was found in MiaPaca2 cells, where vincristine caused death by mitotic catastrophe that switched to apoptosis when cyclin B1 degradation was prevented by proteasome inhibition. Overexpression of Bcl-x{sub L} or silencing Bax and Bak expression delayed the onset of apoptosis in Jurkat and RPMI 8226 cells, enabling mitotic slippage and endoreduplication. In HeLa cells, overexpression of Bcl-x{sub L} switched cell death from apoptosis to mitotic catastrophe. Mcl-1 offered limited protection to vincristine-induced cell death and Mcl-1 degradation was not essential for vincristine-induced death. All these results, taken together, indicate that the Bcl-x{sub L}/Bak ratio and the ability to degrade cyclin B1 determine cell fate after mitotic arrest in the different tumor cell types. Highlights: ► Vincristine induces cell death by apoptosis or mitotic catastrophe. ► Apoptosis-proficient cells die by apoptosis during mitosis upon vincristine treatment. ► p53wt apoptosis-deficient cells undergo apoptosis from a G1-like tetraploid state. ► p53mt apoptosis-deficient cells can survive and divide giving rise to 8N cells.

  19. CT-image based conformal high-dose rate brachytherapy boost in the conservative treatment of stage I - II breast cancer - introducing the procedure

    International Nuclear Information System (INIS)

    Kubaszewska, M.; Skowronek, J.; Chichel, A.; Kanikowski, M.; Dymnicka, M.

    2008-01-01

    Aim: Breast-conserving surgery (BCS) followed by radiotherapy (RT) has become the standard treatment for the majority of patients with early breast cancer. With regard to boost technique some disagreements are found between groups that are emphasizing the value of electron boost treatment and groups pointing out the value of interstitial brachytherapy (BT) boost treatment. We present the preliminary results in treating selected patients with early-stage breast cancer using high-dose-rate brachytherapy (HD R-BT) as a boost after breast conservation therapy (BCT). Materials/Methods: Between January 2006 and August 2007, a total of 58 female patients with first and second stage breast cancer underwent BCT. This therapeutic procedure involves BCS, whole breast radiation therapy (WBRT) and additional irradiation to the tumour bed (boost) using interstitial HDR-BT via flexible implant tubes. A 10 Gy boost dose was received by all patients. The treatment planning was based on CT-guided 3D (three-dimensional) reconstruction of the surgical clips, implant tubes and critical structures localization (skin and ribs). The accuracy of tumour bed localization, the conformity of planning target volume and treated volume were analyzed. Results: The evaluations of implant parameters involved the use of: dose volume histogram (DVH), the volume encompassed by the 100% reference isodose surface (V100%), the high dose volumecalculation (V150%, V200%, V300%), the dose non-uniformity ratio (DNR), and the conformity index (COIN). Our results were as follows: the mean PTV volume, the mean high dose volume (V150%; V200%; V300%), the DNR and COIN mean value were estimated at 57.38, 42.98, 21.38, 7.90, 0.52 and 0.83 respectively. Conclusions: CT-guided 3D HDR-BT is most appropriate for planning the boost procedure after BT especially in large breast volume, in cases with a deep seated tumour bed, as well as in patients with high risk for local recurrences. This technique reduces the

  20. Importance of glomerular filtration rate change as surrogate endpoint for the future incidence of end-stage renal disease in general Japanese population: community-based cohort study.

    Science.gov (United States)

    Kanda, Eiichiro; Usui, Tomoko; Kashihara, Naoki; Iseki, Chiho; Iseki, Kunitoshi; Nangaku, Masaomi

    2018-04-01

    Because of the necessity for extended period and large costs until the event occurs, surrogate endpoints are indispensable for implementation of clinical studies to improve chronic kidney disease (CKD) patients' prognosis. Subjects with serum creatinine level for a baseline period over 1-3 years were enrolled (n = 69,238) in this community-based prospective cohort study in Okinawa, Japan, and followed up for 15 years. The endpoint was end-stage renal disease (ESRD). The percent of estimated glomerular filtration rate (%eGFR) change was calculated on the basis of the baseline period. Subjects had a mean ± SD age, 55.59 ± 14.69 years; eGFR, 80.15 ± 21.15 ml/min/1.73 m 2 . Among the subjects recruited, 15.81% had a low eGFR (<60 ml/min/1.73 m 2 ) and 36.1/100,000 person years developed ESRD. Cox proportional hazards models adjusted for baseline characteristics showed that the risk of ESRD tended to be high with high rates of decrease in %eGFR changes over 2 or 3 years in the high- and low-eGFR groups. The specificities and positive predictive values for ESRD based on a cutoff value of %eGFR change of less than -30% over 2 or 3 years were high in the high- and low-eGFR groups. %eGFR change tends to be associated with the risk of ESRD. %eGFR change of less than -30% over 2 or 3 years can be a candidate surrogate endpoint for ESRD in the general Japanese population.

  1. The Drosophila Microtubule-Associated Protein Mars Stabilizes Mitotic Spindles by Crosslinking Microtubules through Its N-Terminal Region

    DEFF Research Database (Denmark)

    Zhang, Gang; Beati, Hamze; Nilsson, Jakob

    2013-01-01

    Correct segregation of genetic material relies on proper assembly and maintenance of the mitotic spindle. How the highly dynamic microtubules (MTs) are maintained in stable mitotic spindles is a key question to be answered. Motor and non-motor microtubule associated proteins (MAPs) have been...

  2. Spatial Reorganization of the Endoplasmic Reticulum during Mitosis Relies on Mitotic Kinase Cyclin A in the Early Drosophila Embryo

    Science.gov (United States)

    Bergman, Zane J.; Mclaurin, Justin D.; Eritano, Anthony S.; Johnson, Brittany M.; Sims, Amanda Q.; Riggs, Blake

    2015-01-01

    Mitotic cyclin-dependent kinase with their cyclin partners (cyclin:Cdks) are the master regulators of cell cycle progression responsible for regulating a host of activities during mitosis. Nuclear mitotic events, including chromosome condensation and segregation have been directly linked to Cdk activity. However, the regulation and timing of cytoplasmic mitotic events by cyclin:Cdks is poorly understood. In order to examine these mitotic cytoplasmic events, we looked at the dramatic changes in the endoplasmic reticulum (ER) during mitosis in the early Drosophila embryo. The dynamic changes of the ER can be arrested in an interphase state by inhibition of either DNA or protein synthesis. Here we show that this block can be alleviated by micro-injection of Cyclin A (CycA) in which defined mitotic ER clusters gathered at the spindle poles. Conversely, micro-injection of Cyclin B (CycB) did not affect spatial reorganization of the ER, suggesting CycA possesses the ability to initiate mitotic ER events in the cytoplasm. Additionally, RNAi-mediated simultaneous inhibition of all 3 mitotic cyclins (A, B and B3) blocked spatial reorganization of the ER. Our results suggest that mitotic ER reorganization events rely on CycA and that control and timing of nuclear and cytoplasmic events during mitosis may be defined by release of CycA from the nucleus as a consequence of breakdown of the nuclear envelope. PMID:25689737

  3. The reduction of radiation-induced mitotic delay by caffeine: a test of the cyclic AMP hypothesis

    International Nuclear Information System (INIS)

    Oleinick, N.L.; Brewer, E.N.; Rustad, R.C.

    1978-01-01

    A study has been made of the reduction in γ-radiation-induced mitotic delay by caffeine in the naturally-synchronous plasmodial slime mould. Physarum polycephalum during late G 2 and early prophase, and the results compared with those obtained with other compounds of similar structure and/or physiological function. The reduction of radiation-induced mitotic delay was related to increasing concentrations of caffeine over at least two orders of magnitude. Pre-irradiation treatment with caffeine had no detectable effect. Caffeine had to be present for most, if not all, of the post-irradiation pre-mitotic period. Other chemicals which are reported to inhibit cyclic AMP phosphodiesterase either reduce or increase radiation-induced mitotic delay. The results therefore indicate that the reduction of mitotic delay by caffeine is not a result of altered cyclic AMP levels. (UK)

  4. Loading of PAX3 to Mitotic Chromosomes Is Mediated by Arginine Methylation and Associated with Waardenburg Syndrome*

    Science.gov (United States)

    Wu, Tsu-Fang; Yao, Ya-Li; Lai, I-Lu; Lai, Chien-Chen; Lin, Pei-Lun; Yang, Wen-Ming

    2015-01-01

    PAX3 is a transcription factor critical to gene regulation in mammalian development. Mutations in PAX3 are associated with Waardenburg syndrome (WS), but the mechanism of how mutant PAX3 proteins cause WS remains unclear. Here, we found that PAX3 loads on mitotic chromosomes using its homeodomain. PAX3 WS mutants with mutations in homeodomain lose the ability to bind mitotic chromosomes. Moreover, loading of PAX3 on mitotic chromosomes requires arginine methylation, which is regulated by methyltransferase PRMT5 and demethylase JMJD6. Mutant PAX3 proteins that lose mitotic chromosome localization block cell proliferation and normal development of zebrafish. These results reveal the molecular mechanism of PAX3s loading on mitotic chromosomes and the importance of this localization pattern in normal development. Our findings suggest that PAX3 WS mutants interfere with the normal functions of PAX3 in a dominant negative manner, which is important to the understanding of the pathogenesis of Waardenburg syndrome. PMID:26149688

  5. The Drosophila Microtubule-Associated Protein Mars Stabilizes Mitotic Spindles by Crosslinking Microtubules through Its N-Terminal Region

    Science.gov (United States)

    Zhang, Gang; Beati, Hamze; Nilsson, Jakob; Wodarz, Andreas

    2013-01-01

    Correct segregation of genetic material relies on proper assembly and maintenance of the mitotic spindle. How the highly dynamic microtubules (MTs) are maintained in stable mitotic spindles is a key question to be answered. Motor and non-motor microtubule associated proteins (MAPs) have been reported to stabilize the dynamic spindle through crosslinking adjacent MTs. Mars, a novel MAP, is essential for the early development of Drosophila embryos. Previous studies showed that Mars is required for maintaining an intact mitotic spindle but did not provide a molecular mechanism for this function. Here we show that Mars is able to stabilize the mitotic spindle in vivo. Both in vivo and in vitro data reveal that the N-terminal region of Mars functions in the stabilization of the mitotic spindle by crosslinking adjacent MTs. PMID:23593258

  6. The Drosophila microtubule-associated protein mars stabilizes mitotic spindles by crosslinking microtubules through its N-terminal region.

    Directory of Open Access Journals (Sweden)

    Gang Zhang

    Full Text Available Correct segregation of genetic material relies on proper assembly and maintenance of the mitotic spindle. How the highly dynamic microtubules (MTs are maintained in stable mitotic spindles is a key question to be answered. Motor and non-motor microtubule associated proteins (MAPs have been reported to stabilize the dynamic spindle through crosslinking adjacent MTs. Mars, a novel MAP, is essential for the early development of Drosophila embryos. Previous studies showed that Mars is required for maintaining an intact mitotic spindle but did not provide a molecular mechanism for this function. Here we show that Mars is able to stabilize the mitotic spindle in vivo. Both in vivo and in vitro data reveal that the N-terminal region of Mars functions in the stabilization of the mitotic spindle by crosslinking adjacent MTs.

  7. The Drosophila microtubule-associated protein mars stabilizes mitotic spindles by crosslinking microtubules through its N-terminal region.

    Science.gov (United States)

    Zhang, Gang; Beati, Hamze; Nilsson, Jakob; Wodarz, Andreas

    2013-01-01

    Correct segregation of genetic material relies on proper assembly and maintenance of the mitotic spindle. How the highly dynamic microtubules (MTs) are maintained in stable mitotic spindles is a key question to be answered. Motor and non-motor microtubule associated proteins (MAPs) have been reported to stabilize the dynamic spindle through crosslinking adjacent MTs. Mars, a novel MAP, is essential for the early development of Drosophila embryos. Previous studies showed that Mars is required for maintaining an intact mitotic spindle but did not provide a molecular mechanism for this function. Here we show that Mars is able to stabilize the mitotic spindle in vivo. Both in vivo and in vitro data reveal that the N-terminal region of Mars functions in the stabilization of the mitotic spindle by crosslinking adjacent MTs.

  8. Induction of mitotic recombination by UV and diepoxybutane and its enhancement by hydroxyurea in Saccharomyces cerevisae

    Energy Technology Data Exchange (ETDEWEB)

    Zaborowska, D.; Swietlinska, Z.; Zuk, J. (Polska Akademia Nauk, Warsaw. Inst. Biochemii i Biofizyki)

    1983-04-01

    Mitotic inter- and intra-genic recombination was induced by UV-irradiation and treatment with diepoxybutane (DEB) in 2 heteroallelic diploid strains of Saccharomyces cerevisiae SBTD and D7. Induction of the events tested was strongly potentiated by plating of mutagen-treated cells on growth media containing 0.03 M hydroxyurea (HU).

  9. INFLUENCE OF SUMIDAN ON MITOTIC DIVISION IN TRIGONELLA FOENUM GRAECUM L. SPECIES

    Directory of Open Access Journals (Sweden)

    Florina Mihaela Axente

    2006-08-01

    Full Text Available : This paper includes the cytogenetic effects induced by sumidan insectofungicide in meristematic cells of Trigonella foenum graecum L. root tips. The increase of pesticide concentration determined the decrease of mitotic index, while the frequency and the type of chromosome aberrations are much greater in treated variants, comparatively with control.

  10. Frequencies of mutagen-induced coincident mitotic recombination at unlinked loci in Saccharomyces cerevisiae

    Energy Technology Data Exchange (ETDEWEB)

    Freeman, Kathryn M. [Department of Biology, College of the Holy Cross, One College Street, Worcester, MA 01610-2395 (United States); Hoffmann, George R. [Department of Biology, College of the Holy Cross, One College Street, Worcester, MA 01610-2395 (United States)]. E-mail: ghoffmann@holycross.edu

    2007-03-01

    Frequencies of coincident genetic events were measured in strain D7 of Saccharomyces cerevisiae. This diploid strain permits the detection of mitotic gene conversion involving the trp5-12 and trp5-27 alleles, mitotic crossing-over and gene conversion leading to the expression of the ade2-40 and ade2-119 alleles as red and pink colonies, and reversion of the ilv1-92 allele. The three genes are on different chromosomes, and one might expect that coincident (simultaneous) genetic alterations at two loci would occur at frequencies predicted by those of the single alterations acting as independent events. Contrary to this expectation, we observed that ade2 recombinants induced by bleomycin, {beta}-propiolactone, and ultraviolet radiation occur more frequently among trp5 convertants than among total colonies. This excess among trp5 recombinants indicates that double recombinants are more common than expected for independent events. No similar enrichment was found among Ilv{sup +} revertants. The possibility of an artifact in which haploid yeasts that mimic mitotic recombinants are generated by a low frequency of cryptic meiosis has been excluded. Several hypotheses that can explain the elevated incidence of coincident mitotic recombination have been evaluated, but the cause remains uncertain. Most evidence suggests that the excess is ascribable to a subset of the population being in a recombination-prone state.

  11. Influence of the circadian rhythm in cell division on radiation-induced mitotic delay in vivo

    International Nuclear Information System (INIS)

    Rubin, N.A.

    1980-01-01

    All mitotically active normal tissues in mammals investigated to date demonstrate a circadian rhythm in cell division. The murine corneal epithelium is a practical and advantageous tissue model for studying this phenomenon. In animals synchronized to a light-dark (LD) schedule, one sees predictably reproducible occurrences of peaks and troughs in the mitotic index (MI) within each 24-hour (h) period. One of the harmful effects of ionizing radiation on dividing cells is mitotic delay, reported to be a G 2 block in cells approaching mitosis. Affected cells are not killed but are inhibited from entering mitosis and are delayed for a span of time reported to be dose and cell cycle dependent. In the classical description of mitotic delay, MI of irradiated cells begins to drop in relation to the control, which is plotted as a straight line, uniform throughout the experiment. After the damage is repaired, delayed cells can enter mitosis along with other cells in the pool unaffected by the radiation, resulting in a MI higher than control levels. The span of delay and the occurrence of recovery are assumed to be constant for a given dose and tissue under similar experimental conditions. First described in asynchronously-dividing tissue culture cells, this concept is also extrapolated to the in vivo situation

  12. Prediction of X-ray induced mitotic delay and recovery of G2 cells

    International Nuclear Information System (INIS)

    Easton, D.M.; Schneiderman, M.H.

    1987-01-01

    A mathematical model is presented that predicts the delay of mitosis caused by X-irradiation of an asynchronous, exponentially growing cell culture. In the model, based on Gompertz kinetics, the driving function to generate the curves is a simple exponential decay expression. For the delayed mitotic progress curves, this function characterizes the distribution of the time required for cells to enter mitosis. (author)

  13. Involvement of CNOT3 in mitotic progression through inhibition of MAD1 expression

    Energy Technology Data Exchange (ETDEWEB)

    Takahashi, Akinori [Division of Oncology, Department of Cancer Biology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639 (Japan); Kikuguchi, Chisato [Cell Signal Unit, Okinawa Institute of Science and Technology, Kunigami, Okinawa 904-0412 (Japan); Morita, Masahiro; Shimodaira, Tetsuhiro; Tokai-Nishizumi, Noriko; Yokoyama, Kazumasa; Ohsugi, Miho; Suzuki, Toru [Division of Oncology, Department of Cancer Biology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639 (Japan); Yamamoto, Tadashi, E-mail: tyamamot@ims.u-tokyo.ac.jp [Division of Oncology, Department of Cancer Biology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639 (Japan); Cell Signal Unit, Okinawa Institute of Science and Technology, Kunigami, Okinawa 904-0412 (Japan)

    2012-03-09

    Highlights: Black-Right-Pointing-Pointer CNOT3 depletion increases the mitotic index. Black-Right-Pointing-Pointer CNOT3 inhibits the expression of MAD1. Black-Right-Pointing-Pointer CNOT3 destabilizes the MAD1 mRNA. Black-Right-Pointing-Pointer MAD1 knockdown attenuates the CNOT3 depletion-induced mitotic arrest. -- Abstract: The stability of mRNA influences the dynamics of gene expression. The CCR4-NOT complex, the major deadenylase in mammalian cells, shortens the mRNA poly(A) tail and contributes to the destabilization of mRNAs. The CCR4-NOT complex plays pivotal roles in various physiological functions, including cell proliferation, apoptosis, and metabolism. Here, we show that CNOT3, a subunit of the CCR4-NOT complex, is involved in the regulation of the spindle assembly checkpoint, suggesting that the CCR4-NOT complex also plays a part in the regulation of mitosis. CNOT3 depletion increases the population of mitotic-arrested cells and specifically increases the expression of MAD1 mRNA and its protein product that plays a part in the spindle assembly checkpoint. We showed that CNOT3 depletion stabilizes the MAD1 mRNA, and that MAD1 knockdown attenuates the CNOT3 depletion-induced increase of the mitotic index. Basing on these observations, we propose that CNOT3 is involved in the regulation of the spindle assembly checkpoint through its ability to regulate the stability of MAD1 mRNA.

  14. Discrimination of bromodeoxyuridine labelled and unlabelled mitotic cells in flow cytometric bromodeoxyuridine/DNA analysis

    DEFF Research Database (Denmark)

    Jensen, P O; Larsen, J K; Christensen, I J

    1994-01-01

    Bromodeoxyuridine (BrdUrd) labelled and unlabelled mitotic cells, respectively, can be discriminated from interphase cells using a new method, based on immunocytochemical staining of BrdUrd and flow cytometric four-parameter analysis of DNA content, BrdUrd incorporation, and forward and orthogona...

  15. Cell cycle-dependent SUMO-1 conjugation to nuclear mitotic apparatus protein (NuMA)

    Energy Technology Data Exchange (ETDEWEB)

    Seo, Jae Sung; Kim, Ha Na; Kim, Sun-Jick; Bang, Jiyoung; Kim, Eun-A; Sung, Ki Sa [Department of Biological Sciences, Sungkyunkwan University, Suwon 440-746 (Korea, Republic of); Yoon, Hyun-Joo [TissueGene Inc. 9605 Medical Center Dr., Rockville, MD 20850 (United States); Yoo, Hae Yong [Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Samsung Medical Center, Sungkyunkwan University, Seoul 135-710 (Korea, Republic of); Choi, Cheol Yong, E-mail: choicy@skku.ac.kr [Department of Biological Sciences, Sungkyunkwan University, Suwon 440-746 (Korea, Republic of)

    2014-01-03

    Highlights: •NuMA is modified by SUMO-1 in a cell cycle-dependent manner. •NuMA lysine 1766 is the primary target site for SUMOylation. •SUMOylation-deficient NuMA induces multiple spindle poles during mitosis. •SUMOylated NuMA induces microtubule bundling. -- Abstract: Covalent conjugation of proteins with small ubiquitin-like modifier 1 (SUMO-1) plays a critical role in a variety of cellular functions including cell cycle control, replication, and transcriptional regulation. Nuclear mitotic apparatus protein (NuMA) localizes to spindle poles during mitosis, and is an essential component in the formation and maintenance of mitotic spindle poles. Here we show that NuMA is a target for covalent conjugation to SUMO-1. We find that the lysine 1766 residue is the primary NuMA acceptor site for SUMO-1 conjugation. Interestingly, SUMO modification of endogenous NuMA occurs at the entry into mitosis and this modification is reversed after exiting from mitosis. Knockdown of Ubc9 or forced expression of SENP1 results in impairment of the localization of NuMA to mitotic spindle poles during mitosis. The SUMOylation-deficient NuMA mutant is defective in microtubule bundling, and multiple spindles are induced during mitosis. The mitosis-dependent dynamic SUMO-1 modification of NuMA might contribute to NuMA-mediated formation and maintenance of mitotic spindle poles during mitosis.

  16. The flavonoid eupatorin inactivates the mitotic checkpoint leading to polyploidy and apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Salmela, Anna-Leena [VTT Technical Research Centre of Finland, Medical Biotechnology, P.O. Box 106, Turku (Finland); Turku Graduate School of Biomedical Sciences, Turku (Finland); Turku Centre for Biotechnology, P.O. Box 123, University of Turku (Finland); Pouwels, Jeroen; Kukkonen-Macchi, Anu [VTT Technical Research Centre of Finland, Medical Biotechnology, P.O. Box 106, Turku (Finland); Waris, Sinikka; Toivonen, Pauliina [Turku Centre for Biotechnology, P.O. Box 123, University of Turku (Finland); Jaakkola, Kimmo [VTT Technical Research Centre of Finland, Medical Biotechnology, P.O. Box 106, Turku (Finland); Maeki-Jouppila, Jenni [VTT Technical Research Centre of Finland, Medical Biotechnology, P.O. Box 106, Turku (Finland); Turku Centre for Biotechnology, P.O. Box 123, University of Turku (Finland); Drug Discovery Graduate School, University of Turku (Finland); Kallio, Lila, E-mail: lila.kallio@vtt.fi [VTT Technical Research Centre of Finland, Medical Biotechnology, P.O. Box 106, Turku (Finland); Kallio, Marko J. [VTT Technical Research Centre of Finland, Medical Biotechnology, P.O. Box 106, Turku (Finland); Turku Centre for Biotechnology, P.O. Box 123, University of Turku (Finland); Centre of Excellence for Translational Genome-Scale Biology, P.O. Box 106, Academy of Finland (Finland)

    2012-03-10

    The spindle assembly checkpoint (SAC) is a conserved mechanism that ensures the fidelity of chromosome distribution in mitosis by preventing anaphase onset until the correct bipolar microtubule-kinetochore attachments are formed. Errors in SAC function may contribute to tumorigenesis by inducing numerical chromosome anomalies (aneuploidy). On the other hand, total disruption of SAC can lead to massive genomic imbalance followed by cell death, a phenomena that has therapeutic potency. We performed a cell-based high-throughput screen with a compound library of 2000 bioactives for novel SAC inhibitors and discovered a plant-derived phenolic compound eupatorin (3 Prime ,5-dihydroxy-4 Prime ,6,7-trimethoxyflavone) as an anti-mitotic flavonoid. The premature override of the microtubule drug-imposed mitotic arrest by eupatorin is dependent on microtubule-kinetochore attachments but not interkinetochore tension. Aurora B kinase activity, which is essential for maintenance of normal SAC signaling, is diminished by eupatorin in cells and in vitro providing a mechanistic explanation for the observed forced mitotic exit. Eupatorin likely has additional targets since eupatorin treatment of pre-mitotic cells causes spindle anomalies triggering a transient M phase delay followed by impaired cytokinesis and polyploidy. Finally, eupatorin potently induces apoptosis in multiple cancer cell lines and suppresses cancer cell proliferation in organotypic 3D cell culture model.

  17. Mitotic phosphorylation of VCIP135 blocks p97ATPase-mediated Golgi membrane fusion

    Energy Technology Data Exchange (ETDEWEB)

    Totsukawa, Go; Matsuo, Ayaka; Kubota, Ayano; Taguchi, Yuya; Kondo, Hisao, E-mail: hk228@med.kyushu-u.ac.jp

    2013-04-05

    Highlights: •VCIP135 is mitotically phosphorylated on Threonine-760 and Serine-767 by Cdc2. •Phosphorylated VCIP135 does not bind to p97ATPase. •The phosphorylation of VCIP135 inhibits p97ATPase-mediated Golgi membrane fusion. -- Abstract: In mammals, the Golgi apparatus is disassembled early mitosis and reassembled at the end of mitosis. For Golgi disassembly, membrane fusion needs to be blocked. Golgi biogenesis requires two distinct p97ATPase-mediated membrane fusion, the p97/p47 and p97/p37 pathways. We previously reported that p47 phosphorylation on Serine-140 and p37 phosphorylation on Serine-56 and Threonine-59 result in mitotic inhibition of the p97/p47 and the p97/p37 pathways, respectively [11,14]. In this study, we show another mechanism of mitotic inhibition of p97-mediated Golgi membrane fusion. We clarified that VCIP135, an essential factor in both p97 membrane fusion pathways, is phosphorylated on Threonine-760 and Serine-767 by Cdc2 at mitosis and that this phosphorylated VCIP135 does not bind to p97. An in vitro Golgi reassembly assay revealed that VCIP135(T760E, S767E), which mimics mitotic phosphorylation, caused no cisternal regrowth. Our results indicate that the phosphorylation of VCIP135 on Threonine-760 and Serine-767 inhibits p97-mediated Golgi membrane fusion at mitosis.

  18. Involvement of CNOT3 in mitotic progression through inhibition of MAD1 expression

    International Nuclear Information System (INIS)

    Takahashi, Akinori; Kikuguchi, Chisato; Morita, Masahiro; Shimodaira, Tetsuhiro; Tokai-Nishizumi, Noriko; Yokoyama, Kazumasa; Ohsugi, Miho; Suzuki, Toru; Yamamoto, Tadashi

    2012-01-01

    Highlights: ► CNOT3 depletion increases the mitotic index. ► CNOT3 inhibits the expression of MAD1. ► CNOT3 destabilizes the MAD1 mRNA. ► MAD1 knockdown attenuates the CNOT3 depletion-induced mitotic arrest. -- Abstract: The stability of mRNA influences the dynamics of gene expression. The CCR4–NOT complex, the major deadenylase in mammalian cells, shortens the mRNA poly(A) tail and contributes to the destabilization of mRNAs. The CCR4–NOT complex plays pivotal roles in various physiological functions, including cell proliferation, apoptosis, and metabolism. Here, we show that CNOT3, a subunit of the CCR4–NOT complex, is involved in the regulation of the spindle assembly checkpoint, suggesting that the CCR4–NOT complex also plays a part in the regulation of mitosis. CNOT3 depletion increases the population of mitotic-arrested cells and specifically increases the expression of MAD1 mRNA and its protein product that plays a part in the spindle assembly checkpoint. We showed that CNOT3 depletion stabilizes the MAD1 mRNA, and that MAD1 knockdown attenuates the CNOT3 depletion-induced increase of the mitotic index. Basing on these observations, we propose that CNOT3 is involved in the regulation of the spindle assembly checkpoint through its ability to regulate the stability of MAD1 mRNA.

  19. Mediator can regulate mitotic entry and direct periodic transcription in fission yeast.

    Science.gov (United States)

    Banyai, Gabor; Lopez, Marcela Davila; Szilagyi, Zsolt; Gustafsson, Claes M

    2014-11-01

    Cdk8 is required for correct timing of mitotic progression in fission yeast. How the activity of Cdk8 is regulated is unclear, since the kinase is not activated by T-loop phosphorylation and its partner, CycC, does not oscillate. Cdk8 is, however, a component of the multiprotein Mediator complex, a conserved coregulator of eukaryotic transcription that is connected to a number of intracellular signaling pathways. We demonstrate here that other Mediator components regulate the activity of Cdk8 in vivo and thereby direct the timing of mitotic entry. Deletion of Mediator components Med12 and Med13 leads to higher cellular Cdk8 protein levels, premature phosphorylation of the Cdk8 target Fkh2, and earlier entry into mitosis. We also demonstrate that Mediator is recruited to clusters of mitotic genes in a periodic fashion and that the complex is required for the transcription of these genes. We suggest that Mediator functions as a hub for coordinated regulation of mitotic progression and cell cycle-dependent transcription. The many signaling pathways and activator proteins shown to function via Mediator may influence the timing of these cell cycle events. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

  20. Frequencies of mutagen-induced coincident mitotic recombination at unlinked loci in Saccharomyces cerevisiae

    International Nuclear Information System (INIS)

    Freeman, Kathryn M.; Hoffmann, George R.

    2007-01-01

    Frequencies of coincident genetic events were measured in strain D7 of Saccharomyces cerevisiae. This diploid strain permits the detection of mitotic gene conversion involving the trp5-12 and trp5-27 alleles, mitotic crossing-over and gene conversion leading to the expression of the ade2-40 and ade2-119 alleles as red and pink colonies, and reversion of the ilv1-92 allele. The three genes are on different chromosomes, and one might expect that coincident (simultaneous) genetic alterations at two loci would occur at frequencies predicted by those of the single alterations acting as independent events. Contrary to this expectation, we observed that ade2 recombinants induced by bleomycin, β-propiolactone, and ultraviolet radiation occur more frequently among trp5 convertants than among total colonies. This excess among trp5 recombinants indicates that double recombinants are more common than expected for independent events. No similar enrichment was found among Ilv + revertants. The possibility of an artifact in which haploid yeasts that mimic mitotic recombinants are generated by a low frequency of cryptic meiosis has been excluded. Several hypotheses that can explain the elevated incidence of coincident mitotic recombination have been evaluated, but the cause remains uncertain. Most evidence suggests that the excess is ascribable to a subset of the population being in a recombination-prone state

  1. Induction of mitotic recombination by UV and diepoxybutane and its enhancement by hydroxyurea in Saccharomyces cerevisae

    International Nuclear Information System (INIS)

    Zaborowska, D.; Swietlinska, Z.; Zuk, J.

    1983-01-01

    Mitotic inter- and intra-genic recombination was induced by UV-irradiation and treatment with diepoxybutane (DEB) in 2 heteroallelic diploid strains of Saccharomyces cerevisiae SBTD and D7. Induction of the events tested was strongly potentiated by plating of mutagen-treated cells on growth media containing 0.03 M hydroxyurea (HU). (orig.)

  2. Akt Inhibitor A-443654 Interferes with Mitotic Progression by Regulating Aurora A Kinase Expression

    Directory of Open Access Journals (Sweden)

    Xuesong Liu

    2008-08-01

    Full Text Available Both Akt and Aurora A kinase have been shown to be important targets for intervention for cancer therapy. We report here that Compound A (A-443654, a specific Akt inhibitor, interferes with mitotic progression and bipolar spindle formation. Compound A induces G2/M accumulation, defects in centrosome separation, and formation of either monopolar arrays or disorganized spindles. On the basis of gene expression array studies, we identified Aurora A as one of the genes regulated transcriptionally by Akt inhibitors including Compound A. Inhibition of the phosphatidylinositol 3-kinase (PI3K/Akt pathway, either by PI3K inhibitor LY294002 or by Compound A, dramatically inhibits the promoter activity of Aurora A, whereas the mammalian target of rapamycin inhibitor has little effect, suggesting that Akt might be responsible for up-regulating Aurora A for mitotic progression. Further analysis of the Aurora A promoter region indicates that the Ets element but not the Sp1 element is required for Compound A-sensitive transcriptional control of Aurora A. Overexpression of Aurora A in cells treated with Compound A attenuates the mitotic arrest and the defects in bipolar spindle formation induced by Akt inhibition. Our studies suggest that that Akt may promote mitotic progression through the transcriptional regulation of Aurora A.

  3. Deficiency of RITA results in multiple mitotic defects by affecting microtubule dynamics.

    Science.gov (United States)

    Steinhäuser, K; Klöble, P; Kreis, N-N; Ritter, A; Friemel, A; Roth, S; Reichel, J M; Michaelis, J; Rieger, M A; Louwen, F; Oswald, F; Yuan, J

    2017-04-01

    Deregulation of mitotic microtubule (MT) dynamics results in defective spindle assembly and chromosome missegregation, leading further to chromosome instability, a hallmark of tumor cells. RBP-J interacting and tubulin-associated protein (RITA) has been identified as a negative regulator of the Notch signaling pathway. Intriguingly, deregulated RITA is involved in primary hepatocellular carcinoma and other malignant entities. We were interested in the potential molecular mechanisms behind its involvement. We show here that RITA binds to tubulin and localizes to various mitotic MT structures. RITA coats MTs and affects their structures in vitro as well as in vivo. Tumor cell lines deficient of RITA display increased acetylated α-tubulin, enhanced MT stability and reduced MT dynamics, accompanied by multiple mitotic defects, including chromosome misalignment and segregation errors. Re-expression of wild-type RITA, but not RITA Δtub ineffectively binding to tubulin, restores the phenotypes, suggesting that the role of RITA in MT modulation is mediated via its interaction with tubulin. Mechanistically, RITA interacts with tubulin/histone deacetylase 6 (HDAC6) and its suppression decreases the binding of the deacetylase HDAC6 to tubulin/MTs. Furthermore, the mitotic defects and increased MT stability are also observed in RITA -/- mouse embryonic fibroblasts. RITA has thus a novel role in modulating MT dynamics and its deregulation results in erroneous chromosome segregation, one of the major reasons for chromosome instability in tumor cells.

  4. Heart Rate Variability in Patients with Acute Ischemic Stroke at Different Stages of Renal Dysfunction: A Cross-sectional Observational Study

    Directory of Open Access Journals (Sweden)

    Lin Wei

    2017-01-01

    Conclusions: Autonomic dysfunction is aggravated with the progression of eGFR stage in patients with acute ischemic stroke; the eGFR is an independent factor of LF/HF in the adjusted models. Stroke severity and a history of diabetes are more significantly associated with HRV in patients with acute ischemic stroke at different stages of renal dysfunction.

  5. Effect of hydroxyurea on mitotic activity 3H-thymidine and 3H-phenylalanine incorporation in the antheridial filament cells of Chara vulgaris

    International Nuclear Information System (INIS)

    Bielecka, A.

    1979-01-01

    Hydroxyurea inhibits mitotic activity in cells of the antheridial filaments of Chara vulgaris by blocking phase S and phase G 2 . Blocking of cells in phase G 2 also occurs in the case of the root meristem cells of Helianthus annuus and Vicia faba var. minor. 3 H-thine incorporation confirmed autoradiographically the blocking of cells of the antheridial filaments in Chara vulgaris at phase S and slowing down of the rate of DNA replication. Incubation with 3 H-phenylalanine demonstrated that hydroxyurea inhibits protein synthesis. (author)

  6. Hydrogen peroxide induced loss of heterozygosity correlates with replicative lifespan and mitotic asymmetry in Saccharomyces cerevisiae

    Science.gov (United States)

    Jackson, Erin D.; Parker, Meighan C.; Gupta, Nilin; Rodrigues, Jenny

    2016-01-01

    Cellular aging in Saccharomyces cerevisiae can lead to genomic instability and impaired mitotic asymmetry. To investigate the role of oxidative stress in cellular aging, we examined the effect of exogenous hydrogen peroxide on genomic instability and mitotic asymmetry in a collection of yeast strains with diverse backgrounds. We treated yeast cells with hydrogen peroxide and monitored the changes of viability and the frequencies of loss of heterozygosity (LOH) in response to hydrogen peroxide doses. The mid-transition points of viability and LOH were quantified using sigmoid mathematical functions. We found that the increase of hydrogen peroxide dependent genomic instability often occurs before a drop in viability. We previously observed that elevation of genomic instability generally lags behind the drop in viability during chronological aging. Hence, onset of genomic instability induced by exogenous hydrogen peroxide treatment is opposite to that induced by endogenous oxidative stress during chronological aging, with regards to the midpoint of viability. This contrast argues that the effect of endogenous oxidative stress on genome integrity is well suppressed up to the dying-off phase during chronological aging. We found that the leadoff of exogenous hydrogen peroxide induced genomic instability to viability significantly correlated with replicative lifespan (RLS), indicating that yeast cells’ ability to counter oxidative stress contributes to their replicative longevity. Surprisingly, this leadoff is positively correlated with an inverse measure of endogenous mitotic asymmetry, indicating a trade-off between mitotic asymmetry and cell’s ability to fend off hydrogen peroxide induced oxidative stress. Overall, our results demonstrate strong associations of oxidative stress to genomic instability and mitotic asymmetry at the population level of budding yeast. PMID:27833823

  7. Dataset from the global phosphoproteomic mapping of early mitotic exit in human cells

    Directory of Open Access Journals (Sweden)

    Samuel Rogers

    2015-12-01

    Full Text Available The presence or absence of a phosphorylation on a substrate at any particular point in time is a functional readout of the balance in activity between the regulatory kinase and the counteracting phosphatase. Understanding how stable or short-lived a phosphorylation site is required for fully appreciating the biological consequences of the phosphorylation. Our current understanding of kinases and their substrates is well established; however, the role phosphatases play is less understood. Therefore, we utilized a phosphatase dependent model of mitotic exit to identify potential substrates that are preferentially dephosphorylated. Using this method, we identified >16,000 phosphosites on >3300 unique proteins, and quantified the temporal phosphorylation changes that occur during early mitotic exit (McCloy et al., 2015 [1]. Furthermore, we annotated the majority of these phosphorylation sites with a high confidence upstream kinase using published, motif and prediction based methods. The results from this study have been deposited into the ProteomeXchange repository with identifier PXD001559. Here we provide additional analysis of this dataset; for each of the major mitotic kinases we identified motifs that correlated strongly with phosphorylation status. These motifs could be used to predict the stability of phosphorylated residues in proteins of interest, and help infer potential functional roles for uncharacterized phosphorylations. In addition, we provide validation at the single cell level that serine residues phosphorylated by Cdk are stable during phosphatase dependent mitotic exit. In summary, this unique dataset contains information on the temporal mitotic stability of thousands of phosphorylation sites regulated by dozens of kinases, and information on the potential preference that phosphatases have at both the protein and individual phosphosite level. The compellation of this data provides an invaluable resource for the wider research

  8. Drug-induced premature chromosome condensation (PCC) protocols: cytogenetic approaches in mitotic chromosome and interphase chromatin.

    Science.gov (United States)

    Gotoh, Eisuke

    2015-01-01

    Chromosome analysis is a fundamental technique which is used in wide areas of cytogenetic study including karyotyping species, hereditary diseases diagnosis, or chromosome biology study. Chromosomes are usually prepared from mitotic cells arrested by colcemid block protocol. However, obtaining mitotic chromosomes is often hampered under several circumstances. As a result, cytogenetic analysis will be sometimes difficult or even impossible in such cases. Premature chromosome condensation (PCC) (see Note 1) is an alternative method that has proved to be a unique and useful way in chromosome analysis. Former, PCC has been achieved following cell fusion method (cell-fusion PCC) mediated either by fusogenic viruses (e.g., Sendai virus) or cell fusion chemicals (e.g., polyethylene glycol), but the cell fusion PCC has several drawbacks. The novel drug-induced PCC using protein phosphatase inhibitors was introduced about 20 years ago. This method is much simpler and easier even than the conventional mitotic chromosome preparation protocol use with colcemid block and furthermore obtained PCC index (equivalent to mitotic index for metaphase chromosome) is usually much higher than colcemid block method. Moreover, this method allows the interphase chromatin to be condensed to visualize like mitotic chromosomes. Therefore drug-induced PCC has opened the way for chromosome analysis not only in metaphase chromosomes but also in interphase chromatin. The drug-induced PCC has thus proven the usefulness in cytogenetics and other cell biology fields. For this second edition version, updated modifications/changes are supplemented in Subheadings 2, 3, and 4, and a new section describing the application of PCC in chromosome science fields is added with citation of updated references.

  9. Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade

    Science.gov (United States)

    Purrington, Kristen S.; Slettedahl, Seth; Bolla, Manjeet K.; Michailidou, Kyriaki; Czene, Kamila; Nevanlinna, Heli; Bojesen, Stig E.; Andrulis, Irene L.; Cox, Angela; Hall, Per; Carpenter, Jane; Yannoukakos, Drakoulis; Haiman, Christopher A.; Fasching, Peter A.; Mannermaa, Arto; Winqvist, Robert; Brenner, Hermann; Lindblom, Annika; Chenevix-Trench, Georgia; Benitez, Javier; Swerdlow, Anthony; Kristensen, Vessela; Guénel, Pascal; Meindl, Alfons; Darabi, Hatef; Eriksson, Mikael; Fagerholm, Rainer; Aittomäki, Kristiina; Blomqvist, Carl; Nordestgaard, Børge G.; Nielsen, Sune F.; Flyger, Henrik; Wang, Xianshu; Olswold, Curtis; Olson, Janet E.; Mulligan, Anna Marie; Knight, Julia A.; Tchatchou, Sandrine; Reed, Malcolm W.R.; Cross, Simon S.; Liu, Jianjun; Li, Jingmei; Humphreys, Keith; Clarke, Christine; Scott, Rodney; Fostira, Florentia; Fountzilas, George; Konstantopoulou, Irene; Henderson, Brian E.; Schumacher, Fredrick; Le Marchand, Loic; Ekici, Arif B.; Hartmann, Arndt; Beckmann, Matthias W.; Hartikainen, Jaana M.; Kosma, Veli-Matti; Kataja, Vesa; Jukkola-Vuorinen, Arja; Pylkäs, Katri; Kauppila, Saila; Dieffenbach, Aida Karina; Stegmaier, Christa; Arndt, Volker; Margolin, Sara; Balleine, Rosemary; Arias Perez, Jose Ignacio; Pilar Zamora, M.; Menéndez, Primitiva; Ashworth, Alan; Jones, Michael; Orr, Nick; Arveux, Patrick; Kerbrat, Pierre; Truong, Thérèse; Bugert, Peter; Toland, Amanda E.; Ambrosone, Christine B.; Labrèche, France; Goldberg, Mark S.; Dumont, Martine; Ziogas, Argyrios; Lee, Eunjung; Dite, Gillian S.; Apicella, Carmel; Southey, Melissa C.; Long, Jirong; Shrubsole, Martha; Deming-Halverson, Sandra; Ficarazzi, Filomena; Barile, Monica; Peterlongo, Paolo; Durda, Katarzyna; Jaworska-Bieniek, Katarzyna; Tollenaar, Robert A.E.M.; Seynaeve, Caroline; Brüning, Thomas; Ko, Yon-Dschun; Van Deurzen, Carolien H.M.; Martens, John W.M.; Kriege, Mieke; Figueroa, Jonine D.; Chanock, Stephen J.; Lissowska, Jolanta; Tomlinson, Ian; Kerin, Michael J.; Miller, Nicola; Schneeweiss, Andreas; Tapper, William J.; Gerty, Susan M.; Durcan, Lorraine; Mclean, Catriona; Milne, Roger L.; Baglietto, Laura; dos Santos Silva, Isabel; Fletcher, Olivia; Johnson, Nichola; Van'T Veer, Laura J.; Cornelissen, Sten; Försti, Asta; Torres, Diana; Rüdiger, Thomas; Rudolph, Anja; Flesch-Janys, Dieter; Nickels, Stefan; Weltens, Caroline; Floris, Giuseppe; Moisse, Matthieu; Dennis, Joe; Wang, Qin; Dunning, Alison M.; Shah, Mitul; Brown, Judith; Simard, Jacques; Anton-Culver, Hoda; Neuhausen, Susan L.; Hopper, John L.; Bogdanova, Natalia; Dörk, Thilo; Zheng, Wei; Radice, Paolo; Jakubowska, Anna; Lubinski, Jan; Devillee, Peter; Brauch, Hiltrud; Hooning, Maartje; García-Closas, Montserrat; Sawyer, Elinor; Burwinkel, Barbara; Marmee, Frederick; Eccles, Diana M.; Giles, Graham G.; Peto, Julian; Schmidt, Marjanka; Broeks, Annegien; Hamann, Ute; Chang-Claude, Jenny; Lambrechts, Diether; Pharoah, Paul D.P.; Easton, Douglas; Pankratz, V. Shane; Slager, Susan; Vachon, Celine M.; Couch, Fergus J.

    2014-01-01

    Mitotic index is an important component of histologic grade and has an etiologic role in breast tumorigenesis. Several small candidate gene studies have reported associations between variation in mitotic genes and breast cancer risk. We measured associations between 2156 single nucleotide polymorphisms (SNPs) from 194 mitotic genes and breast cancer risk, overall and by histologic grade, in the Breast Cancer Association Consortium (BCAC) iCOGS study (n = 39 067 cases; n = 42 106 controls). SNPs in TACC2 [rs17550038: odds ratio (OR) = 1.24, 95% confidence interval (CI) 1.16–1.33, P = 4.2 × 10−10) and EIF3H (rs799890: OR = 1.07, 95% CI 1.04–1.11, P = 8.7 × 10−6) were significantly associated with risk of low-grade breast cancer. The TACC2 signal was retained (rs17550038: OR = 1.15, 95% CI 1.07–1.23, P = 7.9 × 10−5) after adjustment for breast cancer risk SNPs in the nearby FGFR2 gene, suggesting that TACC2 is a novel, independent genome-wide significant genetic risk locus for low-grade breast cancer. While no SNPs were individually associated with high-grade disease, a pathway-level gene set analysis showed that variation across the 194 mitotic genes was associated with high-grade breast cancer risk (P = 2.1 × 10−3). These observations will provide insight into the contribution of mitotic defects to histological grade and the etiology of breast cancer. PMID:24927736

  10. Elevated global cerebral blood flow, oxygen extraction fraction and unchanged metabolic rate of oxygen in young adults with end-stage renal disease: an MRI study

    Energy Technology Data Exchange (ETDEWEB)

    Zheng, Gang; Lou, Yaxian; Pan, Zhiying; Liu, Ya [Medical School of Nanjing University, Department of Medical Imaging, Jinling Hospital, Nanjing, Jiangsu (China); Nanjing University of Aeronautics and Astronautics, College of Aivil Aviation, Nanjing, Jiangsu (China); Wen, Jiqiu; Li, Xue; Zhang, Zhe [Medical School of Nanjing University, National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing, Jiangsu (China); Lu, Hanzhang [University of Texas Southwestern Medical Center, Advanced Imaging Research Center, Dallas, TX (United States); Liu, Wei [Siemens Shenzhen Magnetic Resonance Ltd., Shenzhen, Guangdong (China); Liu, Hui [Siemens MR NEA Collaboration, Siemens Ltd., Shanghai (China); Chen, Huijuan; Kong, Xiang; Luo, Song; Jiang, Xiaolu; Zhang, Zongjun; Zhang, Long Jiang; Lu, Guang Ming [Medical School of Nanjing University, Department of Medical Imaging, Jinling Hospital, Nanjing, Jiangsu (China)

    2016-06-15

    To noninvasively assess global cerebral blood flow (CBF), oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO{sub 2}) in young adults with end-stage renal disease (ESRD). Thirty-six patients and 38 healthy volunteers were included and took part in MR examinations, blood and neuropsychological tests. CBF and OEF were measured by phase-contrast and T2-relaxation-under-spin-tagging MRI techniques, respectively. CMRO{sub 2} was computed from CBF, OEF and hematocrit according to Fick's principle. Correlations were performed between MR measurements, blood biochemistry measurements and neuropsychological test scores. Compared with controls, ESRD patients had elevated CBF (72.9 ± 12.5 vs. 63.8 ± 8.5 ml min{sup -1} 100 g{sup -1}, P < 0.001), elevated OEF (47.2 ± 10.2 vs. 35.8 ± 5.4 %, P < 0.001), but unaffected CMRO{sub 2} (199.5 ± 36.4 vs. 193.8 ± 28.6 μmol O{sub 2} min{sup -1} 100 g{sup -1}, P = 0.879). Hematocrit negatively correlated with CBF (r = -0.640, P < 0.001) and OEF (r = -0.701, P < 0.001), but not with CMRO{sub 2}. Altered neuropsychological test scores of ESRD patients were associated with OEF and CBF, but not with CMRO{sub 2}. There were weak relationships between eGFR and hematocrit (r = 0.308, P = 0.068) or CBF (r = 0.318, P = 0.059). Our findings suggested that anaemic young adults with ESRD may afford higher CBF and OEF to maintain a normal CMRO{sub 2}. Despite this compensatory process, however, cognitive function was still impaired and its severity was correlated with their CBF and OEF abnormality. (orig.)

  11. Elevated global cerebral blood flow, oxygen extraction fraction and unchanged metabolic rate of oxygen in young adults with end-stage renal disease: an MRI study

    International Nuclear Information System (INIS)

    Zheng, Gang; Lou, Yaxian; Pan, Zhiying; Liu, Ya; Wen, Jiqiu; Li, Xue; Zhang, Zhe; Lu, Hanzhang; Liu, Wei; Liu, Hui; Chen, Huijuan; Kong, Xiang; Luo, Song; Jiang, Xiaolu; Zhang, Zongjun; Zhang, Long Jiang; Lu, Guang Ming

    2016-01-01

    To noninvasively assess global cerebral blood flow (CBF), oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO 2 ) in young adults with end-stage renal disease (ESRD). Thirty-six patients and 38 healthy volunteers were included and took part in MR examinations, blood and neuropsychological tests. CBF and OEF were measured by phase-contrast and T2-relaxation-under-spin-tagging MRI techniques, respectively. CMRO 2 was computed from CBF, OEF and hematocrit according to Fick's principle. Correlations were performed between MR measurements, blood biochemistry measurements and neuropsychological test scores. Compared with controls, ESRD patients had elevated CBF (72.9 ± 12.5 vs. 63.8 ± 8.5 ml min -1 100 g -1 , P < 0.001), elevated OEF (47.2 ± 10.2 vs. 35.8 ± 5.4 %, P < 0.001), but unaffected CMRO 2 (199.5 ± 36.4 vs. 193.8 ± 28.6 μmol O 2 min -1 100 g -1 , P = 0.879). Hematocrit negatively correlated with CBF (r = -0.640, P < 0.001) and OEF (r = -0.701, P < 0.001), but not with CMRO 2 . Altered neuropsychological test scores of ESRD patients were associated with OEF and CBF, but not with CMRO 2 . There were weak relationships between eGFR and hematocrit (r = 0.308, P = 0.068) or CBF (r = 0.318, P = 0.059). Our findings suggested that anaemic young adults with ESRD may afford higher CBF and OEF to maintain a normal CMRO 2 . Despite this compensatory process, however, cognitive function was still impaired and its severity was correlated with their CBF and OEF abnormality. (orig.)

  12. Effect of cell cycle stage, dose rate and repair of sublethal damage of radiation-induced apoptosis in F9 teratocarcinoma cells

    International Nuclear Information System (INIS)

    Langley, R.E.; Quartuccio, S.G.; Kennealey, P.T.

    1995-01-01

    There are at least two different models of cell death after treatment with ionizing radiation. The first is a failure to undergo sustained cell division despite metabolic survival, and we refer to this end point as open-quotes classical reproductive cell death.close quotes The second is a process that results in loss of cell integrity. This second category includes cellular necrosis as well as apoptosis. Earlier studies in our laboratory showed that the predominant mechanism of cell death for irradiated F9 cell is apoptosis, and there is no indication that these cells die by necrosis. We have therefore used cells of this cell line to reassess basic radiobiological principles with respect to apoptosis. Classical reproductive cell death was determined by staining colonies derived from irradiated cells and scoring colonies of less than 50 cells as reproductively dead and colonies of more than 50 cells as survivors. Cells that failed to produce either type of colony (detached from the plate or disintegrated) were scored as having undergone apoptosis. Using these criteria we found that the fraction of the radiation-killed F9 cells that died by apoptosis did not vary when cells were irradiated at different stages of the cell cycle despite large variations in overall survival. This suggests that the factors that influence radiation sensitivity throughout the cell cycle have an equal impact on apoptosis and classical reproductive cell death. There was no difference in cell survival between split doses and single doses of X rays, suggesting that sublethal damage repair is not a factor in radiation-induced apoptosis of F9 cells. Apoptosis was not affected by changes in dose rate in the range of 0.038-4.96 Gy/min. 48 refs., 6 figs., 1 tab

  13. Blunted cyclic variation of heart rate predicts mortality risk in post-myocardial infarction, end-stage renal disease, and chronic heart failure patients

    Science.gov (United States)

    Hayano, Junichiro; Yasuma, Fumihiko; Watanabe, Eiichi; Carney, Robert M.; Stein, Phyllis K.; Blumenthal, James A.; Arsenos, Petros; Gatzoulis, Konstantinos A.; Takahashi, Hiroshi; Ishii, Hideki; Kiyono, Ken; Yamamoto, Yoshiharu; Yoshida, Yutaka; Yuda, Emi; Kodama, Itsuo

    2017-01-01

    Abstract Aims Cyclic variation of heart rate (CVHR) associated with sleep-disordered breathing is thought to reflect cardiac autonomic responses to apnoeic/hypoxic stress. We examined whether blunted CVHR observed in ambulatory ECG could predict the mortality risk. Methods and results CVHR in night-time Holter ECG was detected by an automated algorithm, and the prognostic relationships of the frequency (FCV) and amplitude (ACV) of CVHR were examined in 717 patients after myocardial infarction (post-MI 1, 6% mortality, median follow-up 25 months). The predictive power was prospectively validated in three independent cohorts: a second group of 220 post-MI patients (post-MI 2, 25.5% mortality, follow-up 45 months); 299 patients with end-stage renal disease on chronic haemodialysis (ESRD, 28.1% mortality, follow-up 85 months); and 100 patients with chronic heart failure (CHF, 35% mortality, follow-up 38 months). Although CVHR was observed in ≥96% of the patients in all cohorts, FCV did not predict mortality in any cohort. In contrast, decreased ACV was a powerful predictor of mortality in the post-MI 1 cohort (hazard ratio [95% CI] per 1 ln [ms] decrement, 2.9 [2.2–3.7], P < 0.001). This prognostic relationship was validated in the post-MI 2 (1.8 [1.4–2.2], P < 0.001), ESRD (1.5 [1.3–1.8], P < 0.001), and CHF (1.4 [1.1–1.8], P = 0.02) cohorts. The prognostic value of ACV was independent of age, gender, diabetes, β-blocker therapy, left ventricular ejection fraction, sleep-time mean R-R interval, and FCV. Conclusion Blunted CVHR detected by decreased ACV in a night-time Holter ECG predicts increased mortality risk in post-MI, ESRD, and CHF patients. PMID:27789562

  14. Blunted cyclic variation of heart rate predicts mortality risk in post-myocardial infarction, end-stage renal disease, and chronic heart failure patients.

    Science.gov (United States)

    Hayano, Junichiro; Yasuma, Fumihiko; Watanabe, Eiichi; Carney, Robert M; Stein, Phyllis K; Blumenthal, James A; Arsenos, Petros; Gatzoulis, Konstantinos A; Takahashi, Hiroshi; Ishii, Hideki; Kiyono, Ken; Yamamoto, Yoshiharu; Yoshida, Yutaka; Yuda, Emi; Kodama, Itsuo

    2017-08-01

    Cyclic variation of heart rate (CVHR) associated with sleep-disordered breathing is thought to reflect cardiac autonomic responses to apnoeic/hypoxic stress. We examined whether blunted CVHR observed in ambulatory ECG could predict the mortality risk. CVHR in night-time Holter ECG was detected by an automated algorithm, and the prognostic relationships of the frequency (FCV) and amplitude (ACV) of CVHR were examined in 717 patients after myocardial infarction (post-MI 1, 6% mortality, median follow-up 25 months). The predictive power was prospectively validated in three independent cohorts: a second group of 220 post-MI patients (post-MI 2, 25.5% mortality, follow-up 45 months); 299 patients with end-stage renal disease on chronic haemodialysis (ESRD, 28.1% mortality, follow-up 85 months); and 100 patients with chronic heart failure (CHF, 35% mortality, follow-up 38 months). Although CVHR was observed in ≥96% of the patients in all cohorts, FCV did not predict mortality in any cohort. In contrast, decreased ACV was a powerful predictor of mortality in the post-MI 1 cohort (hazard ratio [95% CI] per 1 ln [ms] decrement, 2.9 [2.2-3.7], P < 0.001). This prognostic relationship was validated in the post-MI 2 (1.8 [1.4-2.2], P < 0.001), ESRD (1.5 [1.3-1.8], P < 0.001), and CHF (1.4 [1.1-1.8], P = 0.02) cohorts. The prognostic value of ACV was independent of age, gender, diabetes, β-blocker therapy, left ventricular ejection fraction, sleep-time mean R-R interval, and FCV. Blunted CVHR detected by decreased ACV in a night-time Holter ECG predicts increased mortality risk in post-MI, ESRD, and CHF patients. © The Author 2016. Published by Oxford University Press on behalf of the European Society of Cardiology.

  15. Mitotic Stress Is an Integral Part of the Oncogene-Induced Senescence Program that Promotes Multinucleation and Cell Cycle Arrest

    Directory of Open Access Journals (Sweden)

    Dina Dikovskaya

    2015-09-01

    Full Text Available Oncogene-induced senescence (OIS is a tumor suppression mechanism that blocks cell proliferation in response to oncogenic signaling. OIS is frequently accompanied by multinucleation; however, the origin of this is unknown. Here, we show that multinucleate OIS cells originate mostly from failed mitosis. Prior to senescence, mutant H-RasV12 activation in primary human fibroblasts compromised mitosis, concordant with abnormal expression of mitotic genes functionally linked to the observed mitotic spindle and chromatin defects. Simultaneously, H-RasV12 activation enhanced survival of cells with damaged mitoses, culminating in extended mitotic arrest and aberrant exit from mitosis via mitotic slippage. ERK-dependent transcriptional upregulation of Mcl1 was, at least in part, responsible for enhanced survival and slippage of cells with mitotic defects. Importantly, mitotic slippage and oncogene signaling cooperatively induced senescence and key senescence effectors p21 and p16. In summary, activated Ras coordinately triggers mitotic disruption and enhanced cell survival to promote formation of multinucleate senescent cells.

  16. Down-regulation of tricarboxylic acid (TCA) cycle genes blocks progression through the first mitotic division in Caenorhabditis elegans embryos.

    Science.gov (United States)

    Rahman, Mohammad M; Rosu, Simona; Joseph-Strauss, Daphna; Cohen-Fix, Orna

    2014-02-18

    The cell cycle is a highly regulated process that enables the accurate transmission of chromosomes to daughter cells. Here we uncover a previously unknown link between the tricarboxylic acid (TCA) cycle and cell cycle progression in the Caenorhabditis elegans early embryo. We found that down-regulation of TCA cycle components, including citrate synthase, malate dehydrogenase, and aconitase, resulted in a one-cell stage arrest before entry into mitosis: pronuclear meeting occurred normally, but nuclear envelope breakdown, centrosome separation, and chromosome condensation did not take place. Mitotic entry is controlled by the cyclin B-cyclin-dependent kinase 1 (Cdk1) complex, and the inhibitory phosphorylation of Cdk1 must be removed in order for the complex to be active. We found that following down-regulation of the TCA cycle, cyclin B levels were normal but CDK-1 remained inhibitory-phosphorylated in one-cell stage-arrested embryos, indicative of a G2-like arrest. Moreover, this was not due to an indirect effect caused by checkpoint activation by DNA damage or replication defects. These observations suggest that CDK-1 activation in the C. elegans one-cell embryo is sensitive to the metabolic state of the cell, and that down-regulation of the TCA cycle prevents the removal of CDK-1 inhibitory phosphorylation. The TCA cycle was previously shown to be necessary for the development of the early embryo in mammals, but the molecular processes affected were not known. Our study demonstrates a link between the TCA cycle and a specific cell cycle transition in the one-cell stage embryo.

  17. Elevated global cerebral blood flow, oxygen extraction fraction and unchanged metabolic rate of oxygen in young adults with end-stage renal disease: an MRI study.

    Science.gov (United States)

    Zheng, Gang; Wen, Jiqiu; Lu, Hanzhang; Lou, Yaxian; Pan, Zhiying; Liu, Wei; Liu, Hui; Li, Xue; Zhang, Zhe; Chen, Huijuan; Kong, Xiang; Luo, Song; Jiang, Xiaolu; Liu, Ya; Zhang, Zongjun; Zhang, Long Jiang; Lu, Guang Ming

    2016-06-01

    To noninvasively assess global cerebral blood flow (CBF), oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2) in young adults with end-stage renal disease (ESRD). Thirty-six patients and 38 healthy volunteers were included and took part in MR examinations, blood and neuropsychological tests. CBF and OEF were measured by phase-contrast and T2-relaxation-under-spin-tagging MRI techniques, respectively. CMRO2 was computed from CBF, OEF and hematocrit according to Fick's principle. Correlations were performed between MR measurements, blood biochemistry measurements and neuropsychological test scores. Compared with controls, ESRD patients had elevated CBF (72.9 ± 12.5 vs. 63.8 ± 8.5 ml min(-1) 100 g(-1), P < 0.001), elevated OEF (47.2 ± 10.2 vs. 35.8 ± 5.4 %, P < 0.001), but unaffected CMRO2 (199.5 ± 36.4 vs. 193.8 ± 28.6 μmol O2 min(-1) 100 g(-1), P = 0.879). Hematocrit negatively correlated with CBF (r = -0.640, P < 0.001) and OEF (r = -0.701, P < 0.001), but not with CMRO2. Altered neuropsychological test scores of ESRD patients were associated with OEF and CBF, but not with CMRO2. There were weak relationships between eGFR and hematocrit (r = 0.308, P = 0.068) or CBF (r = 0.318, P = 0.059). Our findings suggested that anaemic young adults with ESRD may afford higher CBF and OEF to maintain a normal CMRO2. Despite this compensatory process, however, cognitive function was still impaired and its severity was correlated with their CBF and OEF abnormality. • Anaemic young adults with ESRD may afford higher CBF and OEF. • Anaemic young adults with ESRD maintain a normal CMRO 2 . • Cognitive function was still impaired in young ESRD adults. • The severity of cognitive dysfunction correlated with CBF and OEF changes.

  18. Anti-mitotic activity towards sea urchin eggs of dichloromethane fraction obtained from Allamanda schottii Pohl (Apocynaceae

    Directory of Open Access Journals (Sweden)

    Louisa M. A. Sousa

    Full Text Available Allamanda (Apocynaceae is a genus of climbing shrubs known for producing compounds with a range of biological activities. Previous works have shown the anti-proliferative effect of the ethanolic extract of Allamanda schottii on leukemic cells. The present work was conducted to evaluate the effects of dichloromethane fraction, obtained from Allamanda schottii, on sea urchin Echinometra lucunter eggs, as a multicellular model for evaluating anti-tumor activity. Our results show an inhibition of sea urchin development in a dose-dependent manner in the presence of dichloromethane fraction. The IC50 values for first and third cleavage and blastulae stage were 103.7 µg/mL, 33.1 µg/mL and 10.2 µg/mL, respectively. These results also demonstrate the cumulative effect of this fraction on sea urchin embryos. In the present work, the expressive anti-mitotic activity of dichloromethane fraction towards sea urchin eggs, a multicellular model, reinforces the anti-tumor potential of the Allamanda schotti.

  19. Multicentric evaluation of the impact of central tumour location when comparing rates of N1 upstaging in patients undergoing video-assisted and open surgery for clinical Stage I non-small-cell lung cancer

    DEFF Research Database (Denmark)

    Decaluwé, Herbert; Petersen, René Horsleben; Brunelli, Alex

    2018-01-01

    OBJECTIVES: Large retrospective series have indicated lower rates of cN0 to pN1 nodal upstaging after video-assisted thoracic surgery (VATS) compared with open resections for Stage I non-small-cell lung cancer (NSCLC). The objective of our multicentre study was to investigate whether the presumed...

  20. PLK1 regulation of PCNT cleavage ensures fidelity of centriole separation during mitotic exit.

    Science.gov (United States)

    Kim, Jaeyoun; Lee, Kwanwoo; Rhee, Kunsoo

    2015-12-09

    Centrioles are duplicated and segregated in close link to the cell cycle. During mitosis, daughter centrioles are disengaged and eventually separated from mother centrioles. New daughter centrioles may be generated only after centriole separation. Therefore, centriole separation is considered a licensing step for centriole duplication. It was previously known that separase specifically cleaves pericentrin (PCNT) during mitotic exit. Here we report that PCNT has to be phosphorylated by PLK1 to be a suitable substrate of separase. Phospho-resistant mutants of PCNT are not cleaved by separase and eventually inhibit centriole separation. Furthermore, phospho-mimetic PCNT mutants rescue centriole separation even in the presence of a PLK1 inhibitor. On the basis on these results, we propose that PLK1 phosphorylation is a priming step for separase-mediated cleavage of PCNT and eventually for centriole separation. PLK1 phosphorylation of PCNT provides an additional layer of regulatory mechanism to ensure the fidelity of centriole separation during mitotic exit.

  1. Analysis of the Ceratitis capitata y chromosome using in situ hybridization to mitotic chromosomes

    International Nuclear Information System (INIS)

    Willhoeft, U.; Franz, G.

    1998-01-01

    In Ceratitis capitata the Y chromosome is responsible for sex-determination. We used fluorescence in situ hybridization (FISH) for cytogenetic analysis of mitotic chromosomes. FISH with the wild-type strain EgyptII and two repetitive DNA probes enabled us to differentiate between the short and the long arm of the Y chromosome and gives a much better resolution than C-banding of mitotic chromosomes. We identified the Y-chromosomal breakpoints in Y-autosome translocations using FISH. Even more complex rearrangements i.e. deletions and insertions in some translocation strains were detected by this method. A strategy for mapping the primary sex determination factor in Ceratitis capitata by FISH is presented. (author)

  2. SON is a spliceosome-associated factor required for mitotic progression.

    Science.gov (United States)

    Huen, Michael S Y; Sy, Shirley M H; Leung, Ka Man; Ching, Yick-Pang; Tipoe, George L; Man, Cornelia; Dong, Shuo; Chen, Junjie

    2010-07-01

    The eukaryotic RNA splicing machinery is dedicated to the daunting task of excising intronic sequences on the many nascent RNA transcripts in a cell, and in doing so facilitates proper translation of its transcriptome. Notably, emerging evidence suggests that RNA splicing may also play direct roles in maintaining genome stability. Here we report the identification of the RNA/DNA-binding protein SON as a component of spliceosome that plays pleiotropic roles during mitotic progression. We found that SON is essential for cell proliferation, and that its inactivation triggers a MAD2-dependent mitotic delay. Moreover, SON deficiency is accompanied by defective chromosome congression, compromised chromosome segregation and cytokinesis, which in turn contributes to cellular aneuploidy and cell death. In summary, our study uncovers a specific link between SON and mitosis, and highlights the potential of RNA processing as additional regulatory mechanisms that govern cell proliferation and division. © 2010 Landes Bioscience

  3. Stage design

    International Nuclear Information System (INIS)

    Shacter, J.

    1975-01-01

    A method is described of cycling gases through a plurality of diffusion stages comprising the steps of admitting the diffused gases from a first diffusion stage into an axial compressor, simultaneously admitting the undiffused gases from a second diffusion stage into an intermediate pressure zone of said compressor corresponding in pressure to the pressure of said undiffused gases, and then admitting the resulting compressed mixture of diffused and undiffused gases into a third diffusion stage

  4. Staging Mobilities

    DEFF Research Database (Denmark)

    Jensen, Ole B.

    and lived as people are “staging themselves” (from below). Staging mobilities is a dynamic process between “being staged” (for example, being stopped at traffic lights) and the “mobile staging” of interacting individuals (negotiating a passage on the pavement). Staging Mobilities is about the fact...

  5. Effects of mutagen-sensitive mus mutations on spontaneous mitotic recombination in Aspergillus.

    Science.gov (United States)

    Zhao, P; Kafer, E

    1992-04-01

    Methyl methane-sulfonate (MMS)-sensitive, radiation-induced mutants of Aspergillus were shown to define nine new DNA repair genes, musK to musS. To test mus mutations for effects on mitotic recombination, intergenic crossing over was assayed between color markers and their centromeres, and intragenic recombination between two distinguishable adE alleles. Of eight mutants analyzed, four showed significant deviations from mus+ controls in both tests. Two mutations, musK and musL, reduced recombination, while musN and musQ caused increases. In contrast, musO diploids produced significantly higher levels only for intragenic recombination. Effects were relatively small, but averages between hypo- and hyperrec mus differed 15-20-fold. In musL diploids, most of the rare color segregants resulted from mitotic malsegregation rather than intergenic crossing over. This indicates that the musL gene product is required for recombination and that DNA lesions lead to chromosome loss when it is deficient. In addition, analysis of the genotypes of intragenic (ad+) recombinants showed that the musL mutation specifically reduced single allele conversion but increased complex conversion types (especially recombinants homozygous for ad+). Similar analysis revealed differences between the effects of two hyperrec mutations; musN apparently caused high levels solely of mitotic crossing over, while musQ increased various conversion types but not reciprocal crossovers. These results suggest that mitotic gene conversion and crossing over, while generally associated, are affected differentially in some of the mus strains of Aspergillus nidulans.

  6. Determining local and contextual features describing appearance of difficult to identify mitotic figures

    Science.gov (United States)

    Gandomkar, Ziba; Brennan, Patrick C.; Mello-Thoms, Claudia

    2017-03-01

    Mitotic count is helpful in determining the aggressiveness of breast cancer. In previous studies, it was shown that the agreement among pathologists for grading mitotic index is fairly modest, as mitoses have a large variety of appearances and they could be mistaken for other similar objects. In this study, we determined local and contextual features that differ significantly between easily identifiable mitoses and challenging ones. The images were obtained from the Mitosis-Atypia 2014 challenge. In total, the dataset contained 453 mitotic figures. Two pathologists annotated each mitotic figure. In case of disagreement, an opinion from a third pathologist was requested. The mitoses were grouped into three categories, those recognized as "a true mitosis" by both pathologists ,those labelled as "a true mitosis" by only one of the first two readers and also the third pathologist, and those annotated as "probably a mitosis" by all readers or the majority of them. After color unmixing, the mitoses were segmented from H channel. Shape-based features along with intensity-based and textural features were extracted from H-channel, blue ratio channel and five different color spaces. Holistic features describing each image were also considered. The Kruskal-Wallis H test was used to identify significantly different features. Multiple comparisons were done using the rank-based version of Tukey-Kramer test. The results indicated that there are local and global features which differ significantly among different groups. In addition, variations between mitoses in different groups were captured in the features from HSL and LCH color space more than other ones.

  7. The role of p53 in the response to mitotic spindle damage

    International Nuclear Information System (INIS)

    Meek, D.W.

    2000-01-01

    The p53 tumour suppressor protein has defined roles in G1/S and G2/M cell cycle checkpoint in response to a range of cellular stresses including DNA damage, dominant oncogene expression, hypoxia, metabolic changes and viral infection. In addition to these responses, p53 can also be activated when damage occurs to the mitotic spindle. Initially, spindle damage activates a p53-independent checkpoint which functions at the metaphase-anaphase transition and prevents cells from progressing through mitosis until the completion of spindle formation. Cells eventually escape from this block (a process termed 'mitotic slippage'), and an aberrant mitosis ensues in which sister chromatids fail to segregate properly. After a delay period, p53 responds to this mitotic failure by instituting a G1-like growth arrest, with an intact nucleus containing 4N DNA, but without the cells undergoing division. Cells lacking wild-type p53 are still able to arrest transiently at mitosis, and also fail to undergo division, underscoring that the delay in mitosis is p53-independent. However, these cells are not prevented from re-entering the cell cycle and can reduplicate their DNA unchecked, leading to polyploidy. Additionally, p53-null cells which experience spindle failure often show the appearance of micronuclei arising from poorly segregated chromosomes which have de-condensed and been enclosed in a nuclear envelope. The ability of p53 to prevent their formation suggests an additional G2 involvement which prevents nuclear breakdown prior to mitosis. The molecular mechanism by which p53 is able to sense mitotic failure is still unknown, but may be linked to the ability of p53 to regulate duplication of the centrosome, the organelle which nucleates spindle formation. (authors)

  8. Genetic control of mitotic crossing over in yeast. 2. Influence of UV irradiation

    International Nuclear Information System (INIS)

    Zakharov, I.A.; Marfin, S.V.; Koval'tsova, S.V.; Kasinova, G.V.

    1982-01-01

    UV-induced crossing-over and general mitotic segregation of the following strains of Saccharomyces cerevisiae yeasts were studied: a wild-type diploid, diploids homozygous with respect to the radiosensitivity of rad 2, rad 15, rad 54, xrs 4, rad 2 rad 54, rad 15 rad 54. Wild-type diploids rad 2 and rad 15 have a high frequency of the induced mitotic crossing-over. Diploids rad 15, rad 54 can not cause UV-induced mitotic crossing-over. Reddish-pink and reddish-pink-white colonies ratio (the first appear if the crossing-over occurs during the first after the irradiation division, the second - during the second division) is 4.8:1 for the wild type, 1.6:1 for rad 2, and 1.1:1 for rad 15. Nonreciprocal mitotic segregation of high frequency was observed for the wild type rad 2, rad 15, xrs 4, and diploids rad 54, rad 2 rad 54, rad 15 rad 54 had a lower frequency. We suppose that after UV-irradiation there exist at least three types of repair in yeast diploid cells: excision repair, prereplication recombinating repair after the excision of dimers, and post-replication recombinating repair. Rad 2 and rad 15 mutations blow the first and second types, rad 54 mutation partially block the second and third parths. It seems that xrs 4 mutation does not block the recombinating capability but somehow changes the process of recombination in such a way that much nonreciprocal products recorded as seqregants are produced [ru

  9. Rates of mass gain and energy deposition in red knot on their final spring staging site is both time- and condition-dependent

    NARCIS (Netherlands)

    Atkinson, Philip W.; Baker, Allan J.; Bennett, Karen A.; Clark, Nigel A.; Clark, Jacquie A.; Cole, Kimberly B.; Dekinga, Anne; Dey, Amanda; Gillings, Simon; Gonzalez, Patricia M.; Kalasz, Kevin; Minton, Clive D. T.; Newton, Jason; Niles, Lawrence J.; Piersma, Theunis; Robinson, Robert A.; Sitters, Humphrey P.; Stevens, Phil

    1. Millions of shorebirds migrate each year through a small number of highly productive staging areas where they often conflict with fisheries interests. Delaware Bay, USA, is a major shorebird stopover site where, in spring, many thousands of shorebirds undergo rapid mass gain by feeding on the

  10. Effect of volumetric organic loading rate (OLR) on H2 and CH4 production by two-stage anaerobic co-digestion of food waste and brown water.

    Science.gov (United States)

    Paudel, Sachin; Kang, Youngjun; Yoo, Yeong-Seok; Seo, Gyu Tae

    2017-03-01

    Two-stage anaerobic digestion system consisting of two continuously stirred tank reactors (CSTRs) operating at mesophillic conditions (37°C) were studied. The aim of this study is to determine optimum Hydraulic Retention Time (HRT) of the two-stage anaerobic digester system for hydrogen and methane production. This paper also discusses the effect of OLR with change in HRT on the system. Four different HRTs of 48, 24, 12, 8h were monitored for acidogenic reactor, which provided OLR of 17.7, 34.8, 70.8, 106gVS/L·d respectively. Two HRTs of 15days and 20days were studied with OLR of 1.24 and 1.76gVS/L·d respectively in methanogenic reactor. Hydrogen production at higher OLR and shorter HRT seemed favorable 106gVS/L·d (8h) in acidogenic reactor system. In methanogenic reactor system HRT of 20day with OLR of 1.24gVS/L·d was found optimum in terms of methane production and organic removal. The result of this study illustrated the optimum HRT of 8h and 20days in acidogenic stage and methanogenic stage for maximum hydrogen and methane production. Copyright © 2016 Elsevier Ltd. All rights reserved.

  11. Decreased stage migration rate of early gastric cancer with a new reconstruction algorithm using dual-energy CT images: a preliminary study

    Energy Technology Data Exchange (ETDEWEB)

    Shi, Cen [Shanghai Jiao Tong University School of Medicine, Department of Radiology, Ruijin Hospital, Shanghai (China); First Affiliated Hospital of Soochow University, Department of Radiology, Suzhou (China); Zhang, Huan; Du, Lianjun; Pan, Zilai; Yan, Fuhua [Shanghai Jiao Tong University School of Medicine, Department of Radiology, Ruijin Hospital, Shanghai (China); Yan, Jing [Siemens Medical System, Shanghai (China); Wang, Baisong [Shanghai Jiao Tong University School of Medicine, Department of Biological Statistics, Shanghai (China)

    2017-02-15

    To evaluate the potential value of advanced monoenergetic images (AMEIs) on early gastric cancer (EGC) using dual-energy CT (DECT). 31 EGC patients (19 men, 12 women; age range, 38-81 years; mean age, 57.19 years) were retrospectively enrolled in this study. Conventionally reconstructed polyenergetic images (PEIs) at 120 kV and virtual monoenergetic images (MEIs) and AMEIs at six different kiloelectron volt (keV) levels (from 40 to 90 keV) were evaluated from the 100 and Sn 140 kV dual energy image data, respectively. The visibility and stage migration of EGC for all three image data sets were evaluated and statistically analyzed. The objective and subjective image qualities were also evaluated. AMEIs at 40 keV showed the best visibility (80.7 %) and the lowest stage migration (35.5 %) for EGC. The stage migration for AMEIs at 40 keV was significantly lower than that for PEIs (p = 0.026). AMEIs at 40 keV had statistically higher CNR in the arterial and portal phases, gastric-specific diagnostic performance and visual sharpness compared with other AMEIs, MEIs and PEIs (all p < 0.05). AMEIs at 40 keV with MPR increase the CNR of EGC and thus potentially lower the stage migration of EGC. (orig.)

  12. Human papillomavirus type 16 E7 oncoprotein engages but does not abrogate the mitotic spindle assembly checkpoint

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Yueyang [Division of Infectious Diseases, Brigham and Women' s Hospital and Biological and Biomedical Sciences Program, Harvard Medical School, Boston, MA 02115 (United States); Munger, Karl, E-mail: kmunger@rics.bwh.harvard.edu [Division of Infectious Diseases, Brigham and Women' s Hospital and Biological and Biomedical Sciences Program, Harvard Medical School, Boston, MA 02115 (United States)

    2012-10-10

    The mitotic spindle assembly checkpoint (SAC) ensures faithful chromosome segregation during mitosis by censoring kinetochore-microtubule interactions. It is frequently rendered dysfunctional during carcinogenesis causing chromosome missegregation and genomic instability. There are conflicting reports whether the HPV16 E7 oncoprotein drives chromosomal instability by abolishing the SAC. Here we report that degradation of mitotic cyclins is impaired in cells with HPV16 E7 expression. RNAi-mediated depletion of Mad2 or BubR1 indicated the involvement of the SAC, suggesting that HPV16 E7 expression causes sustained SAC engagement. Mutational analyses revealed that HPV16 E7 sequences that are necessary for retinoblastoma tumor suppressor protein binding as well as sequences previously implicated in binding the nuclear and mitotic apparatus (NuMA) protein and in delocalizing dynein from the mitotic spindle contribute to SAC engagement. Importantly, however, HPV16 E7 does not markedly compromise the SAC response to microtubule poisons.

  13. Critical Importance of Protein 4.1 in Centrosome and Mitotic Spindle Aberrations in Breast Cancer Pathogenesis

    National Research Council Canada - National Science Library

    Krauss, Sharon W

    2006-01-01

    We proposed to test the novel hypothesis that protein 4.1 is of critical importance to centrosome and mitotic spindle aberrations that directly impact aspects of breast cancer pathogenesis. We characterized...

  14. Mitotic catastrophe is the mechanism of lethality for mutations that confer mutagen sensitivity in Aspergillus nidulans.

    Science.gov (United States)

    Denison, S H; May, G S

    1994-01-16

    We have examined the consequences of treatment with DNA-damaging agents of uvs mutants and the bimD6 mutant of Aspergillus nidulans. We first established that wild-type Aspergillus undergoes a cell cycle delay following treatment with the DNA-damaging agents methyl methanesulfonate (MMS) or ultraviolet light (UV). We have also determined that strains carrying the bimD6, uvsB110, uvsH77, uvsF201 and the uvsC114 mutations, all of which cause an increased sensitivity to DNA-damaging agents, undergo a cell-cycle delay following DNA damage. These mutations therefore do not represent nonfunctional checkpoints in Aspergillus. However, all of the mutant strains accumulated nuclear defects after a period of delay following mutagen treatment. The nuclear defects in the uvsB110 and bimD6 strains following MMS treatment were shown to be dependent on passage through mitosis after DNA damage, as the defects were prevented with benomyl. Checkpoint controls responding to DNA damage thus only temporarily halt cell-cycle progression in response to DNA damage. The conditional bimD6 mutation also results in a defective mitosis at restrictive temperatures. This mitotic defect is similar to that seen with MMS treatment at temperatures permissive for the mitotic defect. Thus the bimD gene product may perform dual roles, one in DNA repair and the other during the mitotic cell cycle in the absence of damage.

  15. Kinesin-8 effects on mitotic microtubule dynamics contribute to spindle function in fission yeast

    Science.gov (United States)

    Gergely, Zachary R.; Crapo, Ammon; Hough, Loren E.; McIntosh, J. Richard; Betterton, Meredith D.

    2016-01-01

    Kinesin-8 motor proteins destabilize microtubules. Their absence during cell division is associated with disorganized mitotic chromosome movements and chromosome loss. Despite recent work studying effects of kinesin-8s on microtubule dynamics, it remains unclear whether the kinesin-8 mitotic phenotypes are consequences of their effect on microtubule dynamics, their well-established motor activity, or additional, unknown functions. To better understand the role of kinesin-8 proteins in mitosis, we studied the effects of deletion of the fission yeast kinesin-8 proteins Klp5 and Klp6 on chromosome movements and spindle length dynamics. Aberrant microtubule-driven kinetochore pushing movements and tripolar mitotic spindles occurred in cells lacking Klp5 but not Klp6. Kinesin-8–deletion strains showed large fluctuations in metaphase spindle length, suggesting a disruption of spindle length stabilization. Comparison of our results from light microscopy with a mathematical model suggests that kinesin-8–induced effects on microtubule dynamics, kinetochore attachment stability, and sliding force in the spindle can explain the aberrant chromosome movements and spindle length fluctuations seen. PMID:27146110

  16. Quantitative phosphoproteomics reveals new roles for the protein phosphatase PP6 in mitotic cells.

    Science.gov (United States)

    Rusin, Scott F; Schlosser, Kate A; Adamo, Mark E; Kettenbach, Arminja N

    2015-10-13

    Protein phosphorylation is an important regulatory mechanism controlling mitotic progression. Protein phosphatase 6 (PP6) is an essential enzyme with conserved roles in chromosome segregation and spindle assembly from yeast to humans. We applied a baculovirus-mediated gene silencing approach to deplete HeLa cells of the catalytic subunit of PP6 (PP6c) and analyzed changes in the phosphoproteome and proteome in mitotic cells by quantitative mass spectrometry-based proteomics. We identified 408 phosphopeptides on 272 proteins that increased and 298 phosphopeptides on 220 proteins that decreased in phosphorylation upon PP6c depletion in mitotic cells. Motif analysis of the phosphorylated sites combined with bioinformatics pathway analysis revealed previously unknown PP6c-dependent regulatory pathways. Biochemical assays demonstrated that PP6c opposed casein kinase 2-dependent phosphorylation of the condensin I subunit NCAP-G, and cellular analysis showed that depletion of PP6c resulted in defects in chromosome condensation and segregation in anaphase, consistent with dysregulation of condensin I function in the absence of PP6 activity. Copyright © 2015, American Association for the Advancement of Science.

  17. Inhibition of the mitotic exit network in response to damaged telomeres.

    Directory of Open Access Journals (Sweden)

    Mauricio Valerio-Santiago

    Full Text Available When chromosomal DNA is damaged, progression through the cell cycle is halted to provide the cells with time to repair the genetic material before it is distributed between the mother and daughter cells. In Saccharomyces cerevisiae, this cell cycle arrest occurs at the G2/M transition. However, it is also necessary to restrain exit from mitosis by maintaining Bfa1-Bub2, the inhibitor of the Mitotic Exit Network (MEN, in an active state. While the role of Bfa1 and Bub2 in the inhibition of mitotic exit when the spindle is not properly aligned and the spindle position checkpoint is activated has been extensively studied, the mechanism by which these proteins prevent MEN function after DNA damage is still unclear. Here, we propose that the inhibition of the MEN is specifically required when telomeres are damaged but it is not necessary to face all types of chromosomal DNA damage, which is in agreement with previous data in mammals suggesting the existence of a putative telomere-specific DNA damage response that inhibits mitotic exit. Furthermore, we demonstrate that the mechanism of MEN inhibition when telomeres are damaged relies on the Rad53-dependent inhibition of Bfa1 phosphorylation by the Polo-like kinase Cdc5, establishing a new key role of this kinase in regulating cell cycle progression.

  18. Insulin growth factors regulate the mitotic cycle in cultured rat sympathetic neuroblasts

    International Nuclear Information System (INIS)

    DiCicco-Bloom, E.; Black, I.B.

    1988-01-01

    While neuronal mitosis is uniquely restricted to early development, the underlying regulation remains to be defined. The authors have now developed a dissociated, embryonic sympathetic neuron culture system that uses fully defined medium in which cells enter the mitotic cycle. The cultured cells expressed two neuronal traits, tyrosine hydroxylase and the neuron-specific 160-kDa neurofilament subunit protein, but were devoid of glial fibrillary acidic protein, a marker for non-myelin-forming Schwann cells in ganglia. Approximately one-third of the tyrosine hydroxylase-positive cells synthesized DNA in culture, specifically incorporating [ 3 H]thymidine into their nuclei. They used this system to define factors regulating the mitotic cycle in sympathetic neuroblasts. Members of the insulin family of growth factors, including insulin and insulin-like growth factors I and II, regulated DNA synthesis in the presumptive neuroblasts. Insulin more than doubled the proportion of tyrosine hydroxylase-positive cells entering the mitotic cycle, as indicated by autoradiography of [ 3 H]thymidine incorporation into nuclei. Scintillation spectrometry was an even more sensitive index of DNA synthesis. In contrast, the trophic protein nerve growth factor exhibited no mitogenic effect, suggesting that the mitogenic action of insulin growth factors is highly specific. The observations are discussed in the context of the detection of insulin growth factors and receptors in the developing brain

  19. Kalanchoe tubiflora extract inhibits cell proliferation by affecting the mitotic apparatus.

    Science.gov (United States)

    Hsieh, Yi-Jen; Yang, Ming-Yeh; Leu, Yann-Lii; Chen, Chinpiao; Wan, Chin-Fung; Chang, Meng-Ya; Chang, Chih-Jui

    2012-09-10

    Kalanchoe tubiflora (KT) is a succulent plant native to Madagascar, and is commonly used as a medicinal agent in Southern Brazil. The underlying mechanisms of tumor suppression are largely unexplored. Cell viability and wound-healing were analyzed by MTT assay and scratch assay respectively. Cell cycle profiles were analyzed by FACS. Mitotic defects were analyzed by indirect immunofluoresence images. An n-Butanol-soluble fraction of KT (KT-NB) was able to inhibit cell proliferation. After a 48 h treatment with 6.75 μg/ml of KT, the cell viability was less than 50% of controls, and was further reduced to less than 10% at higher concentrations. KT-NB also induced an accumulation of cells in the G2/M phase of the cell cycle as well as an increased level of cells in the subG1 phase. Instead of disrupting the microtubule network of interphase cells, KT-NB reduced cell viability by inducing multipolar spindles and defects in chromosome alignment. KT-NB inhibits cell proliferation and reduces cell viability by two mechanisms that are exclusively involved with cell division: first by inducing multipolarity; second by disrupting chromosome alignment during metaphase. KT-NB reduced cell viability by exclusively affecting formation of the proper structure of the mitotic apparatus. This is the main idea of the new generation of anti-mitotic agents. All together, KT-NB has sufficient potential to warrant further investigation as a potential new anticancer agent candidate.

  20. Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade

    DEFF Research Database (Denmark)

    Purrington, Kristen S; Slettedahl, Seth; Bolla, Manjeet K

    2014-01-01

    polymorphisms (SNPs) from 194 mitotic genes and breast cancer risk, overall and by histologic grade, in the Breast Cancer Association Consortium (BCAC) iCOGS study (n = 39 067 cases; n = 42 106 controls). SNPs in TACC2 [rs17550038: odds ratio (OR) = 1.24, 95% confidence interval (CI) 1.16-1.33, P = 4.2 × 10......Mitotic index is an important component of histologic grade and has an etiologic role in breast tumorigenesis. Several small candidate gene studies have reported associations between variation in mitotic genes and breast cancer risk. We measured associations between 2156 single nucleotide......(-10)) and EIF3H (rs799890: OR = 1.07, 95% CI 1.04-1.11, P = 8.7 × 10(-6)) were significantly associated with risk of low-grade breast cancer. The TACC2 signal was retained (rs17550038: OR = 1.15, 95% CI 1.07-1.23, P = 7.9 × 10(-5)) after adjustment for breast cancer risk SNPs in the nearby FGFR2 gene...

  1. Late A-bomb effects on proliferation and mitotic inhibition of T- and B-lymphocytes

    Energy Technology Data Exchange (ETDEWEB)

    Suzuki, Kazuo; Yoshimoto, Yasuhiko; Sasagawa, Sumiko; Sakatani, Tatsuichiro; Macchi, M; Fujikura, Toshio; Pirofsky, B; Hamada, Tadao

    1984-11-01

    In order to investigate late effects of ionization radiation and aging on T- and B-lymphocytes, mitotic ability of T- and B-lymphocytes in the peripheral blood of 266 A-bomb survivors was examined by determining the incorporation of (/sup 3/H)-thymidine. Phytohemagglutinin (PHA) and pokeweed mitogen (PWM) were used as inducers. Furthermore, mitotic inhibition of lymphocytes induced by a lymphatic inhibitor which was in part prepared from ulex seed extracts (USE) was examined. A decreased reaction of peripheral lymphocytes to PHA was seen in men exposed to 100-199 rad; a decreased reaction to PWM was seen in women exposed to more than 200 rad. According to the age group at examination, these decreased reactions were remarkable in men aged 60 years or younger and women aged 60 years or older. Among men less than 60-year-old exposed to 100-199 rad, PWM-induced mitosis of lymphocytes tended to be inhibited remarkably by USE. These results suggest the involvement of late A-bomb effects in mitotic regulation of T- and B-lymphocytes of aged A-bomb survivors.

  2. A method for determining the biological effectiveness of ionizing radiation by evaluating the mitotic inhibition of Ehrlich ascites tumor cells

    International Nuclear Information System (INIS)

    Merkle, K.

    1977-03-01

    The mitotic response of mouse ascites tumor cells to in vivo 60 Co γ-irradiation (50, 100, 200, and 300 rad) was investigated on the fourth day after inoculation at 1 hour postirradiation. In the dose range applied the relationship between the mitotic index (MI) and the gamma dose (D, in rad) could be represented by MI = -35,07 lg D + 105,57. (author)

  3. The SUMO protease SENP1 is required for cohesion maintenance and mitotic arrest following spindle poison treatment

    Energy Technology Data Exchange (ETDEWEB)

    Era, Saho [Fondazione IFOM, Istituto FIRC di Oncologia Molecolare, IFOM-IEO campus, Via Adamello 16, 20139 Milan (Italy); Radiation Genetics, Graduate School of Medicine, Kyoto University, Yoshida-Konoe, Sakyo-ku, Kyoto 606-8501 (Japan); Abe, Takuya; Arakawa, Hiroshi [Fondazione IFOM, Istituto FIRC di Oncologia Molecolare, IFOM-IEO campus, Via Adamello 16, 20139 Milan (Italy); Kobayashi, Shunsuke [Radiation Genetics, Graduate School of Medicine, Kyoto University, Yoshida-Konoe, Sakyo-ku, Kyoto 606-8501 (Japan); Szakal, Barnabas [Fondazione IFOM, Istituto FIRC di Oncologia Molecolare, IFOM-IEO campus, Via Adamello 16, 20139 Milan (Italy); Yoshikawa, Yusuke; Motegi, Akira; Takeda, Shunichi [Radiation Genetics, Graduate School of Medicine, Kyoto University, Yoshida-Konoe, Sakyo-ku, Kyoto 606-8501 (Japan); Branzei, Dana, E-mail: dana.branzei@ifom.eu [Fondazione IFOM, Istituto FIRC di Oncologia Molecolare, IFOM-IEO campus, Via Adamello 16, 20139 Milan (Italy)

    2012-09-28

    Highlights: Black-Right-Pointing-Pointer SENP1 knockout chicken DT40 cells are hypersensitive to spindle poisons. Black-Right-Pointing-Pointer Spindle poison treatment of SENP1{sup -/-} cells leads to increased mitotic slippage. Black-Right-Pointing-Pointer Mitotic slippage in SENP1{sup -/-} cells associates with apoptosis and endoreplication. Black-Right-Pointing-Pointer SENP1 counteracts sister chromatid separation during mitotic arrest. Black-Right-Pointing-Pointer Plk1-mediated cohesion down-regulation is involved in colcemid cytotoxicity. -- Abstract: SUMO conjugation is a reversible posttranslational modification that regulates protein function. SENP1 is one of the six SUMO-specific proteases present in vertebrate cells and its altered expression is observed in several carcinomas. To characterize SENP1 role in genome integrity, we generated Senp1 knockout chicken DT40 cells. SENP1{sup -/-} cells show normal proliferation, but are sensitive to spindle poisons. This hypersensitivity correlates with increased sister chromatid separation, mitotic slippage, and apoptosis. To test whether the cohesion defect had a causal relationship with the observed mitotic events, we restored the cohesive status of sister chromatids by introducing the TOP2{alpha}{sup +/-} mutation, which leads to increased catenation, or by inhibiting Plk1 and Aurora B kinases that promote cohesin release from chromosomes during prolonged mitotic arrest. Although TOP2{alpha} is SUMOylated during mitosis, the TOP2{alpha}{sup +/-} mutation had no obvious effect. By contrast, inhibition of Plk1 or Aurora B rescued the hypersensitivity of SENP1{sup -/-} cells to colcemid. In conclusion, we identify SENP1 as a novel factor required for mitotic arrest and cohesion maintenance during prolonged mitotic arrest induced by spindle poisons.

  4. Cell radiosensitivity variation in synchronously-dividing root meristems of Pisum sativum L. and Zea mays L. during the mitotic cycle

    Energy Technology Data Exchange (ETDEWEB)

    Gudkov, I.N.; Grodzinsky, D.M. (AN Ukrainskoj SSR, Kiev. Inst. Fiziologii Rastenij)

    1982-04-01

    The cell divisions in pea and maize seedling root meristems were synchronized by treatment with 0.03 per cent hydroxyurea for 24 hours. At different times after block cessation (removing seedlings from hydroxyurea), i.e. according to certain phases and subphases of the mitotic cycle, the seedlings were treated with /sup 60/Co ..gamma..-radiation at doses from 3 to 32 Gy. Evaluation of seedling radioresistance by the survival of the main root meristem on the tenth day after irradiation led to the following sequence of cell stages in order of increasing resistance. For the pea root meristem: G/sub 2/, M, late G/sub 1/, early S, late S, middle S and early G/sub 1/. For the maize root meristem: late G/sub 2/, M, G/sub 1/, early S, early G/sub 2/, late S and middle S.

  5. Cell radiosensitivity variation in synchronously-dividing root meristems of Pisum sativum L. and Zea mays L. during the mitotic cycle

    International Nuclear Information System (INIS)

    Gudkov, I.N.; Grodzinsky, D.M.

    1982-01-01

    The cell divisions in pea and maize seedling root meristems were synchronized by treatment with 0.03 per cent hydroxyurea for 24 hours. At different times after block cessation (removing seedlings from hydroxyurea), i.e. according to certain phases and subphases of the mitotic cycle, the seedlings were treated with 60 Co γ-radiation at doses from 3 to 32 Gy. Evaluation of seedling radioresistance by the survival of the main root meristem on the tenth day after irradiation led to the following sequence of cell stages in order of increasing resistance. For the pea root meristem: G 2 , M, late G 1 , early S, late S, middle S and early G 1 . For the maize root meristem: late G 2 , M, G 1 , early S, early G 2 , late S and middle S. (author)

  6. Delayed cell death associated with mitotic catastrophe in γ-irradiated stem-like glioma cells

    International Nuclear Information System (INIS)

    Firat, Elke; Gaedicke, Simone; Tsurumi, Chizuko; Esser, Norbert; Weyerbrock, Astrid; Niedermann, Gabriele

    2011-01-01

    Stem-like tumor cells are regarded as highly resistant to ionizing radiation (IR). Previous studies have focused on apoptosis early after irradiation, and the apoptosis resistance observed has been attributed to reduced DNA damage or enhanced DNA repair compared to non-stem tumor cells. Here, early and late radioresponse of patient-derived stem-like glioma cells (SLGCs) and differentiated cells directly derived from them were examined for cell death mode and the influence of stem cell-specific growth factors. Primary SLGCs were propagated in serum-free medium with the stem-cell mitogens epidermal growth factor (EGF) and fibroblast growth factor-2 (FGF-2). Differentiation was induced by serum-containing medium without EGF and FGF. Radiation sensitivity was evaluated by assessing proliferation, clonogenic survival, apoptosis, and mitotic catastrophe. DNA damage-associated γH2AX as well as p53 and p21 expression were determined by Western blots. SLGCs failed to apoptose in the first 4 days after irradiation even at high single doses up to 10 Gy, but we observed substantial cell death later than 4 days postirradiation in 3 of 6 SLGC lines treated with 5 or 10 Gy. This delayed cell death was observed in 3 of the 4 SLGC lines with nonfunctional p53, was associated with mitotic catastrophe and occurred via apoptosis. The early apoptosis resistance of the SLGCs was associated with lower γH2AX compared to differentiated cells, but we found that the stem-cell culture cytokines EGF plus FGF-2 strongly reduce γH2AX levels. Nonetheless, in two p53-deficient SLGC lines examined γIR-induced apoptosis even correlated with EGF/FGF-induced proliferation and mitotic catastrophe. In a line containing CD133-positive and -negative stem-like cells, the CD133-positive cells proliferated faster and underwent more γIR-induced mitotic catastrophe. Our results suggest the importance of delayed apoptosis, associated mitotic catastrophe, and cellular proliferation for γIR-induced death of

  7. Inhibition of the Ras-ERK pathway in mitotic COS7 cells is due to the inability of EGFR/Raf to transduce EGF signaling to downstream proteins.

    Science.gov (United States)

    Shi, Huaiping; Zhang, Tianying; Yi, Yongqing; Ma, Yue

    2016-06-01

    Although previous studies have shown that Ras-ERK signaling in mitosis is closed due to the inhibition of signal transduction, the events involved in the molecular mechanisms are still unclear. In the present study, we investigated the Ras-ERK signaling pathway in mitotic COS7 cells. The results demonstrated that treatment with epidermal growth factor (EGF) failed to increase the endocytosis of EGF-EGFR (EGF receptor) complexes in mitotic COS7 cells, although a large amount of endosomes were found in asynchronous COS7 cells. Clathrin expression levels in mitotic COS7 cells were inhibited whereas caveolin expression levels in mitotic COS7 cells were almost unaffected. Y1068 and Y1086 residues of EGFR in the mitotic COS7 cells were activated. However, Grb2 and Shc in the mitotic COS7 cells did not bind to activated EGFR. Ras activity was inhibited in the mitotic COS7 cells whereas its downstream protein, Raf, was obviously phosphorylated by EGF in mitosis. Treatment with phorbol 12-myristate 13-acetate (PMA) also increased the phosphorylation levels of Raf in the mitotic COS7 cells. Nevertheless, Raf phosphorylation in mitosis was significantly inhibited by AG1478. Lastly, activation of EGF-mediated MEK and ERK in the mitotic COS7 cells was obviously inhibited. In summary, our results suggest that the Ras-ERK pathway is inhibited in mitotic COS7 cells which may be the dual result of the difficulty in the transduction of EGF signaling by EGFR or Raf to downstream proteins.

  8. Ste12/Fab1 phosphatidylinositol-3-phosphate 5-kinase is required for nitrogen-regulated mitotic commitment and cell size control.

    Directory of Open Access Journals (Sweden)

    David Cobley

    Full Text Available Tight coupling of cell growth and cell cycle progression enable cells to adjust their rate of division, and therefore size, to the demands of proliferation in varying nutritional environments. Nutrient stress promotes inhibition of Target Of Rapamycin Complex 1 (TORC1 activity. In fission yeast, reduced TORC1 activity advances mitotic onset and switches growth to a sustained proliferation at reduced cell size. A screen for mutants, that failed to advance mitosis upon nitrogen stress, identified a mutant in the PIKFYVE 1-phosphatidylinositol-3-phosphate 5-kinase fission yeast homolog Ste12. Ste12PIKFYVE deficient mutants were unable to advance the cell cycle to reduce cell size after a nitrogen downshift to poor nitrogen (proline growth conditions. While it is well established that PI(3,5P2 signalling is required for autophagy and that Ste12PIKFYVE mutants have enlarged vacuoles (yeast lysosomes, neither a block to autophagy or mutants that independently have enlarged vacuoles had any impact upon nitrogen control of mitotic commitment. The addition of rapamycin to Ste12PIKFYVE deficient mutants reduced cell size at division to suggest that Ste12PIKFYVE possibly functions upstream of TORC1. ste12 mutants display increased Torin1 (TOR inhibitor sensitivity. However, no major impact on TORC1 or TORC2 activity was observed in the ste12 deficient mutants. In summary, Ste12PIKFYVE is required for nitrogen-stress mediated advancement of mitosis to reduce cell size at division.

  9. G1- and S-phase syntheses of histones H1 and H1o in mitotically selected CHO cells: utilization of high-performance liquid chromatography

    International Nuclear Information System (INIS)

    D'Anna, J.A.; Thayer, M.M.; Tobey, R.A.; Gurley, L.R.

    1985-01-01

    The authors have employed high-performance liquid chromatography (HPLC) to investigate the syntheses of histones H1 and H1o as synchronized cells traverse from mitosis to S phase. Chinese hamster (line CHO) cells were synchronized by mitotic selection, and, at appropriate times, they were pulse labeled for 1 h with [ 3 H]lysine. Histones H1 and H1o were extracted by blending radiolabeled and carrier cells directly in 0.83 M HC1O 4 ; the total HC1O 4 -soluble, Cl 3 CCO 2 H-precipitable proteins were then separated by a modification of an HPLC system employing three mu Bondapak reversed-phase columns. These procedures (1) produce minimally perturbed populations of synchronized proliferating cells and (2) maximize the recovery of radiolabeled histones during isolation and analysis. Measurements of rates of synthesis indicate that the rate of H1 synthesis increases as cells traverse from early to mid G1; as cells enter S phase, the rate of H1 synthesis increases an additional congruent to 22-fold and is proportional to the number of S-phase cells. In contrast to H1, the rate of H1o synthesis is nearly constant throughout G1. As cells progress into S phase, the rate of H1o synthesis increases so that it also appears to be proportional to the number of S-phase cells. Except for the first 1-2 h after mitotic selection, these results are similar to those obtained when cells are synchronized in G1 with the isoleucine deprivation procedure

  10. Abrupt onset of mutations in a developmentally regulated gene during terminal differentiation of post-mitotic photoreceptor neurons in mice.

    Directory of Open Access Journals (Sweden)

    Ivette M Sandoval

    Full Text Available For sensitive detection of rare gene repair events in terminally differentiated photoreceptors, we generated a knockin mouse model by replacing one mouse rhodopsin allele with a form of the human rhodopsin gene that causes a severe, early-onset form of retinitis pigmentosa. The human gene contains a premature stop codon at position 344 (Q344X, cDNA encoding the enhanced green fluorescent protein (EGFP at its 3' end, and a modified 5' untranslated region to reduce translation rate so that the mutant protein does not induce retinal degeneration. Mutations that eliminate the stop codon express a human rhodopsin-EGFP fusion protein (hRho-GFP, which can be readily detected by fluorescence microscopy. Spontaneous mutations were observed at a frequency of about one per retina; in every case, they gave rise to single fluorescent rod cells, indicating that each mutation occurred during or after the last mitotic division. Additionally, the number of fluorescent rods did not increase with age, suggesting that the rhodopsin gene in mature rod cells is less sensitive to mutation than it is in developing rods. Thus, there is a brief developmental window, coinciding with the transcriptional activation of the rhodopsin locus, in which somatic mutations of the rhodopsin gene abruptly begin to appear.

  11. Evaluation of the response of concurrent high dose rate intracavitary brachytherapy with external beam radiotherapy in management of early stage carcinoma cervix.

    Science.gov (United States)

    Patidar, Arvind Kumar; Kumar, H S; Walke, Rahul V; Hirapara, Pushpendra H; Jakhar, Shankar Lal; Bardia, M R

    2012-10-01

    To evaluate local disease control and early complications of concomitant brachytherapy with external beam-radiotherapy in early stage carcinoma cervix. Fifty patients of early stage carcinoma cervix (FIGO-IB/IIA) were randomly divided into study group concomitant external beam irradiation (EBRT) and HDR-ICBT (intra-cavitary brachytherapy, xrt = 50 Gy/25 Fr, HDR 5.2 Gy*5 Fr) and the control group EBRT followed by HDR-ICBT (xrt = 50 Gy/25 Fr, HDR 7.5 Gy*3 Fr). Acute reactions and local disease response were compared between treatment and at 6-month follow up. Median overall treatment times were 38 and 61 days in the study and the control groups, respectively. Acute skin reactions and diarrhea were more in the study but manageable. At the completion of the study, there were 80 and 68 % complete responses, 16 and 20 % partial responses, 0 and 8 % stable diseases in the study group and the control group, respectively. Response was better in the study group but statistically insignificant. Larger number of patients and longer follow up are required to arrive at concrete conclusion.

  12. The MiAge Calculator: a DNA methylation-based mitotic age calculator of human tissue types.

    Science.gov (United States)

    Youn, Ahrim; Wang, Shuang

    2018-01-01

    Cell division is important in human aging and cancer. The estimation of the number of cell divisions (mitotic age) of a given tissue type in individuals is of great interest as it allows not only the study of biological aging (using a new molecular aging target) but also the stratification of prospective cancer risk. Here, we introduce the MiAge Calculator, a mitotic age calculator based on a novel statistical framework, the MiAge model. MiAge is designed to quantitatively estimate mitotic age (total number of lifetime cell divisions) of a tissue using the stochastic replication errors accumulated in the epigenetic inheritance process during cell divisions. With the MiAge model, the MiAge Calculator was built using the training data of DNA methylation measures of 4,020 tumor and adjacent normal tissue samples from eight TCGA cancer types and was tested using the testing data of DNA methylation measures of 2,221 tumor and adjacent normal tissue samples of five other TCGA cancer types. We showed that within each of the thirteen cancer types studied, the estimated mitotic age is universally accelerated in tumor tissues compared to adjacent normal tissues. Across the thirteen cancer types, we showed that worse cancer survivals are associated with more accelerated mitotic age in tumor tissues. Importantly, we demonstrated the utility of mitotic age by showing that the integration of mitotic age and clinical information leads to improved survival prediction in six out of the thirteen cancer types studied. The MiAge Calculator is available at http://www.columbia.edu/∼sw2206/softwares.htm .

  13. Plk1 inhibition causes post-mitotic DNA damage and senescence in a range of human tumor cell lines.

    Directory of Open Access Journals (Sweden)

    Denise L Driscoll

    Full Text Available Plk1 is a checkpoint protein whose role spans all of mitosis and includes DNA repair, and is highly conserved in eukaryotes from yeast to man. Consistent with this wide array of functions for Plk1, the cellular consequences of Plk1 disruption are diverse, spanning delays in mitotic entry, mitotic spindle abnormalities, and transient mitotic arrest leading to mitotic slippage and failures in cytokinesis. In this work, we present the in vitro and in vivo consequences of Plk1 inhibition in cancer cells using potent, selective small-molecule Plk1 inhibitors and Plk1 genetic knock-down approaches. We demonstrate for the first time that cellular senescence is the predominant outcome of Plk1 inhibition in some cancer cell lines, whereas in other cancer cell lines the dominant outcome appears to be apoptosis, as has been reported in the literature. We also demonstrate strong induction of DNA double-strand breaks in all six lines examined (as assayed by γH2AX, which occurs either during mitotic arrest or mitotic-exit, and may be linked to the downstream induction of senescence. Taken together, our findings expand the view of Plk1 inhibition, demonstrating the occurrence of a non-apoptotic outcome in some settings. Our findings are also consistent with the possibility that mitotic arrest observed as a result of Plk1 inhibition is at least partially due to the presence of unrepaired double-strand breaks in mitosis. These novel findings may lead to alternative strategies for the development of novel therapeutic agents targeting Plk1, in the selection of biomarkers, patient populations, combination partners and dosing regimens.

  14. Interaction between the effects of evaporation rate and amount of simulated rainfall on development of the free-living stages of Haemonchus contortus.

    Science.gov (United States)

    O'Connor, Lauren J; Kahn, Lewis P; Walkden-Brown, Stephen W

    2008-08-17

    A factorial experiment (3 x 4 x 2 x 3) was conducted in programmable incubators to investigate interaction between the effects of rainfall amount, rainfall distribution and evaporation rate on development of Haemonchus contortus to L3. Sheep faeces containing H. contortus eggs were incubated on sterilised soil under variable temperatures typical of summer in the Northern Tablelands of NSW, Australia. Simulated rainfall was applied in 1 of 3 amounts (12, 24 or 32 mm) and 4 distributions (a single event on the day after deposition, or the same total amount split in 2, 3 or 4 equal events over 2, 3 or 4 days, respectively). Samples were incubated at either a Low or High rate of evaporation (Low: 2.1-3.4 mm/day and High: 3.8-6.1 mm/day), and faeces and soil were destructively sampled at 4, 7 and 14 days post-deposition. Recovery of L3 from the soil (extra-pellet L3) increased over time (up to 0.52% at day 14) and with each increment of rainfall (12 mm: evaporation rate (0.01%) compared with the Low evaporation rate (0.31%). All rainfall amounts yielded significantly different recoveries of L3 under Low evaporation rates but there was no difference between the 12 and 24 mm treatments under the High evaporation rate. The distribution of simulated rainfall did not significantly affect recovery of infective larvae. Faecal moisture content was positively associated with L3 recovery, as was the ratio of cumulative precipitation and cumulative evaporation (P/E), particularly when measured in the first 4 days post-deposition. The results show that evaporation rate plays a significant role in regulating the influence of rainfall amount on the success of L3 transmission.

  15. Prospective Multi-Institutional Study of Definitive Radiotherapy With High-Dose-Rate Intracavitary Brachytherapy in Patients With Nonbulky (<4-cm) Stage I and II Uterine Cervical Cancer (JAROG0401/JROSG04-2)

    Energy Technology Data Exchange (ETDEWEB)

    Toita, Takafumi, E-mail: b983255@med.u-ryukyu.ac.jp [Department of Radiology, Graduate School of Medical Science, University of Ryukyus, Okinawa (Japan); Kato, Shingo [Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba (Japan); Niibe, Yuzuru [Department of Radiology, School of Medicine, Kitasato University, Sagamihara (Japan); Ohno, Tatsuya [Gunma University Heavy Ion Medical Center, Maebashi (Japan); Kazumoto, Tomoko [Department of Radiology, Saitama Cancer Center, Saitama (Japan); Kodaira, Takeshi [Department of Radiation Oncology, Aichi Cancer Center, Nagoya (Japan); Kataoka, Masaaki [Department of Radiology, National Shikoku Cancer Center, Ehime (Japan); Shikama, Naoto [Department of Radiation Oncology, Saku Central Hospital, Saku (Japan); Kenjo, Masahiro [Department of Radiation Oncology, Graduate School of Medical Science, Hiroshima University, Hiroshima (Japan); Tokumaru, Sunao [Department of Radiology, Saga University, Saga (Japan); Yamauchi, Chikako [Department of Radiation Oncology, Shiga Medical Center for Adults, Moriyama (Japan); Suzuki, Osamu [Department of Radiation Oncology, Osaka Medical Center for Cancer, Osaka (Japan); Sakurai, Hideyuki [Proton Medical Research Center and Tsukuba University, Tsukuba (Japan); Numasaki, Hodaka; Teshima, Teruki [Department of Medical Physics and Engineering, Graduate School of Medicine, Osaka University, Suita, Osaka (Japan); Oguchi, Masahiko [Department of Radiation Oncology, Cancer Institute Hospital, Tokyo (Japan); Kagami, Yoshikazu [Radiation Oncology Division, National Cancer Center Hospital, Tokyo (Japan); Nakano, Takashi [Department of Radiation Oncology, Gunma University, Graduate School of Medicine, Maebashi (Japan); Hiraoka, Masahiro [Department of Radiation Oncology and Image-applied Therapy, Kyoto University, Graduate School of Medicine, Kyoto (Japan); Mitsuhashi, Norio [Department of Radiation Oncology, Tokyo Women' s Medical University, Tokyo (Japan)

    2012-01-01

    Purpose: To determine the efficacy of a definitive radiotherapy protocol using high-dose-rate intracavitary brachytherapy (HDR-ICBT) with a low cumulative dose schedule in nonbulky early-stage cervical cancer patients, we conducted a prospective multi-institutional study. Methods and Materials: Eligible patients had squamous cell carcinoma of the intact uterine cervix, Federation of Gynecologic Oncology and Obstetrics (FIGO) stages Ib1, IIa, and IIb, tumor size <40 mm in diameter (assessed by T2-weighted magnetic resonance imaging), and no pelvic/para-aortic lymphadenopathy. The treatment protocol consisted of whole-pelvis external beam radiotherapy (EBRT) of 20 Gy/10 fractions, pelvic EBRT with midline block of 30 Gy/15 fractions, and HDR-ICBT of 24 Gy/4 fractions (at point A). The cumulative biologically effective dose (BED) was 62 Gy{sub 10} ({alpha}/{beta} = 10) at point A. The primary endpoint was the 2-year pelvic disease progression-free (PDPF) rate. All patients received a radiotherapy quality assurance review. Results: Between September 2004 and July 2007, 60 eligible patients were enrolled. Thirty-six patients were assessed with FIGO stage Ib1; 12 patients with stage IIa; and 12 patients with stage IIb. Median tumor diameter was 28 mm (range, 6-39 mm). Median overall treatment time was 43 days. Median follow-up was 49 months (range, 7-72 months). Seven patients developed recurrences: 3 patients had pelvic recurrences (2 central, 1 nodal), and 4 patients had distant metastases. The 2-year PDPF was 96% (95% confidence interval [CI], 92%-100%). The 2-year disease-free and overall survival rates were 90% (95% CI, 82%-98%) and 95% (95% CI, 89%-100%), respectively. The 2-year late complication rates (according to Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer of Grade {>=}1) were 18% (95% CI, 8%-28%) for large intestine/rectum, 4% (95% CI, 0%-8%) for small intestine, and 0% for bladder. No Grade {>=}3 cases were

  16. A gene encoding the major beta tubulin of the mitotic spindle in Physarum polycephalum plasmodia

    Energy Technology Data Exchange (ETDEWEB)

    Burland, T.G.; Paul, E.C.A.; Oetliker, M.; Dove, W.F.

    1988-03-01

    The multinucleate plasmodium of Physarum polycephalum is unusual among eucaryotic cells in that it uses tubulins only in mitotic-spindle microtubules; cytoskeletal, flagellar, and centriolar microtubules are absent in this cell type. The authors identified a ..beta..-tubulin cDNA clone, ..beta..105, which is shown to correspond to the transcript of the betC ..beta..-tubulin locus and to encode ..beta..2 tubulin, the ..beta.. tubulin expressed specifically in the plasmodium and used exclusively in the mitotic spindle. Physarum amoebae utilize tubulins in the cytoskeleton, centrioles, and flagella, in addition to the mitotic spindle. Sequence analysis shows that ..beta..2 tubulin is only 83% identical to the two ..beta.. tubulins expressed in amoebae. This compares with 70 to 83% identity between Physarum ..beta..2 tubulin and the ..beta.. tubulins of yeasts, fungi, alga, trypanosome, fruit fly, chicken, and mouse. On the other hand, Physarum ..beta..2 tubulin is no more similar to, for example, Aspergillus ..beta.. tubulins than it is to those of Drosophila melanogaster or mammals. Several eucaryotes express at least one widely diverged ..beta.. tubulin as well as one or more ..beta.. tubulins that conform more closely to a consensus ..beta..-tubulin sequence. The authors suggest that ..beta..-tubulins diverge more when their expression pattern is restricted, especially when this restriction results in their use in fewer functions. This divergence among ..beta.. tubulins could have resulted through neutral drift. For example, exclusive use of Physarum ..beta..2 tubulin in the spindle may have allowed more amino acid substitutions than would be functionally tolerable in the ..beta.. tubulins that are utilized in multiple microtubular organelles. Alternatively, restricted use of ..beta.. tubulins may allow positive selection to operate more freely to refine ..beta..-tubulin function.

  17. Kalanchoe tubiflora extract inhibits cell proliferation by affecting the mitotic apparatus

    Directory of Open Access Journals (Sweden)

    Hsieh Yi-Jen

    2012-09-01

    Full Text Available Abstract Background Kalanchoe tubiflora (KT is a succulent plant native to Madagascar, and is commonly used as a medicinal agent in Southern Brazil. The underlying mechanisms of tumor suppression are largely unexplored. Methods Cell viability and wound-healing were analyzed by MTT assay and scratch assay respectively. Cell cycle profiles were analyzed by FACS. Mitotic defects were analyzed by indirect immunofluoresence images. Results An n-Butanol-soluble fraction of KT (KT-NB was able to inhibit cell proliferation. After a 48 h treatment with 6.75 μg/ml of KT, the cell viability was less than 50% of controls, and was further reduced to less than 10% at higher concentrations. KT-NB also induced an accumulation of cells in the G2/M phase of the cell cycle as well as an increased level of cells in the subG1 phase. Instead of disrupting the microtubule network of interphase cells, KT-NB reduced cell viability by inducing multipolar spindles and defects in chromosome alignment. KT-NB inhibits cell proliferation and reduces cell viability by two mechanisms that are exclusively involved with cell division: first by inducing multipolarity; second by disrupting chromosome alignment during metaphase. Conclusion KT-NB reduced cell viability by exclusively affecting formation of the proper structure of the mitotic apparatus. This is the main idea of the new generation of anti-mitotic agents. All together, KT-NB has sufficient potential to warrant further investigation as a potential new anticancer agent candidate.

  18. Exclusion of NFAT5 from mitotic chromatin resets its nucleo-cytoplasmic distribution in interphase.

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    Anaïs Estrada-Gelonch

    Full Text Available BACKGROUND: The transcription factor NFAT5 is a major inducer of osmoprotective genes and is required to maintain the proliferative capacity of cells exposed to hypertonic stress. In response to hypertonicity, NFAT5 translocates to the nucleus, binds to regulatory regions of osmoprotective genes and activates their transcription. Besides stimulus-specific regulatory mechanisms, the activity of transcription factors in cycling cells is also regulated by the passage through mitosis, when most transcriptional processes are downregulated. It was not known whether mitosis could be a point of control for NFAT5. METHODOLOGY/PRINCIPAL FINDINGS: Using confocal microscopy we observed that NFAT5 was excluded from chromatin during mitosis in both isotonic and hypertonic conditions. Analysis of NFAT5 deletions showed that exclusion was mediated by the carboxy-terminal domain (CTD. NFAT5 mutants lacking this domain showed constitutive binding to mitotic chromatin independent of tonicity, which caused them to localize in the nucleus and remain bound to chromatin in the subsequent interphase without hypertonic stimulation. We analyzed the contribution of the CTD, DNA binding, and nuclear import and export signals to the subcellular localization of this factor. Our results indicated that cytoplasmic localization of NFAT5 in isotonic conditions required both the exclusion from mitotic DNA and active nuclear export in interphase. Finally, we identified several regions within the CTD of NFAT5, some of them overlapping with transactivation domains, which were separately capable of causing its exclusion from mitotic chromatin. CONCLUSIONS/SIGNIFICANCE: Our results reveal a multipart mechanism regulating the subcellular localization of NFAT5. The transactivating module of NFAT5 switches its function from an stimulus-specific activator of transcription in interphase to an stimulus-independent repressor of binding to DNA in mitosis. This mechanism, together with export

  19. Functional characterisation and drug target validation of a mitotic kinesin-13 in Trypanosoma brucei.

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    Kuan Yoow Chan

    2010-08-01

    Full Text Available Mitotic kinesins are essential for faithful chromosome segregation and cell proliferation. Therefore, in humans, kinesin motor proteins have been identified as anti-cancer drug targets and small molecule inhibitors are now tested in clinical studies. Phylogenetic analyses have assigned five of the approximately fifty kinesin motor proteins coded by Trypanosoma brucei genome to the Kinesin-13 family. Kinesins of this family have unusual biochemical properties because they do not transport cargo along microtubules but are able to depolymerise microtubules at their ends, therefore contributing to the regulation of microtubule length. In other eukaryotic genomes sequenced to date, only between one and three Kinesin-13s are present. We have used immunolocalisation, RNAi-mediated protein depletion, biochemical in vitro assays and a mouse model of infection to study the single mitotic Kinesin-13 in T. brucei. Subcellular localisation of all five T. brucei Kinesin-13s revealed distinct distributions, indicating that the expansion of this kinesin family in kinetoplastids is accompanied by functional diversification. Only a single kinesin (TbKif13-1 has a nuclear localisation. Using active, recombinant TbKif13-1 in in vitro assays we experimentally confirm the depolymerising properties of this kinesin. We analyse the biological function of TbKif13-1 by RNAi-mediated protein depletion and show its central role in regulating spindle assembly during mitosis. Absence of the protein leads to abnormally long and bent mitotic spindles, causing chromosome mis-segregation and cell death. RNAi-depletion in a mouse model of infection completely prevents infection with the parasite. Given its essential role in mitosis, proliferation and survival of the parasite and the availability of a simple in vitro activity assay, TbKif13-1 has been identified as an excellent potential drug target.

  20. Being born under adverse economic conditions leads to a higher cardiovascular mortality rate later in life: evidence based on individuals born at different stages of the business cycle.

    Science.gov (United States)

    van den Berg, Gerard J; Doblhammer-Reiter, Gabriele; Christensen, Kaare

    2011-05-01

    We connect the recent medical and economic literatures on the long-run effects of early-life conditions by analyzing the effects of economic conditions on the individual cardiovascular (CV) mortality rate later in life, using individual data records from the Danish Twin Registry covering births since the 1870s and including the cause of death. To capture exogenous variation of conditions early in life, we use the state of the business cycle around birth. We find significant negative effects of economic conditions around birth on the individual CV mortality rate at higher ages. There is no effect on the cancer-specific mortality rate. From variation within and between monozygotic and dizygotic twin pairs born under different conditions, we conclude that the fate of an individual is more strongly determined by genetic and household-environmental factors if early-life conditions are poor. Individual-specific qualities come more to fruition if the starting position in life is better.

  1. Effects of Mutagen-Sensitive Mus Mutations on Spontaneous Mitotic Recombination in Aspergillus

    OpenAIRE

    Zhao, P.; Kafer, E.

    1992-01-01

    Methyl methane-sulfonate (MMS)-sensitive, radiation-induced mutants of Aspergillus were shown to define nine new DNA repair genes, musK to musS. To test mus mutations for effects on mitotic recombination, intergenic crossing over was assayed between color markers and their centromeres, and intragenic recombination between two distinguishable adE alleles. Of eight mutants analyzed, four showed significant deviations from mus(+) controls in both tests. Two mutations, musK and musL, reduced reco...

  2. Mitotic chromosome loss in a radiation-sensitive strain of the yeast Saccharomyces cerevisiae

    International Nuclear Information System (INIS)

    Mortimer, R.K.; Contopoulou, R.; Schild, D.

    1981-01-01

    Cells of Saccharomyces cerevisiae with mutations in the RAD52 gene have previously been shown to be defective in meiotic and mitotic recombination, in sporulation, and in repair of radiation-induced damage to DNA. In this study we show that diploid cells homozygous for rad52 lose chromosomes at high frequencies and that these frequencies of loss can be increased dramatically by exposure of these cells to x-rays. Genetic analyses of survivors of x-ray treatment demonstrate that chromosome loss events result in the conversion of diploid cells to cells with near haploid chromosome numbers

  3. STAG2 and Rad21 mammalian mitotic cohesins are implicated in meiosis

    OpenAIRE

    Prieto, Ignacio; Pezzi, Nieves; Buesa, José M.; Kremer, Leonor; Barthelemy, Isabel; Carreiro, Candelas; Roncal, Fernando; Martínez, Alicia; Gómez, Lucio; Fernández, Raúl; Martínez-A, Carlos; Barbero, José L.

    2002-01-01

    STAG/SA proteins are specific cohesin complex subunits that maintain sister chromatid cohesion in mitosis and meiosis. Two members of this family, STAG1/SA1 and STAG2/SA2,‡ are classified as mitotic cohesins, as they are found in human somatic cells and in Xenopus laevis as components of the cohesinSA1 and cohesinSA2 complexes, in which the shared subunits are Rad21/SCC1, SMC1 and SMC3 proteins. A recently reported third family member, STAG3, is germinal cell-specific and is a subunit of the ...

  4. Evidence that phosphorylation by the mitotic kinase Cdk1 promotes ICER monoubiquitination and nuclear delocalization

    Energy Technology Data Exchange (ETDEWEB)

    Memin, Elisabeth, E-mail: molinac@mail.montclair.edu [Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, NJ 07103 (United States); Genzale, Megan [Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, NJ 07103 (United States); Crow, Marni; Molina, Carlos A. [Department of Biology and Molecular Biology, Montclair State University, Montclair, NJ, 07043 (United States)

    2011-10-15

    In contrast to normal prostatic cells, the transcriptional repressor Inducible cAMP Early Repressor (ICER) is undetected in the nuclei of prostate cancer cells. The molecular mechanisms for ICER abnormal expression in prostate cancer cells remained largely unknown. In this report data is presented demonstrating that ICER is phosphorylated by the mitotic kinase cdk1. Phosphorylation of ICER on a discrete residue targeted ICER to be monoubiquitinated. Different from unphosphorylated, phosphorylated and polyubiquitinated ICER, monoubiquitinated ICER was found to be cytosolic. Taken together, these results hinted on a mechanism for the observed abnormal subcellular localization of ICER in human prostate tumors.

  5. Induction of high mitotic index in Petunia suspension cultures by sequential treatment with aphidicolin and colchicine.

    Science.gov (United States)

    Guri, A; Zelcer, A; Izhar, S

    1984-12-01

    Significantly higher than normal mitotic index (MI) values were induced in Petunia cell suspensions following treatments with colchicine, aphidicolin, drastic medium replacement, or a sequential application of aphidicolin and colchicine. This last treatment yielded the highest MI values: cells incubated with 30 μg/ml aphidicolin for 18 h, then cultured in drug-free medium for 8 h and finally exposed to 0.1% colchicine for 8 additional hours exhibited MI of 62.8% and 65.7% respectively, for the two cell lines in study.

  6. Mitotic and meiotic chromosomes of a southern Brazilian population of Boophilus microplus (Acari, Ixodidae

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    Rosane Nunes Garcia

    Full Text Available Using conventional staining with acetic orcein and C-banding techniques it was investigated constitutive heterochromatin chromosomal polymorphisms and the mitotic and the meiotic behavior of male and female chromosomes of Boophilus microplus (Canestrini, 1887. Some differences were detected in the population of southern Brazil as compared to the data of other authors for populations in other latitudes. The differences being mainly concerned with the distribution of constitutive centromeric heterochromatin and variation in the length of heterochromatic blocks in the pericentromeric regions of some chromosome pairs.

  7. Discrimination of bromodeoxyuridine labelled and unlabelled mitotic cells in flow cytometric bromodeoxyuridine/DNA analysis

    DEFF Research Database (Denmark)

    Jensen, P O; Larsen, J K; Christensen, I J

    1994-01-01

    Bromodeoxyuridine (BrdUrd) labelled and unlabelled mitotic cells, respectively, can be discriminated from interphase cells using a new method, based on immunocytochemical staining of BrdUrd and flow cytometric four-parameter analysis of DNA content, BrdUrd incorporation, and forward and orthogonal...... light scatter. The method was optimized using the human leukemia cell lines HL-60 and K-562. Samples of 10(5) ethanol-fixed cells were treated with pepsin/HCl and stained as a nuclear suspension with anti-BrdUrd antibody, FITC-conjugated secondary antibody, and propidium iodide. Labelled mitoses could...

  8. Combining magnetic sorting of mother cells and fluctuation tests to analyze genome instability during mitotic cell aging in Saccharomyces cerevisiae.

    Science.gov (United States)

    Patterson, Melissa N; Maxwell, Patrick H

    2014-10-16

    Saccharomyces cerevisiae has been an excellent model system for examining mechanisms and consequences of genome instability. Information gained from this yeast model is relevant to many organisms, including humans, since DNA repair and DNA damage response factors are well conserved across diverse species. However, S. cerevisiae has not yet been used to fully address whether the rate of accumulating mutations changes with increasing replicative (mitotic) age due to technical constraints. For instance, measurements of yeast replicative lifespan through micromanipulation involve very small populations of cells, which prohibit detection of rare mutations. Genetic methods to enrich for mother cells in populations by inducing death of daughter cells have been developed, but population sizes are still limited by the frequency with which random mutations that compromise the selection systems occur. The current protocol takes advantage of magnetic sorting of surface-labeled yeast mother cells to obtain large enough populations of aging mother cells to quantify rare mutations through phenotypic selections. Mutation rates, measured through fluctuation tests, and mutation frequencies are first established for young cells and used to predict the frequency of mutations in mother cells of various replicative ages. Mutation frequencies are then determined for sorted mother cells, and the age of the mother cells is determined using flow cytometry by staining with a fluorescent reagent that detects bud scars formed on their cell surfaces during cell division. Comparison of predicted mutation frequencies based on the number of cell divisions to the frequencies experimentally observed for mother cells of a given replicative age can then identify whether there are age-related changes in the rate of accumulating mutations. Variations of this basic protocol provide the means to investigate the influence of alterations in specific gene functions or specific environmental conditions on

  9. Being born under adverse economic conditions leads to a higher cardiovascular mortality rate later in life: evidence based on individuals born at different stages of the business cycle

    DEFF Research Database (Denmark)

    van den Berg, Gerard J; Doblhammer-Reiter, Gabriele; Christensen, Kaare

    2011-01-01

    since the 1870s and including the cause of death. To capture exogenous variation of conditions early in life, we use the state of the business cycle around birth. We find significant negative effects of economic conditions around birth on the individual CV mortality rate at higher ages...

  10. Taxifolin enhances andrographolide-induced mitotic arrest and apoptosis in human prostate cancer cells via spindle assembly checkpoint activation.

    Directory of Open Access Journals (Sweden)

    Zhong Rong Zhang

    Full Text Available Andrographolide (Andro suppresses proliferation and triggers apoptosis in many types of cancer cells. Taxifolin (Taxi has been proposed to prevent cancer development similar to other dietary flavonoids. In the present study, the cytotoxic and apoptotic effects of the addition of Andro alone and Andro and Taxi together on human prostate carcinoma DU145 cells were assessed. Andro inhibited prostate cancer cell proliferation by mitotic arrest and activation of the intrinsic apoptotic pathway. Although the effect of Taxi alone on DU145 cell proliferation was not significant, the combined use of Taxi with Andro significantly potentiated the anti-proliferative effect of increased mitotic arrest and apoptosis by enhancing the cleavage of poly(ADP-ribose polymerase, and caspases-7 and -9. Andro together with Taxi enhanced microtubule polymerization in vitro, and they induced the formation of twisted and elongated spindles in the cancer cells, thus leading to mitotic arrest. In addition, we showed that depletion of MAD2, a component in the spindle assembly checkpoint (SAC, alleviated the mitotic block induced by the two compounds, suggesting that they trigger mitotic arrest by SAC activation. This study suggests that the anti-cancer activity of Andro can be significantly enhanced in combination with Taxi by disrupting microtubule dynamics and activating the SAC.

  11. Taxifolin Enhances Andrographolide-Induced Mitotic Arrest and Apoptosis in Human Prostate Cancer Cells via Spindle Assembly Checkpoint Activation

    Science.gov (United States)

    Wong, Matthew Man-Kin; Chiu, Sung-Kay; Cheung, Hon-Yeung

    2013-01-01

    Andrographolide (Andro) suppresses proliferation and triggers apoptosis in many types of cancer cells. Taxifolin (Taxi) has been proposed to prevent cancer development similar to other dietary flavonoids. In the present study, the cytotoxic and apoptotic effects of the addition of Andro alone and Andro and Taxi together on human prostate carcinoma DU145 cells were assessed. Andro inhibited prostate cancer cell proliferation by mitotic arrest and activation of the intrinsic apoptotic pathway. Although the effect of Taxi alone on DU145 cell proliferation was not significant, the combined use of Taxi with Andro significantly potentiated the anti-proliferative effect of increased mitotic arrest and apoptosis by enhancing the cleavage of poly(ADP-ribose) polymerase, and caspases-7 and -9. Andro together with Taxi enhanced microtubule polymerization in vitro, and they induced the formation of twisted and elongated spindles in the cancer cells, thus leading to mitotic arrest. In addition, we showed that depletion of MAD2, a component in the spindle assembly checkpoint (SAC), alleviated the mitotic block induced by the two compounds, suggesting that they trigger mitotic arrest by SAC activation. This study suggests that the anti-cancer activity of Andro can be significantly enhanced in combination with Taxi by disrupting microtubule dynamics and activating the SAC. PMID:23382917

  12. Loading of PAX3 to Mitotic Chromosomes Is Mediated by Arginine Methylation and Associated with Waardenburg Syndrome.

    Science.gov (United States)

    Wu, Tsu-Fang; Yao, Ya-Li; Lai, I-Lu; Lai, Chien-Chen; Lin, Pei-Lun; Yang, Wen-Ming

    2015-08-14

    PAX3 is a transcription factor critical to gene regulation in mammalian development. Mutations in PAX3 are associated with Waardenburg syndrome (WS), but the mechanism of how mutant PAX3 proteins cause WS remains unclear. Here, we found that PAX3 loads on mitotic chromosomes using its homeodomain. PAX3 WS mutants with mutations in homeodomain lose the ability to bind mitotic chromosomes. Moreover, loading of PAX3 on mitotic chromosomes requires arginine methylation, which is regulated by methyltransferase PRMT5 and demethylase JMJD6. Mutant PAX3 proteins that lose mitotic chromosome localization block cell proliferation and normal development of zebrafish. These results reveal the molecular mechanism of PAX3s loading on mitotic chromosomes and the importance of this localization pattern in normal development. Our findings suggest that PAX3 WS mutants interfere with the normal functions of PAX3 in a dominant negative manner, which is important to the understanding of the pathogenesis of Waardenburg syndrome. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  13. Comparative effects of ionizing radiation on cycle time and mitotic duration. A time-lapse cinematography study

    International Nuclear Information System (INIS)

    D'Hooghe, M.C.; Hemon, D.; Valleron, A.J.; Malaise, E.P.

    1980-01-01

    The effects of 60 Co γ rays on the length of the intermitotic period, the duration of mitosis, and the division probability of EMT6 cells have been studied in vitro using time-lapse cinematography. Irradiation increases the duration of the mitosis and of the cycle in comparable proportions: both parameters are practically doubled by a dose of 10 Gy. When daughters of irradiated cells die, the mitotic delay and lengthening of mitosis of their mother cells are longer than average. Mitotic delay and lengthening of mitosis depend on the age of cells at the moment of irradiation. The mitotic delay increases progressively when cells are irradiated during the first 8 h of their cycle (i.e., before the transition point), whereas mitosis is slightly prolonged. On the other hand, when the cells are irradiated after this transition point the mitotic delay decreases markedly, whereas the lengthening of mitosis increases sharply. These results tend to indicate that two different mechanisms are responsible for mitotic delay and prolongation of mitosis observed after irradiation

  14. Proteasome inhibition enhances the efficacy of volasertib-induced mitotic arrest in AML in vitro and prolongs survival in vivo.

    Science.gov (United States)

    Schnerch, Dominik; Schüler, Julia; Follo, Marie; Felthaus, Julia; Wider, Dagmar; Klingner, Kathrin; Greil, Christine; Duyster, Justus; Engelhardt, Monika; Wäsch, Ralph

    2017-03-28

    Elderly and frail patients, diagnosed with acute myeloid leukemia (AML) and ineligible to undergo intensive treatment, have a dismal prognosis. The small molecule inhibitor volasertib induces a mitotic block via inhibition of polo-like kinase 1 and has shown remarkable anti-leukemic activity when combined with low-dose cytarabine. We have demonstrated that AML cells are highly vulnerable to cell death in mitosis yet manage to escape a mitotic block through mitotic slippage by sustained proteasome-dependent slow degradation of cyclin B. Therefore, we tested whether interfering with mitotic slippage through proteasome inhibition arrests and kills AML cells more efficiently during mitosis. We show that therapeutic doses of bortezomib block the slow degradation of cyclin B during a volasertib-induced mitotic arrest in AML cell lines and patient-derived primary AML cells. In a xenotransplant mouse model of human AML, mice receiving volasertib in combination with bortezomib showed superior disease control compared to mice receiving volasertib alone, highlighting the potential therapeutic impact of this drug combination.

  15. Mitotic catastrophe occurs in the absence of apoptosis in p53-null cells with a defective G1 checkpoint.

    Directory of Open Access Journals (Sweden)

    Michalis Fragkos

    Full Text Available Cell death occurring during mitosis, or mitotic catastrophe, often takes place in conjunction with apoptosis, but the conditions in which mitotic catastrophe may exhibit features of programmed cell death are still unclear. In the work presented here, we studied mitotic cell death by making use of a UV-inactivated parvovirus (adeno-associated virus; AAV that has been shown to induce a DNA damage response and subsequent death of p53-defective cells in mitosis, without affecting the integrity of the host genome. Osteosarcoma cells (U2OSp53DD that are deficient in p53 and lack the G1 cell cycle checkpoint respond to AAV infection through a transient G2 arrest. We found that the infected U2OSp53DD cells died through mitotic catastrophe with no signs of chromosome condensation or DNA fragmentation. Moreover, cell death was independent of caspases, apoptosis-inducing factor (AIF, autophagy and necroptosis. These findings were confirmed by time-lapse microscopy of cellular morphology following AAV infection. The assays used readily revealed apoptosis in other cell types when it was indeed occurring. Taken together the results indicate that in the absence of the G1 checkpoint, mitotic catastrophe occurs in these p53-null cells predominantly as a result of mechanical disruption induced by centrosome overduplication, and not as a consequence of a suicide signal.

  16. Comparative effects of ionizing radiation on cycle time and mitotic duration. A time-lapse cinematography study

    Energy Technology Data Exchange (ETDEWEB)

    D' Hooghe, M.C. (Institut de Recherches sur le Cancer, Lille, France); Hemon, D.; Valleron, A.J.; Malaise, E.P.

    1980-03-01

    The effects of /sup 60/Co ..gamma.. rays on the length of the intermitotic period, the duration of mitosis, and the division probability of EMT6 cells have been studied in vitro using time-lapse cinematography. Irradiation increases the duration of the mitosis and of the cycle in comparable proportions: both parameters are practically doubled by a dose of 10 Gy. When daughters of irradiated cells die, the mitotic delay and lengthening of mitosis of their mother cells are longer than average. Mitotic delay and lengthening of mitosis depend on the age of cells at the moment of irradiation. The mitotic delay increases progressively when cells are irradiated during the first 8 h of their cycle (i.e., before the transition point), whereas mitosis is slightly prolonged. On the other hand, when the cells are irradiated after this transition point the mitotic delay decreases markedly, whereas the lengthening of mitosis increases sharply. These results tend to indicate that two different mechanisms are responsible for mitotic delay and prolongation of mitosis observed after irradiation.

  17. Staging atmospheres

    DEFF Research Database (Denmark)

    Bille, Mikkel; Bjerregaard, Peter; Sørensen, Tim Flohr

    2015-01-01

    The article introduces the special issue on staging atmospheres by surveying the philosophical, political and anthropological literature on atmosphere, and explores the relationship between atmosphere, material culture, subjectivity and affect. Atmosphere seems to occupy one of the classic...

  18. Human SGT interacts with Bag-6/Bat-3/Scythe and cells with reduced levels of either protein display persistence of few misaligned chromosomes and mitotic arrest

    International Nuclear Information System (INIS)

    Winnefeld, Marc; Grewenig, Annabel; Schnoelzer, Martina; Spring, Herbert; Knoch, Tobias A.; Gan, Eugene C.; Rommelaere, Jean; Cziepluch, Celina

    2006-01-01

    The human small glutamine-rich TPR-containing protein (hSGT) is essential for cell division since RNA-interference-mediated strong reduction of hSGT protein levels causes mitotic arrest (M. Winnefeld, J. Rommelaere, and C. Cziepluch, The human small glutamine-rich TPR-containing protein is required for progress through cell division, Exp. Cell Res. 293 (2004), 43-57). Analysis of HeLa cells expressing a histone 2A-YFP fusion protein revealed the continuous presence of few mislocalized chromosomes close to the spindle poles as possible cause for hSGT depletion-dependent prometaphase arrest. Cells unable to rescue these mislocalized chromosomes into the metaphase plate died at this stage through apoptosis. In order to address hSGT function at the molecular level, mass spectrometry analysis of proteins which co-immunoprecipitated with Flag-tagged hSGT was performed. Thereby, Hsp70 and Bag-6/Bat-3/Scythe were identified as novel hSGT interaction partners while interaction with Hsc70 was confirmed. Results obtained with truncated versions of the hSGT protein revealed that Bag-6/Bat-3/Scythe and Hsp70 or Hsc70 were independently able to form complexes with hSGT. Interaction of hSGT with Hsc70, Hsp70 or Bag-6/Bat-3/Scythe was demonstrated in prometaphase, thereby suggesting a possible role for complexes containing hSGT and distinct (co)-chaperones during mitosis. Finally, cells from populations with reduced levels of Bag-6/Bat-3/Scythe also displayed persistence of mislocalized chromosomes and mitotic arrest, which strongly indicated that hSGT-Bag-6/Bat-3/Scythe complexes could be directly or indirectly required for complete chromosome congression

  19. Study of cell cycle parameters of man lymphocytes irradiated at various stages using differential coloring of sister chromatides

    International Nuclear Information System (INIS)

    Poryadkova, N.A.

    1984-01-01

    Parameters of the cell cycle of human lymphocytes are specified, radiation effect applied at various stages of mitotic cycle on the kinetics of cell advance in the cycle is also investigated. It is shown that increasing mitotic index occurs only due to the introduction of cells into the first mitosis. It is not excluded that cells ready to enter the second mitosis died with greater probability as after second synthesis they contained two-fold amount of BDU (5-brominedesoxiuridine) than cells of the first mitosis. In all cases with irradiation of cells of the third mitosis were not found

  20. Isolation of a dinoflagellate mitotic cyclin by functional complementation in yeast

    International Nuclear Information System (INIS)

    Bertomeu, Thierry; Morse, David

    2004-01-01

    Dinoflagellates are parasite with permanently condensed chromosomes that lack histones and whose nuclear membrane remains intact during mitosis. These unusual nuclear characters have suggested that the typical cell cycle regulators might be slightly different than those in more typical eukaryotes. To test this, a cyclin has been isolated from the dinoflagellate Gonyaulax polyedra by functional complementation in cln123 mutant yeast. This GpCyc1 sequence contains two cyclin domains in its C-terminal region and a degradation box typical of mitotic cyclins. Similar to other dinoflagellate genes, GpCyc1 has a high copy number, with ∼5000 copies found in the Gonyaulax genome. An antibody raised against the N-terminal region of the GpCYC1 reacts with a 68 kDa protein on Western blots that is more abundant in cell cultures enriched for G2-phase cells than in those containing primarily G1-phase cells, indicating its cellular level follows a pattern expected for a mitotic cyclin. This is the first report of a cell cycle regulator cloned and sequenced from a dinoflagellate, and our results suggest control of the dinoflagellate cell cycle will be very similar to that of other organisms

  1. Oocyte formation by mitotically-active germ cells purified from ovaries of reproductive age women

    Science.gov (United States)

    White, Yvonne A. R.; Woods, Dori C.; Takai, Yasushi; Ishihara, Osamu; Seki, Hiroyuki; Tilly, Jonathan L.

    2012-01-01

    Germline stem cells that produce oocytes in vitro and fertilization-competent eggs in vivo have been identified in and isolated from adult mouse ovaries. Here we describe and validate a FACS-based protocol that can be used with adult mouse ovaries and human ovarian cortical tissue to purify rare mitotically-active cells that exhibit a gene expression profile consistent with primitive germ cells. Once established in vitro, these cells can be expanded for months and spontaneously generate 35–50 µm oocytes, as determined by morphology, gene expression and attainment of haploid (1n) status. Injection of the human germline cells, engineered to stably express GFP, into human ovarian cortical biopsies leads to formation of follicles containing GFP-positive oocytes 1–2 weeks after xenotransplantation into immunodeficient female mice. Thus, ovaries of reproductive-age women, like adult mice, possess rare mitotically-active germ cells that can be propagated in vitro as well as generate oocytes in vitro and in vivo. PMID:22366948

  2. Oocyte formation by mitotically active germ cells purified from ovaries of reproductive-age women.

    Science.gov (United States)

    White, Yvonne A R; Woods, Dori C; Takai, Yasushi; Ishihara, Osamu; Seki, Hiroyuki; Tilly, Jonathan L

    2012-02-26

    Germline stem cells that produce oocytes in vitro and fertilization-competent eggs in vivo have been identified in and isolated from adult mouse ovaries. Here we describe and validate a fluorescence-activated cell sorting-based protocol that can be used with adult mouse ovaries and human ovarian cortical tissue to purify rare mitotically active cells that have a gene expression profile that is consistent with primitive germ cells. Once established in vitro, these cells can be expanded for months and can spontaneously generate 35- to 50-μm oocytes, as determined by morphology, gene expression and haploid (1n) status. Injection of the human germline cells, engineered to stably express GFP, into human ovarian cortical biopsies leads to formation of follicles containing GFP-positive oocytes 1-2 weeks after xenotransplantation into immunodeficient female mice. Thus, ovaries of reproductive-age women, similar to adult mice, possess rare mitotically active germ cells that can be propagated in vitro as well as generate oocytes in vitro and in vivo.

  3. DNA Strand Breaks in Mitotic Germ Cells of Caenorhabditis elegans Evaluated by Comet Assay

    Science.gov (United States)

    Park, Sojin; Choi, Seoyun; Ahn, Byungchan

    2016-01-01

    DNA damage responses are important for the maintenance of genome stability and the survival of organisms. Such responses are activated in the presence of DNA damage and lead to cell cycle arrest, apoptosis, and DNA repair. In Caenorhabditis elegans, double-strand breaks induced by DNA damaging agents have been detected indirectly by antibodies against DSB recognizing proteins. In this study we used a comet assay to detect DNA strand breaks and to measure the elimination of DNA strand breaks in mitotic germline nuclei of C. elegans. We found that C. elegans brc-1 mutants were more sensitive to ionizing radiation and camptothecin than the N2 wild-type strain and repaired DNA strand breaks less efficiently than N2. This study is the first demonstration of direct measurement of DNA strand breaks in mitotic germline nuclei of C. elegans. This newly developed assay can be applied to detect DNA strand breaks in different C. elegans mutants that are sensitive to DNA damaging agents. PMID:26903030

  4. LOX is a novel mitotic spindle-associated protein essential for mitosis.

    Science.gov (United States)

    Boufraqech, Myriem; Wei, Darmood; Weyemi, Urbain; Zhang, Lisa; Quezado, Martha; Kalab, Petr; Kebebew, Electron

    2016-05-17

    LOX regulates cancer progression in a variety of human malignancies. It is overexpressed in aggressive cancers and higher expression of LOX is associated with higher cancer mortality. Here, we report a new function of LOX in mitosis. We show that LOX co-localizes to mitotic spindles from metaphase to telophase, and p-H3(Ser10)-positive cells harbor strong LOX staining. Further, purification of mitotic spindles from synchronized cells show that LOX fails to bind to microtubules in the presence of nocodazole, whereas paclitaxel treated samples showed enrichment in LOX expression, suggesting that LOX binds to stabilized microtubules. LOX knockdown leads to G2/M phase arrest; reduced p-H3(Ser10), cyclin B1, CDK1, and Aurora B. Moreover, LOX knockdown significantly increased sensitivity of cancer cells to chemotherapeutic agents that target microtubules. Our findings suggest that LOX has a role in cancer cell mitosis and may be targeted to enhance the activity of microtubule inhibitors for cancer therapy.

  5. MiR-210 disturbs mitotic progression through regulating a group of mitosis-related genes.

    Science.gov (United States)

    He, Jie; Wu, Jiangbin; Xu, Naihan; Xie, Weidong; Li, Mengnan; Li, Jianna; Jiang, Yuyang; Yang, Burton B; Zhang, Yaou

    2013-01-07

    MiR-210 is up-regulated in multiple cancer types but its function is disputable and further investigation is necessary. Using a bioinformatics approach, we identified the putative target genes of miR-210 in hypoxia-induced CNE cells from genome-wide scale. Two functional gene groups related to cell cycle and RNA processing were recognized as the major targets of miR-210. Here, we investigated the molecular mechanism and biological consequence of miR-210 in cell cycle regulation, particularly mitosis. Hypoxia-induced up-regulation of miR-210 was highly correlated with the down-regulation of a group of mitosis-related genes, including Plk1, Cdc25B, Cyclin F, Bub1B and Fam83D. MiR-210 suppressed the expression of these genes by directly targeting their 3'-UTRs. Over-expression of exogenous miR-210 disturbed mitotic progression and caused aberrant mitosis. Furthermore, miR-210 mimic with pharmacological doses reduced tumor formation in a mouse metastatic tumor model. Taken together, these results implicate that miR-210 disturbs mitosis through targeting multi-genes involved in mitotic progression, which may contribute to its inhibitory role on tumor formation.

  6. Effect of propolis on mitotic and cellular proliferation indices in human blood lymphocytes

    Energy Technology Data Exchange (ETDEWEB)

    Montoro, A.; Almonacid, M.; Villaescusa, J. [Valencia Hospital Univ. la Fe, Servicio de Proteccion Radiologica (Spain); Barquinero, J. [Barcelona Univ. Autonom, Servicio de Dosimetria Biologica, Unidad de Antropologia, Dept. de Biologia Animal, Vegetal y Ecologia, barcelona (Spain); Barrios, L. [Barcelona Univ. Autonoma, Dept. de Biologia Celular y Fisiologia. Unidad de Biologia Celular (Spain); Verdu, G. [Valencia Univ. Politecnica, Dept. de Ingenieria Quimica y Nuclear (Spain); Perez, J. [Hospital la Fe, Seccion de Radiofisica, Servicio de Radioterapia, valencia (Spain)

    2006-07-01

    The study of the frequency of chromosomal aberrations per cell is the tool used in Biological dosimetry studies. Using dose-effect calibration curve obtained in our laboratory, we can evaluate the radioprotector effect of the EEP (ethanolic extract of propolis) in cultures in vitro. Propolis is the generic name for resinous substance collected by honeybees. The results showed a reduction in chromosomal aberrations's frequency of up to 50 %. The following study consisted of analyzing human peripheral blood lymphocytes exposed to 2 Gy {gamma} rays, in presence and absence of EEP, the change in the frequency of chromosome aberrations was analysed with biological dosimetry. The protection against the formation of dicentric and ring was dose-dependent, but there seemed to be a maximum protection, i.e. a further increase in the concentration of EEP does not show additional protection. This work studies the effect of the EEP of the cellular cycle using the mitotic and cellular proliferation index, as an alternative for the screening cytostatic activity. The results indicate that the lymphocytes which were cultures in presence of EEP exhibited a significant and dependent-concentration decrease in mitotic index and proliferation kinetics. The possible mechanisms involved in the radioprotective influence of EEP are discussed. (authors)

  7. [Intragenic mitotic recombination induced by ultraviolet and gamma rays in radiosensitive mutants of Saccharomyces cerevisiae yeasts].

    Science.gov (United States)

    Zakharov, I A; Kasinova, G V; Koval'tsova, S V

    1983-01-01

    The effect of UV- and gamma-irradiation on the survival and intragenic mitotic recombination (gene conversion) of 5 radiosensitive mutants was studied in comparison with the wild type. The level of spontaneous conversion was similar for RAD, rad2 and rad15, mutations xrs2 and xrs4 increasing and rad54 significantly decreasing it. The frequency of conversion induced by UV-light was greater in rad2, rad15 and xrs2 mutants and lower in xrs4, as compared to RAD. Gamma-irradiation caused induction of gene conversion with an equal frequency in RAD, rad2, rad15. Xrs2 and xrs4 mutations slightly decreased gamma-induced conversion. In rad54 mutant, UV-and gamma-induced conversion was practically absent. In the wild type yeast, a diploid strain is more resistant than a haploid, whereas in rad54 a diploid strain has the same or an increased sensitivity, as compared to a haploid strain (the "inverse ploidy effect"). This effect and also the block of induced mitotic recombination caused by rad54 indicate the presence in the yeast Saccharomyces cerevisiae of repair pathways of UV- and gamma-induced damages acting in diploid cells and realised by recombination. The data obtained as a result of many years' investigation of genetic effects in radiosensitive mutants of yeast are summarised and considered.

  8. Effect of propolis on mitotic and cellular proliferation indices in human blood lymphocytes

    International Nuclear Information System (INIS)

    Montoro, A.; Almonacid, M.; Villaescusa, J.; Barquinero, J.; Barrios, L.; Verdu, G.; Perez, J.

    2006-01-01

    The study of the frequency of chromosomal aberrations per cell is the tool used in Biological dosimetry studies. Using dose-effect calibration curve obtained in our laboratory, we can evaluate the radioprotector effect of the EEP (ethanolic extract of propolis) in cultures in vitro. Propolis is the generic name for resinous substance collected by honeybees. The results showed a reduction in chromosomal aberrations's frequency of up to 50 %. The following study consisted of analyzing human peripheral blood lymphocytes exposed to 2 Gy γ rays, in presence and absence of EEP, the change in the frequency of chromosome aberrations was analysed with biological dosimetry. The protection against the formation of dicentric and ring was dose-dependent, but there seemed to be a maximum protection, i.e. a further increase in the concentration of EEP does not show additional protection. This work studies the effect of the EEP of the cellular cycle using the mitotic and cellular proliferation index, as an alternative for the screening cytostatic activity. The results indicate that the lymphocytes which were cultures in presence of EEP exhibited a significant and dependent-concentration decrease in mitotic index and proliferation kinetics. The possible mechanisms involved in the radioprotective influence of EEP are discussed. (authors)

  9. A link between mitotic entry and membrane growth suggests a novel model for cell size control.

    Science.gov (United States)

    Anastasia, Steph D; Nguyen, Duy Linh; Thai, Vu; Meloy, Melissa; MacDonough, Tracy; Kellogg, Douglas R

    2012-04-02

    Addition of new membrane to the cell surface by membrane trafficking is necessary for cell growth. In this paper, we report that blocking membrane traffic causes a mitotic checkpoint arrest via Wee1-dependent inhibitory phosphorylation of Cdk1. Checkpoint signals are relayed by the Rho1 GTPase, protein kinase C (Pkc1), and a specific form of protein phosphatase 2A (PP2A(Cdc55)). Signaling via this pathway is dependent on membrane traffic and appears to increase gradually during polar bud growth. We hypothesize that delivery of vesicles to the site of bud growth generates a signal that is proportional to the extent of polarized membrane growth and that the strength of the signal is read by downstream components to determine when sufficient growth has occurred for initiation of mitosis. Growth-dependent signaling could explain how membrane growth is integrated with cell cycle progression. It could also control both cell size and morphogenesis, thereby reconciling divergent models for mitotic checkpoint function.

  10. Differences in rates of radiation-induced true and false rib fractures after stereotactic body radiation therapy for Stage I primary lung cancer

    International Nuclear Information System (INIS)

    Miura, Hideharu; Inoue, Toshihiko; Shiomi, Hiroya; Oh, Ryoong-Jin

    2015-01-01

    The purpose of this study was to analyze the dosimetry and investigate the clinical outcomes of radiation-induced rib fractures (RIRFs) after stereotactic body radiotherapy (SBRT). A total of 126 patients with Stage I primary lung cancer treated with SBRT, who had undergone follow-up computed tomography (CT) at least 12 months after SBRT and who had no previous overlapping radiation exposure were included in the study. We used the Mantel-Haenszel method and multiple logistic regression analysis to compare risk factors. We analyzed D(0.5 cm 3 ) (minimum absolute dose received by a 0.5-cm 3 volume) and identified each rib that received a biologically effective dose (BED) (BED3, using the linear-quadratic (LQ) formulation assuming an α/β = 3) of at least 50 Gy. Of the 126 patients, 46 (37%) suffered a total of 77 RIRFs. The median interval from SBRT to RIRF detection was 15 months (range, 3-56 months). The 3-year cumulative probabilities were 45% (95% CI, 34-56%) and 3% (95% CI, 0-6%), for Grades 1 and 2 RIRFs, respectively. Multivariate analysis showed that tumor location was a statistically significant risk factor for the development of Grade 1 RIRFs. Of the 77 RIRFs, 71 (92%) developed in the true ribs (ribs 1-7), and the remaining six developed in the false ribs (ribs 8-12). The BED3 associated with 10% and 50% probabilities of RIRF were 55 and 210 Gy to the true ribs and 240 and 260 Gy to the false ribs. We conclude that RIRFs develop more frequently in true ribs than in false ribs. (author)

  11. Radiation tolerance in the fruit fly, Drosophila Melanogaster - effects of laboratory culturing and stages in life cycle

    International Nuclear Information System (INIS)

    Vas, Iril Prima; Naik, Pramila; Kumar, Vineeth; Naik, Prathima; Patil, Rajashekar K.

    2013-01-01

    Radiation induced damages are due to direct effect of radiation energy or through free radical generation. Recent studies suggest Drosophila to be a good animal model to study radiation tolerance. The present study on female Drosophila melanogaster was conducted to observe 1. Variations in larval and adult radiation tolerance 2. Variations in laboratory culture and field populations of Drosophila. Third instar larvae were exposed to gamma radiation of 6, 10, 20, 30, 40 and 50 Gy in gamma chamber GC 5000 (BRT, India). Larvae of flies collected from the field were reared for two generations in the lab before irradiation. The laboratory cultured files were from stocks that were maintained for more than 1000 generations. The larvae of field populations had higher survival rate at 51% as compared to 43% in case of cultured flies and thus more resistant. The III instar larval stage (lab culture) had a LD50 of 26 Gy as compared to LD 50 of 928 Gy in case of adult flies have ∼ 160 times higher tolerance compared to humans. Prolonged rearing comparable to 'domestication' might have induced reduction in tolerance. Larval stages have a lower tolerance than adults possibly due to higher metabolic rate. Adults are post-mitotic in nature with very low rate of cell division. This may contribute to higher tolerance. This however is in contradiction to studies of midge (Chironomous) where larvae also have higher tolerance. (author)

  12. Action of plasma and liver extract from adult mice on the mitotic activity of young mouse liver.

    Science.gov (United States)

    García, A L; Inda, A M; Echave Llanos, J M

    1991-06-01

    Inbred C3HS male mice, standardized for periodicity analysis were used. A hundred and seventy 25 +/- 2 days old mice were injected at 16:00 hs with saline, plasma or liver extract from 27 mice 90 days old. Controls were made at 08/16, 12/20, 16/24, 08/40, 12/44, 16/48, 08/64, 12/68 and 16/72 (time of day/time post-injection). The mitotic activity of the hepatocytes and litoral cells were determined. The injection of small doses of extract and plasma inhibits the mitotic activity of hepatocytes during the first and second following days. A compensatory wave appears in the third day. The extract inhibits the mitotic activity of litoral cells in the first day of control only, whereas the plasma inhibits this variable in the second and third day.

  13. Correlation between air flow rate and pollutant concentrations during two-stage oak log combustion in a 25 KW residential boiler

    Directory of Open Access Journals (Sweden)

    Juszczak Marek

    2016-09-01

    Full Text Available It can be expected that there is a considerable correlation between combustion air flow rate and the concentrations of carbon monoxide, hydrocarbons and nitrogen oxide in the flue gas. The influence of temperature and oxygen concentration in the combustion zone on the concentrations of carbon monoxide, hydrocarbons and nitrogen oxide in the flue gas, for high and low combustion air flow, was analysed. Oxygen concentration for which the concentration of carbon monoxide is the lowest was determined, as well as the mutual relation between carbon monoxide and nitrogen oxide concentration.

  14. Aurora-B Mediated ATM Serine 1403 Phosphorylation Is Required For Mitotic ATM Activation and the Spindle Checkpoint

    OpenAIRE

    Yang, Chunying; Tang, Xi; Guo, Xiaojing; Niikura, Yohei; Kitagawa, Katsumi; Cui, Kemi; Wong, Stephen T.C.; Fu, Li; Xu, Bo

    2011-01-01

    The ATM kinase plays a critical role in the maintenance of genetic stability. ATM is activated in response to DNA damage and is essential for cell cycle checkpoints. Here, we report that ATM is activated in mitosis in the absence of DNA damage. We demonstrate that mitotic ATM activation is dependent on the Aurora-B kinase and that Aurora-B phosphorylates ATM on serine 1403. This phosphorylation event is required for mitotic ATM activation. Further, we show that loss of ATM function results in...

  15. Evaluation of the recombination in somatic cells induced by radiation in different stages of Drosophila larval development; Evaluacion de la recombinacion en celulas somaticas inducida por radiacion en diferentes etapas del desarrollo larvario de Drosophila

    Energy Technology Data Exchange (ETDEWEB)

    Cruces, M P; Morales R, P [Instituto nacional de Investigaciones Nucleares, A.P. 18-1027, 11801 Mexico D.F. (Mexico)

    1997-07-01

    The mitotic recombination can happen spontaneously and its frequency is very low, however the recombination rate of a cell can be increased by the exposure to agents which cause damage to DNA. This type of agents are knew commonly as recombinogens. The ionizing radiation and a numerous chemical agents can be mentioned (Vogel, 1992). The objective of this work is to determine if the mutation/recombination rate induced by gamma rays varies with the development stage. In order to realize this investigation it was used the mutation and somatic recombination test of Drosophila wing (Graf and col. 1984). The mwh/ mwh and flr{sup 3}/TM3, Ser stocks were used. (Author)

  16. Effect of two-stage injection on combustion and emissions under high EGR rate on a diesel engine by fueling blends of diesel/gasoline, diesel/n-butanol, diesel/gasoline/n-butanol and pure diesel

    International Nuclear Information System (INIS)

    Zheng, Zunqing; Yue, Lang; Liu, Haifeng; Zhu, Yuxuan; Zhong, Xiaofan; Yao, Mingfa

    2015-01-01

    Highlights: • Two-stage injection using diesel blended fuel at high EGR (46%) was studied. • Blending fuels induce retarded pilot heat release and have less effect on MPRR. • Effects of injection parameters of blended fuels on emissions are similar to diesel. • Different fuels have little influence on post combustion heat release. • Small quantity post injection close to main results in better efficiency and emissions. - Abstract: The effect of two-stage injection on combustion and emission characteristics under high EGR (46%) condition were experimentally investigated. Four different fuels including pure diesel and blended fuels of diesel/gasoline, diesel/n-butanol, diesel/gasoline/n-butanol were tested. Results show that blending gasoline or/and n-butanol in diesel improves smoke emissions while induces increase in maximum pressure rise rate (MPRR). Adopting pilot injection close to main injection can effectively reduce the peak of premixed heat release rate and MPRR. However, for fuels blends with high percentage of low cetane number fuel, the effect of pilot fuel on ignition can be neglected and the improvement of MPRR is not that obvious. Pilot-main interval presents more obvious effect on smoke than pilot injection rate does, and the smoke emissions decrease with increasing pilot-main interval. A longer main-post interval results in a lower post heat release rate and prolonged combustion duration. While post injection rate has little effect on the start of ignition for post injection. The variation in fuel properties caused by blending gasoline or/and n-butanol into diesel does not impose obvious influence on post combustion. The smoke emission increases first and then declines with retard of post injection timing. Compared to diesel, the smoke emissions of blended fuels are more sensitive to the variation of post injection strategy

  17. Cremophor EL stimulates mitotic recombination in uvsH//uvsH diploid strain of Aspergillus nidulans

    Directory of Open Access Journals (Sweden)

    Cleverson Busso

    2004-03-01

    Full Text Available Cremophor EL is a solubilizer and emulsifier agent used in the pharmaceutical and foodstuff industries. The solvent is the principal constituent of paclitaxel's clinical formulation vehicle. Since mitotic recombination plays a crucial role in multistep carcinogenesis, the study of the recombinagenic potential of chemical compounds is of the utmost importance. In our research genotoxicity of cremophor EL has been studied by using an uvsH//uvsH diploid strain of Aspergillus nidulans. Since it spends a great part of its cell cycle in the G2period, this fungus is a special screening system for the study of mitotic recombination induced by chemical substances. Homozygotization Indexes (HI for paba and bi markers from heterozygous B211//A837 diploid strain were determined for the evaluation of the recombinagenic effect of cremophor EL. It has been shown that cremophor EL induces increase in mitotic crossing-over events at nontoxic concentrations (0.05 and 0.075% v/v.Cremofor EL (CEL é um solubilizante e emulsificante amplamente utilizado nas indústrias farmacêuticas e de gêneros alimentícios. É o principal veículo empregado nas formulações clínicas do antineoplásico paclitaxel. Considerando-se que a recombinação mitótica desempenha importante função no processo de carcinogênese, o estudo de substâncias químicas com potencial recombinagênico assume importância crucial, no sentido de se detectar aquelas que eventualmente possam atuar como promotoras de neoplasias. A genotoxicidade do cremofor EL foi estudada no presente trabalho, utilizando-se uma linhagem diplóide uvsH//uvsH de Aspergillus nidulans. Neste fungo as células vegetativas comumente repousam no período G2 do ciclo celular, facilitando a ocorrência da recombinação mitótica. O efeito recombinagênico do CEL foi avaliado através da determinação dos Índices de Homozigotização para os marcadores nutricionais paba e bi do diplóide heterozigoto B211//A837. Os

  18. Cytokinesis-block micronucleus assay evolves into a 'cytome' assay of chromosomal instability, mitotic dysfunction and cell death

    International Nuclear Information System (INIS)

    Fenech, Michael

    2006-01-01

    The cytokinesis-block micronucleus (CBMN) assay was originally developed as an ideal system for measuring micronuclei (MNi) however it can also be used to measure nucleoplasmic bridges (NPBs), nuclear buds (NBUDs), cell death (necrosis or apoptosis) and nuclear division rate. Current evidence suggests that (a) NPBs originate from dicentric chromosomes in which the centromeres have been pulled to the opposite poles of the cell at anaphase and are therefore indicative of DNA mis-repair, chromosome rearrangement or telomere end-fusions, (b) NPBs may break to form MNi, (c) the nuclear budding process is the mechanism by which cells remove amplified and/or excess DNA and is therefore a marker of gene amplification and/or altered gene dosage, (d) cell cycle checkpoint defects result in micronucleus formation and (e) hypomethylation of DNA, induced nutritionally or by inhibition of DNA methyl transferase can lead to micronucleus formation either via chromosome loss or chromosome breakage. The strong correlation between micronucleus formation, nuclear budding and NPBs (r = 0.75-0.77, P < 0.001) induced by either folic acid deficiency or exposure to ionising radiation is supportive of the hypothesis that folic acid deficiency and/or ionising radiation cause genomic instability and gene amplification by the initiation of breakage-fusion-bridge cycles. In its comprehensive mode, the CBMN assay measures all cells including necrotic and apoptotic cells as well as number of nuclei per cell to provide a measure of cytotoxicity and mitotic activity. The CBMN assay has in fact evolved into a 'cytome' method for measuring comprehensively chromosomal instability phenotype and altered cellular viability caused by genetic defects and/or nutrional deficiencies and/or exogenous genotoxins thus opening up an exciting future for the use of this methodology in the emerging fields of nutrigenomics and toxicogenomics and their combinations

  19. Effect of caffeine on radiation-induced mitotic delay: delayed expression of G2 arrest

    International Nuclear Information System (INIS)

    Rowley, R.; Zorch, M.; Leeper, D.B.

    1984-01-01

    In the presence of 5 mM caffeine, irradiated (1.5 Gy) S and G 2 cells progressed to mitosis in register and without arrest in G 2 . Caffeine (5 mM) markedly reduced mitotic delay even after radiation doses up to 20 Gy. When caffeine was removed from irradiated (1.5 Gy) and caffeine-treated cells, a period of G 2 arrest followed, similar in length to that produced by radiation alone. The arrest expressed was independent of the duration of the caffeine treatment for exposures up to 3 hr. The similarity of the response to the cited effects of caffeine on S-phase delay suggests a common basis for delay induction in S and G 2 phases

  20. Experimental evidence showing that no mitotically active female germline progenitors exist in postnatal mouse ovaries.

    Science.gov (United States)

    Zhang, Hua; Zheng, Wenjing; Shen, Yan; Adhikari, Deepak; Ueno, Hiroo; Liu, Kui

    2012-07-31

    It has been generally accepted for more than half a century that, in most mammalian species, oocytes cannot renew themselves in postnatal or adult life, and that the number of oocytes is already fixed in fetal or neonatal ovaries. This assumption, however, has been challenged over the past decade. In this study, we have taken an endogenous genetic approach to this question and generated a multiple fluorescent Rosa26(rbw/+);Ddx4-Cre germline reporter mouse model for in vivo and in vitro tracing of the development of female germline cell lineage. Through live cell imaging and de novo folliculogenesis experiments, we show that the Ddx4-expressing cells from postnatal mouse ovaries did not enter mitosis, nor did they contribute to oocytes during de novo folliculogenesis. Our results provide evidence that supports the traditional view that no postnatal follicular renewal occurs in mammals, and no mitotically active Ddx4-expressing female germline progenitors exist in postnatal mouse ovaries.

  1. Loss of p120 catenin and links to mitotic alterations, inflammation, and skin cancer

    DEFF Research Database (Denmark)

    Perez-Moreno, Mirna; Song, Weimin; Pasolli, H Amalia

    2008-01-01

    Tumor formation involves epigenetic modifications and microenvironmental changes as well as cumulative genetic alterations encompassing somatic mutations, loss of heterozygosity, and aneuploidy. Here, we show that conditional targeting of p120 catenin in mice leads to progressive development...... of skin neoplasias associated with intrinsic NF-kappaB activation. We find that, similarly, squamous cell carcinomas in humans display altered p120 and activated NF-kappaB. We show that epidermal hyperproliferation arising from p120 loss can be abrogated by IkappaB kinase 2 inhibitors. Although...... this underscores the importance of this pathway, the role of NF-kappaB in hyperproliferation appears rooted in its impact on epidermal microenvironment because as p120-null keratinocytes display a growth-arrested phenotype in culture. We trace this to a mitotic defect, resulting in unstable, binucleated cells...

  2. Warts phosphorylates mud to promote pins-mediated mitotic spindle orientation in Drosophila, independent of Yorkie.

    Science.gov (United States)

    Dewey, Evan B; Sanchez, Desiree; Johnston, Christopher A

    2015-11-02

    Multicellular animals have evolved conserved signaling pathways that translate cell polarity cues into mitotic spindle positioning to control the orientation of cell division within complex tissue structures. These oriented cell divisions are essential for the development of cell diversity and the maintenance of tissue homeostasis. Despite intense efforts, the molecular mechanisms that control spindle orientation remain incompletely defined. Here, we describe a role for the Hippo (Hpo) kinase complex in promoting Partner of Inscuteable (Pins)-mediated spindle orientation. Knockdown of Hpo, Salvador (Sav), or Warts (Wts) each result in a partial loss of spindle orientation, a phenotype previously described following loss of the Pins-binding protein Mushroom body defect (Mud). Similar to orthologs spanning yeast to mammals, Wts kinase localizes to mitotic spindle poles, a prominent site of Mud localization. Wts directly phosphorylates Mud in vitro within its C-terminal coiled-coil domain. This Mud coiled-coil domain directly binds the adjacent Pins-binding domain to dampen the Pins/Mud interaction, and Wts-mediated phosphorylation uncouples this intramolecular Mud interaction. Loss of Wts prevents cortical Pins/Mud association without affecting Mud accumulation at spindle poles, suggesting phosphorylation acts as a molecular switch to specifically activate cortical Mud function. Finally, loss of Wts in Drosophila imaginal disc epithelial cells results in diminished cortical Mud and defective planar spindle orientation. Our results provide new insights into the molecular basis for dynamic regulation of the cortical Pins/Mud spindle positioning complex and highlight a novel link with an essential, evolutionarily conserved cell proliferation pathway. Copyright © 2015 Elsevier Ltd. All rights reserved.

  3. The participation of elevated levels of cyclic GMP in the recovery from radiation-induced mitotic delay

    International Nuclear Information System (INIS)

    Daniel, J.W.; Oleinick, N.L.

    1984-01-01

    The levels of cyclic AMP and cyclic GMP have been measured in Physarum plasmodia before and after treatment with gamma-radiation, 2 mM caffeine, or combinations of the two agents compared to the length of the radiation-induced mitotic delay. Caffeine alone produces a rapid transient elevation of cyclic AMP and a slower delayed elevation of cyclic GMP. Irradiation elicits an immediate transient increase in cyclic AMP and a later cyclic GMP increase which accompanies or precedes the delayed mitosis. A composite pattern is produced by combinations of radiation and caffeine, a distinctive feature of which is an elevated level of cyclic GMP near the time of the radiation-delayed and caffeine-promoted mitosis. With pretreatment by caffeine, the least radiation-induced mitotic delay occurs when plasmodia are irradiated during the caffeine-elicited increase in cyclic GMP. The plasmodium becomes refractory to the reduction of mitotic delay by caffeine at approximately the time it becomes refractory to the further elevation of cyclic GMP by caffeine. The data support a role for cyclic AMP in the onset of and for cyclic GMP in the recovery from mitotic delay induced by ionizing radiation. (author)

  4. Effect of copper intrauterine device vs. injectable contraceptive on serum hormone levels and cell mitotic activity in endometrium

    Directory of Open Access Journals (Sweden)

    Ebtesam Moustafa Kamal

    2013-09-01

    Conclusion: Either copper intrauterine device or injectable contraceptive usage for more than 9 months results in significant decrease in endometrial proliferative or cell mitotic activity. While copper IUD has no effect on serum estradiol or progesterone levels, DMPA usage increased serum progesterone level with no effect on serum estradiol.

  5. A comparative study of proliferative activity and tumor stage of pregnancy-associated melanoma (PAM) and non-PAM in gestational age women.

    Science.gov (United States)

    Merkel, Emily A; Martini, Mary C; Amin, Sapna M; Yélamos, Oriol; Lee, Christina Y; Sholl, Lauren M; Rademaker, Alfred W; Guitart, Joan; Gerami, Pedram

    2016-01-01

    The influence of pregnancy on the development, progression, and prognosis of melanoma is controversial. We sought to compare clinical characteristics, histologic features, and proliferative activity in pregnancy-associated melanoma (PAM) and melanoma in nonpregnant women of reproductive age (non-PAM). In this retrospective cohort study, we reviewed medical records and pathology reports from women given a diagnosis of melanoma between 2006 and 2015. We also examined tumor proliferation rates using mitotic count and 2 immunohistochemical markers of proliferation, phosphohistone H3 and Ki-67. In 50 PAM and 122 non-PAM cases, a diagnosis of melanoma in situ was associated with PAM. Among invasive melanomas, there was no difference in proliferative activity between groups. Pregnancy status was also not associated with age at diagnosis, tumor site, Breslow depth, Clark level, ulceration, or overall stage. This was a retrospective study with a small sample size of mostly patients with early-stage melanoma. In our study of primarily early-stage melanoma, pregnancy did not have a significant impact on tumor proliferation. Particularly for patients given a diagnosis of stage I melanoma who are undergoing close surveillance, a history of PAM should not outweigh traditional factors, such as advanced maternal age, in planning future pregnancies. Copyright © 2015 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

  6. Melanoma of the vulva and vagina: principles of staging and their relevance to management based on a clinicopathologic analysis of 85 cases.

    Science.gov (United States)

    Seifried, Susan; Haydu, Lauren E; Quinn, Michael J; Scolyer, Richard A; Stretch, Jonathan R; Thompson, John F

    2015-01-01

    Primary melanomas of the vulva and vagina are rare. As a result, it has been difficult to develop evidence-based guidelines for their management. By analyzing a large series of patients with vulval and vaginal melanomas, this study sought to document the most common presenting features, identify clinical and pathologic predictors of outcome, and provide management guidelines. A clinicopathologic analysis of 85 patients with primary melanomas of the vulva or vagina diagnosed and treated at Melanoma Institute Australia and associated units in Sydney, Australia, between 1960 and 2011 was performed. Predictors of disease-free and melanoma-specific survival (MSS) were determined. Patients with American Joint Committee on Cancer (AJCC) stage 0-II had a significantly better MSS (5Y MSS = 63.6 %, n = 59) compared with those with stage III disease (5Y MSS = 0 %, n = 12, p < 0.001). Tumor thickness, ulceration status, and pathologic clearance margin were significant predictors of MSS. Disease-free survival was predicted by these factors and additionally by tumor mitotic rate. The results of this study provide evidence to support the appropriateness of utilizing the AJCC (7th edition) cutaneous melanoma staging system for vulval and vaginal melanomas. Detection and removal of these melanomas at an early stage with pathologically confirmed clear margins confers the best chance of cure.

  7. AUTOMATED DETECTION OF MITOTIC FIGURES IN BREAST CANCER HISTOPATHOLOGY IMAGES USING GABOR FEATURES AND DEEP NEURAL NETWORKS

    Directory of Open Access Journals (Sweden)

    Maqlin Paramanandam

    2016-11-01

    Full Text Available The count of mitotic figures in Breast cancer histopathology slides is the most significant independent prognostic factor enabling determination of the proliferative activity of the tumor. In spite of the strict protocols followed, the mitotic counting activity suffers from subjectivity and considerable amount of observer variability despite being a laborious task. Interest in automated detection of mitotic figures has been rekindled with the advent of Whole Slide Scanners. Subsequently mitotic detection grand challenge contests have been held in recent years and several research methodologies developed by their participants. This paper proposes an efficient mitotic detection methodology for Hematoxylin and Eosin stained Breast cancer Histopathology Images using Gabor features and a Deep Belief Network- Deep Neural Network architecture (DBN-DNN. The proposed method has been evaluated on breast histopathology images from the publicly available dataset from MITOS contest held at the ICPR 2012 conference. It contains 226 mitoses annotated on 35 HPFs by several pathologists and 15 testing HPFs, yielding an F-measure of 0.74. In addition the said methodology was also tested on 3 slides from the MITOSIS- ATYPIA grand challenge held at the ICPR 2014 conference, an extension of MITOS containing 749 mitoses annotated on 1200 HPFs, by pathologists worldwide. This study has employed 3 slides (294 HPFs from the MITOS-ATYPIA training dataset in its evaluation and the results showed F-measures 0.65, 0.72and 0.74 for each slide. The proposed method is fast and computationally simple yet its accuracy and specificity is comparable to the best winning methods of the aforementioned grand challenges

  8. Diverse mitotic functions of the cytoskeletal cross-linking protein Shortstop suggest a role in Dynein/Dynactin activity.

    Science.gov (United States)

    Dewey, Evan B; Johnston, Christopher A

    2017-09-15

    Proper assembly and orientation of the bipolar mitotic spindle is critical to the fidelity of cell division. Mitotic precision fundamentally contributes to cell fate specification, tissue development and homeostasis, and chromosome distribution within daughter cells. Defects in these events are thought to contribute to several human diseases. The underlying mechanisms that function in spindle morphogenesis and positioning remain incompletely defined, however. Here we describe diverse roles for the actin-microtubule cross-linker Shortstop (Shot) in mitotic spindle function in Drosophila Shot localizes to mitotic spindle poles, and its knockdown results in an unfocused spindle pole morphology and a disruption of proper spindle orientation. Loss of Shot also leads to chromosome congression defects, cell cycle progression delay, and defective chromosome segregation during anaphase. These mitotic errors trigger apoptosis in Drosophila epithelial tissue, and blocking this apoptotic response results in a marked induction of the epithelial-mesenchymal transition marker MMP-1. The actin-binding domain of Shot directly interacts with Actin-related protein-1 (Arp-1), a key component of the Dynein/Dynactin complex. Knockdown of Arp-1 phenocopies Shot loss universally, whereas chemical disruption of F-actin does so selectively. Our work highlights novel roles for Shot in mitosis and suggests a mechanism involving Dynein/Dynactin activation. © 2017 Dewey and Johnston. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

  9. Effects of Experimental High Flow Releases and Increased Fluctuations in Flow from Glen Canyon Dam on Abundance, Growth, and Survival Rates of Early Life Stages of Rainbow Trout in the Lee's Ferry Reach of the Colorado River

    Science.gov (United States)

    Korman, Josh

    2010-05-01

    The abundance of adult fish populations is controlled by the growth and survival rates of early life stages. Evaluating the effects of flow regimes on early life stages is therefore critical to determine how these regimes affect the abundance of adult populations. Experimental high flow releases from Glen Canyon Dam, primarily intended to conserve fine sediment and improve habitat conditions for native fish in the Colorado River in Grand Canyon, AZ, have been conducted in 1996, 2004, and 2008. These flows potentially affect the Lee's Ferry reach rainbow trout population, located immediately downstream of the dam, which supports a highly valued fishery and likely influences the abundance of rainbow trout in Grand Canyon. Due to concerns about negative effects of high trout abundance on endangered native fish, hourly variation in flow from Glen Canyon Dam was experimentally increased between 2003 and 2005 to reduce trout abundance. This study reports on the effects of experimental high flow releases and fluctuating flows on early life stages of rainbow trout in the Lee's Ferry reach based on monthly sampling of redds (egg nests) and the abundance and growth of age-0 trout between 2003 and 2009. Data on spawn timing, spawning elevations, and intergravel temperatures were integrated in a model to estimate the magnitude and seasonal trend in incubation mortality resulting from redd dewatering due to fluctuations in flow. Experimental fluctuations from January through March promoted spawning at higher elevations where the duration of dewatering was longer and intergravel temperatures exceeded lethal thresholds. Flow-dependent incubation mortality rates were 24% (2003) and 50% (2004) in years with higher flow fluctuations, compared to 5-11% under normal operations (2006-2009). Spatial and temporal predictions of mortality were consistent with direct observations of egg mortality determined from the excavation of 125 redds. The amount of variation in backcalculated hatch

  10. Stereotactic body radiation therapy versus conventional radiation therapy in patients with early stage non-small cell lung cancer - An updated retrospective study on local failure and survival rates

    International Nuclear Information System (INIS)

    Jeppesen, Stefan S.; Schytte, Tine; Hansen, Olfred; Jensen, Henrik R.; Brink, Carsten

    2013-01-01

    Introduction: Stereotactic body radiation therapy (SBRT) for early stage non-small cell lung cancer (NSCLC) is now an accepted and patient friendly treatment, but still controversy exists about its comparability to conventional radiation therapy (RT). The purpose of this single-institutional report is to describe survival outcome for medically inoperable patients with early stage NSCLC treated with SBRT compared with high dose conventional RT. Material and methods: From August 2005 to June 2012, 100 medically inoperable patients were treated with SBRT at Odense Univ. Hospital. The thoracic RT consisted of 3 fractions (F) of 15-22 Gy delivered in nine days. For comparison a group of 32 medically inoperable patients treated with conventional RT with 80 Gy/35-40 F (5 F/week) in the period of July 1998 to August 2011 were analyzed. All tumors had histological or cytological proven NSCLC T1-2N0M0. Results: The median overall survival was 36.1 months versus 24.4 months for SBRT and conventional RT, respectively (p = 0.015). Local failure-free survival rates at one year were in SBRT group 93 % versus 89 % in the conventional RT group and at five years 69 % versus 66 %, SBRT and conventional RT respectively (p = 0.99). On multivariate analysis, female gender and performance status of 0-1 and SBRT predicted improved prognosis. Conclusion: In a cohort of patients with NSCLC there was a significant difference in overall survival favoring SBRT. Performance status of 0-1, female gender and SBRT predicted improved prognosis. However, staging procedure, confirmation procedure of recurrence and technical improvements of radiation treatment is likely to influence outcomes. However, SBRT seems to be as efficient as conventional RT and is a more convenient treatment for the patients

  11. Fluctuations of Estimated Glomerular Filtration Rate Outside Kidney Disease Improving Global Outcomes Diagnostic Criteria for Acute Kidney Injury in End-Stage Liver Disease Outpatients and Outcome Postliver Transplantation

    Directory of Open Access Journals (Sweden)

    Federica Fiacco, MD

    2018-01-01

    Full Text Available Background. Renal dysfunction in end-stage liver disease (ESLD results from systemic conditions that affect both liver and kidney with activation of vasoconstrictor systems. In this setting, estimated glomerular filtration rate (eGFR may undergo variations often outside Kidney Disease Improving Global Outcomes criteria for acute kidney injury (AKI diagnosis, whose meaning is not clear. The aim of this study was to evaluate eGFR variations in ESLD outpatients listed for liver transplant (liver Tx and the association with post-Tx outcome. Methods. Fifty-one patients with ESLD were retrospectively evaluated from listing to transplant (L-Tx time, intraoperatively (Tx time, and up to 5 years post-Tx time. Variations between the highest and the lowest eGFR occurring in more than 48 hours, not satisfying Kidney Disease Improving Global Outcomes guideline, were considered as fluctuations (eGFR-F. Fluctuations of eGFR greater than 50% were defined as eGFR drops (DeGFR. Early graft dysfunction, AKI within 7 days, chronic kidney disease, and short- and long-term patient survivals were considered as outcomes. Results. All patients presented eGFR-F, whereas DeGFR were observed in 18 (35.3% of 51 (DeGFR+ group. These patients presented higher levels of Model for End-stage Liver Disease score, pre-Tx bilirubin and significantly greater incidence of post-Tx AKI stages 2 to 3 compared with patients without drops (DeGFR−. DeGFR was the only independent predictive factor of the occurrence of post-Tx AKI. The occurrence of AKI post-Tx was associated with the development of chronic kidney disease at 3 months and 5 years post-Tx. Conclusions. Drops of eGFR are more frequently observed in patients with a worse degree of ESLD and are associated with a worse post-Tx kidney outcome.

  12. Fully functional global genome repair of (6-4) photoproducts and compromised transcription-coupled repair of cyclobutane pyrimidine dimers in condensed mitotic chromatin

    Energy Technology Data Exchange (ETDEWEB)

    Komura, Jun-ichiro, E-mail: junkom@med.tohoku.ac.jp [Department of Cell Biology, Tohoku University Graduate School of Medicine, Sendai 980-8575 (Japan); Ikehata, Hironobu [Department of Cell Biology, Tohoku University Graduate School of Medicine, Sendai 980-8575 (Japan); Mori, Toshio [Radioisotope Research Center, Nara Medical University, Kashihara, Nara 634-8521 (Japan); Ono, Tetsuya [Department of Cell Biology, Tohoku University Graduate School of Medicine, Sendai 980-8575 (Japan)

    2012-03-10

    During mitosis, chromatin is highly condensed, and activities such as transcription and semiconservative replication do not occur. Consequently, the condensed condition of mitotic chromatin is assumed to inhibit DNA metabolism by impeding the access of DNA-transacting proteins. However, about 40 years ago, several researchers observed unscheduled DNA synthesis in UV-irradiated mitotic chromosomes, suggesting the presence of excision repair. We re-examined this subject by directly measuring the removal of UV-induced DNA lesions by an ELISA and by a Southern-based technique in HeLa cells arrested at mitosis. We observed that the removal of (6-4) photoproducts from the overall genome in mitotic cells was as efficient as in interphase cells. This suggests that global genome repair of (6-4) photoproducts is fully functional during mitosis, and that the DNA in mitotic chromatin is accessible to proteins involved in this mode of DNA repair. Nevertheless, not all modes of DNA repair seem fully functional during mitosis. We also observed that the removal of cyclobutane pyrimidine dimers from the dihydrofolate reductase and c-MYC genes in mitotic cells was very slow. This suggests that transcription-coupled repair of cyclobutane pyrimidine dimers is compromised or non-functional during mitosis, which is probably the consequence of mitotic transcriptional repression. -- Highlights: Black-Right-Pointing-Pointer Global genome repair of (6-4) photoproducts is fully active in mitotic cells. Black-Right-Pointing-Pointer DNA in condensed mitotic chromatin does not seem inaccessible or inert. Black-Right-Pointing-Pointer Mitotic transcriptional repression may impair transcription-coupled repair.

  13. Fully functional global genome repair of (6-4) photoproducts and compromised transcription-coupled repair of cyclobutane pyrimidine dimers in condensed mitotic chromatin

    International Nuclear Information System (INIS)

    Komura, Jun-ichiro; Ikehata, Hironobu; Mori, Toshio; Ono, Tetsuya

    2012-01-01

    During mitosis, chromatin is highly condensed, and activities such as transcription and semiconservative replication do not occur. Consequently, the condensed condition of mitotic chromatin is assumed to inhibit DNA metabolism by impeding the access of DNA-transacting proteins. However, about 40 years ago, several researchers observed unscheduled DNA synthesis in UV-irradiated mitotic chromosomes, suggesting the presence of excision repair. We re-examined this subject by directly measuring the removal of UV-induced DNA lesions by an ELISA and by a Southern-based technique in HeLa cells arrested at mitosis. We observed that the removal of (6-4) photoproducts from the overall genome in mitotic cells was as efficient as in interphase cells. This suggests that global genome repair of (6-4) photoproducts is fully functional during mitosis, and that the DNA in mitotic chromatin is accessible to proteins involved in this mode of DNA repair. Nevertheless, not all modes of DNA repair seem fully functional during mitosis. We also observed that the removal of cyclobutane pyrimidine dimers from the dihydrofolate reductase and c-MYC genes in mitotic cells was very slow. This suggests that transcription-coupled repair of cyclobutane pyrimidine dimers is compromised or non-functional during mitosis, which is probably the consequence of mitotic transcriptional repression. -- Highlights: ► Global genome repair of (6-4) photoproducts is fully active in mitotic cells. ► DNA in condensed mitotic chromatin does not seem inaccessible or inert. ► Mitotic transcriptional repression may impair transcription-coupled repair.

  14. Incorporation of thymidine into onion root meristematic cell nuclei in presence of hydroxyurea and its role in recovery of mitotic activity

    OpenAIRE

    H. Habdas

    2015-01-01

    Hydroxyurea treatment of onion roots induced mitotic block which was released by transfer of bulbs to water, and also to some extent by addition of cold or 3H-thymidine to hydroxyurea solutions. In presence of hydroxyurea there was noted very intense incorporation of 3H-thymidine into cell nuclei, giving labelling index of 40-70%. However, all the mitotic figures appearing in presence of hydroxyurea and 3H-thymidine were unlabelled. On the other hand, labelled mitotic figures were obtained wh...

  15. The neurogenic factor NeuroD1 is expressed in post-mitotic cells during juvenile and adult Xenopus neurogenesis and not in progenitor or radial glial cells.

    Directory of Open Access Journals (Sweden)

    Laure Anne D'Amico

    Full Text Available In contrast to mammals that have limited proliferation and neurogenesis capacities, the Xenopus frog exhibit a great potential regarding proliferation and production of new cells in the adult brain. This ability makes Xenopus a useful model for understanding the molecular programs required for adult neurogenesis. Transcriptional factors that control adult neurogenesis in vertebrate species undergoing widespread neurogenesis are unknown. NeuroD1 is a member of the family of proneural genes, which function during embryonic neurogenesis as a potent neuronal differentiation factor. Here, we study in detail the expression of NeuroD1 gene in the juvenile and adult Xenopus brains by in situ hybridization combined with immunodetections for proliferation markers (PCNA, BrdU or in situ hybridizations for cell type markers (Vimentin, Sox2. We found NeuroD1 gene activity in many brain regions, including olfactory bulbs, pallial regions of cerebral hemispheres, preoptic area, habenula, hypothalamus, cerebellum and medulla oblongata. We also demonstrated by double staining NeuroD1/BrdU experiments, after long post-BrdU administration survival times, that NeuroD1 gene activity was turned on in new born neurons during post-metamorphic neurogenesis. Importantly, we provided evidence that NeuroD1-expressing cells at this brain developmental stage were post-mitotic (PCNA- cells and not radial glial (Vimentin+ or progenitors (Sox2+ cells.

  16. Multicentric evaluation of the impact of central tumour location when comparing rates of N1 upstaging in patients undergoing video-assisted and open surgery for clinical Stage I non-small-cell lung cancer.

    Science.gov (United States)

    Decaluwé, Herbert; Petersen, René Horsleben; Brunelli, Alex; Pompili, Cecilia; Seguin-Givelet, Agathe; Gust, Lucile; Aigner, Clemens; Falcoz, Pierre-Emmanuel; Rinieri, Philippe; Augustin, Florian; Sokolow, Youri; Verhagen, Ad; Depypere, Lieven; Papagiannopoulos, Kostas; Gossot, Dominique; D'Journo, Xavier Benoit; Guerrera, Francesco; Baste, Jean-Marc; Schmid, Thomas; Stanzi, Alessia; Van Raemdonck, Dirk; Bardet, Jeremy; Thomas, Pascal-Alexandre; Massard, Gilbert; Fieuws, Steffen; Moons, Johnny; Dooms, Christophe; De Leyn, Paul; Hansen, Henrik Jessen

    2017-09-27

    Large retrospective series have indicated lower rates of cN0 to pN1 nodal upstaging after video-assisted thoracic surgery (VATS) compared with open resections for Stage I non-small-cell lung cancer (NSCLC). The objective of our multicentre study was to investigate whether the presumed lower rate of N1 upstaging after VATS disappears after correction for central tumour location in a multivariable analysis. Consecutive patients operated for PET-CT based clinical Stage I NSCLC were selected from prospectively managed surgical databases in 11 European centres. Central tumour location was defined as contact with bronchovascular structures on computer tomography and/or visibility on standard bronchoscopy. Eight hundred and ninety-five patients underwent pulmonary resection by VATS (n = 699, 9% conversions) or an open technique (n = 196) in 2014. Incidence of nodal pN1 and pN2 upstaging was 8% and 7% after VATS and 15% and 6% after open surgery, respectively. pN1 was found in 27% of patients with central tumours. Less central tumours were operated on by VATS compared with the open technique (12% vs 28%, P < 0.001). Logistic regression analysis showed that only tumour location had a significant impact on N1 upstaging (OR 6.2, confidence interval 3.6-10.8; P < 0.001) and that the effect of surgical technique (VATS versus open surgery) was no longer significant when accounting for tumour location. A quarter of patients with central clinical Stage I NSCLC was upstaged to pN1 at resection. Central tumour location was the only independent factor associated with N1 upstaging, undermining the evidence for lower N1 upstaging after VATS resections. Studies investigating N1 upstaging after VATS compared with open surgery should be interpreted with caution due to possible selection bias, i.e. relatively more central tumours in the open group with a higher chance of N1 upstaging. © The Author 2017. Published by Oxford University Press on behalf of the European

  17. Flow cytometric analysis of mitotic cycle perturbation by chemical carcinogens in cultured epithelial cells. [Effects of benzo(a)pyrene-diol-epoxide on mitotic cycle of cultural mouse liver epithelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Pearlman, Andrew Leonard [Univ. of California, Berkeley, CA (United States)

    1978-08-01

    A system for kinetic analysis of mitotic cycle perturbation by various agents was developed and applied to the study of the mitotic cycle effects and dependency of the chemical carcinogen benzo(a)pyrene-diolepoxide, DE, upon a mouse lever epithelial cell line, NMuLi. The study suggests that the targets of DE action are not confined to DNA alone but may include cytoplasmic structures as well. DE was found to affect cells located in virtually every phase of the mitotic cycle, with cells that were actively synthesizing DNA showing the strongest response. However, the resulting perturbations were not confined to S-phase alone. DE slowed traversal through S-phase by about 40% regardless of the cycle phase of the cells exposed to it, and slowed traversal through G2M by about 50%. When added to G1 cells, DE delayed recruitment of apparently quiescent (G0) cells by 2 hours, and reduced the synchrony of the cohort of cells recruited into active proliferation. The kinetic analysis system consists of four elements: tissue culture methods for propagating and harvesting cell populations; an elutriation centrifugation system for bulk synchronization of cells in various phases of the mitotic cycle; a flow cytometer (FCM), coupled with appropriate staining protocols, to enable rapid analysis of the DNA distribution of any given cell population; and data reduction and analysis methods for extracting information from the DNA histograms produced by the FCM. The elements of the system are discussed. A mathematical analysis of DNA histograms obtained by FCM is presented. The analysis leads to the detailed implementation of a new modeling approach. The new modeling approach is applied to the estimation of cell cycle kinetic parameters from time series of DNA histograms, and methods for the reduction and interpretation of such series are suggested.

  18. Heavy rare earth elements affect early life stages in Paracentrotus lividus and Arbacia lixula sea urchins

    International Nuclear Information System (INIS)

    Oral, Rahime; Pagano, Giovanni; Siciliano, Antonietta; Gravina, Maria; Palumbo, Anna; Castellano, Immacolata; Migliaccio, Oriana; Thomas, Philippe J.; Guida, Marco; Tommasi, Franca; Trifuoggi, Marco

    2017-01-01

    Background: Heavy rare earth elements (HREEs) have been scarcely studied for their toxicity, in spite of their applications in several technologies. Thus HREEs require timely investigations for their adverse health effects. Methods: Paracentrotus lividus and Arbacia lixula embryos and sperm were exposed to trichloride salts of five HREEs (Dy, Ho, Er, Yb and Lu) and to Ce(III) as a light REE (LREE) reference to evaluate: 1) developmental defects (% DD) in HREE-exposed larvae or in the offspring of HREE-exposed sperm; 2) mitotic anomalies; 3) fertilization success; and 4) reactive oxygen species (ROS) formation, and nitric oxide (NO) and malondialdehyde (MDA) levels. Nominal HREE concentrations were confirmed by inductively coupled plasma mass spectrometry (ICP-MS). Results: HREEs induced concentration-related DD increases in P. lividus and A. lixula larvae, ranging from no significant DD increase at 10 −7 M HREEs up to ≅100% DD at 10 −5 M HREE. Larvae exposed to 10 −5 M Ce(III) resulted in less severe DD rates compared to HREEs. Decreased mitotic activity and increased aberration rates were found in HREE-exposed P. lividus embryos. Significant increases in ROS formation and NO levels were found both in HREE-exposed and in Ce(III) embryos, whereas only Ce(III), but not HREEs resulted in significant increase in MDA levels. Sperm exposure to HREEs (10 −5 –10 −4 M) resulted in a concentration-related decrease in fertilization success along with increase in offspring damage. These effects were significantly enhanced for Dy(III), Ho(III), Er(III) and Yb(III), compared to Lu(III) and to Ce(III). Conclusion: HREE-associated toxicity affected embryogenesis, fertilization, cytogenetic and redox endpoints showing different toxicities of tested HREEs. - Highlights: • Different toxicities were exerted by five tested HREEs on sea urchin early life stages. • Sea urchin embryos and sperm were sensitive to HREE levels ranging from 1 to 100 μM, according to

  19. Heavy rare earth elements affect early life stages in Paracentrotus lividus and Arbacia lixula sea urchins

    Energy Technology Data Exchange (ETDEWEB)

    Oral, Rahime [Ege University, Faculty of Fisheries, TR-35100 Bornova, İzmir (Turkey); Pagano, Giovanni, E-mail: gbpagano@tin.it [“Federico II” University of Naples, Department of Chemical Sciences, I-80126 Naples (Italy); Stazione Zoologica Anton Dohrn, Villa Comunale, 80121 Naples (Italy); Siciliano, Antonietta; Gravina, Maria [“Federico II” University of Naples, Department of Biology, I-80126 Naples (Italy); Palumbo, Anna; Castellano, Immacolata; Migliaccio, Oriana [Stazione Zoologica Anton Dohrn, Villa Comunale, 80121 Naples (Italy); Thomas, Philippe J. [Environment and Climate Change Canada, Science & Technology Branch, National Wildlife Research Center – Carleton University, Ottawa, Ontario, Canada K1A 0H3 (Canada); Guida, Marco [“Federico II” University of Naples, Department of Biology, I-80126 Naples (Italy); Tommasi, Franca [University of Bari, Department of Biology, Bari (Italy); Trifuoggi, Marco [“Federico II” University of Naples, Department of Chemical Sciences, I-80126 Naples (Italy)

    2017-04-15

    Background: Heavy rare earth elements (HREEs) have been scarcely studied for their toxicity, in spite of their applications in several technologies. Thus HREEs require timely investigations for their adverse health effects. Methods: Paracentrotus lividus and Arbacia lixula embryos and sperm were exposed to trichloride salts of five HREEs (Dy, Ho, Er, Yb and Lu) and to Ce(III) as a light REE (LREE) reference to evaluate: 1) developmental defects (% DD) in HREE-exposed larvae or in the offspring of HREE-exposed sperm; 2) mitotic anomalies; 3) fertilization success; and 4) reactive oxygen species (ROS) formation, and nitric oxide (NO) and malondialdehyde (MDA) levels. Nominal HREE concentrations were confirmed by inductively coupled plasma mass spectrometry (ICP-MS). Results: HREEs induced concentration-related DD increases in P. lividus and A. lixula larvae, ranging from no significant DD increase at 10{sup −7} M HREEs up to ≅100% DD at 10{sup −5} M HREE. Larvae exposed to 10{sup −5} M Ce(III) resulted in less severe DD rates compared to HREEs. Decreased mitotic activity and increased aberration rates were found in HREE-exposed P. lividus embryos. Significant increases in ROS formation and NO levels were found both in HREE-exposed and in Ce(III) embryos, whereas only Ce(III), but not HREEs resulted in significant increase in MDA levels. Sperm exposure to HREEs (10{sup −5}–10{sup −4} M) resulted in a concentration-related decrease in fertilization success along with increase in offspring damage. These effects were significantly enhanced for Dy(III), Ho(III), Er(III) and Yb(III), compared to Lu(III) and to Ce(III). Conclusion: HREE-associated toxicity affected embryogenesis, fertilization, cytogenetic and redox endpoints showing different toxicities of tested HREEs. - Highlights: • Different toxicities were exerted by five tested HREEs on sea urchin early life stages. • Sea urchin embryos and sperm were sensitive to HREE levels ranging from 1 to 100

  20. EFHC1, a protein mutated in juvenile myoclonic epilepsy, associates with the mitotic spindle through its N-terminus

    International Nuclear Information System (INIS)

    Nijs, Laurence de; Lakaye, Bernard; Coumans, Bernard; Leon, Christine; Ikeda, Takashi; Delgado-Escueta, Antonio V.; Grisar, Thierry; Chanas, Grazyna

    2006-01-01

    A novel gene, EFHC1, mutated in juvenile myoclonic epilepsy (JME) encodes a protein with three DM10 domains of unknown function and one putative EF-hand motif. To study the properties of EFHC1, we expressed EGFP-tagged protein in various cell lines. In interphase cells, the fusion protein was present in the cytoplasm and in the nucleus with specific accumulation at the centrosome. During mitosis EGFP-EFHC1 colocalized with the mitotic spindle, especially at spindle poles and with the midbody during cytokinesis. Using a specific antibody, we demonstrated the same distribution of the endogenous protein. Deletion analyses revealed that the N-terminal region of EFHC1 is crucial for the association with the mitotic spindle and the midbody. Our results suggest that EFHC1 could play an important role during cell division

  1. 53BP1 nuclear bodies form around DNA lesions generated by mitotic transmission of chromosomes under replication stress

    DEFF Research Database (Denmark)

    Lukas, Claudia; Savic, Velibor; Bekker-Jensen, Simon

    2011-01-01

    stress increases the frequency of chromosomal lesions that are transmitted to daughter cells. Throughout G1, these lesions are sequestered in nuclear compartments marked by p53-binding protein 1 (53BP1) and other chromatin-associated genome caretakers. We show that the number of such 53BP1 nuclear bodies...... increases after genetic ablation of BLM, a DNA helicase associated with dissolution of entangled DNA. Conversely, 53BP1 nuclear bodies are partially suppressed by knocking down SMC2, a condensin subunit required for mechanical stability of mitotic chromosomes. Finally, we provide evidence that 53BP1 nuclear...... bodies shield chromosomal fragile sites sequestered in these compartments against erosion. Together, these data indicate that restoration of DNA or chromatin integrity at loci prone to replication problems requires mitotic transmission to the next cell generations....

  2. Effect of AC magnetic fields on ultraviolet light-induced mutation and mitotic recombination in Saccharomyces cerevisiae

    International Nuclear Information System (INIS)

    Ager, D.D.; Radul, J.A.

    1994-01-01

    The ability of 60-Hz magnetic fields to induce genetic damage in Saccharomyces cerevisiae was studied. The frequencies of induced mutation, gene conversion, and reciprocal mitotic crossing over were measured for exposures to 1-millitesla magnetic fields alone or in combination with various preliminary exposures to 254-nm ultraviolet light at intensities of 2-50 J/m 2 . These experiments were performed using a repair-proficient strain as well as a strain incapable of excising ultraviolet-induced thymine dimers. Magnetic field exposures did not induce mutation, gene conversion, or reciprocal mitotic crossing over in either of these strains, nor did the fields influence the frequencies of ultraviolet-induced genetic events. 32 refs., 4 tabs

  3. Influence of radiation (Co60) in pre-implant rabbit embryos: effect on mitotic index and embryonic pole malformations

    International Nuclear Information System (INIS)

    Approbato, M.S.; Moura, K.K.V.O.; Florencio, R.S.; Cunha Junior, C.; Garcia, R.; Faria, R.S.; Benedetti, L.N.; Goulart, F.B.

    1995-01-01

    We studied the effect of ionizing irradiation on 12 New Zealand rabbits (65 embryos), at three different times: at match time (zero hour), two days after and four days after, with two different irradiation doses: five c Gy and ten c Gy. Six rabbits (36 blastocysts) were used as controls. the matching instant was the zero hour. Exactly six days after (± 60 minutes) the embryos of each rabbit was picked up by flushing the uterus with culture media. the embryos were fixed in methanol for 48 hours, and colored with acid Mayer hematoxylin. The following embryo parameters were studied: mitotic index; embryonic pole malformations. There were no gross abnormalities of embryo pole. The mitotic index were altered both by the time and doses. (author)

  4. Radiation induced asymmetries in mitotic recombination: evidence for a directional bias in the formation of asymmetric hybrid DNA in yeast

    International Nuclear Information System (INIS)

    Friedman, L.R.; Sobell, H.M.

    We have examined radiation-induced mitotic recombination using two alleles (his1-36, his1-49) in the his1 gene. When the haploid containing his1-36 is irradiated with varying doses of γ rays and then mated with the unirradiated strain containing his1-49, analyses of the selected prototrophs show them to be primarily + +/+ 49. If, on the other hand, the haploid strain containing his1-49 is the irradiated parent, the prototrophic diploids are primarily + +/36 +. In control experiments, where either both strains are irradiated or not irradiated, no such asymmetries are found. These data indicate that the irradiated haploid chromosome tends to be the recipient of genetic information. We interpret these results as indicating a directional bias in the formation of hybrid DNA in radiation-induced mitotic recombination, and discuss these results in terms of current models of genetic recombination

  5. Number of nuclei, mitotic activity and cell length in Cladophora sp thallus treated with cadmium and chromium

    Directory of Open Access Journals (Sweden)

    Monika Krajewska

    2014-01-01

    Full Text Available Cladophora sp., a fresh water, filamentous, multi-nucleate alga growing 16 days in the presence of cadmium and chromium at concentrations 10-4 10-8M was the subject of the experiment. Chromium ions reduced the number of nuclei and mitotic activity, and disturbed the correlation between cell length and number of nuclei, more than cadmium ions. Moreover, both tested metals caused the disappearance of cells with numerous nuclei with time of the culture. Only during the first (1-4 days of culture for both metals the concentration of 10-4M and especially of 10-8M increased the number of nuclei, mitotic index and the length of cells. Apical cells were more sensitive to metals than other thallus cells.

  6. Clinical significance of fluoroscopic patterns specific for the mitotic spindle in patients with reumatic diseases

    Directory of Open Access Journals (Sweden)

    S. Todesco

    2011-09-01

    Full Text Available Objective: we proposed to determine the clinical significance of anti-NuMA and anti-HsEg5 antibodies in a group of patients affected with rheumatic diseases. Materials and methods: indirect immunofluorescence on HEp-2000 cells at serum dilution of 1:40 was used to examin 26 sera which had previously showed a “mitotic spindle” fluoroscopic pattern type during laboratory routine. Results: 21 sera (80,7% were identified with NuMA and 5 (19,3% with HsEg5 patterns alone or associated with other ANA patterns. However only patients with isolated positiveness and that is 15 with NuMA and 4 with HsEg5 stainings were included in this study. Of the NuMA positive patients 5 were affected with arthropathies associated to different forms of thyroiditis, 2 with seronegative arthritis, 2 with antiphospholipid syndrome, 1 with systemic lupus erythematosus (SLE, 1 with rheumatoid arthritis, 1 with sicca syndrome, 1 with undifferentiated connective tissue disease, 1 with Mycoplasma pneumaniae infection and 1 with retinal thrombosis. Of the HsEg5 positive patients 3 were affected with SLE and 1 with seronegative arthritis. Conclusions: NuMA does not prevail in any defined rheumatic disease, while HsEg5 staining were more frequent (75% in patients affected with SLE all of whom showing high antibody titres.

  7. Phosphatase PP2A and microtubule-mediated pulling forces disassemble centrosomes during mitotic exit

    Directory of Open Access Journals (Sweden)

    Stephen J. Enos

    2018-01-01

    Full Text Available Centrosomes are microtubule-nucleating organelles that facilitate chromosome segregation and cell division in metazoans. Centrosomes comprise centrioles that organize a micron-scale mass of protein called pericentriolar material (PCM from which microtubules nucleate. During each cell cycle, PCM accumulates around centrioles through phosphorylation-mediated assembly of PCM scaffold proteins. During mitotic exit, PCM swiftly disassembles by an unknown mechanism. Here, we used Caenorhabditis elegans embryos to determine the mechanism and importance of PCM disassembly in dividing cells. We found that the phosphatase PP2A and its regulatory subunit SUR-6 (PP2ASUR-6, together with cortically directed microtubule pulling forces, actively disassemble PCM. In embryos depleted of these activities, ∼25% of PCM persisted from one cell cycle into the next. Purified PP2ASUR-6 could dephosphorylate the major PCM scaffold protein SPD-5 in vitro. Our data suggest that PCM disassembly occurs through a combination of dephosphorylation of PCM components and force-driven fragmentation of the PCM scaffold.

  8. Establishment and mitotic stability of an extra-chromosomal mammalian replicon

    Directory of Open Access Journals (Sweden)

    Jackson Dean A

    2007-08-01

    Full Text Available Abstract Background Basic functions of the eukaryotic nucleus, like transcription and replication, are regulated in a hierarchic fashion. It is assumed that epigenetic factors influence the efficiency and precision of these processes. In order to uncouple local and long-range epigenetic features we used an extra-chromosomal replicon to study the requirements for replication and segregation and compared its behavior to that of its integrated counterpart. Results The autonomous replicon replicates in all eukaryotic cells and is stably maintained in the absence of selection but, as other extra-chromosomal replicons, its establishment is very inefficient. We now show that following establishment the vector is stably associated with nuclear compartments involved in gene expression and chromosomal domains that replicate at the onset of S-phase. While the vector stays autonomous, its association with these compartments ensures the efficiency of replication and mitotic segregation in proliferating cells. Conclusion Using this novel minimal model system we demonstrate that relevant functions of the eukaryotic nucleus are strongly influenced by higher nuclear architecture. Furthermore our findings have relevance for the rational design of episomal vectors to be used for genetic modification of cells: in order to improve such constructs with respect to efficiency elements have to be identified which ensure that such constructs reach regions of the nucleus favorable for replication and transcription.

  9. Plk1 phosphorylation of IRS2 prevents premature mitotic exit via AKT inactivation

    Science.gov (United States)

    Chen, Long; Li, Zhiguo; Ahmad, Nihal; Liu, Xiaoqi

    2016-01-01

    Insulin receptor substrate (IRS) proteins play important roles by acting as a platform in transducing signals from transmembrane receptors upon growth factor stimulation. Although tyrosine phosphorylation on IRS proteins plays critical roles in signal transduction, phosphorylation of IRS proteins on serine/threonine residues are believed to play various regulatory roles on IRS protein function. However, studies on serine/threonine phosphorylation of IRS proteins are very limited, especially for insulin receptor substrate 2 (IRS2), one member of the IRS protein family. In this study, we identify Polo-like kinase 1 (Plk1) as the responsible kinase for phosphorylation of IRS2 on two serine residues, Ser 556 and Ser 1098. Phosphorylation of IRS2 on these two serine residues by Plk1 prevents the activation of the PI3K pathway upon growth factor stimulation by inhibiting the binding between IRS2 and the PI3K pathway components and increasing IRS2 protein degradation. Of significance, we show that IRS2 phosphorylation is cell cycle regulated and that Plk1 phosphorylation of IRS2 prevents premature mitotic exit via AKT inactivation. PMID:25830382

  10. Interlaboratory assessment of mitotic index by flow cytometry confirms superior reproducibility relative to microscopic scoring.

    Science.gov (United States)

    Roberts, D J; Spellman, R A; Sanok, K; Chen, H; Chan, M; Yurt, P; Thakur, A K; DeVito, G L; Murli, H; Stankowski, L F

    2012-05-01

    A flow cytometric procedure for determining mitotic index (MI) as part of the metaphase chromosome aberrations assay, developed and utilized routinely at Pfizer as part of their standard assay design, has been adopted successfully by Covance laboratories. This method, using antibodies against phosphorylated histone tails (H3PS10) and nucleic acid stain, has been evaluated by the two independent test sites and compared to manual scoring. Primary human lymphocytes were treated with cyclophosphamide, mitomycin C, benzo(a)pyrene, and etoposide at concentrations inducing dose-dependent cytotoxicity. Deming regression analysis indicates that the results generated via flow cytometry (FCM) were more consistent between sites than those generated via microscopy. Further analysis using the Bland-Altman modification of the Tukey mean difference method supports this finding, as the standard deviations (SDs) of differences in MI generated by FCM were less than half of those generated manually. Decreases in scoring variability owing to the objective nature of FCM, and the greater number of cells analyzed, make FCM a superior method for MI determination. In addition, the FCM method has proven to be transferable and easily integrated into standard genetic toxicology laboratory operations. Copyright © 2012 Wiley Periodicals, Inc.

  11. Establishment and mitotic characterization of new Drosophila acentriolar cell lines from DSas-4 mutant

    Directory of Open Access Journals (Sweden)

    Nicolas Lecland

    2013-01-01

    In animal cells the centrosome is commonly viewed as the main cellular structure driving microtubule (MT assembly into the mitotic spindle apparatus. However, additional pathways, such as those mediated by chromatin and augmin, are involved in the establishment of functional spindles. The molecular mechanisms involved in these pathways remain poorly understood, mostly due to limitations inherent to current experimental systems available. To overcome these limitations we have developed six new Drosophila cell lines derived from Drosophila homozygous mutants for DSas-4, a protein essential for centriole biogenesis. These cells lack detectable centrosomal structures, astral MT, with dispersed pericentriolar proteins D-PLP, Centrosomin and γ-tubulin. They show poorly focused spindle poles that reach the plasma membrane. Despite being compromised for functional centrosome, these cells could successfully undergo mitosis. Live-cell imaging analysis of acentriolar spindle assembly revealed that nascent MTs are nucleated from multiple points in the vicinity of chromosomes. These nascent MTs then grow away from kinetochores allowing the expansion of fibers that will be part of the future acentriolar spindle. MT repolymerization assays illustrate that acentriolar spindle assembly occurs “inside-out” from the chromosomes. Colchicine-mediated depolymerization of MTs further revealed the presence of a functional Spindle Assembly Checkpoint (SAC in the acentriolar cells. Finally, pilot RNAi experiments open the potential use of these cell lines for the molecular dissection of anastral pathways in spindle and centrosome assembly.

  12. Influence of novobiocin on mitotic events and radiation-induced G2-arrest

    International Nuclear Information System (INIS)

    Rowley, R.

    1987-01-01

    Novobiocin was used in CHO cells to test for an involvement of topoisomerase II activity in; 1) the induction of, and recovery from, radiation-induced G 2 -arrest and 2) progression through mitosis. Novobiocin blocked recovery from G 2 -arrest with a concentration dependency which suggested that this effect resulted from protein synthesis inhibition. Novobiocin alone, at concentrations above 500 μgml, blocked cell progression in early mitosis. The transition point was distinct from that of protein and RNA synthesis inhibitors and was the only arrest point in mitosis. A similar block was imposed by coumermycin. While this may indicate a requirement for topoisomerase II activity during chromosome condensation, it was also associated with inhibition of histone phosphorylation. Histone H3 phosphorylation is believed to be necessary for chromosome condensation and, when inhibited by novobiocin, correlates with a block in premature chromatin condensation in tsBN2 cells. The authors' data thus unite these two findings, provide an opportunity to analyse the temporal relationship between histone phosphorylation and mitotic events and suggest that topological reorganization of the chromatin is not involved in radiation-induced G 2 arrest

  13. Conditional mutation of Smc5 in mouse embryonic stem cells perturbs condensin localization and mitotic progression.

    Science.gov (United States)

    Pryzhkova, Marina V; Jordan, Philip W

    2016-04-15

    Correct duplication of stem cell genetic material and its appropriate segregation into daughter cells are requisites for tissue, organ and organism homeostasis. Disruption of stem cell genomic integrity can lead to developmental abnormalities and cancer. Roles of the Smc5/6 structural maintenance of chromosomes complex in pluripotent stem cell genome maintenance have not been investigated, despite its important roles in DNA synthesis, DNA repair and chromosome segregation as evaluated in other model systems. Using mouse embryonic stem cells (mESCs) with a conditional knockout allele of Smc5, we showed that Smc5 protein depletion resulted in destabilization of the Smc5/6 complex, accumulation of cells in G2 phase of the cell cycle and apoptosis. Detailed assessment of mitotic mESCs revealed abnormal condensin distribution and perturbed chromosome segregation, accompanied by irregular spindle morphology, lagging chromosomes and DNA bridges. Mutation of Smc5 resulted in retention of Aurora B kinase and enrichment of condensin on chromosome arms. Furthermore, we observed reduced levels of Polo-like kinase 1 at kinetochores during mitosis. Our study reveals crucial requirements of the Smc5/6 complex during cell cycle progression and for stem cell genome maintenance. © 2016. Published by The Company of Biologists Ltd.

  14. UV-induced mitotic co-segregation of genetic markers in Candida albicans: Evidence for linkage

    International Nuclear Information System (INIS)

    Crandall, M.

    1983-01-01

    Parasexual genetic studies of the medically important yeast Candida albicans were performed using the method of UV-induced mitotic segregation. UV-irradiation of the Hoffmann-La Roche type culture of C. albicans yielded a limited spectrum of mutants at a relatively high fequency. This observation suggested natural heterozygosity. Canavanine-sensitive (CanS) segregants were induced at a frequency of 7.6 . 10 -3 . Double mutants that were both CanS and methionine (Met - ) auxotrophs were induced at a frequency of 7.4 . 10 -3 . The single Met - segregant class was missing indicating linkage. UV-induced CanS or Met - CanS segregants occurred occasionally in twin-sectored colonies. Analyses of the sectors as well as the observed and missing classes of segregants indicated that genes met and can are linked in the cis configuration. The proposed gene order is: centromere - met - can. Thus, it is concluded that the Hoffmann-La Roche strain of C. albicans is naturally heterozygous at two linked loci. These findings are consistent with diploidy. (orig.)

  15. Spatial Rule-Based Modeling: A Method and Its Application to the Human Mitotic Kinetochore

    Directory of Open Access Journals (Sweden)

    Jan Huwald

    2013-07-01

    Full Text Available A common problem in the analysis of biological systems is the combinatorial explosion that emerges from the complexity of multi-protein assemblies. Conventional formalisms, like differential equations, Boolean networks and Bayesian networks, are unsuitable for dealing with the combinatorial explosion, because they are designed for a restricted state space with fixed dimensionality. To overcome this problem, the rule-based modeling language, BioNetGen, and the spatial extension, SRSim, have been developed. Here, we describe how to apply rule-based modeling to integrate experimental data from different sources into a single spatial simulation model and how to analyze the output of that model. The starting point for this approach can be a combination of molecular interaction data, reaction network data, proximities, binding and diffusion kinetics and molecular geometries at different levels of detail. We describe the technique and then use it to construct a model of the human mitotic inner and outer kinetochore, including the spindle assembly checkpoint signaling pathway. This allows us to demonstrate the utility of the procedure, show how a novel perspective for understanding such complex systems becomes accessible and elaborate on challenges that arise in the formulation, simulation and analysis of spatial rule-based models.

  16. Effect of X-rays on the mitotic frequency in the fish Tilapia mossambica

    International Nuclear Information System (INIS)

    Manna, G.K.; Som, R.C.

    1977-01-01

    Male and female Tilapia mossambica were irradiated by X-rays with a dose of 100 r. The mitotic frequency in 4,000 cells from their kidney was determined at each of 10 intervals between 1 hour and 120 hour. In irradiated males the frequency of dividing cells was 3.12% at 1 hour, 2.55% at 2 hour, 2.07% at 3 hour, 2.02% at 6 hour, 1.25% at 18 hours, 2.05% at 24 hour, 2.60% at 48 hour, 3.37% at 72 hour, 3.77% at 96 hour and 3.87% at 120 hour while in the irradiated females at the above intervals the frequencies were 5.62%, 3.25%, 2.35%, 2.50%, 2.00%, 5.00%, 6.00%, 6.67% and 6.77% respectively. In the normal individuals the frequency of dividing cells was 4.25% in males and 7.50% in females. The data of the normal and treated series have been analysed and the time factor, sex factors etc., on the inhibitory effect of ionizing radiations in kidney cells of the fish have been discussed. (author)

  17. A Subpopulation of the K562 Cells Are Killed by Curcumin Treatment after G2/M Arrest and Mitotic Catastrophe.

    Directory of Open Access Journals (Sweden)

    Macario Martinez-Castillo

    Full Text Available Curcumin is extensively investigated as a good chemo-preventive agent in the development of many cancers and particularly in leukemia, including treatment of chronic myelogenous leukemia and it has been proposed as an adjuvant for leukemia therapies. Human chronic myeloid leukemia cells (K562, were treated with 20 μM of curcumin, and we found that a subpopulation of these cells were arrested and accumulate in the G2/M phase of the cell cycle. Characterization of this cell subpopulation showed that the arrested cells presented nuclear morphology changes resembling those described for mitotic catastrophe. Mitotic cells displayed abnormal chromatin organization, collapse of the mitotic spindle and abnormal chromosome segregation. Then, these cells died in an apoptosis dependent manner and showed diminution in the protein levels of BCL-2 and XIAP. Moreover, our results shown that a transient activation of the nuclear factor κB (NFκB occurred early in these cells, but decreased after 6 h of the treatment, explaining in part the diminution of the anti-apoptotic proteins. Additionally, P73 was translocated to the cell nuclei, because the expression of the C/EBPα, a cognate repressor of the P73 gene, was decreased, suggesting that apoptosis is trigger by elevation of P73 protein levels acting in concert with the diminution of the two anti-apoptotic molecules. In summary, curcumin treatment might produce a P73-dependent apoptotic cell death in chronic myelogenous leukemia cells (K562, which was triggered by mitotic catastrophe, due to sustained BAX and survivin expression and impairment of the anti-apoptotic proteins BCL-2 and XIAP.

  18. Kaposi's sarcoma herpesvirus C-terminal LANA concentrates at pericentromeric and peri-telomeric regions of a subset of mitotic chromosomes

    International Nuclear Information System (INIS)

    Kelley-Clarke, Brenna; Ballestas, Mary E.; Komatsu, Takashi; Kaye, Kenneth M.

    2007-01-01

    The Kaposi's sarcoma-associated herpesvirus (KSHV) latency-associated nuclear antigen (LANA) tethers KSHV terminal repeat (TR) DNA to mitotic chromosomes to efficiently segregate episomes to progeny nuclei. LANA contains N- and C-terminal chromosome binding regions. We now show that C-terminal LANA preferentially concentrates to paired dots at pericentromeric and peri-telomeric regions of a subset of mitotic chromosomes through residues 996-1139. Deletions within C-terminal LANA abolished both self-association and chromosome binding, consistent with a requirement for self-association to bind chromosomes. A deletion abolishing TR DNA binding did not affect chromosome targeting, indicating LANA's localization is not due to binding its recognition sequence in chromosomal DNA. LANA distributed similarly on human and non-human mitotic chromosomes. These results are consistent with C-terminal LANA interacting with a cell factor that concentrates at pericentromeric and peri-telomeric regions of mitotic chromosomes

  19. Automatic Detection of Mitosis and Nuclei From Cytogenetic Images by CellProfiler Software for Mitotic Index Estimation.

    Science.gov (United States)

    González, Jorge Ernesto; Radl, Analía; Romero, Ivonne; Barquinero, Joan Francesc; García, Omar; Di Giorgio, Marina

    2016-12-01

    Mitotic Index (MI) estimation expressed as percentage of mitosis plays an important role as quality control endpoint. To this end, MI is applied to check the lot of media and reagents to be used throughout the assay and also to check cellular viability after blood sample shipping, indicating satisfactory/unsatisfactory conditions for the progression of cell culture. The objective of this paper was to apply the CellProfiler open-source software for automatic detection of mitotic and nuclei figures from digitized images of cultured human lymphocytes for MI assessment, and to compare its performance to that performed through semi-automatic and visual detection. Lymphocytes were irradiated and cultured for mitosis detection. Sets of images from cultures were analyzed visually and findings were compared with those using CellProfiler software. The CellProfiler pipeline includes the detection of nuclei and mitosis with 80% sensitivity and more than 99% specificity. We conclude that CellProfiler is a reliable tool for counting mitosis and nuclei from cytogenetic images, saves considerable time compared to manual operation and reduces the variability derived from the scoring criteria of different scorers. The CellProfiler automated pipeline achieves good agreement with visual counting workflow, i.e. it allows fully automated mitotic and nuclei scoring in cytogenetic images yielding reliable information with minimal user intervention. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  20. Exposure of Human Lung Cancer Cells to 8-Chloro-Adenosine Induces G2/M Arrest and Mitotic Catastrophe

    Directory of Open Access Journals (Sweden)

    Hong-Yu Zhang

    2004-11-01

    Full Text Available 8-Chloro-adenosine (8-CI-Ado is a potent chemotherapeutic agent whose cytotoxicity in a variety of tumor cell lines has been widely investigated. However, the molecular mechanisms are uncertain. In this study, we found that exposure of human lung cancer cell lines A549 (p53-wt and H1299 (p53-depleted to 8-CI-Ado induced cell arrest in the G2/M phase, which was accompanied by accumulation of binucleated and polymorphonucleated cells resulting from aberrant mitosis and failed cytokinesis. Western blotting showed the loss of phosphorylated forms of Cdc2 and Cdc25C that allowed progression into mitosis. Furthermore, the increase in Ser10-phosphorylated histone H3-positive cells revealed by fluorescence-activated cell sorting suggested that the agent-targeted cells were able to exit the G2 phase and enter the M phase. Immunocytochemistry showed that microtubule and microfilament arrays were changed in exposed cells, indicating that the dynamic instability of microtubules and microfilaments was lost, which may correlate with mitotic dividing failure. Aberrant mitosis resulted in mitotic catastrophe followed by varying degrees of apoptosis, depending on the cell lines. Thus, 8-CI-Ado appears to exert its cytotoxicity toward cells in culture by inducing mitotic catastrophe.