A novel interation of nucleolin with Rad51

International Nuclear Information System (INIS)

De, Ananya; Donahue, Sarah L.; Tabah, Azah; Castro, Nancy E.; Mraz, Naomi; Cruise, Jennifer L.; Campbell, Colin

2006-01-01

Nucleolin associates with various DNA repair, recombination, and replication proteins, and possesses DNA helicase, strand annealing, and strand pairing activities. Examination of nuclear protein extracts from human somatic cells revealed that nucleolin and Rad51 co-immunoprecipitate. Furthermore, purified recombinant Rad51 associates with in vitro transcribed and translated nucleolin. Electroporation-mediated introduction of anti-nucleolin antibody resulted in a 10- to 20-fold reduction in intra-plasmid homologous recombination activity in human fibrosarcoma cells. Additionally, introduction of anti-nucleolin antibody sensitized cells to death induced by the topoisomerase II inhibitor, amsacrine. Introduction of anti-Rad51 antibody also reduced intra-plasmid homologous recombination activity and induced hypersensitivity to amsacrine-induced cell death. Co-introduction of anti-nucleolin and anti-Rad51 antibodies did not produce additive effects on homologous recombination or on cellular sensitivity to amsacrine. The association of the two proteins raises the intriguing possibility that nucleolin binding to Rad51 may function to regulate homologous recombinational repair of chromosomal DNA

Roles of C-Terminal Region of Yeast and Human Rad52 in Rad51-Nucleoprotein Filament Formation and ssDNA Annealing.

Directory of Open Access Journals (Sweden)

Nilesh V Khade

Full Text Available Yeast Rad52 (yRad52 has two important functions at homologous DNA recombination (HR; annealing complementary single-strand DNA (ssDNA molecules and recruiting Rad51 recombinase onto ssDNA (recombination mediator activity. Its human homolog (hRAD52 has a lesser role in HR, and apparently lacks mediator activity. Here we show that yRad52 can load human Rad51 (hRAD51 onto ssDNA complexed with yeast RPA in vitro. This is biochemically equivalent to mediator activity because it depends on the C-terminal Rad51-binding region of yRad52 and on functional Rad52-RPA interaction. It has been reported that the N-terminal two thirds of both yRad52 and hRAD52 is essential for binding to and annealing ssDNA. Although a second DNA binding region has been found in the C-terminal region of yRad52, its role in ssDNA annealing is not clear. In this paper, we also show that the C-terminal region of yRad52, but not of hRAD52, is involved in ssDNA annealing. This suggests that the second DNA binding site is required for the efficient ssDNA annealing by yRad52. We propose an updated model of Rad52-mediated ssDNA annealing.

RadGenomics project

Energy Technology Data Exchange (ETDEWEB)

Iwakawa, Mayumi; Imai, Takashi; Harada, Yoshinobu [National Inst. of Radiological Sciences, Chiba (Japan). Frontier Research Center] [and others

2002-06-01

Human health is determined by a complex interplay of factors, predominantly between genetic susceptibility, environmental conditions and aging. The ultimate aim of the RadGenomics (Radiation Genomics) project is to understand the implications of heterogeneity in responses to ionizing radiation arising from genetic variation between individuals in the human population. The rapid progression of the human genome sequencing and the recent development of new technologies in molecular genetics are providing us with new opportunities to understand the genetic basis of individual differences in susceptibility to natural and/or artificial environmental factors, including radiation exposure. The RadGenomics project will inevitably lead to improved protocols for personalized radiotherapy and reductions in the potential side effects of such treatment. The project will contribute to future research into the molecular mechanisms of radiation sensitivity in humans and will stimulate the development of new high-throughput technologies for a broader application of biological and medical sciences. The staff members are specialists in a variety of fields, including genome science, radiation biology, medical science, molecular biology, and informatics, and have joined the RadGenomics project from various universities, companies, and research institutes. The project started in April 2001. (author)

RadGenomics project

International Nuclear Information System (INIS)

Iwakawa, Mayumi; Imai, Takashi; Harada, Yoshinobu

2002-01-01

Human health is determined by a complex interplay of factors, predominantly between genetic susceptibility, environmental conditions and aging. The ultimate aim of the RadGenomics (Radiation Genomics) project is to understand the implications of heterogeneity in responses to ionizing radiation arising from genetic variation between individuals in the human population. The rapid progression of the human genome sequencing and the recent development of new technologies in molecular genetics are providing us with new opportunities to understand the genetic basis of individual differences in susceptibility to natural and/or artificial environmental factors, including radiation exposure. The RadGenomics project will inevitably lead to improved protocols for personalized radiotherapy and reductions in the potential side effects of such treatment. The project will contribute to future research into the molecular mechanisms of radiation sensitivity in humans and will stimulate the development of new high-throughput technologies for a broader application of biological and medical sciences. The staff members are specialists in a variety of fields, including genome science, radiation biology, medical science, molecular biology, and informatics, and have joined the RadGenomics project from various universities, companies, and research institutes. The project started in April 2001. (author)

Dihydrocoumarin, an HDAC Inhibitor, Increases DNA Damage Sensitivity by Inhibiting Rad52

Directory of Open Access Journals (Sweden)

Chin-Chuan Chen

2017-12-01

Full Text Available Effective DNA repair enables cancer cells to survive DNA damage induced by chemotherapeutic or radiotherapeutic treatments. Therefore, inhibiting DNA repair pathways is a promising therapeutic strategy for increasing the efficacy of such treatments. In this study, we found that dihydrocoumarin (DHC, a flavoring agent, causes deficiencies in double-stand break (DSB repair and prolonged DNA damage checkpoint recovery in yeast. Following DNA damage, Rad52 recombinase was revealed to be inhibited by DHC, which results in deficiencies in DSB repair and prolonged DNA damage checkpoint recovery. The deletion of RPD3, a class I histone deacetylase (HDAC, was found to mimic DHC-induced suppression of Rad52 expression, suggesting that the HDAC inhibitor activity of DHC is critical to DSB repair and DNA damage sensitivity. Overall, our findings delineate the regulatory mechanisms of DHC in DSB repair and suggest that it might potentially be used as an inhibitor of the DNA repair pathway in human cells.

Rad50S alleles of the Mre11 complex: questions answered and questions raised.

Science.gov (United States)

Usui, Takehiko; Petrini, John H J; Morales, Monica

2006-08-15

We find that Rad50S mutations in yeast and mammals exhibit constitutive PIKK (PI3-kinase like kinase)-dependent signaling [T. Usui, H. Ogawa, J.H. Petrini, A DNA damage response pathway controlled by Tel1 and the Mre11 complex. Mol. Cell 7 (2001) 1255-1266.; M. Morales, J.W. Theunissen, C.F. Kim, R. Kitagawa, M.B. Kastan, J.H. Petrini, The Rad50S allele promotes ATM-dependent DNA damage responses and suppresses ATM deficiency: implications for the Mre11 complex as a DNA damage sensor. Genes Dev. 19 (2005) 3043-4354.]. The signaling depends on Mre11 complex functions, consistent with its role as a DNA damage sensor. Rad50S is distinct from hypomorphic mutations of Mre11 and Nbs1 in mammals [M. Morales, J.W. Theunissen, C.F. Kim, R. Kitagawa, M.B. Kastan, J.H. Petrini, The Rad50S allele promotes ATM-dependent DNA damage responses and suppresses ATM deficiency: implications for the Mre11 complex as a DNA damage sensor. Genes Dev. 19 (2005) 3043-3054.; J.P. Carney, R.S. Maser, H. Olivares, E.M. Davis, Le M. Beau, J.R. Yates, III, L. Hays, W.F. Morgan, J.H. Petrini, The hMre11/hRad50 protein complex and Nijmegen breakage syndrome: linkage of double-strand break repair to the cellular DNA damage response. Cell 93 (1998) 477-486.; G.S. Stewart, R.S. Maser, T. Stankovic, D.A. Bressan, M.I. Kaplan, N.G. Jaspers, A. Raams, P.J. Byrd, J.H. Petrini, A.M. Taylor, The DNA double-strand break repair gene hMRE11 is mutated in individuals with an ataxia-telangiectasia-like disorder. Cell 99 (1999) 577-587.; B.R. Williams, O.K. Mirzoeva, W.F. Morgan, J. Lin, W. Dunnick, J.H. Petrini, A murine model of nijmegen breakage syndrome. Curr. Biol. 12 (2002) 648-653.; J.W. Theunissen, M.I. Kaplan, P.A. Hunt, B.R. Williams, D.O. Ferguson, F.W. Alt, J.H. Petrini, Checkpoint failure and chromosomal instability without lymphomagenesis in Mre11(ATLD1/ATLD1) mice. Mol. Cell 12 (2003) 1511-1523.] and the Mre11 complex deficiency in yeast [T. Usui, H. Ogawa, J.H. Petrini, A DNA damage response

Human RAD18 interacts with ubiquitylated chromatin components and facilitates RAD9 recruitment to DNA double strand breaks.

Directory of Open Access Journals (Sweden)

Akiko Inagaki

Full Text Available RAD18 is an ubiquitin ligase involved in replicative damage bypass and DNA double-strand break (DSB repair processes. We found that RPA is required for the dynamic pattern of RAD18 localization during the cell cycle, and for accumulation of RAD18 at sites of γ-irradiation-induced DNA damage. In addition, RAD18 colocalizes with chromatin-associated conjugated ubiquitin and ubiquitylated H2A throughout the cell cycle and following irradiation. This localization pattern depends on the presence of an intact, ubiquitin-binding Zinc finger domain. Using a biochemical approach, we show that RAD18 directly binds to ubiquitylated H2A and several other unknown ubiquitylated chromatin components. This interaction also depends on the RAD18 Zinc finger, and increases upon the induction of DSBs by γ-irradiation. Intriguingly, RAD18 does not always colocalize with regions that show enhanced H2A ubiquitylation. In human female primary fibroblasts, where one of the two X chromosomes is inactivated to equalize X-chromosomal gene expression between male (XY and female (XX cells, this inactive X is enriched for ubiquitylated H2A, but only rarely accumulates RAD18. This indicates that the binding of RAD18 to ubiquitylated H2A is context-dependent. Regarding the functional relevance of RAD18 localization at DSBs, we found that RAD18 is required for recruitment of RAD9, one of the components of the 9-1-1 checkpoint complex, to these sites. Recruitment of RAD9 requires the functions of the RING and Zinc finger domains of RAD18. Together, our data indicate that association of RAD18 with DSBs through ubiquitylated H2A and other ubiquitylated chromatin components allows recruitment of RAD9, which may function directly in DSB repair, independent of downstream activation of the checkpoint kinases CHK1 and CHK2.

p53 is involved in clearance of ionizing radiation-induced RAD51 foci in a human colon cancer cell line

International Nuclear Information System (INIS)

Orre, Lukas M.; Stenerloew, Bo; Dhar, Sumeer; Larsson, Rolf; Lewensohn, Rolf; Lehtioe, Janne

2006-01-01

We have investigated p53-related differences in cellular response to DNA damaging agents, focusing on p53s effects on RAD51 protein level and sub-cellular localization post exposure to ionizing radiation. In a human colon cancer cell line, HCT116 and its isogenic p53-/- subcell line we show here p53-independent RAD51 foci formation but interestingly the resolution of RAD51 foci showed clear p53 dependence. In p53 wt cells, but not in p53-/- cells, RAD51 protein level decreased 48 h post irradiation and fluorescence immunostaining showed resolution of RAD51 foci and relocalization of RAD51 to nucleoli at time points corresponding to the decrease in RAD51 protein level. Both cell lines rejoined DNA double strand breaks efficiently with similar kinetics and p53 status did not influence sensitivity to DNA damaging agents. We suggest that p53 has a role in RAD51 clearance post DSB repair and that nucleoli might be sites of RAD51 protein degradation

Mimivirus reveals Mre11/Rad50 fusion proteins with a sporadic distribution in eukaryotes, bacteria, viruses and plasmids

Directory of Open Access Journals (Sweden)

Ogata Hiroyuki

2011-09-01

Full Text Available Abstract Background The Mre11/Rad50 complex and the homologous SbcD/SbcC complex in bacteria play crucial roles in the metabolism of DNA double-strand breaks, including DNA repair, genome replication, homologous recombination and non-homologous end-joining in cellular life forms and viruses. Here we investigated the amino acid sequence of the Mimivirus R555 gene product, originally annotated as a Rad50 homolog, and later shown to have close homologs in marine microbial metagenomes. Results Our bioinformatics analysis revealed that R555 protein sequence is constituted from the fusion of an N-terminal Mre11-like domain with a C-terminal Rad50-like domain. A systematic database search revealed twelve additional cases of Mre11/Rad50 (or SbcD/SbcC fusions in a wide variety of unrelated organisms including unicellular and multicellular eukaryotes, the megaplasmid of a bacterium associated to deep-sea hydrothermal vents (Deferribacter desulfuricans and the plasmid of Clostridium kluyveri. We also showed that R555 homologs are abundant in the metagenomes from different aquatic environments and that they most likely belong to aquatic viruses. The observed phyletic distribution of these fusion proteins suggests their recurrent creation and lateral gene transfers across organisms. Conclusions The existence of the fused version of protein sequences is consistent with known functional interactions between Mre11 and Rad50, and the gene fusion probably enhanced the opportunity for lateral transfer. The abundance of the Mre11/Rad50 fusion genes in viral metagenomes and their sporadic phyletic distribution in cellular organisms suggest that viruses, plasmids and transposons played a crucial role in the formation of the fusion proteins and their propagation into cellular genomes.

Development and application of the Chinese adult female computational phantom Rad-HUMAN

International Nuclear Information System (INIS)

Wu, Yican; Cheng, Mengyun; Wang, Wen; Fan, Yanchang; Zhao, Kai; He, Tao; Pei, Xi; Shang, Leiming; Chen, Chaobin; Long, Pengcheng; Cao, Ruifen; Wang, Guozhong; Zhou, Shaoheng; Yu, Shengpeng; Hu, Liqin; Zeng, Q.

2013-01-01

Rad-HUMAN is a whole-body numerical phantom of a Chinese adult woman which contains 46 organs and tissues and was created by MCAM6 software using the color photographs of the Chinese Visible Human dataset. This dataset was obtained from a 22-year old Chinese female cadaver judged to represent normal human anatomy as much as possible. The density and elemental composition recommended in the ICRP Publication 89 and in the ICRU report 44 were assigned to the organ and tissue in Rad-HUMAN for radiation protection purpose. The last step was to implement the anatomical data into a Monte Carlo code. Rad-HUMAN contains more than 28.8 billion tiny volume units, which produces an accurately whole-body numerical phantom of a Chinese adult female

Rad9 Has a Functional Role in Human Prostate Carcinogenesis

Science.gov (United States)

Zhu, Aiping; Zhang, Charles Xia; Lieberman, Howard B.

2013-01-01

Prostate cancer is currently the most common type of neoplasm found in American men, other than skin cancer, and is the second leading cause of cancer death in males. Because cell cycle checkpoint proteins stabilize the genome, the relationship of one such protein, Rad9, to prostate cancer was investigated. We found that four prostate cancer cell lines (CWR22, DU145, LNCaP, and PC-3), relative to PrEC normal prostate cells, have aberrantly high levels of Rad9 protein. The 3′-end region of intron 2 of Rad9 in DU145 cells is hypermethylated at CpG islands, and treatment with 5′-aza-2′-deoxycytidine restores near-normal levels of methylation and reduces Rad9 protein abundance. Southern blot analyses indicate that PC-3 cells contain an amplified Rad9 copy number. Therefore, we provide evidence that Rad9 levels are high in prostate cancer cells due at least in part to aberrant methylation or gene amplification. The effectiveness of small interfering RNA to lower Rad9 protein levels in CWR22, DU145, and PC-3 cells correlated with reduction of tumorigenicity in nude mice, indicating that Rad9 actively contributes to the disease. Rad9 protein levels were high in 153 of 339 human prostate tumor biopsy samples examined and detectable in only 2 of 52 noncancerous prostate tissues. There was a strong correlation between Rad9 protein abundance and cancer stage. Rad9 protein level can thus provide a biomarker for advanced prostate cancer and is causally related to the disease, suggesting the potential for developing novel diagnostic, prognostic, and therapeutic tools based on detection or manipulation of Rad9 protein abundance. PMID:18316588

Protein dynamics of human RPA and RAD51 on ssDNA during assembly and disassembly of the RAD51 filament.

Science.gov (United States)

Ma, Chu Jian; Gibb, Bryan; Kwon, YoungHo; Sung, Patrick; Greene, Eric C

2017-01-25

Homologous recombination (HR) is a crucial pathway for double-stranded DNA break (DSB) repair. During the early stages of HR, the newly generated DSB ends are processed to yield long single-stranded DNA (ssDNA) overhangs, which are quickly bound by replication protein A (RPA). RPA is then replaced by the DNA recombinase Rad51, which forms extended helical filaments on the ssDNA. The resulting nucleoprotein filament, known as the presynaptic complex, is responsible for pairing the ssDNA with homologous double-stranded DNA (dsDNA), which serves as the template to guide DSB repair. Here, we use single-molecule imaging to visualize the interplay between human RPA (hRPA) and human RAD51 during presynaptic complex assembly and disassembly. We demonstrate that ssDNA-bound hRPA can undergo facilitated exchange, enabling hRPA to undergo rapid exchange between free and ssDNA-bound states only when free hRPA is present in solution. Our results also indicate that the presence of free hRPA inhibits RAD51 filament nucleation, but has a lesser impact upon filament elongation. This finding suggests that hRPA exerts important regulatory influence over RAD51 and may in turn affect the properties of the assembled RAD51 filament. These experiments provide an important basis for further investigations into the regulation of human presynaptic complex assembly. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

Rad9 contribution to radiosensitivity and the G2 checkpoint in a DT40 cell line

Energy Technology Data Exchange (ETDEWEB)

Kumano, Tomoyasu [Kanazawa Univ. (Japan). Graduate School of Medical Science

2002-12-01

In fission yeast, the rad9 (radiation sensitive) gene was cloned from a mutant that is sensitive to ionizing radiation, ultraviolet and hydroxyurea. This gene has also been shown to be required for a DNA damage checkpoint. Orthologues of the rad9 gene have recently been identified in higher eukaryote cells including human. Here we generated Rad9 knockout (Rad9-/-) cells from the chicken B lymphocyte line DT40 to examine the role of Rad9 in higher eukaryotes. First we isolated a part of the chicken Rad9 gene which was 54% identical with human Rad9 at the amino acid sequence level. Next we isolated genomic clones, determined exons and introns, and constructed targeting vectors designed to disrupt exon 1-3 of the chicken Rad9 gene by replacement with a drug-resistant gene. Successful targeted integration was verified by Southern blot analysis and the disruption of the Rad9 gene was confirmed by reverse transcription polymerase chain reaction (RT-PCR). To analyze the radiosensitivity of these Rad9-/- cells, we monitored the clonogenic survival after various degrees of X-ray irradiation. Rad9-/- cells were more sensitive to X-rays than wild type cells at all dosages. However, these cells were less sensitive than ATM knockout (ATM-/-) cells that are known to be X-ray sensitive and that showed a defective checkpoint control. In contrast, Rad9-/- cells were markedly more sensitive to ultraviolet and hydroxyruea. In addition, we assessed the G2 checkpoint by measurement of the mitotic index that is the fraction of the accumulating number of cells in mitosis at various times after X-ray irradiation. While the number of mitotic wild type cells did not increase until 2 hrs after X-ray irradiation, the number of mitotic Rad9-/- cells showed an increase similar to that of ATM-/- cells. These results suggest that just as in fission yeast, in higher eukaryotes Rad9 also contributes to X-ray, ultraviolet and hydroxyurea sensitivity, and plays an important role in the G2 checkpoint

Rad9 contribution to radiosensitivity and the G2 checkpoint in a DT40 cell line

International Nuclear Information System (INIS)

Kumano, Tomoyasu

2002-01-01

In fission yeast, the rad9 (radiation sensitive) gene was cloned from a mutant that is sensitive to ionizing radiation, ultraviolet and hydroxyurea. This gene has also been shown to be required for a DNA damage checkpoint. Orthologues of the rad9 gene have recently been identified in higher eukaryote cells including human. Here we generated Rad9 knockout (Rad9-/-) cells from the chicken B lymphocyte line DT40 to examine the role of Rad9 in higher eukaryotes. First we isolated a part of the chicken Rad9 gene which was 54% identical with human Rad9 at the amino acid sequence level. Next we isolated genomic clones, determined exons and introns, and constructed targeting vectors designed to disrupt exon 1-3 of the chicken Rad9 gene by replacement with a drug-resistant gene. Successful targeted integration was verified by Southern blot analysis and the disruption of the Rad9 gene was confirmed by reverse transcription polymerase chain reaction (RT-PCR). To analyze the radiosensitivity of these Rad9-/- cells, we monitored the clonogenic survival after various degrees of X-ray irradiation. Rad9-/- cells were more sensitive to X-rays than wild type cells at all dosages. However, these cells were less sensitive than ATM knockout (ATM-/-) cells that are known to be X-ray sensitive and that showed a defective checkpoint control. In contrast, Rad9-/- cells were markedly more sensitive to ultraviolet and hydroxyruea. In addition, we assessed the G2 checkpoint by measurement of the mitotic index that is the fraction of the accumulating number of cells in mitosis at various times after X-ray irradiation. While the number of mitotic wild type cells did not increase until 2 hrs after X-ray irradiation, the number of mitotic Rad9-/- cells showed an increase similar to that of ATM-/- cells. These results suggest that just as in fission yeast, in higher eukaryotes Rad9 also contributes to X-ray, ultraviolet and hydroxyurea sensitivity, and plays an important role in the G2 checkpoint

Ionizing radiation-induced foci formation of mammalian Rad51 and Rad54 depends on the Rad51 paralogs, but not on Rad52

International Nuclear Information System (INIS)

Veelen, Lieneke R. van; Essers, Jeroen; Rakt, Mandy W.M.M. van de; Odijk, Hanny; Pastink, Albert; Zdzienicka, MaIgorzata Z.; Paulusma, Coen C.; Kanaar, Roland

2005-01-01

Homologous recombination is of major importance for the prevention of genomic instability during chromosome duplication and repair of DNA damage, especially double-strand breaks. Biochemical experiments have revealed that during the process of homologous recombination the RAD52 group proteins, including Rad51, Rad52 and Rad54, are involved in an essential step: formation of a joint molecule between the broken DNA and the intact repair template. Accessory proteins for this reaction include the Rad51 paralogs and BRCA2. The significance of homologous recombination for the cell is underscored by the evolutionary conservation of the Rad51, Rad52 and Rad54 proteins from yeast to humans. Upon treatment of cells with ionizing radiation, the RAD52 group proteins accumulate at the sites of DNA damage into so-called foci. For the yeast Saccharomyces cerevisiae, foci formation of Rad51 and Rad54 is abrogated in the absence of Rad52, while Rad51 foci formation does occur in the absence of the Rad51 paralog Rad55. By contrast, we show here that in mammalian cells, Rad52 is not required for foci formation of Rad51 and Rad54. Furthermore, radiation-induced foci formation of Rad51 and Rad54 is impaired in all Rad51 paralog and BRCA2 mutant cell lines tested, while Rad52 foci formation is not influenced by a mutation in any of these recombination proteins. Despite their evolutionary conservation and biochemical similarities, S. cerevisiae and mammalian Rad52 appear to differentially contribute to the DNA-damage response

RAD52 Facilitates Mitotic DNA Synthesis Following Replication Stress

DEFF Research Database (Denmark)

Bhowmick, Rahul; Minocherhomji, Sheroy; Hickson, Ian D

2016-01-01

Homologous recombination (HR) is necessary to counteract DNA replication stress. Common fragile site (CFS) loci are particularly sensitive to replication stress and undergo pathological rearrangements in tumors. At these loci, replication stress frequently activates DNA repair synthesis in mitosis...... replication stress at CFS loci during S-phase. In contrast, MiDAS is RAD52 dependent, and RAD52 is required for the timely recruitment of MUS81 and POLD3 to CFSs in early mitosis. Our results provide further mechanistic insight into MiDAS and define a specific function for human RAD52. Furthermore, selective...

The SRS2 suppressor of rad6 mutations of Saccharomyces cerevisiae acts by channeling DNA lesions into the RAD52 DNA repair pathway

International Nuclear Information System (INIS)

Schiestl, R.H.; Prakash, S.; Prakash, L.

1990-01-01

rad6 mutants of Saccharomyces cerevisiae are defective in the repair of damaged DNA, DNA damage induced mutagenesis, and sporulation. In order to identify genes that can substitute for RAD6 function, the authors have isolated genomic suppressors of the UV sensitivity of rad6 deletion (rad6Δ) mutations and show that they also suppress the γ-ray sensitivity but not the UV mutagenesis or sporulation defects of rad6. The suppressors show semidominance for suppression of UV sensitivity and dominance for suppression of γ-ray sensitivity. The six suppressor mutations they isolated are all alleles of the same locus and are also allelic to a previously described suppressor of the rad6-1 nonsense mutation, SRS2. They show that suppression of rad6Δ is dependent on the RAD52 recombinational repair pathway since suppression is not observed in the rad6Δ SRS2 strain containing an additional mutation in either the RAD51, RAD52, RAD54, RAD55 or RAD57 genes. Possible mechanisms by which SRS2 may channel unrepaired DNA lesions into the RAD52 DNA repair pathway are discussed

Disparate requirements for the Walker A and B ATPase motifs of human RAD51D in homologous recombination.

Science.gov (United States)

Wiese, Claudia; Hinz, John M; Tebbs, Robert S; Nham, Peter B; Urbin, Salustra S; Collins, David W; Thompson, Larry H; Schild, David

2006-01-01

In vertebrates, homologous recombinational repair (HRR) requires RAD51 and five RAD51 paralogs (XRCC2, XRCC3, RAD51B, RAD51C and RAD51D) that all contain conserved Walker A and B ATPase motifs. In human RAD51D we examined the requirement for these motifs in interactions with XRCC2 and RAD51C, and for survival of cells in response to DNA interstrand crosslinks (ICLs). Ectopic expression of wild-type human RAD51D or mutants having a non-functional A or B motif was used to test for complementation of a rad51d knockout hamster CHO cell line. Although A-motif mutants complement very efficiently, B-motif mutants do not. Consistent with these results, experiments using the yeast two- and three-hybrid systems show that the interactions between RAD51D and its XRCC2 and RAD51C partners also require a functional RAD51D B motif, but not motif A. Similarly, hamster Xrcc2 is unable to bind to the non-complementing human RAD51D B-motif mutants in co-immunoprecipitation assays. We conclude that a functional Walker B motif, but not A motif, is necessary for RAD51D's interactions with other paralogs and for efficient HRR. We present a model in which ATPase sites are formed in a bipartite manner between RAD51D and other RAD51 paralogs.

The role of Candida albicans homologous recombination factors Rad54 and Rdh54 in DNA damage sensitivity

Directory of Open Access Journals (Sweden)

White Theodore C

2011-09-01

Full Text Available Abstract Background The fungal pathogen Candida albicans is frequently seen in immune suppressed patients, and resistance to one of the most widely used antifungals, fluconazole (FLC, can evolve rapidly. In recent years it has become clear that plasticity of the Candida albicans genome contributes to drug resistance through loss of heterozygosity (LOH at resistance genes and gross chromosomal rearrangements that amplify gene copy number of resistance associated genes. This study addresses the role of the homologous recombination factors Rad54 and Rdh54 in cell growth, DNA damage and FLC resistance in Candida albicans. Results The data presented here support a role for homologous recombination in cell growth and DNA damage sensitivity, as Candida albicans rad54Δ/rad54Δ mutants were hypersensitive to MMS and menadione, and had an aberrant cell and nuclear morphology. The Candida albicans rad54Δ/rad54Δ mutant was defective in invasion of Spider agar, presumably due to the altered cellular morphology. In contrast, mutation of the related gene RDH54 did not contribute significantly to DNA damage resistance and cell growth, and deletion of either Candida albicans RAD54 or Candida albicans RDH54 did not alter FLC susceptibility. Conclusions Together, these results support a role for homologous recombination in genome stability under nondamaging conditions. The nuclear morphology defects in the rad54Δ/rad54Δ mutants show that Rad54 performs an essential role during mitotic growth and that in its absence, cells arrest in G2. The viability of the single mutant rad54Δ/rad54Δ and the inability to construct the double mutant rad54Δ/rad54Δ rdh54Δ/rdh54Δ suggests that Rdh54 can partially compensate for Rad54 during mitotic growth.

Characterization of mutants of yeast sensitive to x rays

International Nuclear Information System (INIS)

Strike, T.L.

1978-01-01

This study deals with the characterization of mutants at the rad50 to rad57 loci selected on the basis of their sensitivity to x rays. They were also examined for sensitivity to uv and mms and for characteristics of mutation induction, heteroallelic reversion (gene conversion), liquid holding recovery from x rays, and sporulation. All the mutants were slightly to moderately sensitive to uv though they did not show the extreme sensitivity of the rad1 to rad22 mutations, and all demonstrated cross sensitivity to both x rays and MMS. If a mutant was very sensitive to x-rays, it was usually very sensitive to MMS also

Variations in Mre11/Rad50/Nbs1 status and DNA damage-induced S-phase arrest in the cell lines of the NCI60 panel

Directory of Open Access Journals (Sweden)

Eastman Alan

2011-05-01

Full Text Available Abstract Background The Mre11/Rad50/Nbs1 (MRN complex is a regulator of cell cycle checkpoints and DNA repair. Defects in MRN can lead to defective S-phase arrest when cells are damaged. Such defects may elicit sensitivity to selected drugs providing a chemical synthetic lethal interaction that could be used to target therapy to tumors with these defects. The goal of this study was to identify these defects in the NCI60 panel of cell lines and identify compounds that might elicit selective cytotoxicity. Methods We screened the NCI60 panel in search of cell lines that express low levels of MRN proteins, or that fail to arrest in S-phase in response to the topisomerase I inhibitor SN38. The NCI COMPARE program was used to discover compounds that preferentially target cells with these phenotypes. Results HCT116 cells were initially identified as defective in MRN and S phase arrest. Transfection with Mre11 also elevated Rad50 and Nbs1, and rescued the defective S-phase arrest. Cells of the NCI60 panel exhibited a large range of protein expression but a strong correlation existed between Mre11, Rad50 and Nbs1 consistent with complex formation determining protein stability. Mre11 mRNA correlated best with protein level suggesting it was the primary determinant of the overall level of the complex. Three other cell lines failed to arrest in response to SN38, two of which also had low MRN. However, other cell lines with low MRN still arrested suggesting low MRN does not predict an inability to arrest. Many compounds, including a family of benzothiazoles, correlated with the failure to arrest in S phase. The activity of benzothiazoles has been attributed to metabolic activation and DNA alkylation, but we note several cell lines in which sensitivity does not correlate with metabolism. We propose that the checkpoint defect imposes an additional mechanism of sensitivity on cells. Conclusions We have identified cells with possible defects in the MRN complex

Variations in Mre11/Rad50/Nbs1 status and DNA damage-induced S-phase arrest in the cell lines of the NCI60 panel

International Nuclear Information System (INIS)

Garner, Kristen M; Eastman, Alan

2011-01-01

The Mre11/Rad50/Nbs1 (MRN) complex is a regulator of cell cycle checkpoints and DNA repair. Defects in MRN can lead to defective S-phase arrest when cells are damaged. Such defects may elicit sensitivity to selected drugs providing a chemical synthetic lethal interaction that could be used to target therapy to tumors with these defects. The goal of this study was to identify these defects in the NCI60 panel of cell lines and identify compounds that might elicit selective cytotoxicity. We screened the NCI60 panel in search of cell lines that express low levels of MRN proteins, or that fail to arrest in S-phase in response to the topisomerase I inhibitor SN38. The NCI COMPARE program was used to discover compounds that preferentially target cells with these phenotypes. HCT116 cells were initially identified as defective in MRN and S phase arrest. Transfection with Mre11 also elevated Rad50 and Nbs1, and rescued the defective S-phase arrest. Cells of the NCI60 panel exhibited a large range of protein expression but a strong correlation existed between Mre11, Rad50 and Nbs1 consistent with complex formation determining protein stability. Mre11 mRNA correlated best with protein level suggesting it was the primary determinant of the overall level of the complex. Three other cell lines failed to arrest in response to SN38, two of which also had low MRN. However, other cell lines with low MRN still arrested suggesting low MRN does not predict an inability to arrest. Many compounds, including a family of benzothiazoles, correlated with the failure to arrest in S phase. The activity of benzothiazoles has been attributed to metabolic activation and DNA alkylation, but we note several cell lines in which sensitivity does not correlate with metabolism. We propose that the checkpoint defect imposes an additional mechanism of sensitivity on cells. We have identified cells with possible defects in the MRN complex and S phase arrest, and a series of compounds that may

Rad51C deficiency destabilizes XRCC3, impairs recombination and radiosensitizes S/G2-phase cells

Energy Technology Data Exchange (ETDEWEB)

Lio, Yi-Ching; Schild, David; Brenneman, Mark A.; Redpath, J. Leslie; Chen, David J.

2004-05-01

The highly conserved Rad51 protein plays an essential role in repairing DNA damage through homologous recombination. In vertebrates, five Rad51 paralogs (Rad51B, Rad51C, Rad51D, XRCC2, XRCC3) are expressed in mitotically growing cells, and are thought to play mediating roles in homologous recombination, though their precise functions remain unclear. Here we report the use of RNA interference to deplete expression of Rad51C protein in human HT1080 and HeLa cells. In HT1080 cells, depletion of Rad51C by small interfering RNA caused a significant reduction of frequency in homologous recombination. The level of XRCC3 protein was also sharply reduced in Rad51C-depleted HeLa cells, suggesting that XRCC3 is dependent for its stability upon heterodimerization with Rad51C. In addition, Rad51C-depleted HeLa cells showed hypersensitivity to the DNA cross-linking agent mitomycin C, and moderately increased sensitivity to ionizing radiation. Importantly, the radiosensitivity of Rad51C-deficient HeLa cells was evident in S and G{sub 2}/M phases of the cell cycle but not in G{sub 1} phase. Together, these results provide direct cellular evidence for the importance of human Rad51C in homologous recombinational repair.

The role of RAD51 in etoposide (VP16) resistance in small cell lung cancer

DEFF Research Database (Denmark)

Hansen, Lasse Tengbjerg; Lundin, Cecilia; Spang-Thomsen, Mogens

2003-01-01

Etoposide (VP16) is a potent inducer of DNA double-strand breaks (DSBs) and is efficiently used in small cell lung cancer (SCLC) therapy. However, acquired VP16 resistance remains an important barrier to effective treatment. To understand the underlying mechanisms for VP16 resistance in SCLC, we...... investigated DSB repair and cellular VP16 sensitivity of SCLC cells. VP16 sensitivity and RAD51, DNA-PK(cs), topoisomerase IIalpha and P-glycoprotein protein levels were determined in 17 SCLC cell lines. In order to unravel the role of RAD51 in VP16 resistance, we cloned the human RAD51 gene, transfected SCLC...... cells with RAD51 sense or antisense constructs and measured the VP16 resistance. Finally, we measured VP16-induced DSBs in the 17 SCLC cell lines. Two cell lines exhibited a multidrug-resistant phenotype. In the other SCLC cell lines, the cellular VP16 resistance was positively correlated with the RAD51...

Correlation of RAD51 and radiosensitization of methotrexate

International Nuclear Information System (INIS)

Du Liqing; Bai Jianqiang; Liu Qiang; Wang Yan; Zhao Peng; Chen Fenghua; Wang Hong; Fan Feiyue

2012-01-01

Objective: To evaluate the correlation between homologous recombination repair protein RAD51 and methotrexate-enhanced radiosensitivity. Methods: Western blot and RT-PCR assays were used to detect RAD51 expression in HOS osteosarcoma cells exposed to γ-ray irradiation alone and in combination with methotrexate. Colony formation assay was used to test the survival fraction of HOS cells exposed to γ-rays and methotrexate. Results: Methotrexate inhibited both protein and RNA expressions of RAD51, and the combination of radiation and methotrexate enhanced the inhibition of RAD51 expression. Moreover, transfection of cells with RAD51 gene decreased cellular sensitivity to methotrexate and γ-rays. The sensitizer enhancement ratios after irradiation in combination with methotrexate were 1.51 and 0.99, respectively. Methotrexate was a preferred radiosensitizer to HOS cell. Conclusions: RAD51 might be involved in the methotrexate-enhanced radiosensitivity. (authors)

Genetic variation in the NBS1, MRE11, RAD50 and BLM genes and susceptibility to non-Hodgkin lymphoma

Directory of Open Access Journals (Sweden)

Gascoyne Randy D

2009-11-01

Full Text Available Abstract Background Translocations are hallmarks of non-Hodgkin lymphoma (NHL genomes. Because lymphoid cell development processes require the creation and repair of double stranded breaks, it is not surprising that disruption of this type of DNA repair can cause cancer. The members of the MRE11-RAD50-NBS1 (MRN complex and BLM have central roles in maintenance of DNA integrity. Severe mutations in any of these genes cause genetic disorders, some of which are characterized by increased risk of lymphoma. Methods We surveyed the genetic variation in these genes in constitutional DNA of NHL patients by means of gene re-sequencing, then conducted genetic association tests for susceptibility to NHL in a population-based collection of 797 NHL cases and 793 controls. Results 114 SNPs were discovered in our sequenced samples, 61% of which were novel and not previously reported in dbSNP. Although four variants, two in RAD50 and two in NBS1, showed association results suggestive of an effect on NHL, they were not significant after correction for multiple tests. Conclusion These results suggest an influence of RAD50 and NBS1 on susceptibility to diffuse large B-cell lymphoma and marginal zone lymphoma. Larger association and functional studies could confirm such a role.

Three additional genes involved in pyrimidine dimer removal in Saccharomyces cerevisiae: RAD7, RAD14, and MMS19

Energy Technology Data Exchange (ETDEWEB)

Prakash, L; Prakash, S

1979-01-01

The ability to remove ultraviolet (uv)-induced pyrimidine dimers from the nuclear DNA of yeast was examined in two radiation-sensitive (rad) mutants and one methyl methanesulfonate-sensitive (mms) mutant of the yeast Saccharomyces cerevisiae. The susceptibility of DNA from irradiated cells to nicking by an endonuclease activity prepared from crude extracts of Micrococcus luteus was used to measure the presence of dimers in DNA. The rad7, rad14, and mms19 mutants were found to be defective in their ability to remove uv-induced dimers from nuclear DNA. All three mutants belong to the same episatic group as the other mutants involved in excision-repair. All three mutants show enhanced uv-induced mutations. The rad 14 mutant also shows epistatic interactions with genes in the other two uv repair pathways.

RAD51AP2, a novel vertebrate- and meiotic-specific protein, sharesa conserved RAD51-interacting C-terminal domain with RAD51AP1/PIR51

Energy Technology Data Exchange (ETDEWEB)

Kovalenko, Oleg V.; Wiese, Claudia; Schild, David

2006-07-25

Many interacting proteins regulate and/or assist the activities of RAD51, a recombinase which plays a critical role in both DNA repair and meiotic recombination. Yeast two-hybrid screening of a human testis cDNA library revealed a new protein, RAD51AP2 (RAD51 Associated Protein 2), that interacts strongly with RAD51. A full-length cDNA clone predicts a novel vertebrate specific protein of 1159 residues, and the RAD51AP2 transcript was observed only in meiotic tissue (i.e. adult testis and fetal ovary), suggesting a meiotic-specific function for RAD51AP2. In HEK293 cells the interaction of RAD51 with an ectopically-expressed recombinant large fragment of RAD51AP2 requires the C-terminal 57 residues of RAD51AP2. This RAD51-binding region shows 81% homology to the C-terminus of RAD51AP1/PIR51, an otherwise totally unrelated RAD51-binding partner that is ubiquitously expressed. Analyses using truncations and point mutations in both RAD51AP1 and RAD51AP2 demonstrate that these proteins use the same structural motif for RAD51 binding. RAD54 shares some homology with this RAD51-binding motif, but this homologous region plays only an accessory role to the adjacent main RAD51-interacting region, which has been narrowed here to 40 amino acids. A novel protein, RAD51AP2, has been discovered that interacts with RAD51 through a C-terminal motif also present in RAD51AP1.

PI-RADS v2: Current standing and future outlook.

Science.gov (United States)

Smith, Clayton P; Türkbey, Barış

2018-05-01

The Prostate Imaging-Reporting and Data System (PI-RADS) was created in 2012 to establish standardization in prostate multiparametric magnetic resonance imaging (mpMRI) acquisition, interpretation, and reporting. In hopes of improving upon some of the PI-RADS v1 shortcomings, the PI-RADS Steering Committee released PI-RADS v2 in 2015. This paper reviews the accuracy, interobserver agreement, and clinical outcomes of PI-RADS v2 and comments on the limitations of the current literature. Overall, PI-RADS v2 shows improved sensitivity and similar specificity compared to PI-RADS v1. However, concerns exist regarding interobserver agreement and the heterogeneity of the study methodology.

Specific inhibition of Wee1 kinase and Rad51 recombinase: A strategy to enhance the sensitivity of leukemic T-cells to ionizing radiation-induced DNA double-strand breaks

International Nuclear Information System (INIS)

Havelek, Radim; Cmielova, Jana; Kralovec, Karel; Bruckova, Lenka; Bilkova, Zuzana; Fousova, Ivana; Sinkorova, Zuzana; Vavrova, Jirina; Rezacova, Martina

2014-01-01

Highlights: • Pre-treatment with the inhibitors increased the sensitivity of Jurkat cells to irradiation. • Combining both inhibitors together resulted in a G2 cell cycle arrest abrogation in Jurkat. • Jurkat cells pre-treated with inhibitors were positive for γH2AX foci 24 h upon irradiation. • Pre-treatment with Rad51 RI-1 had no effect on apoptosis induction in MOLT-4 cells. • When dosed together, the combination decreased MOLT-4 cell survival. - Abstract: Present-day oncology sees at least two-thirds of cancer patients receiving radiation therapy as a part of their anticancer treatment. The objectives of the current study were to investigate the effects of the small molecule inhibitors of Wee1 kinase II (681641) and Rad51 (RI-1) on cell cycle progression, DNA double-strand breaks repair and apoptosis following ionizing radiation exposure in human leukemic T-cells Jurkat and MOLT-4. Pre-treatment with the Wee1 681641 or Rad51 RI-1 inhibitor alone increased the sensitivity of Jurkat cells to irradiation, however combining both inhibitors together resulted in a further enhancement of apoptosis. Jurkat cells pre-treated with inhibitors were positive for γH2AX foci 24 h upon irradiation. MOLT-4 cells were less affected by inhibitors application prior to ionizing radiation exposure. Pre-treatment with Rad51 RI-1 had no effect on apoptosis induction; however Wee1 681641 increased ionizing radiation-induced cell death in MOLT-4 cells

Physical mapping and cloning of RAD56

DEFF Research Database (Denmark)

Mathiasen, David P; Gallina, Irene; Germann, Susanne Manuela

2013-01-01

Here we report the physical mapping of the rad56-1 mutation to the NAT3 gene, which encodes the catalytic subunit of the NatB N-terminal acetyltransferase in Saccharomyces cerevisiae. Mutation of RAD56 causes sensitivity to X-rays, methyl methanesulfonate, zeocin, camptothecin and hydroxyurea...

Specific absorbed fractions of electrons and photons for Rad-HUMAN phantom using Monte Carlo method

International Nuclear Information System (INIS)

Wang Wen; Hu Liqin; Cheng Mengyun; Long Pengcheng

2015-01-01

The specific absorbed fractions (SAF) for self- and cross-irradiation are effective tools for the internal dose estimation of inhalation and ingestion intakes of radionuclides. A set of SAFs of photons and electrons were calculated using the Rad-HUMAN phantom, which is a computational voxel phantom of a Chinese adult female that was created using the color photographic image of the Chinese Visible Human (CVH) data set by the FDS Team. The model can represent most Chinese adult female anatomical characteristics and can be taken as an individual phantom to investigate the difference of internal dose with Caucasians. In this study, the emission of mono-energetic photons and electrons of 10 keV to 4 MeV energy were calculated using the Monte Carlo particle transport calculation code MCNP. Results were compared with the values from ICRP reference and ORNL models. The results showed that SAF from the Rad-HUMAN have similar trends but are larger than those from the other two models. The differences were due to the racial and anatomical differences in organ mass and inter-organ distance. The SAFs based on the Rad-HUMAN phantom provide an accurate and reliable data for internal radiation dose calculations for Chinese females. (authors)

Cloning of an E. coli RecA and yeast RAD51 homolog, radA, an allele of the uvsC in Aspergillus nidulans and its mutator effects.

Science.gov (United States)

Seong, K Y; Chae, S K; Kang, H S

1997-04-30

An E. coli RecA and yeast RAD51 homolog from Aspergillus nidulans, radA, has been cloned by screening genomic and cDNA libraries with a PCR-amplified probe. This probe was generated using primers carrying the conserved sequences of eukaryotic RecA homologs. The deduced amino acid sequence revealed two conserved Walker-A and -B type nucleotide-binding domains and exhibited 88%, 60%, and 53% identity with Mei-3 of Neurospora crassa, rhp51+ of Schizosaccharomyces pombe, and Rad51 of Saccharomyces cerevisiae, respectively. radA null mutants constructed by replacing the whole coding region with a selection marker showed high methyl methanesulfonate (MMS) sensitivity. Heterozygous diploids of radA disruptant with the uvsC114 mutant failed to complement with respect to MMS-sensitivity, indicating that radA is an allele of uvsC. In selecting spontaneous forward selenate resistant mutations, mutator effects were observed in radA null mutants similarly to those shown in uvsC114 mutant strains.

Comparison of clastogen-induced gene expression profiles in wild-type and DNA repair-deficient Rad54/Rad54B cells

Directory of Open Access Journals (Sweden)

van Benthem Jan

2010-01-01

Full Text Available Abstract Background Previously we found that Rad54/Rad54B cells are more sensitive towards mitomycin C (MMC as compared to wild-type (WT cells. This difference in sensitivity was absent upon exposure to other clastogens like bleomycin (BLM and γ-radiation. In order to get further insight into possible underlying mechanisms, gene expression changes in WT and Rad54/Rad54B MEFs (mouse embryonic fibroblasts after exposure to the clastogens MMC and BLM were investigated. Exposures of these cells to mutagens (N-ac-AAF and ENU and vehicle were taken as controls. Results Most exposures resulted in an induction of DNA damage signaling and apoptosis genes and a reduced expression of cell division genes in cells of both genotypes. As expected, responses to N-ac-AAF were very similar in both genotypes. ENU exposure did not lead to significant gene expression changes in cells of both genotypes, presumably due to its short half-life. Gene expression responses to clastogens, however, showed a genotype-dependent effect for BLM and MMC. MMC treated Rad54/Rad54B MEFs showed no induction of p53-signaling, DNA damage response and apoptosis as seen for all the other treatments. Conclusion These data support our finding that different types of clastogens exist and that responses to these types depend on the DNA repair status of the cells.

A mutation (radA100) in Escherichia coli that selectively sensitizes cells grown in rich medium to X- or U.V.-radiation, or methyl methanesulphonate

International Nuclear Information System (INIS)

Diver, W.P.; Sargentini, N.J.; Smith, K.C.

1982-01-01

The radA100 mutant was isolated from Escherichia coli K-12 after mutagenesis with N-methyl-N'-nitro-N-nitrosoguanidine and selection for gamma radiation sensitivity. The radA100 mutation sensitized stationary phase cells to X-rays if they had been grown in glucose-supplemented rich medium, but not if they had been grown in nonsupplemented rich medium (indicating a defect in glucose-induced resistance). Similarly, logarithmic phase cells were sensitized to X-rays, U.V. radiation and methyl methanesulphonate if they had been grown in rich medium, but not if they had been grown in minimal medium (indicating a defect in medium-dependent resistance). Relative to the wild-type strain, the radA100 mutant was deficient in the repair of X-ray-induced DNA single-strand breaks when grown to logarithmic phase in rich medium, but not when grown in minimal medium. This is a novel mutation amongst the known DNA repair defects in that it did not sensitize logarithmic phase cells, grown in minimal medium, to either X- or U.V.-radiation. (author)

Effect of Rad 51 overexpression on chromosomal stability and radiation sensitivity in tumour cells

International Nuclear Information System (INIS)

Jend, C.; Stuerzbecher, H.W.; Dikomey, E.; Borgmann, K.

2004-01-01

The present study was dedicated to examining the effects of Rad51 overexpression on genomic instability, expressed in terms of chromosomal aberrations in G1 and G2 phases following X-ray irradiation. For this purpose an osteosarcoma cell line (Ui-OS) which shows inducing Rad51 overexpression (UiRad5-2) after stable transfection was compared with an isogenetic line (UiLacZ) which overexpresses beta-galactosidase instead of Rad51 [de

Pir51, a Rad51-interacting protein with high expression in aggressive lymphoma, controls mitomycin C sensitivity and prevents chromosomal breaks

Energy Technology Data Exchange (ETDEWEB)

Henson, Sarah E. [Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 (United States); Tsai, Shih-Chang [Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 (United States); Malone, Cindy Sue [Department of Biology, California State University Northridge, Northridge, CA 91330 (United States); Soghomonian, Shahe V. [Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 (United States); Ouyang, Yan [Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 (United States); Wall, Randolph [Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 (United States); Molecular Biology Institute and Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 (United States); Marahrens, York [Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 (United States) and Molecular Biology Institute and Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 (United States)]. E-mail: YMarahrens@mednet.ucla.edu; Teitell, Michael A. [Molecular Biology Institute and Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 (United States) and Department of Pathology and Laboratory Medicine, California NanoSystems Institute, and Institute for Stem Cell Biology and Medicine, University of California Los Angeles, Los Angeles, CA 90095 (United States)]. E-mail: mteitell@ucla.edu

2006-10-10

Pir51, a protein of unknown function that interacts with Rad51, was identified in a screen for genes that were highly expressed in aggressive mantle cell lymphoma (MCL) versus indolent small lymphocytic lymphoma (SLL) patient samples. We show that Pir51 is a nuclear protein expressed in a variety of cell types and that its expression is regulated during the cell cycle in a pattern nearly identical to Rad51. Also similar to Rad51, Pir51 levels did not change in response to a variety of DNA damaging agents. siRNA depletion of Pir51 did not reduce homologous recombination repair (HRR), but sensitized cells to mitomycin C (MMC)-induced DNA crosslinking and resulted in elevated levels of double-strand breaks (DSBs) in metaphase chromosome spreads and reduced colony formation. Therefore, Pir51 maintains genomic integrity and potentially connects the early response to DNA crosslinks, orchestrated by the ATR kinase and Fanconi Anemia (FA) proteins, to later stages of Rad51-dependent repair. Our results provide the first example of a Rad51-binding protein that influences DNA crosslink repair without affecting homologous recombination repair.

Pir51, a Rad51-interacting protein with high expression in aggressive lymphoma, controls mitomycin C sensitivity and prevents chromosomal breaks

International Nuclear Information System (INIS)

Henson, Sarah E.; Tsai, Shih-Chang; Malone, Cindy Sue; Soghomonian, Shahe V.; Ouyang, Yan; Wall, Randolph; Marahrens, York; Teitell, Michael A.

2006-01-01

Pir51, a protein of unknown function that interacts with Rad51, was identified in a screen for genes that were highly expressed in aggressive mantle cell lymphoma (MCL) versus indolent small lymphocytic lymphoma (SLL) patient samples. We show that Pir51 is a nuclear protein expressed in a variety of cell types and that its expression is regulated during the cell cycle in a pattern nearly identical to Rad51. Also similar to Rad51, Pir51 levels did not change in response to a variety of DNA damaging agents. siRNA depletion of Pir51 did not reduce homologous recombination repair (HRR), but sensitized cells to mitomycin C (MMC)-induced DNA crosslinking and resulted in elevated levels of double-strand breaks (DSBs) in metaphase chromosome spreads and reduced colony formation. Therefore, Pir51 maintains genomic integrity and potentially connects the early response to DNA crosslinks, orchestrated by the ATR kinase and Fanconi Anemia (FA) proteins, to later stages of Rad51-dependent repair. Our results provide the first example of a Rad51-binding protein that influences DNA crosslink repair without affecting homologous recombination repair

Ca2+ improves organization of single-stranded DNA bases in human Rad51 filament, explaining stimulatory effect on gene recombination.

KAUST Repository

Fornander, Louise H; Frykholm, Karolin; Reymer, Anna; Renodon-Corniè re, Axelle; Takahashi, Masayuki; Nordé n, Bengt

2012-01-01

Human RAD51 protein (HsRad51) catalyses the DNA strand exchange reaction for homologous recombination. To clarify the molecular mechanism of the reaction in vitro being more effective in the presence of Ca(2+) than of Mg(2+), we have investigated

TOPBP1 regulates RAD51 phosphorylation and chromatin loading and determines PARP inhibitor sensitivity

DEFF Research Database (Denmark)

Moudry, Pavel; Watanabe, Kenji; Wolanin, Kamila M.

2016-01-01

to chromatin and formation of RAD51 foci, but without affecting the upstream HR steps of DNA end resection and RPA loading. Furthermore, TOPBP1 BRCT domains 7/8 are essential for RAD51 foci formation. Mechanistically, TOPBP1 physically binds PLK1 and promotes PLK1 kinase-mediated phosphorylation of RAD51...

Intact Mre11/Rad50/Nbs1 Complex Predicts Good Response to Radiotherapy in Early Breast Cancer

International Nuclear Information System (INIS)

Soederlund, Karin; Stal, Olle; Skoog, Lambert; Rutqvist, Lars Erik; Nordenskjoeld, Bo; Askmalm, Marie Stenmark

2007-01-01

Purpose: To investigate the expression and predictive role of the Mre11/Rad50/Nbs1 (MRN) complex and the ataxia-telangiectasia mutated protein (ATM) for the outcome of radiotherapy in breast cancer patients. Methods and Materials: The protein expression of ATM and the DNA repair proteins in the MRN complex were investigated using immunohistochemistry in tumors from 224 women with early breast cancer, who were randomized to receive postoperative radiotherapy or adjuvant chemotherapy. Results: Compared with normal breast tissue, the staining intensity of Mre11, Rad50, Nbs1, and ATM was reduced in a majority of the tumors. Weak expression of the MRN complex was correlated with high histologic grade and estrogen receptor negativity (p = 0.01 and p 0.0001, respectively). Radiotherapy significantly reduced the risk of local recurrence as compared with chemotherapy (p = 0.04). The greatest benefit of radiotherapy was seen in patients with moderate/strong expression of the MRN complex (relative risk = 0.27, 95% confidence interval = 0.098-0.72, p 0.009), whereas patients with negative/weak MRN expression had no benefit of radiotherapy compared with adjuvant chemotherapy. These results suggest that an intact MRN complex is important for the tumor cell eradicating effect of radiotherapy. Conclusions: Reduced expression of the MRN complex predicts a poor effect of radiotherapy in patients with early breast cancer

Preferential binding of yeast Rad4-Rad23 complex to damaged DNA

International Nuclear Information System (INIS)

Jansen, L.E.T.; Verhage, R.A.; Brouwer, J.

1998-01-01

The yeast Rad4 and Rad23 proteins form a complex that is involved in nucleotide excision repair (NER). Their function in this process is not known yet, but genetic data suggest that they act in an early step in NER. We have purified an epitope-tagged Rad4.Rad23 (tRad4. Rad23) complex from yeast cells, using a clone overproducing Rad4 with a hemagglutinin-tag at its C terminus. tRad4.Rad23 complex purified by both conventional and immuno-affinity chromatography complements the in vitro repair defect of rad4 and rad23 mutant extracts, demonstrating that these proteins are functional in NER. Using electrophoretic mobility shift assays, we show preferential binding of the tRad4.Rad23 complex to damaged DNA in vitro. UV-irradiated, as well as N-acetoxy-2-(acetylamino)fluorene-treated DNA, is efficiently bound by the protein complex. These data suggest that Rad4.Rad23 interacts with DNA damage during NER and may play a role in recognition of the damage

Single Cell Analysis of Human RAD18-Dependent DNA Post-Replication Repair by Alkaline Bromodeoxyuridine Comet Assay

Science.gov (United States)

Mórocz, Mónika; Gali, Himabindu; Raskó, István; Downes, C. Stephen; Haracska, Lajos

2013-01-01

Damage to DNA can block replication progression resulting in gaps in the newly synthesized DNA. Cells utilize a number of post-replication repair (PRR) mechanisms such as the RAD18 controlled translesion synthesis or template switching to overcome the discontinuities formed opposite the DNA lesions and to complete DNA replication. Gaining more insights into the role of PRR genes promotes better understanding of DNA damage tolerance and of how their malfunction can lead to increased genome instability and cancer. However, a simple and efficient method to characterise gene specific PRR deficiencies at a single cell level has not been developed. Here we describe the so named BrdU comet PRR assay to test the contribution of human RAD18 to PRR at a single cell level, by which we kinetically characterized the consequences of the deletion of human RAD18 on the replication of UV-damaged DNA. Moreover, we demonstrate the capability of our method to evaluate PRR at a single cell level in unsynchronized cell population. PMID:23936422

Assay for Human Rad51-Mediated DNA Displacement Loop Formation

OpenAIRE

sprotocols

2014-01-01

Authors: Steven Raynard and Patrick Sung Corresponding author ([]()) ### INTRODUCTION Homologous recombination is an important mechanism for the repair of damaged chromosomes, for preventing the demise of damaged replication forks, and for several other aspects of chromosome metabolism and maintenance. The homologous recombination reaction is mediated by the Rad51 recombinase. In the presence of ATP, Rad51 polymerizes on single-stranded D...

Effects of age and liquid holding on the UV-radiation sensitivities of wild-type and mutant Caenorhabditis elegans dauer larvae

Energy Technology Data Exchange (ETDEWEB)

Hartman, P S

1984-01-01

The dauer larva is a facultative developmental stage in the life cycle of the nematode Caenorhabditis elegans. Dauer larvae, which can survive under starvation for over 60 days, resume normal development when feeding is resumed. Wild-type (N2) and 4 radiation-sensitive (rad) mutant dauer larvae were tested for their abilities to develop into adults after UV-irradiation. The rad-3 mutant was over 30 times as sensitive as N2; rad-1, rad-2 and rad-7 mutants were not hypersensitive. Irradiation also delayed development in survivors. Wild-type dauer larvae did not differ in radiation sensitivity from 0 through 50 days of age. There was no liquid holding recovery (LHR); that is, survival did not increase when wild-type dauer larvae were held in buffer after irradiation. (orig.). 28 refs.; 4 figs.

Effect of 680 rad whole-body irradiation of a human fetus, 27 years afterwards

International Nuclear Information System (INIS)

Kallinger, W.; Granninger, W.

1982-01-01

In 1953 a 38-year-old pregnant woman was given radiation treatment with Ra-226 due to a vaginal carcinoma. The radiation field was reproduced by means of a computer program. It was proved that the fetus was exposed to radiation doses of 50-2000 rad. Despite this high dose no abnormalities were found during clinical examination of the now 27-year-old man who has already fathered a healthy son. (orig.) [de

Hybridization Capture Using RAD Probes (hyRAD, a New Tool for Performing Genomic Analyses on Collection Specimens.

Directory of Open Access Journals (Sweden)

Tomasz Suchan

Full Text Available In the recent years, many protocols aimed at reproducibly sequencing reduced-genome subsets in non-model organisms have been published. Among them, RAD-sequencing is one of the most widely used. It relies on digesting DNA with specific restriction enzymes and performing size selection on the resulting fragments. Despite its acknowledged utility, this method is of limited use with degraded DNA samples, such as those isolated from museum specimens, as these samples are less likely to harbor fragments long enough to comprise two restriction sites making possible ligation of the adapter sequences (in the case of double-digest RAD or performing size selection of the resulting fragments (in the case of single-digest RAD. Here, we address these limitations by presenting a novel method called hybridization RAD (hyRAD. In this approach, biotinylated RAD fragments, covering a random fraction of the genome, are used as baits for capturing homologous fragments from genomic shotgun sequencing libraries. This simple and cost-effective approach allows sequencing of orthologous loci even from highly degraded DNA samples, opening new avenues of research in the field of museum genomics. Not relying on the restriction site presence, it improves among-sample loci coverage. In a trial study, hyRAD allowed us to obtain a large set of orthologous loci from fresh and museum samples from a non-model butterfly species, with a high proportion of single nucleotide polymorphisms present in all eight analyzed specimens, including 58-year-old museum samples. The utility of the method was further validated using 49 museum and fresh samples of a Palearctic grasshopper species for which the spatial genetic structure was previously assessed using mtDNA amplicons. The application of the method is eventually discussed in a wider context. As it does not rely on the restriction site presence, it is therefore not sensitive to among-sample loci polymorphisms in the restriction sites

Disruption of mouse RAD54 reduces ionizing radiation resistance and homologous recombination.

NARCIS (Netherlands)

J. Essers (Jeroen); R.W. Hendriks (Rudi); S.M.A. Swagemakers (Sigrid); C. Troelstra (Christine); J. de Wit (Jan); D. Bootsma (Dirk); J.H.J. Hoeijmakers (Jan); R. Kanaar (Roland)

1997-01-01

textabstractDouble-strand DNA break (DSB) repair by homologous recombination occurs through the RAD52 pathway in Saccharomyces cerevisiae. Its biological importance is underscored by the conservation of many RAD52 pathway genes, including RAD54, from fungi to humans. We have analyzed the phenotype

RAD24 (=R1/sup S/) gene product of Saccharomyces cerevisiae participates in two different pathways of DNA repair

International Nuclear Information System (INIS)

Eckardt-Schupp, F.; Siede, W.; Game, J.C.

1987-01-01

The moderately UV- and X-ray-sensitive mutant of Saccharomyces cerevisiae originally designated r 1 /sup s/ complements all rad and mms mutants available. Therefore, the new nomination rad24-1 according to the RAD nomenclature is suggested. RAD24 maps on chromosome V, close to RAD3 (1.3 cM). In order to associate the RAD24 gene with one of the three repair pathways, double mutants of rad24 and various representative genes of each pathway were constructed. The UV and X-ray sensitivities of the double mutants compared to the single mutants indicate that RAD24 is involved in excision repair of UV damage (RAD3 epistasis group), as well as in recombination repair of UV and X-ray damage (RAD52 epistasis group). Properties of the mutant are discussed which hint at the control of late steps in the pathways

Survey of radiosensitivity in a variety of human cell strains

Energy Technology Data Exchange (ETDEWEB)

Arlett, C.F.; Harcourt, S.A.

1980-03-01

Gamma-ray sensitivity for cell killing was assayed in 54 human cell strains, including some derived from individuals suffering from certain hereditary diseases. The overall range of Do values in this study was 38 to 180 rads, indicating a considerable range of variability in humans. The normal sensitivity was described by a range of Do values of 97 to 180 rads. All ten ataxia telangiectasia cell strains tested proved radiosensitive and gave a mean Do value of 57 +- 15 (S.E.) rads, and these represent the most radiosensitive human skin fibroblasts currently available. Representative cell strains from familial retinoblastoma, Fanconi's anemia, and Hutchinson-Gilford progeria occupied positions of intermediate sensitivity, as did one of two ataxia telangiectasia heterozygotes. Six xeroderma pigmentosum cell strains together with two Cockayne's syndrome cell strains (all known to be sensitive to ultraviolet light) fell into the normal range, indicating an absence of cross-sensitivity between ultraviolet light and gamma-irradiation.

X-ray survival characteristics and genetic analysis for nineSaccharomyces deletion mutants that affect radiation sensitivity

Energy Technology Data Exchange (ETDEWEB)

Game, John C.; Williamson, Marsha S.; Baccari, Clelia

2006-07-21

We examine ionizing radiation (IR) sensitivity and epistasisrelationships of several Saccharomyces mutants affectingpost-translational modifications of histones H2B and H3. Mutantsbre1delta, lge1delta, and rtf1delta, defective in histone H2B lysine 123ubiquitination, show IR sensitivity equivalent to that of the dot1deltamutant that we reported on earlier, consistent with published findingsthat Dot1p requires H2B K123 ubiquitination to fully methylate histone H3K79. This implicates progressive K79 methylation rather thanmono-methylation in IR resistance. The set2delta mutant, defective in H3K36 methylation, shows mild IR sensitivity whereas mutants that abolishH3 K4 methylation resemble wild type. The dot1delta, bre1delta, andlge1delta mutants show epistasis for IR sensitivity. The paf1deltamutant, also reportedly defective in H2B K123 ubiquitination, confers nosensitivity. The rad6delta, rad51null, rad50delta, and rad9deltamutations are epistatic to bre1? and dot1delta, but rad18delta andrad5delta show additivity with bre1delta, dot1delta, and each other. Thebre1delta rad18delta double mutant resembles rad6delta in sensitivity;thus the role of Rad6p in ubiquitinating H2B accounts for its extrasensitivity compared to rad18delta. We conclude that IR resistanceconferred by BRE1 and DOT1 is mediated through homologous recombinationalrepair, not postreplication repair, and confirm findings of a G1checkpoint role for the RAD6/BRE1/DOT1 pathway.

Disparate requirements for the Walker A and B ATPase motifs ofhuman RAD51D in homologous recombination

Energy Technology Data Exchange (ETDEWEB)

Wiese, Claudia; Hinz, John M.; Tebbs, Robert S.; Nham, Peter B.; Urbin, Salustra S.; Collins, David W.; Thompson, Larry H.; Schild, David

2006-04-21

In vertebrates, homologous recombinational repair (HRR) requires RAD51 and five RAD51 paralogs (XRCC2, XRCC3, RAD51B, RAD51C, and RAD51D) that all contain conserved Walker A and B ATPase motifs. In human RAD51D we examined the requirement for these motifs in interactions with XRCC2 and RAD51C, and for survival of cells in response to DNA interstrand crosslinks. Ectopic expression of wild type human RAD51D or mutants having a non-functional A or B motif was used to test for complementation of a rad51d knockout hamster CHO cell line. Although A-motif mutants complement very efficiently, B-motif mutants do not. Consistent with these results, experiments using the yeast two- and three-hybrid systems show that the interactions between RAD51D and its XRCC2 and RAD51C partners also require a functional RAD51D B motif, but not motif A. Similarly, hamster Xrcc2 is unable to bind to the non-complementing human RAD51D B-motif mutants in co-immunoprecipitation assays. We conclude that a functional Walker B motif, but not A motif, is necessary for RAD51D's interactions with other paralogs and for efficient HRR. We present a model in which ATPase sites are formed in a bipartite manner between RAD51D and other RAD51 paralogs.

Design of potent inhibitors of human RAD51 recombinase based on BRC motifs of BRCA2 protein: modeling and experimental validation of a chimera peptide.

KAUST Repository

Nomme, Julian; Renodon-Corniè re, Axelle; Asanomi, Yuya; Sakaguchi, Kazuyasu; Stasiak, Alicja Z; Stasiak, Andrzej; Norden, Bengt; Tran, Vinh; Takahashi, Masayuki

2010-01-01

We have previously shown that a 28-amino acid peptide derived from the BRC4 motif of BRCA2 tumor suppressor inhibits selectively human RAD51 recombinase (HsRad51). With the aim of designing better inhibitors for cancer treatment, we combined an in silico docking approach with in vitro biochemical testing to construct a highly efficient chimera peptide from eight existing human BRC motifs. We built a molecular model of all BRC motifs complexed with HsRad51 based on the crystal structure of the BRC4 motif-HsRad51 complex, computed the interaction energy of each residue in each BRC motif, and selected the best amino acid residue at each binding position. This analysis enabled us to propose four amino acid substitutions in the BRC4 motif. Three of these increased the inhibitory effect in vitro, and this effect was found to be additive. We thus obtained a peptide that is about 10 times more efficient in inhibiting HsRad51-ssDNA complex formation than the original peptide.

Design of potent inhibitors of human RAD51 recombinase based on BRC motifs of BRCA2 protein: modeling and experimental validation of a chimera peptide.

KAUST Repository

Nomme, Julian

2010-08-01

We have previously shown that a 28-amino acid peptide derived from the BRC4 motif of BRCA2 tumor suppressor inhibits selectively human RAD51 recombinase (HsRad51). With the aim of designing better inhibitors for cancer treatment, we combined an in silico docking approach with in vitro biochemical testing to construct a highly efficient chimera peptide from eight existing human BRC motifs. We built a molecular model of all BRC motifs complexed with HsRad51 based on the crystal structure of the BRC4 motif-HsRad51 complex, computed the interaction energy of each residue in each BRC motif, and selected the best amino acid residue at each binding position. This analysis enabled us to propose four amino acid substitutions in the BRC4 motif. Three of these increased the inhibitory effect in vitro, and this effect was found to be additive. We thus obtained a peptide that is about 10 times more efficient in inhibiting HsRad51-ssDNA complex formation than the original peptide.

Mediator links transcription and DNA repair by facilitating Rad2/XPG recruitment.

Science.gov (United States)

Eyboulet, Fanny; Cibot, Camille; Eychenne, Thomas; Neil, Helen; Alibert, Olivier; Werner, Michel; Soutourina, Julie

2013-12-01

Mediator is a large multiprotein complex conserved in all eukaryotes. The crucial function of Mediator in transcription is now largely established. However, we found that this complex also plays an important role by connecting transcription with DNA repair. We identified a functional contact between the Med17 Mediator subunit and Rad2/XPG, the 3' endonuclease involved in nucleotide excision DNA repair. Genome-wide location analyses revealed that Rad2 is associated with RNA polymerase II (Pol II)- and Pol III-transcribed genes and telomeric regions in the absence of exogenous genotoxic stress. Rad2 occupancy of Pol II-transcribed genes is transcription-dependent. Genome-wide Rad2 occupancy of class II gene promoters is well correlated with that of Mediator. Furthermore, UV sensitivity of med17 mutants is correlated with reduced Rad2 occupancy of class II genes and concomitant decrease of Mediator interaction with Rad2 protein. Our results suggest that Mediator is involved in DNA repair by facilitating Rad2 recruitment to transcribed genes.

Structured reporting platform improves CAD-RADS assessment.

Science.gov (United States)

Szilveszter, Bálint; Kolossváry, Márton; Karády, Júlia; Jermendy, Ádám L; Károlyi, Mihály; Panajotu, Alexisz; Bagyura, Zsolt; Vecsey-Nagy, Milán; Cury, Ricardo C; Leipsic, Jonathon A; Merkely, Béla; Maurovich-Horvat, Pál

2017-11-01

Structured reporting in cardiac imaging is strongly encouraged to improve quality through consistency. The Coronary Artery Disease - Reporting and Data System (CAD-RADS) was recently introduced to facilitate interdisciplinary communication of coronary CT angiography (CTA) results. We aimed to assess the agreement between manual and automated CAD-RADS classification using a structured reporting platform. Five readers prospectively interpreted 500 coronary CT angiographies using a structured reporting platform that automatically calculates the CAD-RADS score based on stenosis and plaque parameters manually entered by the reader. In addition, all readers manually assessed CAD-RADS blinded to the automatically derived results, which was used as the reference standard. We evaluated factors influencing reader performance including CAD-RADS training, clinical load, time of the day and level of expertise. Total agreement between manual and automated classification was 80.2%. Agreement in stenosis categories was 86.7%, whereas the agreement in modifiers was 95.8% for "N", 96.8% for "S", 95.6% for "V" and 99.4% for "G". Agreement for V improved after CAD-RADS training (p = 0.047). Time of the day and clinical load did not influence reader performance (p > 0.05 both). Less experienced readers had a higher total agreement as compared to more experienced readers (87.0% vs 78.0%, respectively; p = 0.011). Even though automated CAD-RADS classification uses data filled in by the readers, it outperforms manual classification by preventing human errors. Structured reporting platforms with automated calculation of the CAD-RADS score might improve data quality and support standardization of clinical decision making. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

RAD18 and associated proteins are immobilized in nuclear foci in human cells entering S-phase with ultraviolet light-induced damage

International Nuclear Information System (INIS)

Watson, Nicholas B.; Nelson, Eric; Digman, Michelle; Thornburg, Joshua A.; Alphenaar, Bruce W.; McGregor, W. Glenn

2008-01-01

Proteins required for translesion DNA synthesis localize in nuclear foci of cells with replication-blocking lesions. The dynamics of this process were examined in human cells with fluorescence-based biophysical techniques. Photobleaching recovery and raster image correlation spectroscopy experiments indicated that involvement in the nuclear foci reduced the movement of RAD18 from diffusion-controlled to virtual immobility. Examination of the mobility of REV1 indicated that it is similarly immobilized when it is observed in nuclear foci. Reducing the level of RAD18 greatly reduced the focal accumulation of REV1 and reduced UV mutagenesis to background frequencies. Fluorescence lifetime measurements indicated that RAD18 and RAD6A or polη only transferred resonance energy when these proteins colocalized in damage-induced nuclear foci, indicating a close physical association only within such foci. Our data support a model in which RAD18 within damage-induced nuclear foci is immobilized and is required for recruitment of Y-family DNA polymerases and subsequent mutagenesis. In the absence of damage these proteins are not physically associated within the nucleoplasm

Acorrelation study between histological results and thyroid ultrasound findings. The TI-RADS classification.

Science.gov (United States)

García-Moncó Fernández, Carlos; Serrano-Moreno, Clara; Donnay-Candil, Sergio; Carrero-Alvaro, Juan

2018-04-01

There are several classifications based on thyroid ultrasound for selecting suspected malignant thyroid nodules. The Thyroid Imaging Reporting and Data System (TI-RADS) classification proposed by Horvath in 2009 includes 6 categories. To assess the sensitivity of the TI-RADS classification for diagnosing thyroid nodules. A retrospective study of all patients who underwent thyroidectomy at our hospital (n=263) from September 2013 to December 2015. After thyroidectomy, histological results were correlated to the ultrasound findings reported. Of the 263 study patients, 75 (28.5%) were diagnosed with thyroid cancer and 188 (71.5%) with benign disease. Correlation of histological results with preoperative ultrasound reports showed an initial sensitivity of 65%. After excluding 15 patients diagnosed with occult microcarcinoma, sensitivity increased to 81.6%. The ultrasound images from 11 false negatives cases were then reassessed by a radiologist who knew histological diagnosis and reclassified 10 of them as TI-RADS≥4. This procedure could have increased sensitivity up to 98.3%. Although the sensitivity initially found in our study using the TI-RADS scale was relatively low, the value markedly improved when patients with occult microcarcinoma were excluded. Thus, use of the TI-RADS scale would allow for an adequate selection of patients amenable to fine needle aspiration of the nodule. Copyright © 2018 SEEN y SED. Publicado por Elsevier España, S.L.U. All rights reserved.

Prolonged exposure to particulate chromate inhibits RAD51 nuclear import mediator proteins.

Science.gov (United States)

Browning, Cynthia L; Wise, John Pierce

2017-09-15

Particulate hexavalent chromium (Cr(VI)) is a human lung carcinogen and a human health concern. The induction of structural chromosome instability is considered to be a driving mechanism of Cr(VI)-induced carcinogenesis. Homologous recombination repair protects against Cr(VI)-induced chromosome damage, due to its highly accurate repair of Cr(VI)-induced DNA double strand breaks. However, recent studies demonstrate Cr(VI) inhibits homologous recombination repair through the misregulation of RAD51. RAD51 is an essential protein in HR repair that facilitates the search for a homologous sequence. Recent studies show prolonged Cr(VI) exposure prevents proper RAD51 subcellular localization, causing it to accumulate in the cytoplasm. Since nuclear import of RAD51 is crucial to its function, this study investigated the effect of Cr(VI) on the RAD51 nuclear import mediators, RAD51C and BRCA2. We show acute (24h) Cr(VI) exposure induces the proper localization of RAD51C and BRCA2. In contrast, prolonged (120h) exposure increased the cytoplasmic localization of both proteins, although RAD51C localization was more severely impaired. These results correlate temporally with the previously reported Cr(VI)-induced RAD51 cytoplasmic accumulation. In addition, we found Cr(VI) does not inhibit interaction between RAD51 and its nuclear import mediators. Altogether, our results suggest prolonged Cr(VI) exposure inhibits the nuclear import of RAD51C, and to a lesser extent, BRCA2, which results in the cytoplasmic accumulation of RAD51. Cr(VI)-induced inhibition of nuclear import may play a key role in its carcinogenic mechanism since the nuclear import of many tumor suppressor proteins and DNA repair proteins is crucial to their function. Copyright © 2017 Elsevier Inc. All rights reserved.

Rad51-Rad52 mediated maintenance of centromeric chromatin in Candida albicans.

Directory of Open Access Journals (Sweden)

Sreyoshi Mitra

2014-04-01

Full Text Available Specification of the centromere location in most eukaryotes is not solely dependent on the DNA sequence. However, the non-genetic determinants of centromere identity are not clearly defined. While multiple mechanisms, individually or in concert, may specify centromeres epigenetically, most studies in this area are focused on a universal factor, a centromere-specific histone H3 variant CENP-A, often considered as the epigenetic determinant of centromere identity. In spite of variable timing of its loading at centromeres across species, a replication coupled early S phase deposition of CENP-A is found in most yeast centromeres. Centromeres are the earliest replicating chromosomal regions in a pathogenic budding yeast Candida albicans. Using a 2-dimensional agarose gel electrophoresis assay, we identify replication origins (ORI7-LI and ORI7-RI proximal to an early replicating centromere (CEN7 in C. albicans. We show that the replication forks stall at CEN7 in a kinetochore dependent manner and fork stalling is reduced in the absence of the homologous recombination (HR proteins Rad51 and Rad52. Deletion of ORI7-RI causes a significant reduction in the stalled fork signal and an increased loss rate of the altered chromosome 7. The HR proteins, Rad51 and Rad52, have been shown to play a role in fork restart. Confocal microscopy shows declustered kinetochores in rad51 and rad52 mutants, which are evidence of kinetochore disintegrity. CENP-ACaCse4 levels at centromeres, as determined by chromatin immunoprecipitation (ChIP experiments, are reduced in absence of Rad51/Rad52 resulting in disruption of the kinetochore structure. Moreover, western blot analysis reveals that delocalized CENP-A molecules in HR mutants degrade in a similar fashion as in other kinetochore mutants described before. Finally, co-immunoprecipitation assays indicate that Rad51 and Rad52 physically interact with CENP-ACaCse4 in vivo. Thus, the HR proteins Rad51 and Rad52

Effect of MRE11 loss on PARP-inhibitor sensitivity in endometrial cancer in vitro.

Directory of Open Access Journals (Sweden)

Romana Koppensteiner

Full Text Available To evaluate the frequency of MRE11/RAD50/NBS1 (MRN-complex loss of protein expression in endometrial cancers (EC and to determine whether loss of MRE11 renders the cancer cells sensitive to Poly(ADP-ribose polymerase (PARP-inhibitory treatment.MRN expression was examined in 521 samples of endometrial carcinomas and in 10 cancer cell lines. A putative mutation hotspot in the form of an intronic poly(T allele in MRE11 was sequenced in selected cases (n = 26. Sensitivity to the PARP-inhibitor, BMN673 was tested in colony formation assays before and after MRE11 silencing using siRNA. Homologous recombination (HR DNA repair was evaluated by RAD51-foci formation assay upon irradiation and drug treatment.Loss of MRE11 protein was found in 30.7% of EC tumours and significantly associated with loss of RAD50, NBS1 and mismatch repair protein expression. One endometrial cell line showed a markedly reduced MRE11 expression due to a homozygous poly(T mutation of MRE11, thereby exhibiting an increased sensitivity to BMN673. MRE11 depletion sensitizes MRE11 expressing EC cell lines to the treatment with BMN673. The increased sensitivity to PARP-inhibition correlates with reduced RAD51 foci formation upon ionizing radiation in MRE11-depleted cells.Loss of the MRE11 protein predicts sensitivity to PARP-inhibitor sensitivity in vitro, defining it as an additional synthetic lethal gene with PARP. The high incidence of MRE11 loss in ECs can be potentially exploited for PARP-inhibitor therapy. Furthermore, MRE11 protein expression using immunohistochemistry could be investigated as a predictive biomarker for PARP-inhibitor treatment.

Radiation-induced inhibition of human endothelial cells replicating in culture

International Nuclear Information System (INIS)

DeGowin, R.L.; Lewis, L.J.; Mason, R.E.; Borke, M.K.; Hoak, J.C.

1976-01-01

The radiosensitivity of some tumors may depend upon the sensitivity of their microvasculature to radiation. Heretofore, the dose-response of human endothelial cells replicating in tissue culture has not been published. In studies reported here, we exposed flasks containing 4 to 7 x 10 4 genetically identical human endothelial cells to doses of x irradiation from 125 to 1000 rad. During the phase of logarithmic growth, cell counts were compared to those of an unirradiated control to construct a dose--response curve. Similar studies were performed with normal fibroblasts. We found that 160 rad suppressed endothelial cell replication by 37 percent. Although recovery was evident with doses of 500 rad, no net increase in cell number occurred in 3 weeks in flasks of endothelial cells that received 750 or 1000 rad. Fibroblasts were slightly less sensitive under these conditions. To our knowledge, this is the first report of a radiation dose--response curve for human endothelial cells replicating in culture

Roles for the yeast RAD18 and RAD52 DNA repair genes in UV mutagenesis.

Science.gov (United States)

Armstrong, J D; Chadee, D N; Kunz, B A

1994-11-01

Experimental evidence indicates that although the Saccharomyces cerevisiae RAD18 and RAD52 genes are not required for nucleotide excision repair, they function in the processing of UV-induced DNA damage in yeast. Conflicting statements regarding the UV mutability of strains deleted for RAD18 prompted us to re-examine the influence of RAD18, and RAD52, on UV mutagenesis. To do so, we characterized mutations induced by UV in SUP4-o, a yeast suppressor tRNA gene. SUP4-o was maintained on a plasmid in isogenic strains that either carried one of two different rad18 deletions (rad18 delta) or had RAD52 disrupted. Both rad18 deletions decreased the frequency of UV-induced SUP4-o mutations to levels close to those for spontaneous mutagenesis in the rad18 delta backgrounds, and prevented a net increase in mutant yield. A detailed analysis of mutations isolated after UV irradiation of one of the rad18 delta strains uncovered little evidence of the specificity features typical for UV mutagenesis in the isogenic repair-proficient (RAD) parent (e.g., predominance of G.C-->A.T transitions). Evidently, UV induction of SUP4-o mutations is highly dependent on the RAD18 gene. Compared to the RAD strain, disruption of RAD52 reduced the frequency and yield of UV mutagenesis by about two-thirds. Closer inspection revealed that 80% of this reduction was due to a decrease in the frequency of G.C-->A.T transitions. In addition, there were differences in the distributions and site specificities of single base-pair substitutions. Thus, RAD52 also participates in UV mutagenesis of a plasmid-borne gene in yeast, but to a lesser extent than RAD18.

Ca2+ improves organization of single-stranded DNA bases in human Rad51 filament, explaining stimulatory effect on gene recombination.

KAUST Repository

Fornander, Louise H

2012-02-22

Human RAD51 protein (HsRad51) catalyses the DNA strand exchange reaction for homologous recombination. To clarify the molecular mechanism of the reaction in vitro being more effective in the presence of Ca(2+) than of Mg(2+), we have investigated the effect of these ions on the structure of HsRad51 filament complexes with single- and double-stranded DNA, the reaction intermediates. Flow linear dichroism spectroscopy shows that the two ionic conditions induce significantly different structures in the HsRad51/single-stranded DNA complex, while the HsRad51/double-stranded DNA complex does not demonstrate this ionic dependence. In the HsRad51/single-stranded DNA filament, the primary intermediate of the strand exchange reaction, ATP/Ca(2+) induces an ordered conformation of DNA, with preferentially perpendicular orientation of nucleobases relative to the filament axis, while the presence of ATP/Mg(2+), ADP/Mg(2+) or ADP/Ca(2+) does not. A high strand exchange activity is observed for the filament formed with ATP/Ca(2+), whereas the other filaments exhibit lower activity. Molecular modelling suggests that the structural variation is caused by the divalent cation interfering with the L2 loop close to the DNA-binding site. It is proposed that the larger Ca(2+) stabilizes the loop conformation and thereby the protein-DNA interaction. A tight binding of DNA, with bases perpendicularly oriented, could facilitate strand exchange.

Impact of the integration of proton magnetic resonance imaging spectroscopy to PI-RADS 2 for prediction of high grade and high stage prostate cancer

Energy Technology Data Exchange (ETDEWEB)

Leapman, Michael S.; Wang, Zhen J.; Behr, Spencer C.; Kurhanewicz, John; Zagoria, Ronald J.; Carroll, Peter R.; Westphalen, Antonio C., E-mail: antonio.westphalen@ucsf.edu [University of California, San Francisco, CA (United States)

2017-09-15

Objective: To compare the predictions of dominant Gleason pattern ≥ 4 or non-organ confined disease with Prostate Imaging Reporting and Data System (PI-RADS v2) with or without proton magnetic resonance spectroscopic imaging ({sup 1}H-MRSI). Materials and Methods: Thirty-nine men underwent 3-tesla endorectal multiparametric MRI including {sup 1}H-MRSI and prostatectomy. Two radiologists assigned PI-RADS v2 and {sup 1}H-MRSI scores to index lesions. Statistical analyses used logistic regressions, receiver operating characteristic (ROC) curves, and 2 x 2 tables for diagnostic accuracies. Results: The sensitivity and specificity of {sup 1}H-MRSI and PI-RADS v2 for high-grade prostate cancer (PCa) were 85.7% (57.1%) and 92.9% (100%), and 56% (68.0%) and 24.0% (24.0%). The sensitivity and specificity of {sup 1}H-MRSI and PI-RADS v2 for extra-prostatic extension (EPE) were 64.0% (40%) and 20.0% (48%), and 50.0% (57.1%) and 71.4% (64.3%). The area under the ROC curves (AUC) for prediction of high-grade prostate cancer were 0.65 and 0.61 for PI-RADS v2 and 0.72 and 0.70 when combined with {sup 1}H-MRSI (readers 1 and 2, p = 0.04 and 0.21). For prediction of EPE the AUC were 0.54 and 0.60 for PI-RADS v2 and 0.55 and 0.61 when combined with {sup 1}H-MRSI (p > 0.05). Conclusion: {sup 1}H-MRSI might improve the discrimination of high-grade prostate cancer when combined to PI-RADS v2, particularly for PI-RADS v2 score 4 lesions, but it does not affect the prediction of EPE. (author)

Impact of the integration of proton magnetic resonance imaging spectroscopy to PI-RADS 2 for prediction of high grade and high stage prostate cancer

International Nuclear Information System (INIS)

Leapman, Michael S.; Wang, Zhen J.; Behr, Spencer C.; Kurhanewicz, John; Zagoria, Ronald J.; Carroll, Peter R.; Westphalen, Antonio C.

2017-01-01

Objective: To compare the predictions of dominant Gleason pattern ≥ 4 or non-organ confined disease with Prostate Imaging Reporting and Data System (PI-RADS v2) with or without proton magnetic resonance spectroscopic imaging ("1H-MRSI). Materials and Methods: Thirty-nine men underwent 3-tesla endorectal multiparametric MRI including "1H-MRSI and prostatectomy. Two radiologists assigned PI-RADS v2 and "1H-MRSI scores to index lesions. Statistical analyses used logistic regressions, receiver operating characteristic (ROC) curves, and 2 x 2 tables for diagnostic accuracies. Results: The sensitivity and specificity of "1H-MRSI and PI-RADS v2 for high-grade prostate cancer (PCa) were 85.7% (57.1%) and 92.9% (100%), and 56% (68.0%) and 24.0% (24.0%). The sensitivity and specificity of "1H-MRSI and PI-RADS v2 for extra-prostatic extension (EPE) were 64.0% (40%) and 20.0% (48%), and 50.0% (57.1%) and 71.4% (64.3%). The area under the ROC curves (AUC) for prediction of high-grade prostate cancer were 0.65 and 0.61 for PI-RADS v2 and 0.72 and 0.70 when combined with "1H-MRSI (readers 1 and 2, p = 0.04 and 0.21). For prediction of EPE the AUC were 0.54 and 0.60 for PI-RADS v2 and 0.55 and 0.61 when combined with "1H-MRSI (p > 0.05). Conclusion: "1H-MRSI might improve the discrimination of high-grade prostate cancer when combined to PI-RADS v2, particularly for PI-RADS v2 score 4 lesions, but it does not affect the prediction of EPE. (author)

Could ultrasonic elastography help the diagnosis of small (≤2 cm) breast cancer with the usage of sonographic BI-RADS classification?

International Nuclear Information System (INIS)

Zhi, Hui; Xiao, Xiao-yun; Ou, Bing; Zhong, Wen-jing; Zhao, Zi-zhuo; Zhao, Xin-bao; Yang, Hai-yun; Luo, Bao-ming

2012-01-01

Objectives: To evaluate the additive value of ultrasound strain elastography (USE) to BI-RADS for the differentiation of benign and malignant breast small lesions. Methods: Breast masses (≤2 cm) with histological diagnosis examined by ultrasonography and USE in our department from April 2004 to December 2009 were reviewed. Conventional B-mode ultrasound findings were classified according to the BI-RADS classification. USE findings were classified according to the 5-point scale. Histological diagnosis was used as the reference standard. Results: 401 (246 benign (61.3%), 155 malignant (38.7%)) from 370 consecutive patients were included in the study. Sensitivity and specificity were 90.3%, 68.3% for BI-RADS; 72.3%, 91.9% for USE. The sensitivity of BI-RADS was better than that of USE (P < 0.05), while the specificity of USE was better than that of BI-RADS (P < 0.05). A revised BI-RADS combined with USE results was proposed in this study. Sensitivity and specificity were 83.9% and 87.8% for revised BI-RADS. The diagnostic performance of revised BI-RADS was better than BI-RADS (P < 0.05). Conclusions: USE could give BI-RADS some help in the differentiation of benign and malignant breast small lesions. The addition of elastography to BI-RADS could improve the diagnostic performance in <2 cm lesions.

Isolation and characterization of MMS-sensitive mutants of Saccharomyces cerevisiae

International Nuclear Information System (INIS)

Prakash, L.; Prakash, S.

1977-01-01

We have isolated mutants sensitive to methyl methanesulfonate (MMS) in Saccharomyces cerevisiae. Alleles of rad1, rad4, rad6, rad52, rad55 and rad57 were found among these mms mutants. Twenty-nine of the mms mutants which complement the existing radiation-sensitive (rad and rev) mutants belong to 22 new complementation groups. Mutants from five complementation groups are sensitive only to MMS. Mutants of 11 complementation groups are sensitive to uv or x rays in addition to MMS, mutants of six complementation groups are sensitive to all three agents. The cross-sensitivities of these mms mutants to uv and x rays are discussed in terms of their possible involvement in DNA repair. Sporulation is reduced or absent in homozygous diploids of mms mutants from nine complementation groups

Molecular Basis for Enhancement of the Meiotic DMCI Recombinase by RAD51AP1

Energy Technology Data Exchange (ETDEWEB)

Dray, Eloise; Dunlop, Myun Hwa; Kauppi, Liisa; San Filippo, Joseph San; Wiese, Claudia; Tsai, Miaw-Sheue; Begovic, Sead; Schild, David; Jasin, Maria; Keeney, Scott; Sung, Patrick

2010-11-05

Homologous recombination is needed for meiotic chromosome segregation, genome maintenance, and tumor suppression. RAD51AP1 (RAD51 Associated Protein 1) has been shown to interact with and enhance the recombinase activity of RAD51. Accordingly, genetic ablation of RAD51AP1 leads to enhanced sensitivity to and also chromosome aberrations upon DNA damage, demonstrating a role for RAD51AP1 in mitotic homologous recombination. Here we show physical association of RAD51AP1 with the meiosis-specific recombinase DMC1 and a stimulatory effect of RAD51AP1 on the DMC1-mediated D-loop reaction. Mechanistic studies have revealed that RAD51AP1 enhances the ability of the DMC1 presynaptic filament to capture the duplex DNA partner and to assemble the synaptic complex, in which the recombining DNA strands are homologously aligned. We also provide evidence that functional co-operation is dependent on complex formation between DMC1 and RAD51AP1, and that distinct epitopes in RAD51AP1 mediate interactions with RAD51 and DMC1. Finally, we show that RAD51AP1 is expressed in mouse testes, and that RAD51AP1 foci co-localize with a subset of DMC1 foci in spermatocytes. These results suggest that RAD51AP1 also serves an important role in meiotic homologous recombination.

Schizosaccharomyces pombe Rad22A and Rad22B have similar biochemical properties and form multimeric structures

Energy Technology Data Exchange (ETDEWEB)

Vries, Femke A.T. de [Department of Toxicogenetics, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden (Netherlands); Zonneveld, Jose B.M. [Department of Toxicogenetics, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden (Netherlands); Groot, Anton J. de [Department of Toxicogenetics, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden (Netherlands); Koning, Roman I. [Department of Molecular Cell Biology, Leiden University Medical Center, Leiden (Netherlands); Zeeland, Albert A. van [Department of Toxicogenetics, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden (Netherlands); Pastink, Albert [Department of Toxicogenetics, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden (Netherlands)]. E-mail: A.Pastink@lumc.nl

2007-02-03

The Saccharomyces cerevisiae Rad52 protein has a crucial role in the repair of DNA double-strand breaks by homologous recombination. In vitro, Rad52 displays DNA binding and strand annealing activities and promotes Rad51-mediated strand exchange. Schizosaccharomyces pombe has two Rad52 homologues, Rad22A and Rad22B. Whereas rad22A deficient strains exhibit severe defects in repair and recombination, rad22B mutants have a much less severe phenotype. To better understand the role of Rad22A and Rad22B in double-strand break repair, both proteins were purified to near homogeneity. Using gel retardation and filter binding assays, binding of Rad22A and Rad22B to short single-stranded DNAs was demonstrated. Binding of Rad22A to double-stranded oligonucleotides or linearized plasmid molecules containing blunt ends or short single-stranded overhangs could not be detected. Rad22B also does not bind efficiently to short duplex oligonucleotides but binds readily to DNA fragments containing 3'-overhangs. Rad22A as well as Rad22B efficiently promote annealing of complementary single-stranded DNAs. In the presence of Rad22A annealing of complementary DNAs is almost 90%. Whereas in reactions containing Rad22B the maximum level of annealing is 60%, most likely due to inhibition of the reaction by duplex DNA. Gel-filtration experiments and electron microscopic analyses indicate self-association of Rad22A and Rad22B and the formation of multimeric structures as has been observed for Rad52 in yeast and man.

Structure of human Rad51 protein filament from molecular modeling and site-specific linear dichroism spectroscopy

KAUST Repository

Reymer, A.

2009-07-08

To get mechanistic insight into the DNA strand-exchange reaction of homologous recombination, we solved a filament structure of a human Rad51 protein, combining molecular modeling with experimental data. We build our structure on reported structures for central and N-terminal parts of pure (uncomplexed) Rad51 protein by aid of linear dichroism spectroscopy, providing angular orientations of substituted tyrosine residues of Rad51-dsDNA filaments in solution. The structure, validated by comparison with an electron microscopy density map and results from mutation analysis, is proposed to represent an active solution structure of the nucleo-protein complex. An inhomogeneously stretched double-stranded DNA fitted into the filament emphasizes the strategic positioning of 2 putative DNA-binding loops in a way that allows us speculate about their possibly distinct roles in nucleo-protein filament assembly and DNA strand-exchange reaction. The model suggests that the extension of a single-stranded DNA molecule upon binding of Rad51 is ensured by intercalation of Tyr-232 of the L1 loop, which might act as a docking tool, aligning protein monomers along the DNA strand upon filament assembly. Arg-235, also sitting on L1, is in the right position to make electrostatic contact with the phosphate backbone of the other DNA strand. The L2 loop position and its more ordered compact conformation makes us propose that this loop has another role, as a binding site for an incoming double-stranded DNA. Our filament structure and spectroscopic approach open the possibility of analyzing details along the multistep path of the strand-exchange reaction.

Two mutations which confer temperature-sensitive radiation sensitivity in the yeast Saccharomyces cerevisiae

International Nuclear Information System (INIS)

Ho, K.S.Y.; Mortimer, R.K.

1975-01-01

X-ray survival curves for two mutations, rad54 and rad55, in the yeast Saccharomyces cerevisiae are presented. These mutations confer temperature sensitive X-ray sensitivity; that is, rad54 and rad55 strains display a wild type X-ray survival response at permissive temperatures and a radiosensitive X-ray survival response at restrictive temperatures. The survival response of cells which were shifted from a permissive to a restrictive temperature or vice versa at various post-irradiation times indicates that repair and fixation of X-ray induced lesions is largely complete three hours after X-irradiation. Experiments to determine the utilization sequence of the rad54 and rad55 gene products in the repair of X-ray induced damage suggest that the two products are required in an interdependent manner

RadNet Radiological Air Monitoring Network

International Nuclear Information System (INIS)

Scott Telofski, J.; Askren, D.R.; Petko, Ch.M.; Fraass, R.G.

2010-01-01

The United States Environmental Protection Agency operates a national environmental radiation monitoring program called RadNet. RadNet monitors airborne particulates, precipitation, milk, and drinking water for radiation levels. The primary purpose of the original program in the 1950's and 1960's was to collect and analyze samples in various media to assess the effects of radioactive fallout from above-ground nuclear weapon testing. As above-ground testing diminished in the 1970's, the program, especially the air network, became critical in evaluating effects of other types of nuclear incidents, such as the nuclear reactor accident at Chernobyl, as well as monitoring trends in environmental radioactive contamination. The value of rapid data collection subsequent to such incidents led to the consideration of developing air monitors with radiation detectors and telecommunication equipment for real-time radiation measurement. The strengthened United States homeland security posture after 2001 led to production and installation of the current real-time RadNet air monitors. There are now 118 stationary, continuously operating air monitoring stations and 40 mobile air monitors for site specific monitoring. The stationary air monitors include radiation detectors, meteorological sensors, a high-volume air sampler, and communication devices for hourly data transfers. When unusual levels are detected, scientists download a full sodium iodide detector spectrum for analysis. The real-time data collected by RadNet stationary systems permit rapid identification and quantification of airborne nuclides with sufficient sensitivity to provide critical information to help determine protective actions. The data also may help to rapidly refine long-range radioactive plume models and estimate exposure to the population. This paper provides an overview of the airborne particulate monitoring conducted during above-ground nuclear weapon testing, summarizes the uses of data from the program

Dosimetric properties of the pocket alarm dosimeter type Alnor RAD 21L, RAD 21H, RAD 22

International Nuclear Information System (INIS)

Hauser, M.; Burgkhardt, B.; Piesch, E.

1981-02-01

In personnel monitoring pocket dosimeters with build-in alarm devices are increasingly in use. The report presents results of a test performed at Karlsruhe for the pocket dose and alarm meter type Alnor RAD 21L, RAD 21H, RAD 22. The properties investigated are above all linearity and reproducibility of the dose reading as well as of the acoustic alarm indication, dependence of the dose reading on the photon energy, the direction of the radiation incidence, the dose rate, the temperature, operational characteristic of the batteries. (orig.) [de

MRI for the assessment of malignancy in BI-RADS 4 mammographic microcalcifications.

Directory of Open Access Journals (Sweden)

Barbara Bennani-Baiti

Full Text Available Assess the performance of breast MRI to diagnose breast cancer in BI-RADS 4 microcalcifications detected by mammography.This retrospective, IRB-approved study included 248 consecutive contrast-enhanced breast MRI (1.5T, protocol in accordance with EUSOBI recommendations performed to further diagnose BI-RADS 4 microcalcifications detected at mammography during a 3-year period. Standard of reference had to be established by histopathology. Routine consensus reading results by two radiologists were dichotomized as positive or negative and compared with the reference standard (benign vs malignant to calculate diagnostic parameters.There were 107 malignant and 141 benign microcalcifications. Malignancy rates were 18.3% (23/126 BI-RADS 4a, 41.7% (25/60 BI-RADS 4b and 95% (59/62 BI-RADS 4c. There were 103 true-positive, 116 true-negative, 25 false-positive, and 4 false-negative (one invasive cancer, three DCIS; 2 BI-RADS 4c, 1 BI-RADS 4b on mammography breast MRI findings, effecting a sensitivity, specificity, PPV, and NPV of 96.3% (95%-CI 90.7-99.0%, 82.3% (95%-CI 75.0-88.2%, 80.5% (95%-CI 72.5-87.0% and 96.7% (95%-CI 91.7-99.1%, respectively.MRI is an accurate tool to further diagnose BI-RADS 4a and 4b microcalcifications and may be helpful to avoid unnecessary biopsies in BI-RADS 4a and 4b lesions. BI-RADS 4c microcalcifications should be biopsied irrespective of MRI findings.

Positive Predictive Value of BI-RADS Categorization in an Asian Population

Directory of Open Access Journals (Sweden)

Yah-Yuen Tan

2004-07-01

Full Text Available The Breast Imaging Reporting And Data System (BI-RADS categorization of mammograms is useful in estimating the risk of malignancy, thereby guiding management decisions. However, in Asian women, in whom breast density is increased, the sensitivity of mammography is correspondingly lower. We sought to determine the positive predictive value of BI-RADS categorization for malignancy in our Asian population and, hence, its value in helping us to choose between the various modalities for breast biopsy. We retrospectively reviewed all patients with occult breast lesions detected on mammography or ultrasound who underwent needle-localization open breast biopsy (NLOB in our institution over a 6-year period. There were 470 biopsies in 427 patients; 16% of lesions were malignant. The positive predictive value of BI-RADS 4 and 5 lesions for cancer was 0.27 and 0.84, respectively. While most BI-RADS 5 mass lesions were invasive cancers, the majority of calcifications in this category were in situ carcinomas. We conclude that BI-RADS remains useful in aiding decision-making for biopsy in our Asian population. Based on positive predictive values, we recommend percutaneous breast biopsy for initial evaluation of lesions categorized as BI-RADS 4 or less. For BI-RADS 5 lesions with microcalcifications, open surgical biopsy as a diagnostic and therapeutic procedure may be more appropriate. In the case of a BI-RADS 5 lesion associated with a mass, initial percutaneous biopsy may be useful for diagnosis, followed by a planned single-stage surgical procedure as necessary.

Enhancement of the RAD51 Recombinase Activity by the Tumor Suppressor PALB2

Energy Technology Data Exchange (ETDEWEB)

Dray, Eloise; Etchin, Julia; Wiese, Claudia; Saro, Dorina; Williams, Gareth J.; Hammel, Michal; Yu, Xiong; Galkin, Vitold E.; Liu, Dongqing; Tsai, Miaw-Sheue; Sy, Shirley M-H.; Egelman, Edward; Chen, Junjie; Sung, Patrick; Schild, D.

2010-08-24

Homologous recombination mediated by the RAD51 recombinase helps eliminate chromosomal lesions, such as DNA double-stranded breaks induced by radiation or arising from injured DNA replication forks. The tumor suppressors BRCA2 and PALB2 act together to deliver RAD51 to chromosomal lesions to initiate repair. Here we document a new function of PALB2 in the enhancement of RAD51's ability to form the D-loop. We show that PALB2 binds DNA and physically interacts with RAD51. Importantly, while PALB2 alone stimulates D-loop formation, a cooperative effect is seen with RAD51AP1, an enhancer of RAD51. This stimulation stems from PALB2's ability to function with RAD51 and RAD51AP1 to assemble the synaptic complex. Our results help unveil a multi-faceted role of PALB2 in chromosome damage repair. Since PALB2 mutations can cause breast and other tumors or lead to Fanconi anemia, our findings are important for understanding the mechanism of tumor suppression in humans.

RadBall Technology Testing and MCNP Modeling of the Tungsten Collimator.

Science.gov (United States)

Farfán, Eduardo B; Foley, Trevor Q; Coleman, J Rusty; Jannik, G Timothy; Holmes, Christopher J; Oldham, Mark; Adamovics, John; Stanley, Steven J

2010-01-01

The United Kingdom's National Nuclear Laboratory (NNL) has developed a remote, non-electrical, radiation-mapping device known as RadBall(™), which can locate and quantify radioactive hazards within contaminated areas of the nuclear industry. RadBall(™) consists of a colander-like outer shell that houses a radiation-sensitive polymer sphere. The outer shell works to collimate radiation sources and those areas of the polymer sphere that are exposed react, becoming increasingly more opaque, in proportion to the absorbed dose. The polymer sphere is imaged in an optical-CT scanner, which produces a high resolution 3D map of optical attenuation coefficients. Subsequent analysis of the optical attenuation matrix provides information on the spatial distribution of sources in a given area forming a 3D characterization of the area of interest. RadBall(™) has no power requirements and can be positioned in tight or hard-to reach locations. The RadBall(™) technology has been deployed in a number of technology trials in nuclear waste reprocessing plants at Sellafield in the United Kingdom and facilities of the Savannah River National Laboratory (SRNL). This study focuses on the RadBall(™) testing and modeling accomplished at SRNL.

RadBall™ Technology Testing and MCNP Modeling of the Tungsten Collimator

Science.gov (United States)

Farfán, Eduardo B.; Foley, Trevor Q.; Coleman, J. Rusty; Jannik, G. Timothy; Holmes, Christopher J.; Oldham, Mark; Adamovics, John; Stanley, Steven J.

2010-01-01

The United Kingdom’s National Nuclear Laboratory (NNL) has developed a remote, non-electrical, radiation-mapping device known as RadBall™, which can locate and quantify radioactive hazards within contaminated areas of the nuclear industry. RadBall™ consists of a colander-like outer shell that houses a radiation-sensitive polymer sphere. The outer shell works to collimate radiation sources and those areas of the polymer sphere that are exposed react, becoming increasingly more opaque, in proportion to the absorbed dose. The polymer sphere is imaged in an optical-CT scanner, which produces a high resolution 3D map of optical attenuation coefficients. Subsequent analysis of the optical attenuation matrix provides information on the spatial distribution of sources in a given area forming a 3D characterization of the area of interest. RadBall™ has no power requirements and can be positioned in tight or hard-to reach locations. The RadBall™ technology has been deployed in a number of technology trials in nuclear waste reprocessing plants at Sellafield in the United Kingdom and facilities of the Savannah River National Laboratory (SRNL). This study focuses on the RadBall™ testing and modeling accomplished at SRNL. PMID:21617740

Cohesin Rad21 Mediates Loss of Heterozygosity and Is Upregulated via Wnt Promoting Transcriptional Dysregulation in Gastrointestinal Tumors

Directory of Open Access Journals (Sweden)

Huiling Xu

2014-12-01

Full Text Available Summary: Loss of heterozygosity (LOH of the adenomatous polyposis coli (APC gene triggers a series of molecular events leading to intestinal adenomagenesis. Haploinsufficiency of the cohesin Rad21 influences multiple initiating events in colorectal cancer (CRC. We identify Rad21 as a gatekeeper of LOH and a β-catenin target gene and provide evidence that Wnt pathway activation drives RAD21 expression in human CRC. Genome-wide analyses identified Rad21 as a key transcriptional regulator of critical CRC genes and long interspersed element (LINE-1 or L1 retrotransposons. Elevated RAD21 expression tracks with reactivation of L1 expression in human sporadic CRC, implicating cohesin-mediated L1 expression in global genomic instability and gene dysregulation in cancer. : Rad21 holds the cohesin complex together as part of its role in chromosome partitioning and DNA repair. Xu et al. identify Rad21 as a key mediator of Apc gene heterozygous loss, the event initiating intestinal tumorigenesis. The subsequent activation of the Wnt pathway further induces Rad21, global gene dysregulation, chromosome instability, and pervasive retrotransposon activation.

Diagnostic accuracy of contrast-enhanced ultrasound for the differential diagnosis of hepatocellular carcinoma: ESCULAP versus CEUS-LI-RADS.

Science.gov (United States)

Schellhaas, Barbara; Görtz, Ruediger S; Pfeifer, Lukas; Kielisch, Christian; Neurath, Markus F; Strobel, Deike

2017-09-01

A comparison is made of two contrast-enhanced ultrasound (CEUS) algorithms for the diagnosis of hepatocellular carcinoma (HCC) in high-risk patients: Erlanger Synopsis of Contrast-enhanced Ultrasound for Liver lesion Assessment in Patients at Risk (ESCULAP) and American College of Radiology Contrast-Enhanced Ultrasound-Liver Imaging Reporting and Data System (ACR-CEUS-LI-RADSv.2016). Focal liver lesions in 100 high-risk patients were assessed using both CEUS algorithms (ESCULAP and CEUS-LI-RADSv.2016) for a direct comparison. Lesions were categorized according to size and contrast enhancement in the arterial, portal venous and late phases.For the definite diagnosis of HCC, categories ESCULAP-4, ESCULAP-Tr and ESCULAP-V and CEUS-LI-RADS-LR-5, LR-Tr and LR-5-V were compared. In addition, CEUS-LI-RADS-category LR-M (definitely/probably malignant, but not specific for HCC) and ESCULAP-category C [intrahepatic cholangiocellular carcinoma (ICC)] were compared.Histology, CE-computed tomography and CE-MRI served as reference standards. The reference standard among 100 lesions included 87 HCCs, six ICCs and seven non-HCC-non-ICC-lesions. For the diagnosis of HCC, the diagnostic accuracy of CEUS was significantly higher with ESCULAP versus CEUS-LI-RADS (94.3%/72.4%; pdiagnostic accuracy for ICC (LR-M/ESCULAP-C) was identical with both algorithms (50%), with higher PPV for ESCULAP-C versus LR-M (75 vs. 50%). CEUS-based algorithms contribute toward standardized assessment and reporting of HCC-suspect lesions in high-risk patients. ESCULAP shows significantly higher diagnostic accuracy, sensitivity and negative predictive value with no loss of specificity compared with CEUS-LI-RADS. Both algorithms have an excellent PPV. Arterial hyperenhancement is the key feature for the diagnosis of HCC with CEUS. Washout should not be a necessary prerequisite for the diagnosis of definite HCC. CEUS-LI-RADS in its current version is inferior to ESCULAP for the noninvasive diagnosis of HCC

RadConEd: A Graphical Data Editor for the Radiological Consequences Model, RadCon

International Nuclear Information System (INIS)

Crawford, J.; Domel, R.U.

2000-05-01

This document describes the application, RadConEd, which has been designed and implemented to enable users of the RadCon system to update these parameter files. The RadCon system is written in the Java programming language, and as such provides portability across computer platforms. The software described in this report was developed in line with the portability requirements of RadCon, thus providing a uniform user interface across computer platforms and bypassing the need of using system editors. In addition a number of data integrity measures were implemented

A compromised yeast RNA polymerase II enhances UV sensitivity in the absence of global genome nucleotide excision repair.

Science.gov (United States)

Wong, J M; Ingles, C J

2001-02-01

Nucleotide excision repair is the major pathway responsible for removing UV-induced DNA damage, and is therefore essential for cell survival following exposure to UV radiation. In this report, we have assessed the contributions of some components of the RNA polymerase II (Pol II) transcription machinery to UV resistance in Saccharomyces cerevisiae. Deletion of the gene encoding the Pol II elongation factor TFIIS (SII) resulted in enhanced UV sensitivity, but only in the absence of global genome repair dependent on the RAD7 and RAD16 genes, a result seen previously with deletions of RAD26 and RAD28, yeast homologs of the human Cockayne syndrome genes CSB and CSA, respectively. A RAD7/16-dependent reduction in survival after UV irradiation was also seen in the presence of mutations in RNA Pol II that confer a defect in its response to SII, as well as with other mutations which reside in regions of the largest subunit of Pol II not involved in SII interactions. Indeed, an increase in UV sensitivity was achieved by simply decreasing the steadystate level of RNA Pol II. Truncation of the C-terminal domain and other RNA Pol II mutations conferred sensitivity to the ribonucleotide reductase inhibitor hydroxyurea and induction of RNR1 and RNR2 mRNAs after UV irradiation was attenuated in these mutant cells. That UV sensitivity can be a consequence of mutations in the RNA Pol II machinery in yeast cells suggests that alterations in transcriptional programs could underlie some of the pathophysiological defects seen in the human disease Cockayne syndrome.

OsRAD51C Is Essential for Double Strand Break Repair in Rice Meiosis

Directory of Open Access Journals (Sweden)

Ding eTang

2014-05-01

Full Text Available RAD51C is one of the RAD51 paralogs that plays an important role in DNA double-strand break repair by homologous recombination. Here, we identified and characterized OsRAD51C, the rice homolog of human RAD51C. The Osrad51c mutant plant is normal in vegetative growth but exhibits complete male and female sterility. Cytological investigation revealed that homologous pairing and synapsis were severely disrupted. Massive chromosome fragmentation occurred during metaphase I in Osrad51c meiocytes, and was fully suppressed by the CRC1 mutation. Immunofluorescence analysis showed that OsRAD51C localized onto the chromosomes from leptotene to early pachytene during prophase I, and that normal loading of OsRAD51C was dependent on OsREC8, PAIR2, and PAIR3. Additionally, ZEP1 did not localize properly in Osrad51c, indicating that OsRAD51C is required for synaptonemal complex assembly. Our study also provided evidence in support of a functional divergence in RAD51C among organisms.

Differentiating benign from malignant solid breast masses: value of shear wave elastography according to lesion stiffness combined with greyscale ultrasound according to BI-RADS classification.

Science.gov (United States)

Evans, A; Whelehan, P; Thomson, K; Brauer, K; Jordan, L; Purdie, C; McLean, D; Baker, L; Vinnicombe, S; Thompson, A

2012-07-10

The aim of this study was to assess the performance of shear wave elastography combined with BI-RADS classification of greyscale ultrasound images for benign/malignant differentiation in a large group of patients. One hundred and seventy-five consecutive patients with solid breast masses on routine ultrasonography undergoing percutaneous biopsy had the greyscale findings classified according to the American College of Radiology BI-RADS. The mean elasticity values from four shear wave images were obtained. For mean elasticity vs greyscale BI-RADS, the performance results against histology were sensitivity: 95% vs 95%, specificity: 77% vs 69%, Positive Predictive Value (PPV): 88% vs 84%, Negative Predictive Value (NPV): 90% vs 91%, and accuracy: 89% vs 86% (all P>0.05). The results for the combination (positive result from either modality counted as malignant) were sensitivity 100%, specificity 61%, PPV 82%, NPV 100%, and accuracy 86%. The combination of BI-RADS greyscale and shear wave elastography yielded superior sensitivity to BI-RADS alone (P=0.03) or shear wave alone (P=0.03). The NPV was superior in combination compared with either alone (BI-RADS P=0.01 and shear wave P=0.02). Together, BI-RADS assessment of greyscale ultrasound images and shear wave ultrasound elastography are extremely sensitive for detection of malignancy.

Recovery of deficient homologous recombination in Brca2-depleted mouse cells by wild-type Rad51 expression.

Science.gov (United States)

Lee, Shauna A; Roques, Céline; Magwood, Alissa C; Masson, Jean-Yves; Baker, Mark D

2009-02-01

The BRCA2 tumor suppressor is important in maintaining genomic stability. BRCA2 is proposed to control the availability, cellular localization and DNA binding activity of the central homologous recombination protein, RAD51, with loss of BRCA2 resulting in defective homologous recombination. Nevertheless, the roles of BRCA2 in regulating RAD51 and how other proteins implicated in RAD51 regulation, such as RAD52 and RAD54 function relative to BRCA2 is not known. In this study, we tested whether defective homologous recombination in Brca2-depleted mouse hybridoma cells could be rectified by expression of mouse Rad51 or the Rad51-interacting mouse proteins, Rad52 and Rad54. In the Brca2-depleted cells, defective homologous recombination can be restored by over-expression of wild-type mouse Rad51, but not mouse Rad52 or Rad54. Correction of the homologous recombination defect requires Rad51 ATPase activity. A sizeable fraction ( approximately 50%) of over-expressed wild-type Rad51 is nuclear localized. The restoration of homologous recombination in the presence of a low (i.e., non-functional) level of Brca2 by wild-type Rad51 over-expression is unexpected. We suggest that Rad51 may access the nuclear compartment in a Brca2-independent manner and when Rad51 is over-expressed, the normal requirement for Brca2 control over Rad51 function in homologous recombination is dispensable. Our studies support loss of Rad51 function as a critical underlying factor in the homologous recombination defect in the Brca2-depleted cells.

Cloning of human and mouse genes homologous to RAD52, a yeast gene involved in DNA repair and recombination.

NARCIS (Netherlands)

D.F.R. Muris; O.Y. Bezzubova (Olga); J-M. Buerstedde; K. Vreeken; A.S. Balajee; C.J. Osgood; C. Troelstra (Christine); J.H.J. Hoeijmakers (Jan); K. Ostermann; H. Schmidt (Henning); A.T. Natarajan; J.C.J. Eeken; P.H.M. Lohmann (Paul); A. Pastink (Albert)

1994-01-01

textabstractThe RAD52 gene of Saccharomyces cerevisiae is required for recombinational repair of double-strand breaks. Using degenerate oligonucleotides based on conserved amino acid sequences of RAD52 and rad22, its counterpart from Schizosaccharomyces pombe, RAD52 homologs from man and mouse were

MicroRNA-203 Modulates the Radiation Sensitivity of Human Malignant Glioma Cells

International Nuclear Information System (INIS)

Chang, Ji Hyun; Hwang, Yeo Hyun; Lee, David J.; Kim, Dan Hyo; Park, Ji Min; Wu, Hong-Gyun; Kim, In Ah

2016-01-01

Purpose: We investigated whether miR-203 could modulate the radiation sensitivity of glioblastoma (GBM) cells and which target gene(s) could be involved. Methods and Materials: Three human malignant glioma (MG) cell lines and normal human astrocytes were transfected with control microRNA, pre-miR-203, or antisense miR-203. Real-time PCR (RT-PCR), clonogenic assays, immunofluorescence, and invasion/migration assays were performed. To predict the target(s), bioinformatics analyses using microRNA target databases were performed. Results: Overexpression of miR-203 increased the radiation sensitivity of all 3 human MG cell lines and prolonged radiation-induced γ-H2AX foci formation. Bioinformatics analyses suggested that miR-203 could be involved in post-transcriptional control of DNA repair, PI3K/AKT, SRC, and JAK/STAT3 and the vascular signaling pathway. Western blot analysis validated the fact that miR-203 downregulated ATM, RAD51, SRC, PLD2, PI3K-AKT, JAK-STAT3, VEGF, HIF-1α, and MMP2. Overexpression of miR-203 inhibited invasion and migration potentials, downregulated SLUG and Vimentin, and upregulated Claudin-1 and ZO1. Conclusions: These data demonstrate that miR-203 potentially controls DNA damage repair via the PI3K/AKT and JAK/STAT3 pathways and may collectively contribute to the modulation of radiation sensitivity in MG cells by inhibiting DNA damage repair, prosurvival signaling, and epithelium-mesenchyme transition. Taken together, these findings demonstrate that miR-203 could be a target for overcoming the radiation resistance of GBM.

MicroRNA-203 Modulates the Radiation Sensitivity of Human Malignant Glioma Cells

Energy Technology Data Exchange (ETDEWEB)

Chang, Ji Hyun [Department of Radiation Oncology, Graduate School of Medicine, Seoul National University, Seoul (Korea, Republic of); Hwang, Yeo Hyun; Lee, David J.; Kim, Dan Hyo; Park, Ji Min [Medical Science Research Institute, Seoul National University Bundang Hospital, Kyeonggido (Korea, Republic of); Wu, Hong-Gyun [Department of Radiation Oncology, Graduate School of Medicine, Seoul National University, Seoul (Korea, Republic of); Kim, In Ah, E-mail: inah228@snu.ac.kr [Department of Radiation Oncology, Graduate School of Medicine, Seoul National University, Seoul (Korea, Republic of); Medical Science Research Institute, Seoul National University Bundang Hospital, Kyeonggido (Korea, Republic of); Cancer Research Institute, Seoul National University, Seoul (Korea, Republic of)

2016-02-01

Purpose: We investigated whether miR-203 could modulate the radiation sensitivity of glioblastoma (GBM) cells and which target gene(s) could be involved. Methods and Materials: Three human malignant glioma (MG) cell lines and normal human astrocytes were transfected with control microRNA, pre-miR-203, or antisense miR-203. Real-time PCR (RT-PCR), clonogenic assays, immunofluorescence, and invasion/migration assays were performed. To predict the target(s), bioinformatics analyses using microRNA target databases were performed. Results: Overexpression of miR-203 increased the radiation sensitivity of all 3 human MG cell lines and prolonged radiation-induced γ-H2AX foci formation. Bioinformatics analyses suggested that miR-203 could be involved in post-transcriptional control of DNA repair, PI3K/AKT, SRC, and JAK/STAT3 and the vascular signaling pathway. Western blot analysis validated the fact that miR-203 downregulated ATM, RAD51, SRC, PLD2, PI3K-AKT, JAK-STAT3, VEGF, HIF-1α, and MMP2. Overexpression of miR-203 inhibited invasion and migration potentials, downregulated SLUG and Vimentin, and upregulated Claudin-1 and ZO1. Conclusions: These data demonstrate that miR-203 potentially controls DNA damage repair via the PI3K/AKT and JAK/STAT3 pathways and may collectively contribute to the modulation of radiation sensitivity in MG cells by inhibiting DNA damage repair, prosurvival signaling, and epithelium-mesenchyme transition. Taken together, these findings demonstrate that miR-203 could be a target for overcoming the radiation resistance of GBM.

Analysis list: RAD21 [Chip-atlas[Archive

Lifescience Database Archive (English)

Full Text Available ncedbc.jp/kyushu-u/hg19/target/RAD21.1.tsv http://dbarchive.biosciencedbc.jp/kyushu...-u/hg19/target/RAD21.5.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/target/RAD21.10.tsv http://dbarchive.bioscience...dbc.jp/kyushu-u/hg19/colo/RAD21.Blood.tsv,http://dbarchive.bioscience...dbc.jp/kyushu-u/hg19/colo/RAD21.Breast.tsv,http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/colo/RAD21.Dige...stive_tract.tsv,http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/colo/RAD21.Liver.tsv,http://dbarchive.bioscience

Production and characterization of radiation-sensitive meiotic mutants of Coprinus cinereus

International Nuclear Information System (INIS)

Zolan, M.E.; Tremel, C.J.; Pukkila, P.J.

1988-01-01

We have isolated four gamma-sensitive mutants of the basidiomycete Coprinus cinereus. When homozygous, two of these (rad 3-1 and rad 9-1) produce fruiting bodies with very few viable basidiospores, the products of meiosis in this organism. A less radiation-sensitive allele of RAD 3, rad 3-2, causes no apparent meiotic defect in homozygous strains. Quantitative measurements of oidial survival of rad 3-1;rad 9-1 double mutants compared to the single mutants indicated that rad 3-1 and rad 9-1 mutants are defective in the same DNA repair pathway. In the pew viable basidiospores that are produced by these two strains, essentially normal levels of meiotic recombination can be detected. None of the mutants exhibits increased sensitivity to UV radiation. Cytological examination of meiotic chromosomes from mutant and wild-type fruiting bodies showed that rad 3-1 homozygous strains fail to condense and pair homologous chromosomes during prophase I. Although rad 9-1 strains are successful at chromosome pairing, meiosis is usually not completed in these mutants

Cellular radiation effects and hyperthermia cell cycle kinetics of radiation sensitive mutants of saccharomyces cerevisiae after x-irradiation and hyperthermia

International Nuclear Information System (INIS)

Fingerhut, R.; Kiefer, J.; Otto, F.

1983-01-01

Radiosensitive mutants rad2, rad9, and rad51 of Saccharomyces cerevisiae were X-irradiated with 120 Gy or 60 Gy, heated at 50 0 C for 30 min or treated with a combination of both and incubated in nutrient medium at 30 0 C. Cell number, percentage of budding cells, and cell cycle progression were determined in 45-min intervals. Cell cycle kinetics were investigated by flow cytofluorometry. Hyperthermia leads mainly to a lengthening of G1, whereas X-rays arrest cells of the rad2 and rad9 mutant in G2 and the rad51 - mutant additionaly in a state with DNA contents above G2. Cell division dealy is influenced by oxygen in all strains but to a lesser extent in the rad2 mutant. The effect of the combined treatment appears to be merely additive in the rad2 and rad9 mutant while the rad51 mutant is sensitized to X-irradiation by hyperthermia. No selective action of hyperthermia on hypoxic cells was found. (orig.)

The RadAssessor manual

Energy Technology Data Exchange (ETDEWEB)

Seitz, Sharon L.

2007-02-01

THIS manual will describe the functions and capabilities that are available from the RadAssessor database and will demonstrate how to retrieve and view its information. You’ll learn how to start the database application, how to log in, how to use the common commands, and how to use the online help if you have a question or need extra guidance. RadAssessor can be viewed from any standard web browser. Therefore, you will not need to install any special software before using RadAssessor.

Issues in assessing multi-institutional performance of BI-RADS-based CAD systems

Science.gov (United States)

Markey, Mia K.; Lo, Joseph Y.

2005-04-01

The purpose of this study was to investigate factors that impact the generalization of breast cancer computer-aided diagnosis (CAD) systems that utilize the Breast Imaging Reporting and Data System (BI-RADS). Data sets from four institutions were analyzed: Duke University Medical Center, University of Pennsylvania Medical Center, Massachusetts General Hospital, and Wake Forest University. The latter two data sets are subsets of the Digital Database for Screening Mammography. Each data set consisted of descriptions of mammographic lesions according to the BI-RADS lexicon, patient age, and pathology status (benign/malignant). Models were developed to predict pathology status from the BI-RADS descriptors and the patient age. Comparisons between the models built on data from the different institutions were made in terms of empirical (non-parametric) receiver operating characteristic (ROC) curves. Results suggest that BI-RADS-based CAD systems focused on specific classes of lesions may be more generally applicable than models that cover several lesion types. However, better generalization was seen in terms of the area under the ROC curve than in the partial area index (>90% sensitivity). Previous studies have illustrated the challenges in translating a BI-RADS-based CAD system from one institution to another. This study provides new insights into possible approaches to improve the generalization of BI-RADS-based CAD systems.

Categorization and evaluation of usefulness of breast lesions with using ultrasound BI-RADS (breast imaging reporting and data system)

International Nuclear Information System (INIS)

Kim, Youn Jeong; Choi, Hye Young; Moon, Byung In; Lee, Shi Nae

2006-01-01

The aim of our study was to determine the positive predictive value (PPV) and to evaluate the usefulness on ultrasound BI-RADS, as compared with the histologic results of breast lesions that were categorized and classified by the ultrasound BI-RADS lexicon. Between January and December 2004, the ultrasound features of 471 breast lesions in 368 patients were analyzed and categorized with using ultrasound BI-RADS. All of the lesions were compared with the histological results. We categorized category 2 and 3 lesions as benign lesions, and category 4 and 5 lesions as malignant lesions. We then calculated the sensitivity, specificity, positive, predictive value, negative predictive value and accuracy. The breast lesions were histologically diagnosed as 298 cases of category 2, 21 cases of category 3, 108 cases of category 4 and 44 cases of category 5. The categorical malignancy rate was 1% (3/298) in category 2 lesions, 4.7% (1/21) in category 3 lesions, 8.3% (9/108) in category 4 lesions and 90.9% (40/44) in category 5 lesions. Within category 4, the malignancy rate for category 4a lesions was 5.4% (5/92), the malignancy rate for category 4b lesions was 1.3% (1/8) and the malignancy rate for category 4c lesions was 50% (4/8). The sensitivity, specificity, positive predictive value and negative predictive value were 90.6%, 75.1%, 31.6% and 98.4%, respectively. The statistically valid ultrasound features that were correlated with malignancy were an ill defined margin, a microlobulated mass, an irregular mass, inhomogenic echogenicity, an echogenic halo and an older patient age. Ultrasound BI-RADS was useful in differentiating benign from malignant breast lesions

Regeneration of CFUs in the marrow of mice exposed to 300 rads after having recovered from 950 rads

International Nuclear Information System (INIS)

Kedo, A.; Barone, J.; Fried, W.

1976-01-01

Exposure to 950 rads 60 Co radiation has been reported to cause long-lasting damage to the hematopoietic stroma (HS), although the size of the CFUs population recovers to pre-irradiation levels. In these studies HS damage was detected only after subcutaneously implanting the femurs of the irradiated mice into syngeneic hosts. To exclude the possibility that what was considered to be HS damage was merely caused by artifacts due to the process of implantation in a new host, the rate of regeneration of CFUs in mice which had recovered from 950 rads prior to receiving 300 rads 60 Co radiation (950 + 300 rads group) was compared with that of mice which received only 300 rads (0 + 300 rads group). The CFUs population in the 950 + 300 rads group grew exponentially for 2 weeks at a rate which did not differ significantly from that of CFUs in the 0 + 300 rads group. However, the rate of CFUs growth reached a plateau before full recovery was achieved in contrast to that in the 0 + 300 rads mice. It was therefore concluded that the incomplete regeneration of CFUs in the marrows of 950 + 300 rads mice was most likely caused by X-irradiation-induced damage to the HS rather than damage to the inherent repopulation potential of the CFUs per se. (author)

Rad and Mubad in Shahnameh of Ferdowsi

Directory of Open Access Journals (Sweden)

z Delpazir

2011-09-01

However, the important points overlooked by explicators are the relationship between Rad and Mubad (Zoroastrian priest and the reason why these two words have co-occurred so frequently in Shahnameh, the most famous Persian national epic. It seems that Rad in Shahnameh, based on Avesta and Pahlavi texts, is often construed as Sadane or Dastoor that was a high position in ancient Iran’s religious hierarchy. Thus, Rads and Mubads were both considered members of religious communities. This study tries to investigate the role and position of Rads and Mubads and their relationship with one another, based on Shahnameh of Ferdowsi, in three chapters: The etymology of Rad Rad in Shahnameh The relationship between Rads and Mubads.

Cellular Dynamics of Rad51 and Rad54 in Response to Postreplicative Stress and DNA Damage in HeLa Cells.

Science.gov (United States)

Choi, Eui-Hwan; Yoon, Seobin; Hahn, Yoonsoo; Kim, Keun P

2017-02-01

Homologous recombination (HR) is necessary for maintenance of genomic integrity and prevention of various mutations in tumor suppressor genes and proto-oncogenes. Rad51 and Rad54 are key HR factors that cope with replication stress and DNA breaks in eukaryotes. Rad51 binds to single-stranded DNA (ssDNA) to form the presynaptic filament that promotes a homology search and DNA strand exchange, and Rad54 stimulates the strand-pairing function of Rad51. Here, we studied the molecular dynamics of Rad51 and Rad54 during the cell cycle of HeLa cells. These cells constitutively express Rad51 and Rad54 throughout the entire cell cycle, and the formation of foci immediately increased in response to various types of DNA damage and replication stress, except for caffeine, which suppressed the Rad51-dependent HR pathway. Depletion of Rad51 caused severe defects in response to postreplicative stress. Accordingly, HeLa cells were arrested at the G2-M transition although a small amount of Rad51 was steadily maintained in HeLa cells. Our results suggest that cell cycle progression and proliferation of HeLa cells can be tightly controlled by the abundance of HR proteins, which are essential for the rapid response to postreplicative stress and DNA damage stress.

Structure of human Rad51 protein filament from molecular modeling and site-specific linear dichroism spectroscopy

KAUST Repository

Reymer, A.; Frykholm, K.; Morimatsu, K.; Takahashi, M.; Norden, B.

2009-01-01

for central and N-terminal parts of pure (uncomplexed) Rad51 protein by aid of linear dichroism spectroscopy, providing angular orientations of substituted tyrosine residues of Rad51-dsDNA filaments in solution. The structure, validated by comparison

Oocyte toxicity: female germ-cell loss from radiation and chemical exposures

International Nuclear Information System (INIS)

Dobson, R.L.

1984-01-01

In some mammals, female germ cells are extraordinarily sensitive to killing by exposure to ionizing radiation, especially during development. Immature oocytes, which constitute the lifetime germ-cell pool of the female, have an LD 50 in juvenile mice of only 6 rad (compared with typical LD 50 s of 100-300 rad for most other cell types studied). Essentially, the entire germ-cell supply in female squirrel monkeys is destroyed prenatally by exposure of only 0.7 rad/day. Severe but lesser destruction has been found in other species. However, evidence suggests (though not ruled out for all developmental stages) that unusually high sensitivity probably does not occur in the human female. Germ cells can also be killed by certain chemicals, and similarities exist between chemical and radiation effects. More than 75 compounds have been quantitatively studied in mice, with determination of OTI values (OTI = oocyte toxicity index = mouse LD 50 /oocyte LD 50 ) to measure the degree of preferential oocyte killing. High sensitivity in mice does not mean necessarily high sensitivity in women. Of special interest is the recent discovery that the lethal target in the extremely sensitive mouse immature oocyte is probably the plasma membrane, not DNA. Since mouse data form the main basis from which human genetic hazard (for both radiation and chemicals) is estimated, this has important implications for the determination of genetic risk in women

Survival of human osteosarcoma cells and normal human fibroblasts following alpha particle irradiation

International Nuclear Information System (INIS)

Lloyd, E.L.; Gemmell, M.A.

1981-01-01

Cell survival of human osteosarcoma cells in culture following alpha particle irradiation is reported here for the first time. The osteosarcoma cell line (TE-85) is found to be less sensitive to inactivation by 5.6 MeV alpha particles (LET 86 keV/μm) than normal diploid human fibroblasts (NFS). Values for the mean lethal doses were estimated to be 103 rads for the TE-85 cells compared with 68 rads for the NFS cultures irradiated under identical conditions. It is postulated that the aneuploidy of the tumor cells with increased DNA chromosomal material may confer a selective advantage for the survival of tumor cells relative to normal cells with diploid chromosomes

Suppression of Homologous Recombination by insulin-like growth factor-1 inhibition sensitizes cancer cells to PARP inhibitors

International Nuclear Information System (INIS)

Amin, Oreekha; Beauchamp, Marie-Claude; Nader, Paul Abou; Laskov, Ido; Iqbal, Sanaa; Philip, Charles-André; Yasmeen, Amber; Gotlieb, Walter H.

2015-01-01

Impairment of homologous recombination (HR) is found in close to 50 % of ovarian and breast cancer. Tumors with BRCA1 mutations show increased expression of the Insulin-like growth factor type 1 receptor (IGF-1R). We previously have shown that inhibition of IGF-1R results in growth inhibition and apoptosis of ovarian tumor cells. In the current study, we aimed to investigate the correlation between HR and sensitivity to IGF-1R inhibition. Further, we hypothesized that IGF-1R inhibition might sensitize HR proficient cancers to Poly ADP ribose polymerase (PARP) inhibitors. Using ovarian and breast cancer cellular models with known BRCA1 status, we evaluated their HR functionality by RAD51 foci formation assay. The 50 % lethal concentration (LC50) of Insulin-like growth factor type 1 receptor kinase inhibitor (IGF-1Rki) in these cells was assessed, and western immunoblotting was performed to determine the expression of proteins involved in the IGF-1R pathway. Moreover, IGF-1R inhibitors were added on HR proficient cell lines to assess mRNA and protein expression of RAD51 by qPCR and western blot. Also, we explored the interaction between RAD51 and Insulin receptor substance 1 (IRS-1) by immunoprecipitation. Next, combination effect of IGF-1R and PARP inhibitors was evaluated by clonogenic assay. Cells with mutated/methylated BRCA1 showed an impaired HR function, and had an overactivation of the IGF-1R pathway. These cells were more sensitive to IGF-1R inhibition compared to HR proficient cells. In addition, the IGF-IR inhibitor reduced RAD51 expression at mRNA and protein levels in HR proficient cells, and sensitized these cells to PARP inhibitor. Targeting IGF-1R might lead to improved personalized therapeutic approaches in cancer patients with HR deficiency. Targeting both PARP and IGF-1R might increase the clinical efficacy in HR deficient patients and increase the population of patients who may benefit from PARP inhibitors

Sensitive silicon PIN-diode dosimeter for fast neutrons and method to control and increase its sensitivity

International Nuclear Information System (INIS)

Swinehart, P.R.; Swartz, J.M.

1978-01-01

With the personnel dosimeter, applicable e.g. in medicine, a dose of 0.1 rad for neutrons with an energy greater than 10 keV can be detected. In the range between 0.1 and 20 rad sensitivity is increased to 5 mV/rad. This sensitivity can be achieved by distributing the mass of the semiconductor material of the diode or equal to four times the reciprocal base width. Appropriate dimensions are 750 μm for the edge length of the end surface resp. diameter and 750 μm up to 5000 μm for the base width. (DG) [de

Coordination of Rad1-Rad10 interactions with Msh2-Msh3, Saw1 and RPA is essential for functional 3' non-homologous tail removal.

Science.gov (United States)

Eichmiller, Robin; Medina-Rivera, Melisa; DeSanto, Rachel; Minca, Eugen; Kim, Christopher; Holland, Cory; Seol, Ja-Hwan; Schmit, Megan; Oramus, Diane; Smith, Jessica; Gallardo, Ignacio F; Finkelstein, Ilya J; Lee, Sang Eun; Surtees, Jennifer A

2018-04-06

Double strand DNA break repair (DSBR) comprises multiple pathways. A subset of DSBR pathways, including single strand annealing, involve intermediates with 3' non-homologous tails that must be removed to complete repair. In Saccharomyces cerevisiae, Rad1-Rad10 is the structure-specific endonuclease that cleaves the tails in 3' non-homologous tail removal (3' NHTR). Rad1-Rad10 is also an essential component of the nucleotide excision repair (NER) pathway. In both cases, Rad1-Rad10 requires protein partners for recruitment to the relevant DNA intermediate. Msh2-Msh3 and Saw1 recruit Rad1-Rad10 in 3' NHTR; Rad14 recruits Rad1-Rad10 in NER. We created two rad1 separation-of-function alleles, rad1R203A,K205A and rad1R218A; both are defective in 3' NHTR but functional in NER. In vitro, rad1R203A,K205A was impaired at multiple steps in 3' NHTR. The rad1R218A in vivo phenotype resembles that of msh2- or msh3-deleted cells; recruitment of rad1R218A-Rad10 to recombination intermediates is defective. Interactions among rad1R218A-Rad10 and Msh2-Msh3 and Saw1 are altered and rad1R218A-Rad10 interactions with RPA are compromised. We propose a model in which Rad1-Rad10 is recruited and positioned at the recombination intermediate through interactions, between Saw1 and DNA, Rad1-Rad10 and Msh2-Msh3, Saw1 and Msh2-Msh3 and Rad1-Rad10 and RPA. When any of these interactions is altered, 3' NHTR is impaired.

Regulation of Rad51-Mediated Homologous Recombination by BRCA2, DSS1 and RAD52

DEFF Research Database (Denmark)

Rants, Louise Olthaver Juhl

Homologous recombination (HR) provides a mechanism to restore integrity and maintain stability of the genetic material. HR is a major pathway for repair of DNA double-strand breaks (DSB), recovery of broken replication forks and generation of meiotic crossovers. The defining step in HR is homolog......Homologous recombination (HR) provides a mechanism to restore integrity and maintain stability of the genetic material. HR is a major pathway for repair of DNA double-strand breaks (DSB), recovery of broken replication forks and generation of meiotic crossovers. The defining step in HR...... is homologous strand exchange directed by the RecA-related recombinase Rad51. BRCA2 participates in HR by mediating Rad51 homology-directed repair. Both BRCA2 and Rad51 are essential for HR, DNA repair, and the maintenance of genome stability. In the present study, we seek to understand the mechanism of BRCA2...... with RAD52-mediated repair at sites of CPT-induced DNA damage. The synthetic lethality approach using RAD52 small molecule inhibitors in brca-deficient cancers is a promising therapeutic strategy for cancer treatment....

Function of Rad51 paralogs in eukaryotic homologous recombinational repair

International Nuclear Information System (INIS)

Liu, N.; Skowronek, K.

2003-01-01

Full text: Homologous recombinational repair (HRR) is an important mechanism for maintaining genetic integrity and cancer prevention by accurately repair of DNA double strand breaks induced by environmental insults or occurred in DNA replication. A critical step in HRR is the polymerization of Rad51 on single stranded DNA to form nuclear protein filaments, the later conduct DNA strand paring and exchange between homologous strands. A number of proteins, including replication protein A (RPA), Rad52 and Rad51 paralogs, are suggested to modulate or facilitate the process of Rad51 filament formation. Five Rad51 paralogs, namely XRCC2, XRCC3, Rad51B, Rad51C and Rad51D have been identified in eucaryotic cells. These proteins show distant protein sequence identity to Rad51, to yeast Rad51 paralogs (Rad55 and Rad57) and to each other. Hamster or chicken mutants of Rad51 paralogs exhibit hypersensitivity to a variety of DNA damaging agents, especially cross-linking agents, and are defective in assembly of Rad51 onto HRR site after DNA damage. Recent data from our and other labs showed that Rad51 paralogs constitute two distinct complexes in cell extracts, one contains XRCC2, Rad51B, Rad51C and Rad51D, and the other contains Rad51C and XRCC3. Rad51C is involved in both complexes. Our results also showed that XRCC3-Rad51C complex interacts with Rad51 in vivo. Furthermore, overexpression of Rad52 can partially suppress the hypersensitivity of XRCC2 mutant irs1 to ionizing radiation and corrected the defects in Rad51 focus formation. These results suggest that XRCC2 and other Rad51 paralogs play a mediator function to Rad51 in the early stage of HRR

Rec8p, a meiotic recombination and sister chromatid cohesion phosphoprotein of the Rad21p family conserved from fision yeast to humans.

NARCIS (Netherlands)

S. Parisi; M.J. McKay (Michael); M. Molnar; M.A. Thompson (Anne); P.J. van der Spek (Peter); E. van Drunen-Schoenmaker; R. Kanaar (Roland); E. Lehmann; J.H.J. Hoeijmakers (Jan); J. Kohli

1999-01-01

textabstractOur work and that of others defined mitosis-specific (Rad21 subfamily) and meiosis-specific (Rec8 subfamily) proteins involved in sister chromatid cohesion in several eukaryotes, including humans. Mutation of the fission yeast Schizosaccharomyces pombe rec8 gene was previously shown to

Overexpression of Rad in muscle worsens diet-induced insulin resistance and glucose intolerance and lowers plasma triglyceride level

Science.gov (United States)

Ilany, Jacob; Bilan, Philip J.; Kapur, Sonia; Caldwell, James S.; Patti, Mary-Elizabeth; Marette, Andre; Kahn, C. Ronald

2006-03-01

Rad is a low molecular weight GTPase that is overexpressed in skeletal muscle of some patients with type 2 diabetes mellitus and/or obesity. Overexpression of Rad in adipocytes and muscle cells in culture results in diminished insulin-stimulated glucose uptake. To further elucidate the potential role of Rad in vivo, we have generated transgenic (tg) mice that overexpress Rad in muscle using the muscle creatine kinase (MCK) promoter-enhancer. Rad tg mice have a 6- to 12-fold increase in Rad expression in muscle as compared to wild-type littermates. Rad tg mice grow normally and have normal glucose tolerance and insulin sensitivity, but have reduced plasma triglyceride levels. On a high-fat diet, Rad tg mice develop more severe glucose intolerance than the wild-type mice; this is due to increased insulin resistance in muscle, as exemplified by a rightward shift in the dose-response curve for insulin stimulated 2-deoxyglucose uptake. There is also a unexpected further reduction of the plasma triglyceride levels that is associated with increased levels of lipoprotein lipase in the Rad tg mice. These results demonstrate a potential synergistic interaction between increased expression of Rad and high-fat diet in creation of insulin resistance and altered lipid metabolism present in type 2 diabetes. diabetes mellitus | glucose transport | RGK GTPase | transgenic mouse

Breast MRI in the Evaluation of Locally Recurrent or New Breast Cancer in the Postoperative Patient: Correlation of Morphology and Enhancement Features with the BI-RADS Category

International Nuclear Information System (INIS)

Seely, J.M.; Nguyen, E.T.; Jaffey, J.

2007-01-01

Background: While breast magnetic resonance imaging (MRI) is a highly sensitive test for detecting breast carcinoma, its specificity is lower, and several methods have been described on how to optimize specificity. Purpose: To compare the specificity and sensitivity of the BI-RADS category with the Fischer score in breast MRI for diagnosing cancer in women previously treated for breast cancer. Material and Methods: Women referred for evaluation of possible local recurrence or new breast cancer underwent breast MRI examination. Morphologic and kinetic enhancement characteristics were evaluated. BI-RADS category and Fischer score were assigned for each enhancing lesion and compared using a chi-square test. Sensitivity, specificity, and positive predictive values for 27 morphologic and enhancement characteristics were calculated. Pathologic diagnosis was obtained in all patients with enhancing lesions who had ultrasound or mammographic correlation. In those without correlate, 6-, 12-, and 24-month follow-up breast MRIs were obtained. Interobserver kappa correlation was determined for each variable studied. Results: 34 benign and 32 malignant lesions were identified in 26 of 30 patients. BI-RADS category yielded a specificity of 77.1% and a sensitivity of 81.8%. Fischer score had a lower specificity and sensitivity (62.9% and 72.7%, respectively) (P 100% enhancement was more sensitive than BI-RADS for malignant lesions. Specificity was highest for rim enhancement (97.1%), but sensitivity was low (24.2%). Interobserver kappa correlation was good for all 27 characteristics ( = 0.84), and highest for BI-RADS assessment ( 0.91). Conclusion: BI-RADS category in breast MRI had the highest combination of specificity and sensitivity, and the highest interobserver correlation. Fischer score and other morphologic and enhancement features lack sensitivity or specificity and do not have high positive predictive values when analyzed as single independent variables

Evidence that a recombinationless strain, rad 51, of Saccharomyces cerevisiae lacks the budding cell resistance to γ-rays

International Nuclear Information System (INIS)

Hama-Inaba, Hiroko; Saeki, Tetsuya

1975-01-01

The radiosensitivities of a wild-type and x-ray sensitive mutant, rad 51 (defective in genetic recombination) of Saccharomyces cerevisiae to γ-rays were compared, using non-synchronized and partially synchronized cultures. The rad 51 cells, either haploid or diploid, showed only very small changes in radiosensitivity during cell growth, whereas the wild-type cells, especially haploid, showed the well-known budding resistance. The heterozygous (wild/rad 51) diploid cells showed in a survival curve a remarkable budding resistance and sigmoidal inactivation kinetics similar to those of wild-type homozygous diploid cells. (author)

Genetic analysis of gamma-ray mutagenesis in yeast. I. Reversion in radiation-sensitive strains

International Nuclear Information System (INIS)

McKee, R.H.; Lawrence, C.W.

1979-01-01

The frequency of revertants induced by 60 Co γ rays of the ochre allele, cyc1-9, has been measured in radiation-sensitive strains carrying one of 19 nonallelic mutations and in wild-type strains. The results indicate that ionizing radiation mutagenesis depends on the activity of the RAD6 group of genes and that the gene functions employed are very similar, but probably not identical, to those that mediate uv mutagenesis. Repair activities dependent on the functions of the RAD50 through RAD57 loci, the major pathway for the repair of damage caused by ionizing radiation, do not appear to play any part in mutagenesis. A comparison between the γ-ray data and those obtained previously with uv and chemical mutagens suggests that the RAD6 mutagenic pathway is in fact composed of a set of processes, some of which are concerned with error-prone, and some with error-free, recovery activities

Radiosensitivity in cultured human fibroblasts

International Nuclear Information System (INIS)

Cox, R.; Masson, W.K.

1980-01-01

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

Human genetic marker for resistance to radiations and chemicals. 1998 annual progress report

International Nuclear Information System (INIS)

Lieberman, H.B.

1998-01-01

'The broad objective of the project is to understand the molecular basis for the response of cells to radiations and chemicals, with the pragmatic goal of being able to identify human subpopulations that are exceptionally sensitive to DNA damaging agents. The project focuses on HRAD9, a human orthologue of the fission yeast Schizosaccharomyces pombe gene rad9. S. pombe rad9::ura4+ mutant cells are highly sensitive to ionizing radiation, UV and many chemicals, such as the DNA synthesis inhibitor hydroxyurea. They also lack the ability to delay cycling transiently in S phase or in G2 following a block in DNA replication or after incurring DNA damage, respectively -i.e., they lack checkpoint controls. The attempt by mutant cells to progress through mitosis in the absence of fully intact DNA accounts at least in part for their sensitivity to DNA damaging agents. Cells bearing rad9::ura4+ also aberrantly regulate UVDE, an enzyme that participates in a secondary DNA excision repair pathway. The key role played by S. pombe rad9 in promoting resistance to chemicals and radiations suggests that the evolutionarily conserved human cognate also has important functions in mammals. The first set of aims in this proposal centers on characterizing the structure and expression of HRAD9, to assess structure/function relationships and potentially link protein activity to a specific tissue. The next set of aims focuses on determining the role of HRAD9 in radio/chemoresponsiveness and cancer.'

RadCat 2.0 User Guide.

Energy Technology Data Exchange (ETDEWEB)

Osborn, Douglas.; Weiner, Ruth F.; Mills, George Scott; Hamp, Steve C.; O' Donnell, Brandon, M.; Orcutt, David J.; Heames, Terence J.; Hinojosa, Daniel

2005-01-01

This document provides a detailed discussion and a guide for the use of the RadCat 2.0 Graphical User Interface input file generator for the RADTRAN 5.5 code. The differences between RadCat 2.0 and RadCat 1.0 can be attributed to the differences between RADTRAN 5 and RADTRAN 5.5 as well as clarification for some of the input parameters. 3

Mars science laboratory radiation assessment detector (MSL/RAD) modeling workshop proceedings

Science.gov (United States)

Hassler, Donald M.; Norbury, John W.; Reitz, Günther

2017-08-01

The Radiation Assessment Detector (RAD) (Hassler et al., 2012; Zeitlin et al., 2016) onboard the Mars Science Laboratory (MSL) Curiosity rover (Grotzinger et al., 2012) is a sophisticated charged and neutral particle radiation analyzer developed by an international team of scientists and engineers from Southwest Research Institute in Boulder, Colorado as the leading institution, the University of Kiel and the German Aerospace Center in Cologne, Germany. RAD is a compact, powerful instrument capable of distinguishing between ionizing particles and neutral particles and providing neutron, gamma, and charged particle spectra from protons to iron as well as absorbed dose measurements in tissue-equivalent material. During the 6 month cruise to Mars, inside the MSL spacecraft, RAD served as a proxy to validate models of the radiation levels expected inside a spacecraft that future astronauts might experience (Zeitlin et al., 2013). RAD was turned on one day after the landing on August 7, 2012, exactly 100 years to the day after the discovery of cosmic rays on Earth by Victor Hess. These measurements are the first of their kind on the surface of another planet (Hassler et al., 2014), and the radiation data collected by RAD on the surface of Mars will inform projections of crew health risks and the design of protective surface habitats and other countermeasures for future human missions in the coming decades.

Conservation of the rad21 Schizosaccharomyces pombe DNA double-strand break repair gene in mammals

International Nuclear Information System (INIS)

McKay, Michael J.; Spek, Peter van der; Kanaar, Roland; Smit, Bep; Bootsma, Dirk; Hoeijmakers, Jan H. J.

1996-01-01

Purpose/Objective: Genetic factors are likely to be major determinants of human cellular ionizing radiation sensitivity. DNA double strand breaks (dsbs) are significant ionizing radiation-induced lesions; cellular DNA dsb processing is also important in a number of other contexts. To further the understanding of DNA dsb processing in mammalian cells, we cloned and sequenced mammalian homologs of the rad21 Schizosaccharomyces pombe DNA dsb repair gene. Materials and Methods: The genes were cloned by evolutionary walking, exploiting sequence homology between the yeast and mammalian genes. Results: No major motifs indicative of a particular function were present in the predicted amino acid sequences of the mammalian genes. Alignment of the Rad21 amino acid sequence with its putative homologs showed that similarity was distributed across the length of the proteins, with more highly conserved regions at both termini. The mHR21 sp (mouse homolog ofR ad21, S. pombe) and hHR21 sp (humanh omolog of Rad21, S. pombe) predicted proteins were 96% identical, whereas the human and S. pombe proteins were 25% identical and 47% similar. RNA blot analysis showed that mHR21 sp mRNA was abundant in all adult mouse tissues examined, with highest expression in testis and thymus. In addition to a 3.1kb mRNA transcript in all tissues, an additional 2.2kb transcript was present at a high level in post-meiotic spermatids, white expression of the 3.1kb mRNA in testis was confined to the meiotic compartment. hHR21 sp mRNA was cell cycle regulated in human cells, increasing in late S phase to a peak in G2 phase. The level of hHR21 sp transcripts was not altered by exposure of normal diploid fibroblasts to 10 Gy ionizing radiation. In situ hybridization showed mHR21 sp resided on chromosome 15D3, whereashHR21 sp localized to the syntenic 8q24 region. Conclusion: Cloning these novel mammalian genes and characterization of their protein products should contribute to the understanding of cellular

Requirement of Sequences outside the Conserved Kinase Domain of Fission Yeast Rad3p for Checkpoint Control

Science.gov (United States)

Chapman, Carolyn Riley; Evans, Sarah Tyler; Carr, Antony M.; Enoch, Tamar

1999-01-01

The fission yeast Rad3p checkpoint protein is a member of the phosphatidylinositol 3-kinase-related family of protein kinases, which includes human ATMp. Mutation of the ATM gene is responsible for the disease ataxia-telangiectasia. The kinase domain of Rad3p has previously been shown to be essential for function. Here, we show that although this domain is necessary, it is not sufficient, because the isolated kinase domain does not have kinase activity in vitro and cannot complement a rad3 deletion strain. Using dominant negative alleles of rad3, we have identified two sites N-terminal to the conserved kinase domain that are essential for Rad3p function. One of these sites is the putative leucine zipper, which is conserved in other phosphatidylinositol 3-kinase-related family members. The other is a novel motif, which may also mediate Rad3p protein–protein interactions. PMID:10512862

FANCI-FANCD2 stabilizes the RAD51-DNA complex by binding RAD51 and protects the 5′-DNA end

Science.gov (United States)

Sato, Koichi; Shimomuki, Mayo; Katsuki, Yoko; Takahashi, Daisuke; Kobayashi, Wataru; Ishiai, Masamichi; Miyoshi, Hiroyuki; Takata, Minoru; Kurumizaka, Hitoshi

2016-01-01

The FANCI-FANCD2 (I-D) complex is considered to work with RAD51 to protect the damaged DNA in the stalled replication fork. However, the means by which this DNA protection is accomplished have remained elusive. In the present study, we found that the I-D complex directly binds to RAD51, and stabilizes the RAD51-DNA filament. Unexpectedly, the DNA binding activity of FANCI, but not FANCD2, is explicitly required for the I-D complex-mediated RAD51-DNA filament stabilization. The RAD51 filament stabilized by the I-D complex actually protects the DNA end from nucleolytic degradation by an FA-associated nuclease, FAN1. This DNA end protection is not observed with the RAD51 mutant from FANCR patient cells. These results clearly answer the currently enigmatic question of how RAD51 functions with the I-D complex to prevent genomic instability at the stalled replication fork. PMID:27694619

Human CST Facilitates Genome-wide RAD51 Recruitment to GC-Rich Repetitive Sequences in Response to Replication Stress.

Science.gov (United States)

Chastain, Megan; Zhou, Qing; Shiva, Olga; Fadri-Moskwik, Maria; Whitmore, Leanne; Jia, Pingping; Dai, Xueyu; Huang, Chenhui; Ye, Ping; Chai, Weihang

2016-08-02

The telomeric CTC1/STN1/TEN1 (CST) complex has been implicated in promoting replication recovery under replication stress at genomic regions, yet its precise role is unclear. Here, we report that STN1 is enriched at GC-rich repetitive sequences genome-wide in response to hydroxyurea (HU)-induced replication stress. STN1 deficiency exacerbates the fragility of these sequences under replication stress, resulting in chromosome fragmentation. We find that upon fork stalling, CST proteins form distinct nuclear foci that colocalize with RAD51. Furthermore, replication stress induces physical association of CST with RAD51 in an ATR-dependent manner. Strikingly, CST deficiency diminishes HU-induced RAD51 foci formation and reduces RAD51 recruitment to telomeres and non-telomeric GC-rich fragile sequences. Collectively, our findings establish that CST promotes RAD51 recruitment to GC-rich repetitive sequences in response to replication stress to facilitate replication restart, thereby providing insights into the mechanism underlying genome stability maintenance. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

RadCon: A Radiological Consequences Model

International Nuclear Information System (INIS)

Crawford, J.; Domel, R.U.

2000-05-01

RadCon estimates the dose received by user selected groups in the population from an accidental release of radionuclides to the environment. The exposure pathways considered are external exposure from the cloud and ground and internal exposure from inhalation and ingestion of contaminated food. Atmospheric dispersion modelling is carried out externally to RadCon.Given a two dimensional time varying air and ground concentration of radioactive elements, RadCon allows the user to: view the air and ground concentration over the affected area, select optional parameters and calculate the dose to people,display the results to the user, and change the parameter values. RadCon offers two user interfaces: 1) the standard graphical user interface which is started using Java DoseApp at the command line, or by setting up a shortcut to this command (particularly when RadCon is installed on a PC) and 2) the text based interface used to generate information for the model inter-comparison exercise . This is initiated using Java BIOMASS at the command line, or an equivalent shortcut. The text based interface was developed for research purposes and is not generally available. Appendices A, B and C provide a summary of instructions on setting up RadCon. This will generally be carried out by the computer support personnel

TAS-116, a novel Hsp90 inhibitor, selectively enhances radio-sensitivity of human cancer cells to X-rays and carbon ion radiation

Science.gov (United States)

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

2016-01-01

Hsp90 inhibitors have been investigated as cancer therapeutics in mono-therapy and to augment radiotherapy, however serious adverse effects of early generation Hsp90 inhibitors limited their development. TAS-116 is a novel Hsp90 inhibitor with lower adverse effects than other Hsp90 inhibitors, and here we investigated the radio-sensitizing effects of TAS-116 in low LET X-ray, and high LET carbon ion irradiated human cancer cells and mouse tumor xenografts. TAS-116 decreased cell survival of both X-ray and carbon ion-irradiated human cancer cell lines (HeLa and H1299 cells), and similar to other Hsp90 inhibitors, it did not affect radiosensitivity of non-cancerous human fibroblasts. TAS-116 increased the number of radiation-induced γ-H2AX foci, and delayed the repair of DNA double-strand breaks (DSBs). TAS-116 reduced the expression of proteins that mediate repair of DSBs by homologous recombination (RAD51) and non-homologous end joining (Ku, DNA-PKcs), and suppressed formation of RAD51 foci and phosphorylation/activation of DNA-PKcs. TAS-116 also decreased expression of the cdc25 cell cycle progression marker, markedly increasing G2/M arrest. Combined treatment of mouse tumor xenografts with carbon ions and TAS-116 showed promising delay in tumor growth compared to either individual treatment. These results demonstrate that TAS-116 radio-sensitizes human cancer cells to both X rays and carbon ions by inhibiting the two major DSB repair pathways, and these effects were accompanied by marked cell cycle arrest. The promising results of combination TAS-116 + carbon ion radiation therapy of tumor xenografts justify further exploration of TAS-116 as an adjunct to radiotherapy using low or high LET radiation. PMID:28062703

Implications of a RAD54L polymorphism (2290C/T) in human meningiomas as a risk factor and/or a genetic marker

International Nuclear Information System (INIS)

Leone, Paola E; Mendiola, Marta; Alonso, Javier; Paz-y-Miño, César; Pestaña, Angel

2003-01-01

RAD54L (OMIM 603615, Locus Link 8438) has been proposed as a candidate oncosupressor in tumours bearing a non-random deletion of 1p32, such as breast or colon carcinomas, lymphomas and meningiomas. In a search for RAD54L mutations in 29 menigiomas with allelic deletions in 1p, the only genetic change observed was a silent C/T transition at nucleotide 2290 in exon 18. In this communication the possible association of the 2290C/T polymorphism with the risk of meningiomas was examined. In addition, the usefulness of this polymorphism as a genetic marker within the meningioma consensus deletion region in 1p32 was also verified. The present study comprises 287 blood control samples and 70 meningiomas from Spain and Ecuador. Matched blood samples were only available from Spanish patients. The frequency of the rare allele-T and heterozygotes for the 2290C/T polymorphism in the blood of Spanish meningioma patients and in the Ecuadorian meningioma tumours was higher than in the control population (P < 0.05). Four other rare variants (2290C/G, 2299C/G, 2313G/A, 2344A/G) were found within 50 bp at the 3' end of RAD54L. Frequent loss of heterozygosity for the 2290C/T SNP in meningiomas allowed to further narrow the 1p32 consensus region of deletion in meningiomas to either 2.08 Mbp – within D1S2713 (44.35 Mbp) and RAD54L (46.43 Mbp) – or to 1.47 Mbp – within RAD54L and D1S2134 (47.90 Mbp) – according to recent gene mapping results. The statistical analysis of genotypes at the 2290C/T polymorphism suggest an association between the rare T allele and the development of meningeal tumours. This polymorphism can be used as a genetic marker inside the consensus deletion region at 1p32 in meningiomas

Lymphoid irradiation in intractable rheumatoid arthritis. A double-blind, randomized study comparing 750-rad treatment with 2,000-rad treatment

International Nuclear Information System (INIS)

Hanly, J.G.; Hassan, J.; Moriarty, M.; Barry, C.; Molony, J.; Casey, E.; Whelan, A.; Feighery, C.; Bresnihan, B.

1986-01-01

Twenty patients with intractable rheumatoid arthritis were treated with 750-rad or 2,000-rad lymphoid irradiation in a randomized double-blind comparative study. Over a 12-month followup period, there was a significant improvement in 4 of 7 and 6 of 7 standard parameters of disease activity following treatment with 750 rads and 2,000 rads, respectively. Transient, short-term toxicity was less frequent with the lower dose. In both groups, there was a sustained peripheral blood lymphopenia, a selective depletion of T helper (Leu-3a+) lymphocytes, and reduced in vitro mitogen responses. These changes did not occur, however, in synovial fluid. These results suggest that 750-rad lymphoid irradiation is as effective as, but less toxic than, that with 2,000 rads in the management of patients with intractable rheumatoid arthritis

Mammalian RAD52 Functions in Break-Induced Replication Repair of Collapsed DNA Replication Forks.

Science.gov (United States)

Sotiriou, Sotirios K; Kamileri, Irene; Lugli, Natalia; Evangelou, Konstantinos; Da-Ré, Caterina; Huber, Florian; Padayachy, Laura; Tardy, Sebastien; Nicati, Noemie L; Barriot, Samia; Ochs, Fena; Lukas, Claudia; Lukas, Jiri; Gorgoulis, Vassilis G; Scapozza, Leonardo; Halazonetis, Thanos D

2016-12-15

Human cancers are characterized by the presence of oncogene-induced DNA replication stress (DRS), making them dependent on repair pathways such as break-induced replication (BIR) for damaged DNA replication forks. To better understand BIR, we performed a targeted siRNA screen for genes whose depletion inhibited G1 to S phase progression when oncogenic cyclin E was overexpressed. RAD52, a gene dispensable for normal development in mice, was among the top hits. In cells in which fork collapse was induced by oncogenes or chemicals, the Rad52 protein localized to DRS foci. Depletion of Rad52 by siRNA or knockout of the gene by CRISPR/Cas9 compromised restart of collapsed forks and led to DNA damage in cells experiencing DRS. Furthermore, in cancer-prone, heterozygous APC mutant mice, homozygous deletion of the Rad52 gene suppressed tumor growth and prolonged lifespan. We therefore propose that mammalian RAD52 facilitates repair of collapsed DNA replication forks in cancer cells. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

RAD51C germline mutations in breast and ovarian cancer cases from high-risk families.

Directory of Open Access Journals (Sweden)

Jessica Clague

Full Text Available BRCA1 and BRCA2 are the most well-known breast cancer susceptibility genes. Additional genes involved in DNA repair have been identified as predisposing to breast cancer. One such gene, RAD51C, is essential for homologous recombination repair. Several likely pathogenic RAD51C mutations have been identified in BRCA1- and BRCA2-negative breast and ovarian cancer families. We performed complete sequencing of RAD51C in germline DNA of 286 female breast and/or ovarian cancer cases with a family history of breast and ovarian cancers, who had previously tested negative for mutations in BRCA1 and BRCA2. We screened 133 breast cancer cases, 119 ovarian cancer cases, and 34 with both breast and ovarian cancers. Fifteen DNA sequence variants were identified; including four intronic, one 5' UTR, one promoter, three synonymous, and six non-synonymous variants. None were truncating. The in-silico SIFT and Polyphen programs were used to predict possible pathogenicity of the six non-synonomous variants based on sequence conservation. G153D and T287A were predicted to be likely pathogenic. Two additional variants, A126T and R214C alter amino acids in important domains of the protein such that they could be pathogenic. Two-hybrid screening and immunoblot analyses were performed to assess the functionality of these four non-synonomous variants in yeast. The RAD51C-G153D protein displayed no detectable interaction with either XRCC3 or RAD51B, and RAD51C-R214C displayed significantly decreased interaction with both XRCC3 and RAD51B (p<0.001. Immunoblots of RAD51C-Gal4 activation domain fusion peptides showed protein levels of RAD51C-G153D and RAD51C-R214C that were 50% and 60% of the wild-type, respectively. Based on these data, the RAD51C-G153D variant is likely to be pathogenic, while the RAD51C- R214C variant is hypomorphic of uncertain pathogenicity. These results provide further support that RAD51C is a rare breast and ovarian cancer susceptibility gene.

Functional roles for Rad9 in prostate cancer

International Nuclear Information System (INIS)

Lieberman, H.B.; Broustas, C.G.

2012-01-01

The goal of this work is to understand the mechanistic relationship between high levels of Rad9 protein and prostate cancer. The study is based on several findings suggesting a role for Rad9 in this disease. Rad9 has all the hallmark features of an oncogene or tumor suppressor. It regulates genomic stability, multiple cell cycle checkpoints, apoptosis and DNA repair. In addition, it can transactivate downstream target genes via direct interaction with promoter DNA sequences. We found Rad9 protein levels were very high in prostate cancer cell lines. Furthermore, we examined 52 primary normal prostate and 339 prostate cancer specimens for Rad9 protein by immunohistochemical staining. Statistical significance for Rad9 positive staining versus cancer, and stain intensity versus Stage were tested. We get a p-value of <0.001 when comparing percentage positive by cancer Stage, or stain intensity by cancer Stage. Based on these data, we sought to define the nature of the relationship between Rad9 and prostate cancer. We demonstrate that Rad9 acts as an oncogene in prostate cancer by playing a critical role in tumor formation in a mouse xenograph model. We also show that Rad9 is important for cellular phenotypes essential for metastasis, including tumor cell migration, invasion and resistance to programmed cell death after detachment from extracellular matrix. Therefore, Rad9 is critical for several aspects of prostate tumor progression, and could serve as a novel target for anti-cancer therapy

RadShield: semiautomated shielding design using a floor plan driven graphical user interface.

Science.gov (United States)

DeLorenzo, Matthew C; Wu, Dee H; Yang, Kai; Rutel, Isaac B

2016-09-08

The purpose of this study was to introduce and describe the development of RadShield, a Java-based graphical user interface (GUI), which provides a base design that uniquely performs thorough, spatially distributed calculations at many points and reports the maximum air-kerma rate and barrier thickness for each barrier pursuant to NCRP Report 147 methodology. Semiautomated shielding design calculations are validated by two approaches: a geometry-based approach and a manual approach. A series of geometry-based equations were derived giv-ing the maximum air-kerma rate magnitude and location through a first derivative root finding approach. The second approach consisted of comparing RadShield results with those found by manual shielding design by an American Board of Radiology (ABR)-certified medical physicist for two clinical room situations: two adjacent catheterization labs, and a radiographic and fluoroscopic (R&F) exam room. RadShield's efficacy in finding the maximum air-kerma rate was compared against the geometry-based approach and the overall shielding recommendations by RadShield were compared against the medical physicist's shielding results. Percentage errors between the geometry-based approach and RadShield's approach in finding the magnitude and location of the maximum air-kerma rate was within 0.00124% and 14 mm. RadShield's barrier thickness calculations were found to be within 0.156 mm lead (Pb) and 0.150 mm lead (Pb) for the adjacent catheteriza-tion labs and R&F room examples, respectively. However, within the R&F room example, differences in locating the most sensitive calculation point on the floor plan for one of the barriers was not considered in the medical physicist's calculation and was revealed by the RadShield calculations. RadShield is shown to accurately find the maximum values of air-kerma rate and barrier thickness using NCRP Report 147 methodology. Visual inspection alone of the 2D X-ray exam distribution by a medical physicist may not

RadVel: The Radial Velocity Modeling Toolkit

Science.gov (United States)

Fulton, Benjamin J.; Petigura, Erik A.; Blunt, Sarah; Sinukoff, Evan

2018-04-01

RadVel is an open-source Python package for modeling Keplerian orbits in radial velocity (RV) timeseries. RadVel provides a convenient framework to fit RVs using maximum a posteriori optimization and to compute robust confidence intervals by sampling the posterior probability density via Markov Chain Monte Carlo (MCMC). RadVel allows users to float or fix parameters, impose priors, and perform Bayesian model comparison. We have implemented real-time MCMC convergence tests to ensure adequate sampling of the posterior. RadVel can output a number of publication-quality plots and tables. Users may interface with RadVel through a convenient command-line interface or directly from Python. The code is object-oriented and thus naturally extensible. We encourage contributions from the community. Documentation is available at http://radvel.readthedocs.io.

Transcriptional differences between smokers and non-smokers and variance by obesity as a risk factor for human sensitivity to environmental exposures.

Science.gov (United States)

Nikodemova, Maria; Yee, Jeremiah; Carney, Patrick R; Bradfield, Christopher A; Malecki, Kristen Mc

2018-04-01

Obesity has been shown to alter response to air pollution and smoking but underlying biological mechanisms are largely unknown and few studies have explored mechanisms by which obesity increases human sensitivity to environmental exposures. Overall study goals were to investigate whole blood gene expression in smokers and non-smokers to examine associations between cigarette smoke and changes in gene expression by obesity status and test for effect modification. Relative fold-change in mRNA expression levels of 84 genes were analyzed using a Toxicity and Stress PCR array among 50 21-54 year old adults. Data on smoking status was confirmed using urinary cotinine levels. Adjusted models included age, gender, white blood cell count and body-mass index. Models comparing gene expression of smokers vs. non-smokers identified six differentially expressed genes associated with smoking after adjustments for covariates. Obesity was associated with 29 genes differentially expressed compared to non-obese. We also identified 9 genes with significant smoking/obesity interactions influencing mRNA levels in adjusted models comparing expression between smokers vs non-smokers for four DNA damage related genes (GADD45A, DDB2, RAD51 and P53), two oxidative stress genes (FTH1, TXN), two hypoxia response genes (BN1P3lL, ARNT), and one gene associated with unfolded protein response (ATF6B). Findings suggest that obesity alters human sensitivity to smoke exposures through several biological pathways by modifying gene expression. Additional studies are needed to fully understand the clinical impact of these effects, but risk assessments should consider underlying phenotypes, such as obesity, that may modulate sensitivity of vulnerable populations to environmental exposures. Copyright © 2018 Elsevier Ltd. All rights reserved.

Icotinib hydrochloride enhances chemo- and radiosensitivity by inhibiting EGFR signaling and attenuating RAD51 expression and function in Hela S3 cells

Directory of Open Access Journals (Sweden)

Wang X

2018-03-01

Full Text Available Xuanxuan Wang, Yanjun Gu, Hai Liu, Liming Shi, Xiaonan Sun Department of Radiation Oncology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China Background: Radiotherapy and cisplatin-based chemotherapy are currently considered as standard treatments employed for advanced cervical cancer (CC. However, patients with local recurrence or distant metastasis continue to have poor outcomes. EGFR overexpression correlated with chemo/radioresistance, and disease failure has been well proved in the previous studies. Hence, the aim of this study was to explore the therapeutic efficacy and underlying mechanism of the sensitization to radiation or cisplatin of icotinib hydrochloride (IH, a high-selective EGFR tyrosine kinase inhibitor (TKI, in the Hela S3 human CC cell line.Methods: Cell proliferation was measured with cell counting kit-8 (CCK-8 assay. Flow cytometry analysis was performed to examine cell cycle distribution and apoptosis. The phosphorylation of EGFR and its downstream signaling molecules were measured by Western blot analysis. γ-H2AX foci and RAD51 foci in the cellular nucleus were visualized using immunofluoresence staining. Expression levels of RAD51 in the whole cells and subceullar fractions were detected to demonstrate the impact of IH on DNA repair. Results: IH can significantly inhibit cell proliferation, redistribute cell cycle, enhance apoptosis and impair DNA damage response of Hela S3 cells following radiation or cisplatin treatment through suppressing the activation of the EGFR signaling pathway and attenuating the expression and function of homologous recombination (HR protein RAD51.Conclusion: This study suggests that IH is a potential sensitizer in radiotherapy and cisplatin-based chemotherapy for CC and RAD51 may serve as a prognosis biomarker for this combination treatment. Keywords: icotinib hydrochloride, cervical cancer, EGFR, radiotherapy, chemotherapy

Long Term RadNet Quality Data

Data.gov (United States)

U.S. Environmental Protection Agency — This RadNet Quality Data Asset includes all data since initiation and when ERAMS was expanded to become RadNet, name changed to reflect new mission. This includes...

The recombination protein RAD52 cooperates with the excision repair protein OGG1 for the repair of oxidative lesions in mammalian cells

DEFF Research Database (Denmark)

de Souza-Pinto, Nadja C; Maynard, Scott; Hashiguchi, Kazunari

2009-01-01

number of protein interactions have been identified for OGG1, while very few appear to have functional consequences. We report here that OGG1 interacts with the recombination protein RAD52 in vitro and in vivo. This interaction has reciprocal functional consequences as OGG1 inhibits RAD52 catalytic...... knockdown, and mouse cells lacking the protein via gene knockout showed increased sensitivity to oxidative stress. Moreover, cells depleted of RAD52 show higher accumulation of oxidized bases in their genome than cells with normal levels of RAD52. Our results indicate that RAD52 cooperates with OGG1...... to repair oxidative DNA damage and enhances the cellular resistance to oxidative stress. Our observations suggest a coordinated action between these proteins that may be relevant when oxidative lesions positioned close to strand breaks impose a hindrance to RAD52 catalytic activities....

Tomosynthesis in the Diagnostic Setting: Changing Rates of BI-RADS Final Assessment over Time.

Science.gov (United States)

Raghu, Madhavi; Durand, Melissa A; Andrejeva, Liva; Goehler, Alexander; Michalski, Mark H; Geisel, Jaime L; Hooley, Regina J; Horvath, Laura J; Butler, Reni; Forman, Howard P; Philpotts, Liane E

2016-10-01

Purpose To evaluate the effect of tomosynthesis in diagnostic mammography on the Breast Imaging Reporting and Data System (BI-RADS) final assessment categories over time. Materials and Methods This retrospective study was approved by the institutional review board. The authors reviewed all diagnostic mammograms obtained during a 12-month interval before (two-dimensional [2D] mammography [June 2, 2010, to June 1, 2011]) and for 3 consecutive years after (tomosynthesis year 1 [2012], tomosynthesis year 2 [2013], and tomosynthesis year 3 [2014]) the implementation of tomosynthesis. The requirement to obtain informed consent was waived. The rates of BI-RADS final assessment categories 1-5 were compared between the 2D and tomosynthesis groups. The positive predictive values after biopsy (PPV3) for BI-RADS category 4 and 5 cases were compared. The mammographic features (masses, architectural distortions, calcifications, focal asymmetries) of lesions categorized as probably benign (BI-RADS category 3) and those for which biopsy was recommended (BI-RADS category 4 or 5) were reviewed. The χ(2) test was used to compare the rates of BI-RADS final assessment categories 1-5 between the two groups, and multivariate logistic regression analysis was performed to compare all diagnostic studies categorized as BI-RADS 3-5. Results There was an increase in the percentage of cases reported as negative or benign (BI-RADS category 1 or 2) with tomosynthesis (58.7% with 2D mammography vs 75.8% with tomosynthesis at year 3, P tomosynthesis at year 3, P tomosynthesis (8.0% with 2D mammography vs 7.8% with tomosynthesis at year 3, P = .2), there was a significant increase in the PPV3 (29.6% vs 50%, respectively; P tomosynthesis use. Conclusion Tomosynthesis in the diagnostic setting resulted in progressive shifts in the BI-RADS final assessment categories over time, with a significant increase in the proportion of studies classified as normal, a continued decrease in the rate of studies

Stereotactic vacuum core biopsy of clustered microcalcifications classified as BI-RADS{sup TM} type 3; Stereotaktische Vakuumstanzbiopsie zur Abklaerung von gruppiertem Mikrokalk der Kategorie BI-RADS{sup TM} 3

Energy Technology Data Exchange (ETDEWEB)

Obenauer, S.; Fischer, U.; Baum, F.; Dammert, S.; Grabbe, E. [Goettingen Univ. (Germany). Abt. fuer Roentgendiagnostik; Fuezesi, L. [Goettingen Univ. (Germany). Zentrum Pathologie

2001-08-01

Purpose: Evaluation of stereotactic vacuum core biopsy of clustered microcalcifications categorized as BI-RADS{sup TM} 3. Material and methods: 86 patients with microcalcification BI-RADS{sup TM} 3 (probably benign, <3% malignant) underwent a stereotactic vacuum core biopsy (Mammotome, Fa. Ethicon Endo-Surgery Breast Care) using a digital stereotactic unit (Mammotest, Fa. Fischer Imaging). The removal of the calcifications was judged by two radiologists in consensus and classified as complete (100%), major (55-99%) or incomplete (<50%). Results: 4/86 patients could not be evaluated by vacuum core biopsy due to the localization of the microcalcifications close to the skin or lack of detection. In 40/82 cases a complete, in 38/82 a major, and in 4/82 an incomplete removal was achieved. Histology revealed 67 cases of fibrocystic changes, 4 papillomas, 4 fibroadenomas, 4 cases of atypical ductal hyperplasia (ADH), and 3 ductal carcinomas in situ (DCIS), one of these with a minimal-invasive tumor component. Patients with ADH were advised to undergo surgical biopsy. Histology revealed complete removal. 7 patients had complications or side-effects. Conclusions: Percutaneous vacuum core biopsy is a reliable minimal-invasive diagnostic method to come to the final diagnosis in patients with clustered microcalcifications categorized BI-RADS{sup TM} 3. However, if malignancy is proven (about 4% of our cases) an open biopsy is necessary. (orig.) [German] Zielsetzung: Evaluation der stereotaktischen Vakuumstanzbiopsie bei gruppierten Mikrokalzifikationen vom Typ BI-RADS{sup TM}3. Material und Methodik: Gruppiert angeordneter Mikrokalk der Kategorie BI-RADS{sup TM} 3 (wahrscheinlich benigne, <3% maligne) wurde bei 86 Patientinnen mit einer stereotaktischen Vakuumstanzbiopsie (Mammotome{sup circledR}, Fa. Ethicon Endo-Surgery Breast Care) an einem digitalen Stereotaxietisch (Mammotest, Fa. Fischer Imaging) abgeklaert. Das Ausmass der bioptisch entfernten Kalizifkationen wurde von

DMC1 functions in a Saccharomyces cerevisiae meiotic pathway that is largely independent of the RAD51 pathway

International Nuclear Information System (INIS)

Dresser, M.E.; Ewing, D.J.; Conrad, M.N.; Dominguez, A.M.; Barstead, R.; Jiang, H.; Kodadek, T.

1997-01-01

Meiotic recombination in the yeast Saccharomyces cerevisiae requires two similar recA-like proteins, Dmc1p and Rad51p. A screen for dominant meiotic mutants provided DMC1-G126D, a dominant allele mutated in the conserved ATP-binding site (specifically, the A-loop motif) that confers a null phenotype. A recessive null allele, dmc1-K69E, was isolated as an intragenic suppressor of DMC1-G126D. Dmc1-K69Ep, unlike Dmc1p, does not interact homotypically in a two-hybrid assay, although it does interact with other fusion proteins identified by two-hybrid screen with Dmc1p. Dmc1p, unlike Rad51p, does not interact in the two-hybrid assay with Rad52p or Rad54p. However, Dmc1p does interact with Tid1p, a Rad54p homologue, with Tid4p, a Rad16p homologue, and with other fusion proteins that do not interact with Rad51p, suggesting that Dmc1p and Rad51p function in separate, though possibly overlapping, recombinational repair complexes. Epistasis analysis suggests that DMC1 and RAD51 function in separate pathways responsible for meiotic recombination. Taken together, our results are consistent with a requirement for DMC1 for meiosis-specific entry of DNA double-strand break ends into chromatin. Interestingly, the pattern on CHEF gels of chromosome fragments that result from meiotic DNA double-strand break formation is different in DMC1 mutant strains from that seen in rad50S strains. (author)

RAD9 deficiency enhances radiation induced bystander DNA damage and transcriptomal response

International Nuclear Information System (INIS)

Ghandhi, Shanaz A; Ponnaiya, Brian; Panigrahi, Sunil K; Hopkins, Kevin M; Cui, Qingping; Hei, Tom K; Amundson, Sally A; Lieberman, Howard B

2014-01-01

Radiation induced bystander effects are an important component of the overall response of cells to irradiation and are associated with human health risks. The mechanism responsible includes intra-cellular and inter-cellular signaling by which the bystander response is propagated. However, details of the signaling mechanism are not well defined. We measured the bystander response of Mrad9 +/+ and Mrad9 −/− mouse embryonic stem cells, as well as human H1299 cells with inherent or RNA interference-mediated reduced RAD9 levels after exposure to 1 Gy α particles, by scoring chromosomal aberrations and micronuclei formation, respectively. In addition, we used microarray gene expression analyses to profile the transcriptome of directly irradiated and bystander H1299 cells. We demonstrated that Mrad9 null enhances chromatid aberration frequency induced by radiation in bystander mouse embryonic stem cells. In addition, we found that H1299 cells with reduced RAD9 protein levels showed a higher frequency of radiation induced bystander micronuclei formation, compared with parental cells containing inherent levels of RAD9. The enhanced bystander response in human cells was associated with a unique transcriptomic profile. In unirradiated cells, RAD9 reduction broadly affected stress response pathways at the mRNA level; there was reduction in transcript levels corresponding to genes encoding multiple members of the UVA-MAPK and p38MAPK families, such as STAT1 and PARP1, suggesting that these signaling mechanisms may not function optimally when RAD9 is reduced. Using network analysis, we found that differential activation of the SP1 and NUPR1 transcriptional regulators was predicted in directly irradiated and bystander H1299 cells. Transcription factor prediction analysis also implied that HIF1α (Hypoxia induced factor 1 alpha) activation by protein stabilization in irradiated cells could be a negative predictor of the bystander response, suggesting that local hypoxic stress

The C-terminal region of Rad52 is essential for Rad52 nuclear and nucleolar localization, and accumulation at DNA damage sites immediately after irradiation

Energy Technology Data Exchange (ETDEWEB)

Koike, Manabu, E-mail: m_koike@nirs.go.jp [DNA Repair Gene Res., National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555 (Japan); Yutoku, Yasutomo [DNA Repair Gene Res., National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555 (Japan); Graduate School of Science, Chiba University, Yayoicho, Inage-ku, Chiba 263-8522 (Japan); Koike, Aki [DNA Repair Gene Res., National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555 (Japan)

2013-05-31

Highlights: •Rad52 might play a key role in the repair of DSB immediately after irradiation. •EYFP-Rad52 accumulates rapidly at DSB sites and colocalizes with Ku80. •Accumulation of Rad52 at DSB sites is independent of the core NHEJ factors. •Localization and recruitment of Rad52 to DSB sites are dependent on the Rad52 CTR. •Basic amino acids in Rad52 CTR are highly conserved among vertebrate species. -- Abstract: Rad52 plays essential roles in homologous recombination (HR) and repair of DNA double-strand breaks (DSBs) in Saccharomyces cerevisiae. However, in vertebrates, knockouts of the Rad52 gene show no hypersensitivity to agents that induce DSBs. Rad52 localizes in the nucleus and forms foci at a late stage following irradiation. Ku70 and Ku80, which play an essential role in nonhomologous DNA-end-joining (NHEJ), are essential for the accumulation of other core NHEJ factors, e.g., XRCC4, and a HR-related factor, e.g., BRCA1. Here, we show that the subcellular localization of EYFP-Rad52(1–418) changes dynamically during the cell cycle. In addition, EYFP-Rad52(1–418) accumulates rapidly at microirradiated sites and colocalizes with the DSB sensor protein Ku80. Moreover, the accumulation of EYFP-Rad52(1–418) at DSB sites is independent of the core NHEJ factors, i.e., Ku80 and XRCC4. Furthermore, we observed that EYFP-Rad52(1–418) localizes in nucleoli in CHO-K1 cells and XRCC4-deficient cells, but not in Ku80-deficient cells. We also found that Rad52 nuclear localization, nucleolar localization, and accumulation at DSB sites are dependent on eight amino acids (411–418) at the end of the C-terminal region of Rad52 (Rad52 CTR). Furthermore, basic amino acids on Rad52 CTR are highly conserved among mammalian, avian, and fish homologues, suggesting that Rad52 CTR is important for the regulation and function of Rad52 in vertebrates. These findings also suggest that the mechanism underlying the regulation of subcellular localization of Rad52 is

The role of the Mre11–Rad50–Nbs1 complex in double-strand break repair—facts and myths

International Nuclear Information System (INIS)

Takeda, Shunichi; Hoa, Nguyen Ngoc; Sasanuma, Hiroyuki

2016-01-01

Homologous recombination (HR) initiates double-strand break (DSB) repair by digesting 5′-termini at DSBs, the biochemical reaction called DSB resection, during which DSBs are processed by nucleases to generate 3′ single-strand DNA. Rad51 recombinase polymerizes along resected DNA, and the resulting Rad51–DNA complex undergoes homology search. Although DSB resection by the Mre11 nuclease plays a critical role in HR in Saccharomyces cerevisiae, it remains elusive whether DSB resection by Mre11 significantly contributes to HR-dependent DSB repair in mammalian cells. Depletion of Mre11 decreases the efficiency of DSB resection only by 2- to 3-fold in mammalian cells. We show that although Mre11 is required for efficient HR-dependent repair of ionizing-radiation–induced DSBs, Mre11 is largely dispensable for DSB resection in both chicken DT40 and human TK6 B cell lines. Moreover, a 2- to 3-fold decrease in DSB resection has virtually no impact on the efficiency of HR. Thus, although a large number of researchers have reported the vital role of Mre11-mediated DSB resection in HR, the role may not explain the very severe defect in HR in Mre11-deficient cells, including their lethality. We here show experimental evidence for the additional roles of Mre11 in (i) elimination of chemical adducts from DSB ends for subsequent DSB repair, and (ii) maintaining HR intermediates for their proper resolution

The PCNA interaction protein box sequence in Rad54 is an integral part of its ATPase domain and is required for efficient DNA repair and recombination

DEFF Research Database (Denmark)

Burgess, Rebecca C; Sebesta, Marek; Sisakova, Alexandra

2013-01-01

Rad54 is an ATP-driven translocase involved in the genome maintenance pathway of homologous recombination (HR). Although its activity has been implicated in several steps of HR, its exact role(s) at each step are still not fully understood. We have identified a new interaction between Rad54...... and the replicative DNA clamp, proliferating cell nuclear antigen (PCNA). This interaction was only mildly weakened by the mutation of two key hydrophobic residues in the highly-conserved PCNA interaction motif (PIP-box) of Rad54 (Rad54-AA). Intriguingly, the rad54-AA mutant cells displayed sensitivity to DNA damage...

Overexpressed of RAD51 suppresses recombination defects: a possible mechanism to reverse genomic instability

Energy Technology Data Exchange (ETDEWEB)

Schild, David; Wiese, Claudia

2009-10-15

RAD51, a key protein in the homologous recombinational DNA repair (HRR) pathway, is the major strand-transferase required for mitotic recombination. An important early step in HRR is the formation of single-stranded DNA (ss-DNA) coated by RPA (a ss-DNA binding protein). Displacement of RPA by RAD51 is highly regulated and facilitated by a number of different proteins known as the 'recombination mediators'. To assist these recombination mediators, a second group of proteins also is required and we are defining these proteins here as 'recombination co-mediators'. Defects in either recombination mediators or comediators, including BRCA1 and BRCA2, lead to impaired HRR that can genetically be complemented for (i.e. suppressed) by overexpression of RAD51. Defects in HRR have long been known to contribute to genomic instability leading to tumor development. Since genomic instability also slows cell growth, precancerous cells presumably require genomic restabilization to gain a growth advantage. RAD51 is overexpressed in many tumors, and therefore, we hypothesize that the complementing ability of elevated levels of RAD51 in tumors with initial HRR defects limits genomic instability during carcinogenic progression. Of particular interest, this model may also help explain the high frequency of TP53 mutations in human cancers, since wild-type p53 represses RAD51.

Dynamic changes in Rad51 distribution on chromatin during meiosis in male and female vertebrates.

Science.gov (United States)

Ashley, T; Plug, A W; Xu, J; Solari, A J; Reddy, G; Golub, E I; Ward, D C

1995-10-01

Antibodies against human Rad51 protein were used to examine the distribution of Rad51 on meiotic chromatin in mouse spermatocytes and oocytes as well as chicken oocytes during sequential stages of meiosis. We observed the following dynamic changes in distribution of Rad51 during meiosis: (1) in early leptotene nuclei there are multiple, apparently randomly distributed, foci that by late leptonema become organized into tracks of foci. (2) These foci persist into zygonema, but most foci are now localized on Rad51-positive axes that correspond to lateral elements of the synaptonemal complex. As homologs synapse foci from homologous axes fuse. The distribution and involvement of Rad51 foci as contact points between homologs suggest that they may be components to early recombination nodules. (3) As pachynema progresses the number of foci drops dramatically; the temporal occurrence (mice) and physical and numerical distribution of foci on axes (chickens) suggest that they may be a component of late recombination nodules. (4) In early pachynema there are numerous Rad51 foci on the single axis of the X (mouse spermatocytes) or the Z (chicken oocytes) chromosomes that neither pair, nor recombine. (5) In late pachynema in mouse spermatocytes, but not oocytes, the Rad51 signal is preferentially enhanced at both ends of all the bivalents. As bivalents in spermatocytes, but not oocytes, begin to desynapse at diplonema they are often held together at these Rad51-positive termini. These observations parallel observations that recombination rates are exceptionally high near chromosome ends in male but not female eutherian mammals. (6) From diakinesis through metaphase I, Rad51 protein is detected as low-intensity fluorescent doublets that localize with CREST-specific antigens (kinetochores), suggesting that Rad51 participates, at least as a structural component of the materials involved, in sister kinetochore cohesiveness. Finally, the changes in Rad51 distribution during meiosis

Performance of the RAD-57 pulse CO-oximeter compared with standard laboratory carboxyhemoglobin measurement.

Science.gov (United States)

Touger, Michael; Birnbaum, Adrienne; Wang, Jessica; Chou, Katherine; Pearson, Darion; Bijur, Polly

2010-10-01

We assess agreement between carboxyhemoglobin levels measured by the Rad-57 signal extraction pulse CO-oximeter (RAD), a Food and Drug Administration-approved device for noninvasive bedside measurement, and standard laboratory arterial or venous measurement in a sample of emergency department (ED) patients with suspected carbon monoxide poisoning. The study was a cross-sectional cohort design using a convenience sample of adult and pediatric ED patients in a Level I trauma, burn, and hyperbaric oxygen referral center. Measurement of RAD carboxyhemoglobin was performed simultaneously with blood sampling for laboratory determination of carboxyhemoglobin level. The difference between the measures for each patient was calculated as laboratory carboxyhemoglobin minus carboxyhemoglobin from the carbon monoxide oximeter. The limits of agreement from a Bland-Altman analysis are calculated as the mean of the differences between methods ±1.96 SDs above and below the mean. Median laboratory percentage carboxyhemoglobin level was 2.3% (interquartile range 1 to 8.5; range 0% to 38%). The mean difference between laboratory carboxyhemoglobin values and RAD values was 1.4% carboxyhemoglobin (95% confidence interval [CI] 0.2% to 2.6%). The limits of agreement of differences of measurement made with the 2 devices were -11.6% and 14.4% carboxyhemoglobin. This range exceeded the value of ±5% carboxyhemoglobin defined a priori as clinically acceptable. RAD correctly identified 11 of 23 patients with laboratory values greater than 15% carboxyhemoglobin (sensitivity 48%; 95% CI 27% to 69%). There was one case of a laboratory carboxyhemoglobin level less than 15%, in which the RAD device gave a result greater than 15% (specificity of RAD 96/97=99%; 95% CI 94% to 100%). In the range of carboxyhemoglobin values measured in this sample, the level of agreement observed suggests RAD measurement may not be used interchangeably with standard laboratory measurement. Copyright © 2010 American

Cellular Ubc2/Rad6 E2 ubiquitin-conjugating enzyme facilitates tombusvirus replication in yeast and plants

International Nuclear Information System (INIS)

Imura, Yoshiyuki; Molho, Melissa; Chuang, Chingkai; Nagy, Peter D.

2015-01-01

Mono- and multi-ubiquitination alters the functions and subcellular localization of many cellular and viral proteins. Viruses can co-opt or actively manipulate the ubiquitin network to support viral processes or suppress innate immunity. Using yeast (Saccharomyces cerevisiae) model host, we show that the yeast Rad6p (radiation sensitive 6) E2 ubiquitin-conjugating enzyme and its plant ortholog, AtUbc2, interact with two tombusviral replication proteins and these E2 ubiquitin-conjugating enzymes could be co-purified with the tombusvirus replicase. We demonstrate that TBSV RNA replication and the mono- and bi-ubiquitination level of p33 is decreased in rad6Δ yeast. However, plasmid-based expression of AtUbc2p could complement both defects in rad6Δ yeast. Knockdown of UBC2 expression in plants also decreases tombusvirus accumulation and reduces symptom severity, suggesting that Ubc2p is critical for virus replication in plants. We provide evidence that Rad6p is involved in promoting the subversion of Vps23p and Vps4p ESCRT proteins for viral replicase complex assembly. - Highlights: • Tombusvirus p33 replication protein interacts with cellular RAD6/Ubc2 E2 enzymes. • Deletion of RAD6 reduces tombusvirus replication in yeast. • Silencing of UBC2 in plants inhibits tombusvirus replication. • Mono- and bi-ubiquitination of p33 replication protein in yeast and in vitro. • Rad6p promotes the recruitment of cellular ESCRT proteins into the tombusvirus replicase

Cellular Ubc2/Rad6 E2 ubiquitin-conjugating enzyme facilitates tombusvirus replication in yeast and plants

Energy Technology Data Exchange (ETDEWEB)

Imura, Yoshiyuki, E-mail: imura@brs.nihon-u.ac.jp; Molho, Melissa; Chuang, Chingkai; Nagy, Peter D., E-mail: pdnagy2@uky.edu

2015-10-15

Mono- and multi-ubiquitination alters the functions and subcellular localization of many cellular and viral proteins. Viruses can co-opt or actively manipulate the ubiquitin network to support viral processes or suppress innate immunity. Using yeast (Saccharomyces cerevisiae) model host, we show that the yeast Rad6p (radiation sensitive 6) E2 ubiquitin-conjugating enzyme and its plant ortholog, AtUbc2, interact with two tombusviral replication proteins and these E2 ubiquitin-conjugating enzymes could be co-purified with the tombusvirus replicase. We demonstrate that TBSV RNA replication and the mono- and bi-ubiquitination level of p33 is decreased in rad6Δ yeast. However, plasmid-based expression of AtUbc2p could complement both defects in rad6Δ yeast. Knockdown of UBC2 expression in plants also decreases tombusvirus accumulation and reduces symptom severity, suggesting that Ubc2p is critical for virus replication in plants. We provide evidence that Rad6p is involved in promoting the subversion of Vps23p and Vps4p ESCRT proteins for viral replicase complex assembly. - Highlights: • Tombusvirus p33 replication protein interacts with cellular RAD6/Ubc2 E2 enzymes. • Deletion of RAD6 reduces tombusvirus replication in yeast. • Silencing of UBC2 in plants inhibits tombusvirus replication. • Mono- and bi-ubiquitination of p33 replication protein in yeast and in vitro. • Rad6p promotes the recruitment of cellular ESCRT proteins into the tombusvirus replicase.

Rad51 expression levels predict synthetic lethality and metastatic potential in high grade breast cancers

International Nuclear Information System (INIS)

Wiegmans, A.P.; Al-Ejeh, F.; Khanna, K.K.

2012-01-01

Among women with breast cancer, 30-40% will develop metastatic disease and only achieve an overall survival of less than 5 years. Despite new-targeted therapy, breast tumors that harbour similar histology or molecular phenotype differ in their response to treatment. To uncover potential new therapeutic targets and improve outcome, we performed data mining of cancer micro array databases. We found that high expression of the homologous recombination protein, RAD51, was significantly associated with high-grade breast cancer, aggressive subtypes and increased risk of metastasis. We confirmed using immunohistochemistry that RAD5 1 was highly expressed in metastatic tumours and high-grade triple negative, HER2+ and luminal-B tumours. This provided a rationale for targeting RAD5 1 in high-grade, therapy-resistant breast cancers. Here, we report for the first time preclinical evaluation of RAD5 1 as a therapeutic target. We found that, in-vitro high RAD5 expressing cell lines were resistant to PARP inhibitor while knockdown reversed this resistance. In-vivo, knockdown of RAD5 1 inhibited metastatic progression using a syngeneic breast cancer model and the seeding of human xenografts to distant sites, including brain and lung. Concurrent PARP inhibition reduced primary tumor growth and delayed metastasis supporting synthetic lethality in-vivo. Together these insights provide pre-clinical data demonstrating RAD5 1 as a new biomarker and potential therapeutic target against aggressive metastatic breast cancer. (author)

RadWorks Project

Data.gov (United States)

National Aeronautics and Space Administration — The RadWorks project's overarching objective is the maturation and demonstration of affordable, enabling solutions to the radiation-related challenges presented to...

Scintillation hodoscope with 50x50 cm2 sensitive area on the basis of hodoscopic FEhU's

International Nuclear Information System (INIS)

Borog, V.V.; Dronov, V.V.; Vasil'chenko, V.G.; Rykalin, V.I.; Demekhin, A.B.

1986-01-01

The problems of choosing optimal constructions of sensitive elements of large hodoscopes on the base of hodoscopic photamultipliers are considered. The obtained results of numerical calculations for choosing optimal constructions and materials of hodoscope elements are confirmed by the results of the performed measurements. The measured spatial resolution of one of constructions of scintillation hodoscopes with the 50x50x2 cm 3 sensitive volume using two hodoscopic photomultipliers constituted ±3 mm

HiRadMat: materials under scrutiny

CERN Multimedia

Anaïs Schaeffer

2011-01-01

CERN's new facility, HiRadMat (High Radiation to Materials), which is designed to test materials for the world's future particle accelerators, should be operational and welcoming its first experiments by the end of the year.   The HiRadMat facility, located in the TNC tunnel. The materials used in the LHC and its experiments are exposed to very high-energy particles. The LHC machine experts obviously didn't wait for the first collisions in the world's most powerful accelerator to put the materials through their paces - the equipment was validated following a series of stringent tests. And these tests will get even tougher now, with the arrival of HiRadMat. The tunnel that formerly housed the West Area Neutrino Facility (WANF) has been completely revamped to make way for CERN's latest facility, HiRadMat. Supported by the Radioprotection service, a team from the Engineering (EN) Department handled the dismantling operations from October 2009 to December 2010. "We could only work on disman...

Histone Deacetylase Inhibitor Induced Radiation Sensitization Effects on Human Cancer Cells after Photon and Hadron Radiation Exposure

Directory of Open Access Journals (Sweden)

Ariungerel Gerelchuluun

2018-02-01

Full Text Available Suberoylanilide hydroxamic acid (SAHA is a histone deacetylase inhibitor, which has been widely utilized throughout the cancer research field. SAHA-induced radiosensitization in normal human fibroblasts AG1522 and lung carcinoma cells A549 were evaluated with a combination of γ-rays, proton, and carbon ion exposure. Growth delay was observed in both cell lines during SAHA treatment; 2 μM SAHA treatment decreased clonogenicity and induced cell cycle block in G1 phase but 0.2 μM SAHA treatment did not show either of them. Low LET (Linear Energy Transfer irradiated A549 cells showed radiosensitization effects on cell killing in cycling and G1 phase with 0.2 or 2 μM SAHA pretreatment. In contrast, minimal sensitization was observed in normal human cells after low and high LET radiation exposure. The potentially lethal damage repair was not affected by SAHA treatment. SAHA treatment reduced the rate of γ-H2AX foci disappearance and suppressed RAD51 and RPA (Replication Protein A focus formation. Suppression of DNA double strand break repair by SAHA did not result in the differences of SAHA-induced radiosensitization between human cancer cells and normal cells. In conclusion, our results suggest SAHA treatment will sensitize cancer cells to low and high LET radiation with minimum effects to normal cells.

The gene dosage effect of the rad52 mutation on X-ray survival curves of tetraploid yeast strains

International Nuclear Information System (INIS)

Ho, K.S.Y.

1975-01-01

The mutation rad52 in the yeast Saccharomyces cerevisiae confers sensitivity to X-rays. The gene dosage effect of this mutation on X-ray survival curves of tetraploid yeast strains is shown. With increasing number of rad52 alleles, both a decrease in the survival for a given dose and a decrease in the survival curve shoulder width are observed. The generation of such a family of survival curves using three different mathematical models is discussed

A Rad53 independent function of Rad9 becomes crucial for genome maintenance in the absence of the Recq helicase Sgs1.

Directory of Open Access Journals (Sweden)

Ida Nielsen

Full Text Available The conserved family of RecQ DNA helicases consists of caretaker tumour suppressors, that defend genome integrity by acting on several pathways of DNA repair that maintain genome stability. In budding yeast, Sgs1 is the sole RecQ helicase and it has been implicated in checkpoint responses, replisome stability and dissolution of double Holliday junctions during homologous recombination. In this study we investigate a possible genetic interaction between SGS1 and RAD9 in the cellular response to methyl methane sulphonate (MMS induced damage and compare this with the genetic interaction between SGS1 and RAD24. The Rad9 protein, an adaptor for effector kinase activation, plays well-characterized roles in the DNA damage checkpoint response, whereas Rad24 is characterized as a sensor protein also in the DNA damage checkpoint response. Here we unveil novel insights into the cellular response to MMS-induced damage. Specifically, we show a strong synergistic functionality between SGS1 and RAD9 for recovery from MMS induced damage and for suppression of gross chromosomal rearrangements, which is not the case for SGS1 and RAD24. Intriguingly, it is a Rad53 independent function of Rad9, which becomes crucial for genome maintenance in the absence of Sgs1. Despite this, our dissection of the MMS checkpoint response reveals parallel, but unequal pathways for Rad53 activation and highlights significant differences between MMS- and hydroxyurea (HU-induced checkpoint responses with relation to the requirement of the Sgs1 interacting partner Topoisomerase III (Top3. Thus, whereas earlier studies have documented a Top3-independent role of Sgs1 for an HU-induced checkpoint response, we show here that upon MMS treatment, Sgs1 and Top3 together define a minor but parallel pathway to that of Rad9.

Wallac automatic alarm dosimeter type RAD21

International Nuclear Information System (INIS)

Burgess, P. H.; Iles, W.J.

1980-02-01

The Automatic Alarm Dosimeter type RAD 21 is a batterypowered personal dosemeter and exposure rate alarm monitor, designed to be worn on the body, covering an exposure range from 0.1 to 999.9 mR and has an audible alarm which can be pre-set over the range 1 mR h -1 to 250 mR h -1 . The instrument is designed to measure x- and γ radiation over the energy range 50 keV to 3 MeV. The facilities and controls, the radiation, electrical, environmental and mechanical characteristics, and the manual, have been evaluated. (U.K.)

RadNet Air Quality (Fixed Station) Data

Data.gov (United States)

U.S. Environmental Protection Agency — RadNet is a national network of monitoring stations that regularly collect air for analysis of radioactivity. The RadNet network, which has stations in each State,...

Mouse Rad9b is essential for embryonic development and promotes resistance to DNA damage

Science.gov (United States)

Leloup, Corinne; Hopkins, Kevin M.; Wang, Xiangyuan; Zhu, Aiping; Wolgemuth, Debra J.; Lieberman, Howard B.

2010-01-01

RAD9 participates in promoting resistance to DNA damage, cell cycle checkpoint control, DNA repair, apoptosis, embryogenesis, and regulation of transcription. A paralogue of RAD9 (named RAD9B) has been identified. To define the function of mouse Rad9b (Mrad9b), embryonic stem (ES) cells with a targeted gene deletion were constructed and used to generate Mrad9b mutant mice. Mrad9b−/− embryos are resorbed after E7.5 while some of the heterozygotes die between E12.5 and a few days after birth. Mrad9b is expressed in embryonic brain and Mrad9b+/− embryos exhibit abnormal neural tube closure. Mrad9b−/− mouse embryonic fibroblasts are not viable. Mrad9b−/− ES cells are more sensitive to gamma rays and mitomycin C than Mrad9b+/+ controls, but show normal gamma-ray-induced G2/M checkpoint control. There is no evidence of spontaneous genomic instability in Mrad9b−/− cells. Our findings thus indicate that Mrad9b is essential for embryonic development and mediates resistance to certain DNA damaging agents. PMID:20842695

Skeletal muscle phosphatidylcholine fatty acids and insulin sensitivity in normal humans.

Science.gov (United States)

Clore, J N; Li, J; Gill, R; Gupta, S; Spencer, R; Azzam, A; Zuelzer, W; Rizzo, W B; Blackard, W G

1998-10-01

The fatty acid composition of skeletal muscle membrane phospholipids (PL) is known to influence insulin responsiveness in humans. However, the contribution of the major PL of the outer (phosphatidylcholine, PC) and inner (phosphatidylethanolamine, PE) layers of the sarcolemma to insulin sensitivity is not known. Fatty acid composition of PC and PE from biopsies of vastus lateralis from 27 normal men and women were correlated with insulin sensitivity determined by the hyperinsulinemic euglycemic clamp technique at insulin infusion rates of 0.4, 1.0, and 10.0 mU . kg-1 . min-1. Significant variation in the half-maximal insulin concentration (ED50) was observed in the normal volunteers (range 24.0-146.0 microU/ml), which correlated directly with fasting plasma insulin (r = 0.75, P insulin sensitivity was observed in PE (NS). These studies suggest that the fatty acid composition of PC may be of particular importance in the relationship between fatty acids and insulin sensitivity in normal humans.

The tumor suppressor homolog in fission yeast, myh1+, displays a strong interaction with the checkpoint gene rad1+

International Nuclear Information System (INIS)

Jansson, Kristina; Warringer, Jonas; Farewell, Anne; Park, Han-Oh; Hoe, Kwang-Lae; Kim, Dong-Uk; Hayles, Jacqueline; Sunnerhagen, Per

2008-01-01

The DNA glycosylase MutY is strongly conserved in evolution, and homologs are found in most eukaryotes and prokaryotes examined. This protein is implicated in repair of oxidative DNA damage, in particular adenine mispaired opposite 7,8-dihydro-8-oxoguanine. Previous investigations in Escherichia coli, fission yeast, and mammalian cells show an association of mutations in MutY homologs with a mutator phenotype and carcinogenesis. Eukaryotic MutY homologs physically associate with several proteins with a role in replication, DNA repair, and checkpoint signaling, specifically the trimeric 9-1-1 complex. In a genetic investigation of the fission yeast MutY homolog, myh1 + , we show that the myh1 mutation confers a moderately increased UV sensitivity alone and in combination with mutations in several DNA repair genes. The myh1 rad1, and to a lesser degree myh1 rad9, double mutants display a synthetic interaction resulting in enhanced sensitivity to DNA damaging agents and hydroxyurea. UV irradiation of myh1 rad1 double mutants results in severe chromosome segregation defects and visible DNA fragmentation, and a failure to activate the checkpoint. Additionally, myh1 rad1 double mutants exhibit morphological defects in the absence of DNA damaging agents. We also found a moderate suppression of the slow growth and UV sensitivity of rhp51 mutants by the myh1 mutation. Our results implicate fission yeast Myh1 in repair of a wider range of DNA damage than previously thought, and functionally link it to the checkpoint pathway

RadNet Air Data From Sacramento, CA

Science.gov (United States)

This page presents radiation air monitoring and air filter analysis data for Sacramento, CA from EPA's RadNet system. RadNet is a nationwide network of monitoring stations that measure radiation in air, drinking water and precipitation.

RadNet Air Data From Honolulu, HI

Science.gov (United States)

This page presents radiation air monitoring and air filter analysis data for Honolulu, HI from EPA's RadNet system. RadNet is a nationwide network of monitoring stations that measure radiation in air, drinking water and precipitation.

RadNet Air Data From Houston, TX

Science.gov (United States)

This page presents radiation air monitoring and air filter analysis data for Houston, TX from EPA's RadNet system. RadNet is a nationwide network of monitoring stations that measure radiation in air, drinking water and precipitation.

RadNet Air Data From Austin, TX

Science.gov (United States)

This page presents radiation air monitoring and air filter analysis data for Austin, TX from EPA's RadNet system. RadNet is a nationwide network of monitoring stations that measure radiation in air, drinking water and precipitation.

RadNet Air Data From Orlando, FL

Science.gov (United States)

This page presents radiation air monitoring and air filter analysis data for Orlando, FL from EPA's RadNet system. RadNet is a nationwide network of monitoring stations that measure radiation in air, drinking water and precipitation.

Effects of the rad52 gene on recombination in Saccharomyces cerevisiae

International Nuclear Information System (INIS)

Prakash, S.; Prakash, L.; Burke, W.; Montelone, B.A.

1980-01-01

Effects of the rad 52 mutation in Saccharomyces cerevisiae on meiotic, γ-ray-induced, uv-induced and spontaneous mitotic recombination were studied. The rad52/rad52 diploids undergo premeiotic DNA synthesis; sporulation occurs but inviable spores are produced. Both intra and intergenic recombination during meiosis were examined in cells transferred from sporulation medium to vegetative medium at different time intervals. No intragenic recombination was observed at the his1-1/his1-315 and trp-5-2/trp5-48 heteroalleles. Gene-centromere recombination also was not observed in rad/52/rad52 diploids. No γ-ray- or uv-induced intragenic mitotic recombination is seen in rad52/rad52 diploids. The rate of spontaneous mitotic recombination is lowered five-fold at the his1-1/his1-315 and leu1-c/leu1-12 heteroalleles. Spontaneous reversion rates of both his1-1 and his1-315 were elevated 10 to 20 fold in rad52/rad52 diploids. The RAD52 gene function is required for spontaneous mitotic recombination, uv- and γ-ray-induced mitotic recombination and mitotic recombination

The socio-behavioral development of children with symptoms of attachment disorder: An observational study of teacher sensitivity in special education.

Science.gov (United States)

Spilt, Jantine L; Vervoort, Eleonora; Koenen, Anne-Katrien; Bosmans, Guy; Verschueren, Karine

2016-09-01

Children with Reactive Attachment Disorder (RAD) have serious socio-behavioral problems and often rely on socially abnormal, aggressive, and manipulative forms of communication. Little is known, however, about the influence of teachers on the socio-behavioral development of children with symptoms of RAD. This longitudinal study examined the influence of teacher sensitivity on the socio-behavioral development of children with symptoms of RAD across one school year. The sample included 85 Belgian children and 70 teachers from special education schools. In the previous school year, teachers rated Inhibited and Disinhibited RAD symptoms. In the next school year, teacher Sensitivity was observed in interactions with individual children in the first trimester. Teacher-rated Overt aggression, Relational aggression, and Prosocial behavior was assessed in the first, second, and third trimester. We found no effects of Sensitivity on Prosocial behavior. Also, no effects were found for children with Disinhibited RAD symptoms. For children with Inhibited RAD symptoms, increases in Overt and Relational aggression were observed when Sensitivity was low, whereas decreases were observed when Sensitivity was high. The results suggest that teacher sensitivity is associated with the socio-behavioral development of children with Inhibited RAD symptoms but not with the socio-behavioral development of children with Disinhibited RAD symptoms. Children with Reactive Attachment Disorder (RAD) exhibit socio-behavioral problems that hinder their school adjustment. These socio-behavioral problems appear relatively stable and it is not known what influence special education teachers might have on the development of these problems across a school year. This study suggests that teacher sensitivity is associated with changes in the socio-behavioral development of children with Inhibited RAD symptoms. Whereas high sensitivity was associated with improvements, low sensitivity appeared to exaggerate

High resolution MRI of the breast at 3 T: which BI-RADS registered descriptors are most strongly associated with the diagnosis of breast cancer?

International Nuclear Information System (INIS)

Pinker-Domenig, K.; Helbich, T.H.; Bogner, W.; Gruber, S.; Bickel, H.; Duffy, S.; Schernthaner, M.; Dubsky, P.; Pluschnig, U.; Rudas, M.; Trattnig, S.

2012-01-01

To identify which breast lesion descriptors in the ACR BI-RADS registered MRI lexicon are most strongly associated with the diagnosis of breast cancer when performing breast MR imaging at 3 T. 150 patients underwent breast MR imaging at 3 T. Lesion size, morphology and enhancement kinetics were assessed according to the BI-RADS registered classification. Sensitivity, specificity and diagnostic accuracy were assessed. The effects of the BI-RADS registered descriptors on sensitivity and specificity were evaluated. Data were analysed using logistic regression. Histopathological diagnoses were used as the standard of reference. The sensitivity, specificity and diagnostic accuracy of breast MRI at 3 T was 99%, 81% and 93%, respectively. In univariate analysis, the final diagnosis of malignancy was positively associated with irregular shape (p registered breast lesion descriptors that are mostly strongly associated with breast cancer in breast MR imaging at 3 T are lesion shape, lesion margin, internal enhancement pattern and Type 3 enhancement kinetics. (orig.)

RAD51B in Familial Breast Cancer

OpenAIRE

Pelttari, L.M.; Khan, S.; et al.,

2016-01-01

Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737\\ud and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast\\ud cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer\\ud predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the\\ud coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for\\ud identifi...

RAD51B in familial breast cancer

OpenAIRE

Pelttari, LM; Khan, S; Vuorela, M; Kiiski, JI; Vilske, S; Nevanlinna, V; Ranta, S; Schleutker, J; Winqvist, R; Kallioniemi, A; Dörk, T; Bogdanova, NV; Figueroa, J; Pharoah, PDP; Schmidt, MK

2016-01-01

Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possi...

Loss of the homologous recombination gene rad51 leads to Fanconi anemia-like symptoms in zebrafish.

Science.gov (United States)

Botthof, Jan Gregor; Bielczyk-Maczyńska, Ewa; Ferreira, Lauren; Cvejic, Ana

2017-05-30

RAD51 is an indispensable homologous recombination protein, necessary for strand invasion and crossing over. It has recently been designated as a Fanconi anemia (FA) gene, following the discovery of two patients carrying dominant-negative mutations. FA is a hereditary DNA-repair disorder characterized by various congenital abnormalities, progressive bone marrow failure, and cancer predisposition. In this report, we describe a viable vertebrate model of RAD51 loss. Zebrafish rad51 loss-of-function mutants developed key features of FA, including hypocellular kidney marrow, sensitivity to cross-linking agents, and decreased size. We show that some of these symptoms stem from both decreased proliferation and increased apoptosis of embryonic hematopoietic stem and progenitor cells. Comutation of p53 was able to rescue the hematopoietic defects seen in the single mutants, but led to tumor development. We further demonstrate that prolonged inflammatory stress can exacerbate the hematological impairment, leading to an additional decrease in kidney marrow cell numbers. These findings strengthen the assignment of RAD51 as a Fanconi gene and provide more evidence for the notion that aberrant p53 signaling during embryogenesis leads to the hematological defects seen later in life in FA. Further research on this zebrafish FA model will lead to a deeper understanding of the molecular basis of bone marrow failure in FA and the cellular role of RAD51.

Evidence for three types of x-ray damage repair in yeast and sensitivity of totally repair deficient strains to sunlight

International Nuclear Information System (INIS)

Game, J.C.; Schild, D.; Mortimer, R.K.

1987-01-01

Mutants of yeast that confer sensitivity to x-rays are known to fall into two epistasis groups, called here the RAD51 and RAD18 groups, which are each thought to control a different type of x-ray repair. They examine here the role of genes in a third repair pathways in x-ray repair. RAD1 and RAD3 are known to be important in the repair of pyrimidine dimers after uv-irradiation. They find that these genes can also play an important role in x-ray repair, but that this role is only exposed when both the other pathways of x-ray repair are blocked. Double mutants blocked in the RAD51 and RAD18 pathways are significantly less x-ray sensitive than triple mutants blocked in these pathways but also mutant in either the RAD1 or RAD3 genes. In a related experiment, they tested the importance of DNA repair in nature by determining the sensitivity to natural unfiltered sunlight of a strain lacking all known DNA repair pathways. They constructed a quadruple mutant strain containing RAD1-1, RAD18-2, RAD51-1 and PHR1-1. The latter mutation blocks the cell's ability to photoreactivate uv damage. They found that this strain was so sensitive to sunlight that less than three seconds' exposure would cause an average of one lethal hit per cell, and survival was less than 2% after ten seconds' exposure. Wild type yeast at sea level showed no killing after thirty minutes. the quadruple mutant is approximately one thousand times more sensitive to sunlight than the related wild type

Molecular anatomy of the recombination mediator function of Saccharomyces cerevisiae Rad52

DEFF Research Database (Denmark)

Seong, C.; Sehorn, M.G.; Plate, Iben

2008-01-01

A helical filament of Rad51 on single-strand DNA (ssDNA), called the presynaptic filament, catalyzes DNA joint formation during homologous recombination. Rad52 facilitates presynaptic filament assembly, and this recombination mediator activity is thought to rely on the interactions of Rad52...... with Rad51, the ssDNA-binding protein RPA, and ssDNA. The N-terminal region of Rad52, which has DNA binding activity and an oligomeric structure, is thought to be crucial for mediator activity and recombination. Unexpectedly, we find that the C-terminal region of Rad52 also harbors a DNA binding function....... Importantly, the Rad52 C-terminal portion alone can promote Rad51 presynaptic filament assembly. The middle portion of Rad52 associates with DNA-bound RPA and contributes to the recombination mediator activity. Accordingly, expression of a protein species that harbors the middle and C-terminal regions of Rad...

Effects of the rad52 gene on recombination in Saccharomyces cerevisiae

International Nuclear Information System (INIS)

Prakash, S.; Prakash, L.; Burke, W.; Montelone, B.A.

1979-01-01

Effects of the rad52 mutation in Saccharomyces cerevisiae on meiotic, γ-ray-induced, uv-induced, and spontaneous mitotic recombination were studied. The rad52/rad52 diploids undergo premeiotic DNA synthesis; sporulation occurs but inviable spores are produced. Intra- and intergenic recombination during meiosis were examined in cells transferred from sporulation medium to vegetative medium at different time intervals. No intragenic recombination was observed at the hisl-1/hisl-315 and trp5-2/trp5-48 heteroalleles. Gene-centromere recombination was also not observed in rad52/rad52 diploids. No γ-ray-induced intragenic mitotic recombination is seen in rad52/rad52 diploids and uv-induced intragenic recombination is greatly reduced. However, spontaneous mitotic recombination is not similarly affected. The RAD52 gene thus functions in recombination in meiosis and in γ-ray and uv-induced mitotic recombination but not in spontaneous mitotic recombination

RAD51B in Familial Breast Cancer

DEFF Research Database (Denmark)

Pelttari, Liisa M; Khan, Sofia; Vuorela, Mikko

2016-01-01

Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition......, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD......51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients...

Minocycline enhances mitomycin C-induced cytotoxicity through down-regulating ERK1/2-mediated Rad51 expression in human non-small cell lung cancer cells.

Science.gov (United States)

Ko, Jen-Chung; Wang, Tai-Jing; Chang, Po-Yuan; Syu, Jhan-Jhang; Chen, Jyh-Cheng; Chen, Chien-Yu; Jian, Yun-Ting; Jian, Yi-Jun; Zheng, Hao-Yu; Chen, Wen-Ching; Lin, Yun-Wei

2015-10-01

Minocycline is a semisynthetic tetracycline derivative; it has anti-inflammatory and anti-cancer effects distinct from its antimicrobial function. However, the molecular mechanism of minocycline-induced cytotoxicity in non-small cell lung cancer (NSCLC) cells has not been identified. Rad51 plays a central role in homologous recombination and high levels of Rad51 expression are observed in chemo- or radioresistant carcinomas. Our previous studies have shown that the MKK1/2-ERK1/2 signal pathway maintains the expression of Rad51 in NSCLC cells. In this study, minocycline treatment inhibited cell viability and proliferation of two NSCLC cells, A549 and H1975. Treatment with minocycline decreased Rad51 mRNA and protein levels through MKK1/2-ERK1/2 inactivation. Furthermore, expression of constitutively active MKK1 (MKK1-CA) vectors significantly rescued the decreased Rad51 protein and mRNA levels in minocycline-treated NSCLC cells. However, combined treatment with MKK1/2 inhibitor U0126 and minocycline further decreased the Rad51 expression and cell viability of NSCLC cells. Knocking down Rad51 expression by transfection with small interfering RNA of Rad51 enhanced the cytotoxicity and cell growth inhibition of minocycline. Mitomycin C (MMC) is typically used as a first or second line regimen to treat NSCLC. Compared to a single agent alone, MMC combined with minocycline resulted in cytotoxicity and cell growth inhibition synergistically in NSCLC cells, accompanied with reduced activation of phospho-ERK1/2, and reduced Rad51 protein levels. Overexpression of MKK1-CA or Flag-tagged Rad51 could reverse the minocycline and MMC-induced synergistic cytotoxicity. These findings may have implications for the rational design of future drug regimens incorporating minocycline and MMC for the treatment of NSCLC. Copyright © 2015 Elsevier Inc. All rights reserved.

Caffeine inhibits gene conversion by displacing Rad51 from ssDNA

Science.gov (United States)

Tsabar, Michael; Mason, Jennifer M.; Chan, Yuen-Ling; Bishop, Douglas K.; Haber, James E.

2015-01-01

Efficient repair of chromosomal double-strand breaks (DSBs) by homologous recombination relies on the formation of a Rad51 recombinase filament that forms on single-stranded DNA (ssDNA) created at DSB ends. This filament facilitates the search for a homologous donor sequence and promotes strand invasion. Recently caffeine treatment has been shown to prevent gene targeting in mammalian cells by increasing non-productive Rad51 interactions between the DSB and random regions of the genome. Here we show that caffeine treatment prevents gene conversion in yeast, independently of its inhibition of the Mec1ATR/Tel1ATM-dependent DNA damage response or caffeine's inhibition of 5′ to 3′ resection of DSB ends. Caffeine treatment results in a dosage-dependent eviction of Rad51 from ssDNA. Gene conversion is impaired even at low concentrations of caffeine, where there is no discernible dismantling of the Rad51 filament. Loss of the Rad51 filament integrity is independent of Srs2's Rad51 filament dismantling activity or Rad51's ATPase activity and does not depend on non-specific Rad51 binding to undamaged double-stranded DNA. Caffeine treatment had similar effects on irradiated HeLa cells, promoting loss of previously assembled Rad51 foci. We conclude that caffeine treatment can disrupt gene conversion by disrupting Rad51 filaments. PMID:26019181

Mongoose: Creation of a Rad-Hard MIPS R3000

Science.gov (United States)

Lincoln, Dan; Smith, Brian

1993-01-01

This paper describes the development of a 32 Bit, full MIPS R3000 code-compatible Rad-Hard CPU, code named Mongoose. Mongoose progressed from contract award, through the design cycle, to operational silicon in 12 months to meet a space mission for NASA. The goal was the creation of a fully static device capable of operation to the maximum Mil-883 derated speed, worst-case post-rad exposure with full operational integrity. This included consideration of features for functional enhancements relating to mission compatibility and removal of commercial practices not supported by Rad-Hard technology. 'Mongoose' developed from an evolution of LSI Logic's MIPS-I embedded processor, LR33000, code named Cobra, to its Rad-Hard 'equivalent', Mongoose. The term 'equivalent' is used to infer that the core of the processor is functionally identical, allowing the same use and optimizations of the MIPS-I Instruction Set software tool suite for compilation, software program trace, etc. This activity was started in September of 1991 under a contract from NASA-Goddard Space Flight Center (GSFC)-Flight Data Systems. The approach affected a teaming of NASA-GSFC for program development, LSI Logic for system and ASIC design coupled with the Rad-Hard process technology, and Harris (GASD) for Rad-Hard microprocessor design expertise. The program culminated with the generation of Rad-Hard Mongoose prototypes one year later.

The Saccharomyces cerevisiae RAD30 gene, a homologue of Escherichia coli dinB and umuC, is DNA damage inducible and functions in a novel error-free postreplication repair mechanism

Energy Technology Data Exchange (ETDEWEB)

McDonald, J. P. [NIH, Bethesda, MD. (United States); Levine, A. S.; Woodgate, R.

1997-12-15

Damage-inducible mutagenesis in prokaryotes is largely dependent upon the activity of the UmuD'C-like proteins. Since many DNA repair processes are structurally and/or functionally conserved between prokaryotes and eukaryotes, we investigated the role of RAD30, a previously uncharacterized Saccharomyces cerevisiae DNA repair gene related to the Escherichia coli dinB, umuC and S. cerevisiae REV1 genes, in UV resistance and UV-induced mutagenesis. Similar to its prokaryotic homologues, RAD30 was found to be damage inducible. Like many S. cerevisiae genes involved in error-prone DNA repair, epistasis analysis clearly places RAD30 in the RAD6 group and rad30 mutants display moderate UV sensitivity reminiscent of rev mutants. However, unlike rev mutants, no defect in UV-induced reversion was seen in rad30 strains. While rad6 and rad18 are both epistatic to rad30, no epistasis was observed with rev1, rev3, rev7 or rad5, all of which are members of the RAD6 epistasis group. These findings suggest that RD30 participates in a novel error-free repair pathway dependent on RAD6 and RAD18, but independent of REV1, REV3, REV7 and RAD5. (author)

The Coronary Artery Disease-Reporting and Data System (CAD-RADS): Prognostic and Clinical Implications Associated With Standardized Coronary Computed Tomography Angiography Reporting.

Science.gov (United States)

Xie, Joe X; Cury, Ricardo C; Leipsic, Jonathon; Crim, Matthew T; Berman, Daniel S; Gransar, Heidi; Budoff, Matthew J; Achenbach, Stephan; Ó Hartaigh, Bríain; Callister, Tracy Q; Marques, Hugo; Rubinshtein, Ronen; Al-Mallah, Mouaz H; Andreini, Daniele; Pontone, Gianluca; Cademartiri, Filippo; Maffei, Erica; Chinnaiyan, Kavitha; Raff, Gilbert; Hadamitzky, Martin; Hausleiter, Joerg; Feuchtner, Gudrun; Dunning, Allison; DeLago, Augustin; Kim, Yong-Jin; Kaufmann, Philipp A; Villines, Todd C; Chow, Benjamin J W; Hindoyan, Niree; Gomez, Millie; Lin, Fay Y; Jones, Erica; Min, James K; Shaw, Leslee J

2018-01-01

This study sought to assess clinical outcomes associated with the novel Coronary Artery Disease-Reporting and Data System (CAD-RADS) scores used to standardize coronary computed tomography angiography (CTA) reporting and their potential utility in guiding post-coronary CTA care. Clinical decision support is a major focus of health care policies aimed at improving guideline-directed care. Recently, CAD-RADS was developed to standardize coronary CTA reporting and includes clinical recommendations to facilitate patient management after coronary CTA. In the multinational CONFIRM (COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter) registry, 5,039 patients without known coronary artery disease (CAD) underwent coronary CTA and were stratified by CAD-RADS scores, which rank CAD stenosis severity as 0 (0%), 1 (1% to 24%), 2 (25% to 49%), 3 (50% to 69%), 4A (70% to 99% in 1 to 2 vessels), 4B (70% to 99% in 3 vessels or ≥50% left main), or 5 (100%). Kaplan-Meier and multivariable Cox models were used to estimate all-cause mortality or myocardial infarction (MI). Receiver-operating characteristic (ROC) curves were used to compare CAD-RADS to the Duke CAD Index and traditional CAD classification. Referrals to invasive coronary angiography (ICA) after coronary CTA were also assessed. Cumulative 5-year event-free survival ranged from 95.2% to 69.3% for CAD-RADS 0 to 5 (p data, 57% of CAD-RADS 3 patients who received 30-day ICA were either asymptomatic or not receiving antianginal therapy at baseline, whereas only 32% had angina and were receiving medical therapy. CAD-RADS effectively identified patients at risk for adverse events. Frequent ICA use was observed among patients without severe CAD, many of whom were asymptomatic or not taking antianginal drugs. Incorporating CAD-RADS into coronary CTA reports may provide a novel opportunity to promote evidence-based care post-coronary CTA. Copyright © 2018 American College of Cardiology

The tumor suppressor homolog in fission yeast, myh1{sup +}, displays a strong interaction with the checkpoint gene rad1{sup +}

Energy Technology Data Exchange (ETDEWEB)

Jansson, Kristina; Warringer, Jonas; Farewell, Anne [Department of Cell and Molecular Biology, Lundberg Laboratory, Goeteborg University, P.O. Box 462, Goeteborg SE-405 30 (Sweden); Park, Han-Oh [Bioneer Corporation, 49-3, Munpyeong-dong, Daedeok-gu, Daejon 306-220 (Korea, Republic of); Hoe, Kwang-Lae; Kim, Dong-Uk [Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yusong, Daejeon (Korea, Republic of); Hayles, Jacqueline [Cell Cycle Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln' s Inn Fields, London WC2A 3PX (United Kingdom); Sunnerhagen, Per [Department of Cell and Molecular Biology, Lundberg Laboratory, Goeteborg University, P.O. Box 462, Goeteborg SE-405 30 (Sweden)], E-mail: per.sunnerhagen@cmb.gu.se

2008-09-26

The DNA glycosylase MutY is strongly conserved in evolution, and homologs are found in most eukaryotes and prokaryotes examined. This protein is implicated in repair of oxidative DNA damage, in particular adenine mispaired opposite 7,8-dihydro-8-oxoguanine. Previous investigations in Escherichia coli, fission yeast, and mammalian cells show an association of mutations in MutY homologs with a mutator phenotype and carcinogenesis. Eukaryotic MutY homologs physically associate with several proteins with a role in replication, DNA repair, and checkpoint signaling, specifically the trimeric 9-1-1 complex. In a genetic investigation of the fission yeast MutY homolog, myh1{sup +}, we show that the myh1 mutation confers a moderately increased UV sensitivity alone and in combination with mutations in several DNA repair genes. The myh1 rad1, and to a lesser degree myh1 rad9, double mutants display a synthetic interaction resulting in enhanced sensitivity to DNA damaging agents and hydroxyurea. UV irradiation of myh1 rad1 double mutants results in severe chromosome segregation defects and visible DNA fragmentation, and a failure to activate the checkpoint. Additionally, myh1 rad1 double mutants exhibit morphological defects in the absence of DNA damaging agents. We also found a moderate suppression of the slow growth and UV sensitivity of rhp51 mutants by the myh1 mutation. Our results implicate fission yeast Myh1 in repair of a wider range of DNA damage than previously thought, and functionally link it to the checkpoint pathway.

RadNet Air Data From Fort Smith, AR

Science.gov (United States)

This page presents radiation air monitoring and air filter analysis data for Fort Smith, AR from EPA's RadNet system. RadNet is a nationwide network of monitoring stations that measure radiation in air, drinking water and precipitation.

RadNet Air Data From Little Rock, AR

Science.gov (United States)

This page presents radiation air monitoring and air filter analysis data for Little Rock, AR from EPA's RadNet system. RadNet is a nationwide network of monitoring stations that measure radiation in air, drinking water and precipitation.

RadNet Air Data From Mason City, IA

Science.gov (United States)

This page presents radiation air monitoring and air filter analysis data for Mason City, IA from EPA's RadNet system. RadNet is a nationwide network of monitoring stations that measure radiation in air, drinking water and precipitation.

Reach Address Database (RAD)

Data.gov (United States)

U.S. Environmental Protection Agency — The Reach Address Database (RAD) stores the reach address of each Water Program feature that has been linked to the underlying surface water features (streams,...

Studies on radiation-sensitive nonsilver halide materials, (2)

International Nuclear Information System (INIS)

Komizu, Hideo; Honda, Koichi; Yabe, Akira; Kawasaki, Masami; Yamanaka, Takeshi.

1980-01-01

Dye-precursors made from furfural and some aniline derivatives become red-colored upon irradiation with ionization radiatios in PVC matrix, forming Stenhouse salts with the HCl evolved from the matrix. The coloration of the precursor from N-methylaniline, having the most excellent potential for dosimetry among the precursors, was studied for the irradiation of electron beam (60 kV) and X-ray (50 - 240 kVp). The following conclusions were obtained for the electron beam bombardment. (1) The response range is 10 -8 - 10 -6 C/cm 2 or 10 3 - 10 5 rad, where good linearity between coloration and charge density exists. (2) The highest sensitivity is obtained when the concentration of the precursor is >=5 wt% for the amount of PVC and the film thickness is >=32 μm. (3) Addition of 25 wt% of DOP enhances not only the sensitivity by ca. 20% but also the stability of the color from several days to several months. (4) The sensitivity is increased by ca. 15% when a conductive base is used for the film. (5) G value for the formation of the dye, i.e., that for the formation of HCl is 13.5 - 15.5. The followings were obtained for the irradiation of X-ray. (1) The response range is 10 3 - 10 5 R or rad. (2) The sensitivity for the absorbed dose is independent of the energy but is approximately proportional to the film thickness. (3) The sensitivity is higher than that for electrons by the factor of ca. 1.6, reflecting the higher G(HCl) value, 23 - 25. (author)

The Martian surface radiation environment – a comparison of models and MSL/RAD measurements

Directory of Open Access Journals (Sweden)

Matthiä Daniel

2016-01-01

Full Text Available Context: The Radiation Assessment Detector (RAD on the Mars Science Laboratory (MSL has been measuring the radiation environment on the surface of Mars since August 6th 2012. MSL-RAD is the first instrument to provide detailed information about charged and neutral particle spectra and dose rates on the Martian surface, and one of the primary objectives of the RAD investigation is to help improve and validate current radiation transport models. Aims: Applying different numerical transport models with boundary conditions derived from the MSL-RAD environment the goal of this work was to both provide predictions for the particle spectra and the radiation exposure on the Martian surface complementing the RAD sensitive range and, at the same time, validate the results with the experimental data, where applicable. Such validated models can be used to predict dose rates for future manned missions as well as for performing shield optimization studies. Methods: Several particle transport models (GEANT4, PHITS, HZETRN/OLTARIS were used to predict the particle flux and the corresponding radiation environment caused by galactic cosmic radiation on Mars. From the calculated particle spectra the dose rates on the surface are estimated. Results: Calculations of particle spectra and dose rates induced by galactic cosmic radiation on the Martian surface are presented. Although good agreement is found in many cases for the different transport codes, GEANT4, PHITS, and HZETRN/OLTARIS, some models still show large, sometimes order of magnitude discrepancies in certain particle spectra. We have found that RAD data is helping to make better choices of input parameters and physical models. Elements of these validated models can be applied to more detailed studies on how the radiation environment is influenced by solar modulation, Martian atmosphere and soil, and changes due to the Martian seasonal pressure cycle. By extending the range of the calculated particle

Effectiveness of assigning BI-RADS category-3 to breast lesion with respect to follow-up

International Nuclear Information System (INIS)

Masroor, I.

2008-01-01

To determine the effectiveness of assigning BI-RADS category-3 to breast lesion with respect to follow-up. Women undergoing X-ray mammography and assigned BI-RADS category-3 and recommended short-term (6-monthly) follow-up were included. Out of these, 44 patients were lost to follow-up and were excluded from the study. The lesions that remained stable after short-term follow-up were recommended routine (annual) follow-up. Needle localization and open surgical biopsy was performed, if the lesion progressed or calcifications increased in number/size and/or on physician or patient preference. The effectiveness of this approach was analyzed by determining the sensitivity, specificity, positive and negative predictive value for BI-RADS category-3. Of the 65 lesions, 55 remained stable. Of the remaining 10 lesions, two showed increase in number of microcalcification prompting biopsy. Both turned out to be ductal carcinoma in situ. Eight biopsies were performed on clinician or patient preference which turned out to be benign. The sensitivity, specificity, positive and negative predictive values were 100%, 87%, 20% and 100% respectively. Assessment with short-interval mammographic follow-up is useful to confirm the nature of most non-palpable breast lesions considered probably benign and permits detection of a small number of breast cancers at an early stage. The local setup, patient compliance is a major limitation for performing a follow-up study, as the available numbers can have a profound effect on the determined accuracy value. (author)

Germline RAD51B truncating mutation in a family with cutaneous melanoma

DEFF Research Database (Denmark)

Wadt, Karin A W; Aoude, Lauren G; Golmard, Lisa

2015-01-01

Known melanoma predisposition genes only account for around 40% of high-density melanoma families. Other rare mutations are likely to play a role in melanoma predisposition. RAD51B plays an important role in DNA repair through homologous recombination, and inactivation of RAD51B has been implicated...... in tumorigenesis. Thus RAD51B is a good candidate melanoma susceptibility gene, and previously, a germline splicing mutation in RAD51B has been identified in a family with early-onset breast cancer. In order to find genetic variants associated with melanoma predisposition, whole-exome sequencing was carried out...... on blood samples from a three-case cutaneous melanoma family. We identified a novel germline RAD51B nonsense mutation, and we demonstrate reduced expression of RAD51B in melanoma cells indicating inactivation of RAD51B. This is only the second report of a germline truncating RAD51B mutation. While...

Characterization of iminothiosulfine-type ions [HNCS 2] rad +/ rad - and their neutral counterparts by mass spectrometry and computational chemistry

Science.gov (United States)

Vivekananda, S.; Raghunath, P.; Bhanuprakash, K.; Srinivas, R.; Trikoupis, Moschoula A.; Terlouw, Johan K.

2000-12-01

Electron ionization of rhodanine yields iminothiosulfine ions H- N C- S- Srad + , 1brad + , which readily communicate with the higher energy cyclic isomer H- N CS2rad + , 1arad + . CBS-QB3 and G AUSSIAN-2 model chemistries predict that one electron reduction reverses the stability order but that the (singlet) neutrals remain connected via a negligible energy barrier. Neutralization-reionization (NR) experiments demonstrate that singlet 1a and its heterocumulene isomer 1b are stable species in the gas-phase. However, the co-generated triplet species readily dissociate into 3S2rad + + HNC. Confirmatory experimental evidence comes from charge reversal (CR) and NR experiments on the cyclic anion H- N CS2rad - , 1arad - .

Astaxanthin down-regulates Rad51 expression via inactivation of AKT kinase to enhance mitomycin C-induced cytotoxicity in human non-small cell lung cancer cells.

Science.gov (United States)

Ko, Jen-Chung; Chen, Jyh-Cheng; Wang, Tai-Jing; Zheng, Hao-Yu; Chen, Wen-Ching; Chang, Po-Yuan; Lin, Yun-Wei

2016-04-01

Astaxanthin has been demonstrated to exhibit a wide range of beneficial effects, including anti-inflammatory and anti-cancer properties. However, the molecular mechanism of astaxanthin-induced cytotoxicity in non-small cell lung cancer (NSCLC) cells has not been identified. Rad51 plays a central role in homologous recombination, and studies show that chemo-resistant carcinomas exhibit high levels of Rad51 expression. In this study, astaxanthin treatment inhibited cell viability and proliferation of two NSCLC cells, A549 and H1703. Astaxanthin treatment (2.5-20 μM) decreased Rad51 expression and phospho-AKT(Ser473) protein level in a time and dose-dependent manner. Furthermore, expression of constitutively active AKT (AKT-CA) vector rescued the decreased Rad51 mRNA and protein levels in astaxanthin-treated NSCLC cells. Combined treatment with phosphatidylinositol 3-kinase (PI3K) inhibitors (LY294002 or wortmannin) further decreased the Rad51 expression in astaxanthin-exposed A549 and H1703 cells. Knockdown of Rad51 expression by transfection with si-Rad51 RNA or cotreatment with LY294002 further enhanced the cytotoxicity and cell growth inhibition of astaxanthin. Additionally, mitomycin C (MMC) as an anti-tumor antibiotic is widely used in clinical NSCLC chemotherapy. Combination of MMC and astaxanthin synergistically resulted in cytotoxicity and cell growth inhibition in NSCLC cells, accompanied with reduced phospho-AKT(Ser473) level and Rad51 expression. Overexpression of AKT-CA or Flag-tagged Rad51 reversed the astaxanthin and MMC-induced synergistic cytotoxicity. In contrast, pretreatment with LY294002 further decreased the cell viability in astaxanthin and MMC co-treated cells. In conclusion, astaxanthin enhances MMC-induced cytotoxicity by decreasing Rad51 expression and AKT activation. These findings may provide rationale to combine astaxanthin with MMC for the treatment of NSCLC. Copyright © 2016 Elsevier Inc. All rights reserved.

Radiological information management system (RadIMS)

International Nuclear Information System (INIS)

Oesterling, R.G.; Marko, S.A.; Tschaeche, A.N.

1991-01-01

Westinghouse Idaho Nuclear Company, Inc. (WINCO) is developing and implementing an information management system, known as RadIMS, to track and record personnel exposure to ionizing radiation. RadIMS has been designed to fulfill all the requirements of US Department of Energy (USDOE) Order 5480.11, ''Radiation Protection for Occupational Workers.'' This Order requires the contractor to maintain detailed radiation exposure records on all individuals who work at the facility. These records must be retrievable for the entire working life of the individual and be available to other USDOE contractors on request. To meet these general needs, RadIMS provides for retrieval of detailed, comprehensive individual exposure histories as well as the usual online interactions to accomplish day-today radiation protection operations. These two extremes of functionality require different approaches in the WINCO computing environment. The exposure histories include database text, paper, microfilm, and electronic bitmaps

RadCat 3.0 user guide.

Energy Technology Data Exchange (ETDEWEB)

Hinojosa, Daniel; Penisten, Janelle J.; Dennis, Matthew L.; Osborn, Douglas M.; Weiner, Ruth F.; Heames, Terence John; Marincel, Michelle K.

2009-05-01

RADTRAN is an internationally accepted program and code for calculating the risks of transporting radioactive materials. The first versions of the program, RADTRAN I and II, were developed for NUREG-0170 (USNRC, 1977), the first environmental statement on transportation of radioactive materials. RADTRAN and its associated software have undergone a number of improvements and advances consistent with improvements in both available data and computer technology. The version of RADTRAN currently bundled with RadCat is RADTRAN 6.0. This document provides a detailed discussion and a guide for the use of the RadCat 3.0 Graphical User Interface input file generator for the RADTRAN code. RadCat 3.0 integrates the newest analysis capabilities of RADTRAN 6.0 which includes an economic model, updated loss-of-lead shielding model, and unit conversion. As of this writing, the RADTRAN version in use is RADTRAN 6.0.

Radiological information management system (RadIMS)

Energy Technology Data Exchange (ETDEWEB)

Oesterling, R.G.; Marko, S.A.; Tschaeche, A.N.

1991-08-19

Westinghouse Idaho Nuclear Company, Inc. (WINCO) is developing and implementing an information management system, known as RadIMS, to track and record personnel exposure to ionizing radiation. RadIMS has been designed to fulfill all the requirements of US Department of Energy (USDOE) Order 5480.11, Radiation Protection for Occupational Workers.'' This Order requires the contractor to maintain detailed radiation exposure records on all individuals who work at the facility. These records must be retrievable for the entire working life of the individual and be available to other USDOE contractors on request. To meet these general needs, RadIMS provides for retrieval of detailed, comprehensive individual exposure histories as well as the usual online interactions to accomplish day-today radiation protection operations. These two extremes of functionality require different approaches in the WINCO computing environment. The exposure histories include database text, paper, microfilm, and electronic bitmaps.

Radiological information management system (RadIMS)

Energy Technology Data Exchange (ETDEWEB)

Oesterling, R.G.; Marko, S.A.; Tschaeche, A.N.

1991-08-19

Westinghouse Idaho Nuclear Company, Inc. (WINCO) is developing and implementing an information management system, known as RadIMS, to track and record personnel exposure to ionizing radiation. RadIMS has been designed to fulfill all the requirements of US Department of Energy (USDOE) Order 5480.11, ``Radiation Protection for Occupational Workers.`` This Order requires the contractor to maintain detailed radiation exposure records on all individuals who work at the facility. These records must be retrievable for the entire working life of the individual and be available to other USDOE contractors on request. To meet these general needs, RadIMS provides for retrieval of detailed, comprehensive individual exposure histories as well as the usual online interactions to accomplish day-today radiation protection operations. These two extremes of functionality require different approaches in the WINCO computing environment. The exposure histories include database text, paper, microfilm, and electronic bitmaps.

Development of dosimeters with rad-hard silicon diodes for high dose dosimetry

International Nuclear Information System (INIS)

Camargo, Fabio de

2009-01-01

In this work we report on results obtained with rad-hard Standard Float Zone (FZ), Diffusion Oxygenated Float Zone (DOFZ) and Magnetic Czochralski (MCz) silicon diodes in gamma radiation processing dosimetry. These p ± n-n + junction devices were manufactured by Okmetic Oyj. (Vantaa, Finland) and processed by the Microelectronics Center of Helsinki University of Technology in the framework of the CERN RD50 Collaboration. The dosimetric probes, based on FZ, DOFZ and M Cz devices, were designed to operate without bias voltage in the direct current mode as on-line radiation dosimeter. The irradiations were performed in the Radiation Technology Center (CTR) at IPEN-CNEN/SP using a 60 Co source (Gamma cell 220 - Nordion) with a dose rate around of 2.4 kGy/h. The current response of each diode was measured as a function of the exposure time in steps from 5 kGy up to 50 kGy to achieve a total absorbed dose of 275 kGy. The results obtained showed a significant decrease in the photocurrent generated in all devices for total absorbed doses higher than approximately 25 kGy. To reduce this effect, the samples were pre-irradiated with 60 Co gamma rays at 700 kGy in order to saturate the trap production in the diode's sensitive volume. After pre-irradiation, despite of being less sensitive, all devices exhibited more stable photocurrent signals, even for total absorbed doses of 275 kGy. To monitor possible gamma radiation damage effects produced on the diodes, their dynamic leakage current and capacitance were measured as a function of the absorbed dose. (author)

High resolution MRI of the breast at 3 T: which BI-RADS {sup registered} descriptors are most strongly associated with the diagnosis of breast cancer?

Energy Technology Data Exchange (ETDEWEB)

Pinker-Domenig, K.; Helbich, T.H. [Medical University Vienna, Dept. of Radiology, Division of Molecular and Gender Imaging, Vienna (Austria); Bogner, W.; Gruber, S. [Medical University Vienna, Dept. of Radiology, MR Centre of Excellence, Vienna (Austria); Medical University Vienna, Dept. of Radiology, Vienna (Austria); Bickel, H. [Medical University Vienna, Dept. of Radiology, Division of Molecular and Gender Imaging, Vienna (Austria); Medical University Vienna, Dept. of Radiology, Vienna (Austria); Duffy, S. [Queen Mary University of London, Cancer Research UK Centre for Epidemiology, Mathematics and Statistics, Wolfson Institute of Preventive Medicine, Barts and The London School of Medicine and Dentistry, London (United Kingdom); Schernthaner, M. [Medical University Vienna, Dept. of Radiology, Vienna (Austria); Dubsky, P. [Medical University Vienna, Dept. of Surgery, Vienna (Austria); Pluschnig, U. [Medical University Vienna, Dept. of Internal Medicine, Division of Oncology, Vienna (Austria); Rudas, M. [Medical University Vienna, Clinical Institute of Pathology, Vienna (Austria); Trattnig, S. [Medical University Vienna, Dept. of Radiology, MR Centre of Excellence, Vienna (Austria)

2012-02-15

To identify which breast lesion descriptors in the ACR BI-RADS registered MRI lexicon are most strongly associated with the diagnosis of breast cancer when performing breast MR imaging at 3 T. 150 patients underwent breast MR imaging at 3 T. Lesion size, morphology and enhancement kinetics were assessed according to the BI-RADS {sup registered} classification. Sensitivity, specificity and diagnostic accuracy were assessed. The effects of the BI-RADS {sup registered} descriptors on sensitivity and specificity were evaluated. Data were analysed using logistic regression. Histopathological diagnoses were used as the standard of reference. The sensitivity, specificity and diagnostic accuracy of breast MRI at 3 T was 99%, 81% and 93%, respectively. In univariate analysis, the final diagnosis of malignancy was positively associated with irregular shape (p < 0.001), irregular margin (p < 0.001), heterogeneous enhancement (p < 0.001), Type 3 enhancement kinetics (p = 0.02), increasing patient age (p = 0.02) and larger lesion size (p < 0.001). In multivariate analysis, significant associations with malignancy remained for mass shape (p = 0.06), mass margin (p < 0.001), internal enhancement pattern (p = 0.03) and Type 3 enhancement kinetics (p = 0.06). The ACR BI-RADS {sup registered} breast lesion descriptors that are mostly strongly associated with breast cancer in breast MR imaging at 3 T are lesion shape, lesion margin, internal enhancement pattern and Type 3 enhancement kinetics. (orig.)

Effect of genes controlling radiation sensitivity on chemically induced mutations in Saccharomyces cerevisiae

International Nuclear Information System (INIS)

Prakash, L.

1976-01-01

The effect of 16 different genes (rad) conferring radiation sensitivity on chemically induced reversion in the yeast Saccharomyces cerevisiae was determined. The site of reversion used was a well-defined chain initiation mutant mapping in the structural gene coding for iso-1-cytochrome c. High doses of EMS and HNO 2 resulted in decreased reversion of cyc1-131 in rad6, rad9 and rad15 strains compared to the normal RAD + strains. In addition, rad52 greatly decreased EMS reversion of cyc1-131 but had no effect on HNO 2 -induced reversion; rad18, on the other hand, increased HNO 2 -induced reversion but did not alter EMS-induced reversion. When NQO was used as the mutagen, every rad gene tested, except for rad18, had an effect on reversion; rad6, rad9, rad15, rad17, rad18, rad22, rev1, rev2, and rev3 lowered NQO reversion while rad1, rad2, rad3, rad4, rad10, rad12, and rad16 increased it compared to the RAD + strain. The effect of rad genes on chemical mutagenesis is discussed in terms of their effect on uv mutagenesis. It is concluded that although the nature of the repair pathways may differ for uv- and chemically-induced mutations in yeast, a functional repair system is required for the induction of mutation by the chemical agents NQO, EMS, and HNO 2

Protective effect of the LevRad on treat of paracoccidioidomycosis

International Nuclear Information System (INIS)

Martins, Estefania M.N.; Andrade, Antero S.R.; Fernandes, Viviane Cristina; Morais, Elis Araujo; Goes, Alfredo M.; Resende, Maria Aparecida de

2011-01-01

Paracoccidioides brasiliensis is the agent of Paracoccidioidomycosis (PCM), the most prevalent deep mycosis of Latin America. The period of treat depend on the chemotherapeutic and the severity of disease and its administration not ensure the complete destruction of the fungus. The search for new alternatives is necessary. The aim of this study was to evaluate the protective effect of yeast cells of P. brasiliensis attenuated by gamma irradiation (LevRad) on therapeutic vaccination of BALB/c. The therapeutic potential of LevRad with or without fluconazole was assessed for the first time, intraperitoneally, in BALB/c, 60 days after intratracheal infection with a highly virulent non-irradiated P.brasiliensis isolate. The animals were divided in five experimental groups: uninfected (C-), infected (C+), infected treated with fluconazole (Inmed), infected treated with LevRad (InRad) and infected treated with fluconazole + LevRad (InRadMed). The organs (lungs, spleen and liver) were collected to analyze CFU (colony forming units) and histology. The sera were used to evaluate the immunization efficacy, and to assess IgG subtypes (IgG1, IgG2a, IgG2b, IgG3) and total IgG levels. There was significant decrease in the CFU counts of the lungs of InMed, InRadMed and InRad. No were visualized histopathological alterations in the organs of these groups, except in InRad there was granulomatous lesions unifocal, little and discrete. The levels of IgG and its subtypes IgG2a, IgG2b increased, probably due to the increase of cytokines that promote switching to these isotypes. These preliminary results can provide new prospect for immunotherapy of PCM, but it will be necessary new studies to evaluate administration dose and period treatment. (author)

RAD51 interconnects between DNA replication, DNA repair and immunity.

Science.gov (United States)

Bhattacharya, Souparno; Srinivasan, Kalayarasan; Abdisalaam, Salim; Su, Fengtao; Raj, Prithvi; Dozmorov, Igor; Mishra, Ritu; Wakeland, Edward K; Ghose, Subroto; Mukherjee, Shibani; Asaithamby, Aroumougame

2017-05-05

RAD51, a multifunctional protein, plays a central role in DNA replication and homologous recombination repair, and is known to be involved in cancer development. We identified a novel role for RAD51 in innate immune response signaling. Defects in RAD51 lead to the accumulation of self-DNA in the cytoplasm, triggering a STING-mediated innate immune response after replication stress and DNA damage. In the absence of RAD51, the unprotected newly replicated genome is degraded by the exonuclease activity of MRE11, and the fragmented nascent DNA accumulates in the cytosol, initiating an innate immune response. Our data suggest that in addition to playing roles in homologous recombination-mediated DNA double-strand break repair and replication fork processing, RAD51 is also implicated in the suppression of innate immunity. Thus, our study reveals a previously uncharacterized role of RAD51 in initiating immune signaling, placing it at the hub of new interconnections between DNA replication, DNA repair, and immunity. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

Curcumin enhances the mitomycin C-induced cytotoxicity via downregulation of MKK1/2-ERK1/2-mediated Rad51 expression in non-small cell lung cancer cells

International Nuclear Information System (INIS)

Ko, Jen-Chung; Tsai, Min-Shao; Weng, Shao-Hsing; Kuo, Ya-Hsun; Chiu, Yu-Fan; Lin, Yun-Wei

2011-01-01

Curcumin (diferuloylmethane), a major active component of turmeric (Curcuma longa), has been reported to suppress the proliferation of a wide variety of tumor cells. Rad51 is a key protein in the homologous recombination (HR) pathway of DNA double-strand break repair, and HR represents a novel target for cancer therapy. A high expression of Rad51 has been reported in chemo- or radio-resistant carcinomas. Therefore, in the current study, we will examine whether curcumin could enhance the effects of mitomycin C (MMC), a DNA interstrand cross-linking agent, to induce cytotoxicity by decreasing Rad51 expression. Exposure of two human non-small lung cancer (NSCLC) cell lines (A549 and H1975) to curcumin could suppress MMC-induced MKK1/2-ERK1/2 signal activation and Rad51 protein expression. Enhancement of ERK1/2 activation by constitutively active MKK1/2 (MKK1/2-CA) increased Rad51 protein levels in curcumin and MMC co-treated human lung cells. Moreover, the synergistic cytotoxic effect induced by curcumin combined with MMC was decreased by MKK1-CA-mediated enhancement of ERK1/2 activation by a significant degree. In contrast, MKK1/2 inhibitor, U0126 was shown to augment the cytotoxicity of curcumin and MMC through downregulation of ERK1/2 activation and Rad51 expression. Depletion of endogenous Rad51 expression by siRad51 RNA transfection significantly enhanced MMC and/or curcumin induced cell death and cell growth inhibition. In contrast, an overexpression of Rad51 protected lung cancer cells from synergistic cytotoxic effects induced by curcumin and MMC. We concluded that Rad51 inhibition may be an additional action mechanism for enhancing the chemosensitization of MMC by curcumin in NSCLC. - Highlights: → Curcumin downregulates MKK-ERK-mediated Rad51 expression. → Curcumin enhances mitomycin C-induced cytotoxicity. → Rad51 protects cells from cytotoxic effects induced by curcumin and mitomycin C. → Rad51 inhibition enhances the chemosensitization of

Comparison of Danish dichotomous and BI-RADS classifications of mammographic density.

Science.gov (United States)

Hodge, Rebecca; Hellmann, Sophie Sell; von Euler-Chelpin, My; Vejborg, Ilse; Andersen, Zorana Jovanovic

2014-06-01

In the Copenhagen mammography screening program from 1991 to 2001, mammographic density was classified either as fatty or mixed/dense. This dichotomous mammographic density classification system is unique internationally, and has not been validated before. To compare the Danish dichotomous mammographic density classification system from 1991 to 2001 with the density BI-RADS classifications, in an attempt to validate the Danish classification system. The study sample consisted of 120 mammograms taken in Copenhagen in 1991-2001, which tested false positive, and which were in 2012 re-assessed and classified according to the BI-RADS classification system. We calculated inter-rater agreement between the Danish dichotomous mammographic classification as fatty or mixed/dense and the four-level BI-RADS classification by the linear weighted Kappa statistic. Of the 120 women, 32 (26.7%) were classified as having fatty and 88 (73.3%) as mixed/dense mammographic density, according to Danish dichotomous classification. According to BI-RADS density classification, 12 (10.0%) women were classified as having predominantly fatty (BI-RADS code 1), 46 (38.3%) as having scattered fibroglandular (BI-RADS code 2), 57 (47.5%) as having heterogeneously dense (BI-RADS 3), and five (4.2%) as having extremely dense (BI-RADS code 4) mammographic density. The inter-rater variability assessed by weighted kappa statistic showed a substantial agreement (0.75). The dichotomous mammographic density classification system utilized in early years of Copenhagen's mammographic screening program (1991-2001) agreed well with the BI-RADS density classification system.

Brca2 C-terminus interacts with Rad51 and contributes to nuclear forcus formation in double-strand break repair of DNA

International Nuclear Information System (INIS)

Ochiai, Kazuhiko; Morimatsu, Masami; Yoshikawa, Yasunaga; Syuto, Bunei; Hashizume, Kazuyoshi

2004-01-01

In humans and mice, the interaction between the breast cancer susceptibility protein, Brca2, and Rad51 recombinase is essential for DNA repair by homologous recombination, the failure of this process can predispose to cancer. Cells with mutated Brca2 are hypersensitive to ionizing radiation (IR) and exhibit defective DNA repair. Using yeast and mammalian two-hybrid assays, we demonstrate that canine Rad51 protein interacts specifically with the C-terminus of canine Brca2. In support of the biological significance of this interaction, we found that radiation-induced focus formation of Rad51 in COS-7 cells was compromised by forced expression of the C-terminus of canine Brca2. A similar result was obtained for the murine C-terminus. These data suggest that the C-terminal domain of canine Brca2 functions to bind Rad51 and that this domain contributes to the IR-induced assembly of the Rad51 complex in vivo. (author)

Interactions among Trypanosoma brucei RAD51 paralogues in DNA repair and antigenic variation

Science.gov (United States)

Dobson, Rachel; Stockdale, Christopher; Lapsley, Craig; Wilkes, Jonathan; McCulloch, Richard

2011-01-01

Homologous recombination in Trypanosoma brucei is used for moving variant surface glycoprotein (VSG) genes into expression sites during immune evasion by antigenic variation. A major route for such VSG switching is gene conversion reactions in which RAD51, a universally conserved recombinase, catalyses homology-directed strand exchange. In any eukaryote, RAD51-directed strand exchange in vivo is mediated by further factors, including RAD51-related proteins termed Rad51 paralogues. These appear to be ubiquitously conserved, although their detailed roles in recombination remain unclear. In T. brucei, four putative RAD51 paralogue genes have been identified by sequence homology. Here we show that all four RAD51 paralogues act in DNA repair, recombination and RAD51 subnuclear dynamics, though not equivalently, while mutation of only one RAD51 paralogue gene significantly impedes VSG switching. We also show that the T. brucei RAD51 paralogues interact, and that the complexes they form may explain the distinct phenotypes of the mutants as well as observed expression interdependency. Finally, we document the Rad51 paralogues that are encoded by a wide range of protists, demonstrating that the Rad51 paralogue repertoire in T. brucei is unusually large among microbial eukaryotes and that one member of the protein family corresponds with a key, conserved eukaryotic Rad51 paralogue. PMID:21615552

Fast neutron sensitivity of polymer dosemeters

International Nuclear Information System (INIS)

Harper, M.W.; Pearson, D.W.; Moran, P.R.

1975-01-01

The responses of polymer thermocurrent dosemeters to fission spectrum and 14 MeV neutrons were measured. The dosemeters are in the form of disks 1 cm diam by 0.5 mm thick. Relative to Cobalt 60 gamma responses, teflon PTFE dosemeters show a 6 percent response to 14 MeV neutrons and a 5 percent response to fission neutrons on a tissue rad basis. Polymethylpentene dosemeters show a 49 percent response to 14 MeV neutrons and a 40 percent response to fission neutrons on a tissue rad basis when provided with adequate recoil proton buildup. The sensitivity of these dosemeters is limited to neutron doses greater than 10 rads by spurious background currents

RAD51B in Familial Breast Cancer.

Directory of Open Access Journals (Sweden)

Liisa M Pelttari

Full Text Available Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC that were genotyped on a custom chip (iCOGS. We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259 and population controls (n = 3586 from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR: 1.15, 95% confidence interval (CI: 1.11-1.19, P = 8.88 x 10-16 and among familial cases (OR: 1.24, 95% CI: 1.16-1.32, P = 6.19 x 10-11, compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk.

RAD51B in Familial Breast Cancer

Science.gov (United States)

Pelttari, Liisa M.; Khan, Sofia; Vuorela, Mikko; Kiiski, Johanna I.; Vilske, Sara; Nevanlinna, Viivi; Ranta, Salla; Schleutker, Johanna; Winqvist, Robert; Kallioniemi, Anne; Dörk, Thilo; Bogdanova, Natalia V.; Figueroa, Jonine; Pharoah, Paul D. P.; Schmidt, Marjanka K.; Dunning, Alison M.; García-Closas, Montserrat; Bolla, Manjeet K.; Dennis, Joe; Michailidou, Kyriaki; Wang, Qin; Hopper, John L.; Southey, Melissa C.; Rosenberg, Efraim H.; Fasching, Peter A.; Beckmann, Matthias W.; Peto, Julian; dos-Santos-Silva, Isabel; Sawyer, Elinor J.; Tomlinson, Ian; Burwinkel, Barbara; Surowy, Harald; Guénel, Pascal; Truong, Thérèse; Bojesen, Stig E.; Nordestgaard, Børge G.; Benitez, Javier; González-Neira, Anna; Neuhausen, Susan L.; Anton-Culver, Hoda; Brenner, Hermann; Arndt, Volker; Meindl, Alfons; Schmutzler, Rita K.; Brauch, Hiltrud; Brüning, Thomas; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Hartikainen, Jaana M.; Chenevix-Trench, Georgia; Van Dyck, Laurien; Janssen, Hilde; Chang-Claude, Jenny; Rudolph, Anja; Radice, Paolo; Peterlongo, Paolo; Hallberg, Emily; Olson, Janet E.; Giles, Graham G.; Milne, Roger L.; Haiman, Christopher A.; Schumacher, Fredrick; Simard, Jacques; Dumont, Martine; Kristensen, Vessela; Borresen-Dale, Anne-Lise; Zheng, Wei; Beeghly-Fadiel, Alicia; Grip, Mervi; Andrulis, Irene L.; Glendon, Gord; Devilee, Peter; Seynaeve, Caroline; Hooning, Maartje J.; Collée, Margriet; Cox, Angela; Cross, Simon S.; Shah, Mitul; Luben, Robert N.; Hamann, Ute; Torres, Diana; Jakubowska, Anna; Lubinski, Jan; Couch, Fergus J.; Yannoukakos, Drakoulis; Orr, Nick; Swerdlow, Anthony; Darabi, Hatef; Li, Jingmei; Czene, Kamila; Hall, Per; Easton, Douglas F.; Mattson, Johanna; Blomqvist, Carl; Aittomäki, Kristiina; Nevanlinna, Heli

2016-01-01

Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11–1.19, P = 8.88 x 10−16) and among familial cases (OR: 1.24, 95% CI: 1.16–1.32, P = 6.19 x 10−11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk. PMID:27149063

Sensitivity of the human breast to cancer induction by ionizing radiation

Energy Technology Data Exchange (ETDEWEB)

Mole, R H [Medical Research Council, Harwell (UK). Radiobiological Research Unit

1978-06-01

Available evidence for the induction of cancer in the human breast by small doses of radiation is reviewed. A comparison is made of risk estimates for the frequency of breast cancer in excess of controls, per rad of ionizing radiation, resulting from multiple fluoroscopy, radiotherapy of non-malignant diseases of the breast, or the exposure of Japanese bomb survivors. The significance of the age at exposure is discussed, and consideration is given to the application of the evidence to practical problems in radiography, radiotherapy, screening by mammography, and radiological protection for occupational exposure.

A reliability-risk modelling of nuclear rad-waste facilities

International Nuclear Information System (INIS)

Lehmann, P.H.; El-Bassioni, A.A.

1975-01-01

Rad-waste disposal systems of nuclear power sites are designed and operated to collect, delay, contain, and concentrate radioactive wastes from reactor plant processes such that on-site and off-site exposures to radiation are well below permissible limits. To assist the designer in achieving minimum release/exposure goals, a computerized reliability-risk model has been developed to simulate the rad-waste system. The objectives of the model are to furnish a practical tool for quantifying the effects of changes in system configuration, operation, and equipment, and for the identification of weak segments in the system design. Primarily, the model comprises a marriage of system analysis, reliability analysis, and release-risk assessment. Provisions have been included in the model to permit the optimization of the system design subject to constraints on cost and rad-releases. The system analysis phase involves the preparation of a physical and functional description of the rad-waste facility accompanied by the formation of a system tree diagram. The reliability analysis phase embodies the formulation of appropriate reliability models and the collection of model parameters. Release-risk assessment constitutes the analytical basis whereupon further system and reliability analyses may be warranted. Release-risk represents the potential for release of radioactivity and is defined as the product of an element's unreliability at time, t, and the radioactivity available for release in time interval, Δt. A computer code (RARISK) has been written to simulate the tree diagram of the rad-waste system. Reliability and release-risk results have been generated for cases which examined the process flow paths of typical rad-waste systems, the effects of repair and standby, the variations of equipment failure and repair rates, and changes in system configurations. The essential feature of this model is that a complex system like the rad-waste facility can be easily decomposed into its

A dedicated BI-RADS training programme: Effect on the inter-observer variation among screening radiologists

International Nuclear Information System (INIS)

Timmers, J.M.H.; Doorne-Nagtegaal, H.J. van; Verbeek, A.L.M.; Heeten, G.J. den; Broeders, M.J.M.

2012-01-01

Introduction: The Breast Imaging Reporting and Data System (BI-RADS) was introduced in the Dutch breast cancer screening programme to improve communication between medical specialists. Following introduction, a substantial variation in the use of the BI-RADS lexicon for final assessment categories was noted among screening radiologists. We set up a dedicated training programme to reduce this variation. This study evaluates whether this programme was effective. Materials and methods: Two comparable test sets were read before and after completion of the training programme. Each set contained 30 screening mammograms of referred women selected from screening practice. The sets were read by 25 experienced and 30 new screening radiologists. Cohen's kappa (κ) was used to calculate the inter-observer agreement. The BI-RADS 2003 version was implemented in the screening programme as the BI-RADS 2008 version requires the availability of diagnostic work-up, and this is unavailable. Results: The inter-observer agreement of all participating radiologists (n = 55) with the expert panel increased from a pre-training κ-value of 0.44 to a post-training κ-value of 0.48 (p = 0.14). The inter-observer agreement of the new screening radiologists (n = 30) with the expert panel increased from κ = 0.41 to κ = 0.50 (p = 0.01), whereas there was no difference in agreement among the 25 experienced radiologists (from κ = 0.48 to κ = 0.46, p = 0.60). Conclusion: Our training programme in the BI-RADS lexicon resulted in a significant improvement of agreement among new screening radiologists. Overall, the agreement among radiologists was moderate (guidelines Landis and Koch). This is in line with results found in the literature

Differential expression and requirements for Schizosaccharomyces pombe RAD52 homologs in DNA repair and recombination

OpenAIRE

van den Bosch, Michael; Zonneveld, José B. M.; Vreeken, Kees; de Vries, Femke A. T.; Lohman, Paul H. M.; Pastink, Albert

2002-01-01

In fission yeast two RAD52 homologs have been identified, rad22A+ and rad22B+. Two-hybrid experiments and GST pull-down assays revealed physical interaction between Rad22A and Rad22B, which is dependent on the N-terminal regions. Interaction with Rhp51 is dependent on the C-terminal parts of either protein. Both Rad22A and Rad22B also interact with RPA. The expression of rad22B+ in mitotically dividing cells is very low in comparison with rad22A+ but is strongly enhanced after induction of me...

CAD-RADS - a new clinical decision support tool for coronary computed tomography angiography.

Science.gov (United States)

Foldyna, Borek; Szilveszter, Bálint; Scholtz, Jan-Erik; Banerji, Dahlia; Maurovich-Horvat, Pál; Hoffmann, Udo

2018-04-01

Coronary computed tomography angiography (CTA) has been established as an accurate method to non-invasively assess coronary artery disease (CAD). The proposed 'Coronary Artery Disease Reporting and Data System' (CAD-RADS) may enable standardised reporting of the broad spectrum of coronary CTA findings related to the presence, extent and composition of coronary atherosclerosis. The CAD-RADS classification is a comprehensive tool for summarising findings on a per-patient-basis dependent on the highest-grade coronary artery lesion, ranging from CAD-RADS 0 (absence of CAD) to CAD-RADS 5 (total occlusion of a coronary artery). In addition, it provides suggestions for clinical management for each classification, including further testing and therapeutic options. Despite some limitations, CAD-RADS may facilitate improved communication between imagers and patient caregivers. As such, CAD-RADS may enable a more efficient use of coronary CTA leading to more accurate utilisation of invasive coronary angiograms. Furthermore, widespread use of CAD-RADS may facilitate registry-based research of diagnostic and prognostic aspects of CTA. • CAD-RADS is a tool for standardising coronary CTA reports. • CAD-RADS includes clinical treatment recommendations based on CTA findings. • CAD-RADS has the potential to reduce variability of CTA reports.

Nucleotide sequence, transcript mapping, and regulation of the RAD2 gene of Saccharomyces cerevisiae

International Nuclear Information System (INIS)

Madura, K.; Prakash, S.

1986-01-01

The authors determined the nucleotide sequence, mapped the 5' and 3' nRNA termini, and examined the regulation of the RAD2 gene of Saccharomyces cerevisiae. A long open reading frame within the RAD2 transcribed region encodes a protein of 1031 amino acids with a calculated molecular weight of 117,847. A disruption of the RAD2 gene that deletes the 78 carboxyl terminal codons results in loss of RAD2 function. The 5' ends of RAD2 mRNA show considerable heterogeneity, mapping 5 to 62 nucleotides upstream of the first ATG codon of the long RAD2 open reading frame. The longest RAD2 transcripts also contain a short open reading frame of 37 codons that precedes and overlaps the 5' end of the long RAD2 open reading frame. The RAD2 3' nRNA end maps 171 nucleotides downstream of the TAA termination codon and 20 nucleotides downstream from a 12-base-pair inverted repeat that might function in transcript termination. Northern blot analysis showed a ninefold increase in steady-state levels of RAD2 mRNA after treatment of yeast cells with UV light. The 5' flanking region of the RAD2 gene contains several direct and inverted repeats and a 44-nuclotide-long purine-rich tract. The sequence T G G A G G C A T T A A found at position - 167 to -156 in the RAD2 gene is similar to at sequence present in the 5' flanking regions of the RAD7 and RAD10 genes

RADTRAN 6/RadCat 6 user guide.

Energy Technology Data Exchange (ETDEWEB)

Weiner, Ruth F.; Hinojosa, Daniel; Heames, Terence John; Farnum, Cathy Ottinger; Kalinina, Elena Arkadievna

2013-09-01

This document provides a detailed discussion and a guide for the use of the RadCat 6.0 Graphical User Interface input file generator for the RADTRAN code, Version 6. RadCat 6.0 integrates the newest analysis capabilities of RADTRAN 6.0, including an economic model, updated loss-of-lead shielding model, a new ingestion dose model, and unit conversion. As of this writing, the RADTRAN version in use is RADTRAN 6.02.

Assessment of metal sensitizer potency with the reconstructed human epidermis IL-18 assay.

Science.gov (United States)

Gibbs, Susan; Kosten, Ilona; Veldhuizen, Rosalien; Spiekstra, Sander; Corsini, Emanuela; Roggen, Erwin; Rustemeyer, Thomas; Feilzer, Albert J; Kleverlaan, Cees J

2018-01-15

According to the new EU Medical Devices (MDR) legislation coming into effect in 2017, manufactures will have to comply with higher standards of quality and safety for medical devices in order to meet common safety concerns regarding such products. Metal alloys are extensively used in dentistry and medicine (e.g. orthopedic surgery and cardiology) even though clinical experience suggests that many metals are sensitizers. The aim of this study was to further test the applicability domain of the in vitro reconstructed human epidermis (RhE) IL-18 assay developed to identify contact allergens and in doing so: i) determine whether different metal salts, representing leachables from metal alloys used in medical devices, could be correctly labelled and classified; and ii) assess the ability of different salts for the same metal to penetrate the skin stratum corneum. Twenty eight chemicals including 15 metal salts were topically exposed to RhE. Nickel, chrome, gold, palladium were each tested in two different salt forms, and titanium in 4 different salt forms. Metal salts were labelled (YES/NO) as sensitizer if a threshold of more than 5 fold IL18 release was reached. The in vitro estimation of expected sensitization induction level (potency) was assessed by interpolating in vitro EC50 and IL-18 SI2 with LLNA EC3 and human NOEL values from standard reference curves generated using DNCB (extreme) and benzocaine (weak). Metal salts, in contrast to other chemical sensitizers and with the exception of potassium dichromate (VI) and cobalt (II) chloride, were not identified as contact allergens since they only induced a small or no increase in IL-18 production. This finding was not related to a lack of stratum corneum skin penetration since EC50 values (decrease in metabolic activity; MTT assay) were obtained after topical RhE exposure to 8 of the 15 metal salts. For nickel, gold and palladium salts, differences in EC50 values between two salts for the same metal could not be

HSP90 Inhibitors, Geldanamycin and Radicicol, Enhance Fisetin-Induced Cytotoxicity via Induction of Apoptosis in Human Colonic Cancer Cells

Directory of Open Access Journals (Sweden)

Ming-Shun Wu

2013-01-01

Full Text Available We revealed the cytotoxic effect of the flavonoid, fisetin (FIS, on human COLO205 colon cancer cells in the presence and absence of the HSP90 inhibitors, geldanamycin (GA and radicicol (RAD. Compared to FIS treatment alone of COLO205 cells, GA and RAD significantly enhanced FIS-induced cytotoxicity, increased expression of cleaved caspase-3 and the PAPR protein, and produced a greater density of DNA ladder formation. GA and RAD also reduced the MMPs with induction of caspase-9 protein cleavage in FIS-treated COLO205 cells. Increased caspase-3 and -9 activities were detected in COLO205 cells treated with FIS+GA or FIS+RAD, and the intensity of DNA ladder formation induced by FIS+GA was reduced by adding the caspase-3 inhibitor, DEVD-FMK. A decrease in Bcl-2 but not Bcl-XL or Bax protein by FIS+GA or FIS+RAD was identified in COLO205 cells by Western blotting. A reduction in p53 protein with increased ubiquitin-tagged proteins was observed in COLO205 cells treated with FIS+GA or FIS+RAD. Furthermore, GA and RAD reduced the stability of the p53 protein in COLO205 cells under FIS stimulation. The evidence supports HSP90 inhibitors possibly sensitizing human colon cancer cells to FIS-induced apoptosis, and treating colon cancer by combining HSP90 inhibitors with FIS deserves further in vivo study.

Population structure of Atlantic Mackerel inferred from RAD-seq derived SNP markers: effects of sequence clustering parameters and hierarchical SNP selection

KAUST Repository

Rodríguez-Ezpeleta, Naiara

2016-03-03

Restriction-site associated DNA sequencing (RAD-seq) and related methods are revolutionizing the field of population genomics in non-model organisms as they allow generating an unprecedented number of single nucleotide polymorphisms (SNPs) even when no genomic information is available. Yet, RAD-seq data analyses rely on assumptions on nature and number of nucleotide variants present in a single locus, the choice of which may lead to an under- or overestimated number of SNPs and/or to incorrectly called genotypes. Using the Atlantic mackerel (Scomber scombrus L.) and a close relative, the Atlantic chub mackerel (Scomber colias), as case study, here we explore the sensitivity of population structure inferences to two crucial aspects in RAD-seq data analysis: the maximum number of mismatches allowed to merge reads into a locus and the relatedness of the individuals used for genotype calling and SNP selection. Our study resolves the population structure of the Atlantic mackerel, but, most importantly, provides insights into the effects of alternative RAD-seq data analysis strategies on population structure inferences that are directly applicable to other species.

BI-RADS: Use in the French radiologic community

International Nuclear Information System (INIS)

Stines, Joseph

2007-01-01

In the United States, BI-RADS TM (Breast Imaging Reporting and Data System) has been set up as a quality assurance system for better communication between professionals and for the follow-up of breast screening programs. It has become a reference in the field of mammographic imaging and has been adopted by several countries throughout the world. It has been translated in French. The aim of this article is to discuss the difficulties in using it in the French radiologic communities. There are few problems with vocabulary excepted for microcalcifications. BI-RADS TM includes a guidance chapter giving some recommendations for using properly the lexicon. Classification of normal breast remains of concern, as it is difficult to evaluate precisely the content of fat and as the final image is also dependant of technical factors. The main difficulties are related to final classification in BI-RADS TM categories as the lexicon does not explicit which mammographic features should be included in the categories from three to five. In France, a table concerning the classification of mammographic abnormalities has been established by the HAS (former ANAES) which represents the highest scientific health authority in France. There are no major problems for using the BI-RADS TM for US and MRI. BI-RADS TM is suitable for different categories of women and for male and training has an important impact on acceptance and proper use of the lexicon

Regulation of homologous recombination repair protein Rad51 by Ku70

International Nuclear Information System (INIS)

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

2013-01-01

Objective: To explore the regulative effect of non-homologous end joining (NHEJ)protein Ku70 on homologous recombination repair protein Rad51, and to investigate the synergistic mechanism of homologous recombination repair in combination with NHEJ. Methods: Observed Rad51 protein expression after transfect Ku70 small interfering RNA or Ku70 plasmid DNA into tumor cells using Western blot. Results: Expression of Rad51 was obviously reduced after pretreated with Ku70 small interfering RNA. And with the increasing expression of Ku70 protein after transfection of Ku70 plasmid DNA PGCsi3.0-hKu70 into tumor cell lines, the Rad51 protein expression was increased. Conclusion: Ku70 protein has regulating effect on gene expression of Rad51, and it might participate in the collaboration between homologous recombination repair and NHEJ. (authors)

Investigation of centers sensitive to S1-nuclease in the genoma of the yeast S. cerevisiae after in-vivo exposure to gamma radiation

International Nuclear Information System (INIS)

Geigl, E.M.

1987-09-01

The structure, distribution and repair of basal damage in DNS after exposure to 60 Co gamma radiation were investigated in S. cerevisiae cells. Small DNS regions with mispaired or unpaired bases of rather high stability were found whose rate of incidence and linear dose dependence appear to be similar to those of double strand breaks. In contrast to double strand breaks, they showed no statistical' distribution pattern across the genoma. Liquid holding experiments showed that centers sensitive to S1-nuclease will be repaired in S. cerevisiae by a combined process of recombination and postreplication repair; the gene products of the genes RAD50 and RAD18 are involved. (orig./AJ) [de

EVALUATING THE SENSITIVITY OF RADIONUCLIDE DETECTORS FOR CONDUCTING A MARITIME ON-BOARD SEARCH USING MONTE CARLO SIMULATION IMPLEMENTED IN AVERT(regsign)

International Nuclear Information System (INIS)

Harris, S.; Dave Dunn, D.

2009-01-01

The sensitivity of two specific types of radionuclide detectors for conducting an on-board search in the maritime environment was evaluated using Monte Carlo simulation implemented in AVERT(reg s ign). AVERT(reg s ign), short for the Automated Vulnerability Evaluation for Risk of Terrorism, is personal computer based vulnerability assessment software developed by the ARES Corporation. The sensitivity of two specific types of radionuclide detectors for conducting an on-board search in the maritime environment was evaluated using Monte Carlo simulation. The detectors, a RadPack and also a Personal Radiation Detector (PRD), were chosen from the class of Human Portable Radiation Detection Systems (HPRDS). Human Portable Radiation Detection Systems (HPRDS) serve multiple purposes. In the maritime environment, there is a need to detect, localize, characterize, and identify radiological/nuclear (RN) material or weapons. The RadPack is a commercially available broad-area search device used for gamma and also for neutron detection. The PRD is chiefly used as a personal radiation protection device. It is also used to detect contraband radionuclides and to localize radionuclide sources. Neither device has the capacity to characterize or identify radionuclides. The principal aim of this study was to investigate the sensitivity of both the RadPack and the PRD while being used under controlled conditions in a simulated maritime environment for detecting hidden RN contraband. The detection distance varies by the source strength and the shielding present. The characterization parameters of the source are not indicated in this report so the results summarized are relative. The Monte Carlo simulation results indicate the probability of detection of the RN source at certain distances from the detector which is a function of transverse speed and instrument sensitivity for the specified RN source

Differential hRad17 expression by histologic subtype of ovarian cancer

Directory of Open Access Journals (Sweden)

Young Jennifer L

2011-03-01

Full Text Available Abstract Background In the search for unique ovarian cancer biomarkers, ovarian specific cDNA microarray analysis identified hRad17, a cell cycle checkpoint protein, as over-expressed in ovarian cancer. The aim of this study was to validate this expression. Methods Immunohistochemistry was performed on 72 serous, 19 endometrioid, 10 clear cell, and 6 mucinous ovarian cancers, 9 benign ovarian tumors, and 6 normal ovarian tissue sections using an anti-hRad17 antibody. Western blot analysis and quantitative PCR were performed using cell lysates and total RNA prepared from 17 ovarian cancer cell lines and 6 normal ovarian epithelial cell cultures (HOSE. Results Antibody staining confirmed upregulation of hRad17 in 49.5% of ovarian cancer cases. Immunohistochemistry demonstrated that only 42% of serous and 47% of endometrioid subtypes showed overexpression compared to 80% of clear cell and 100% of mucinous cancers. Western blot confirmed overexpression of hRad17 in cancer cell lines compared to HOSE. Quantitative PCR demonstrated an upregulation of hRad17 RNA by 1.5-7 fold. hRad17 RNA expression differed by subtype. Conclusions hRad17 is over-expressed in ovarian cancer. This over-expression varies by subtype suggesting a role in the pathogenesis of these types. Functional studies are needed to determine the potential role of this protein in ovarian cancer.

The accuracy of the SONOBREAST statistical model in comparison to BI-RADS for the prediction of malignancy in solid breast nodules detected at ultrasonography.

Science.gov (United States)

Paulinelli, Regis R; Oliveira, Luis-Fernando P; Freitas-Junior, Ruffo; Soares, Leonardo R

2016-01-01

The objective of the present study was to compare the accuracy of SONOBREAST for the prediction of malignancy in solid breast nodules detected at ultrasonography with that of the BI-RADS system and to assess the agreement between these two methods. This prospective study included 274 women and evaluated 500 breast nodules detected at ultrasonography. The probability of malignancy was calculated based on the SONOBREAST model, available at www.sonobreast.com.br, and on the BI-RADS system, with results being compared with the anatomopathology report. The lesions were considered suspect in 171 cases (34.20%), according to both SONOBREAST and BI-RADS. Agreement between the methods was perfect, as shown by a Kappa coefficient of 1 (pBI-RADS proved identical insofar as sensitivity (95.40%), specificity (78.69%), positive predictive value (48.54%), negative predictive value (98.78%) and accuracy (81.60%) are concerned. With respect to the categorical variables (BI-RADS categories 3, 4 and 5), the area under the receiver operating characteristic (ROC) curve was 94.41 for SONOBREAST (range 92.20-96.62) and 89.99 for BI-RADS (range 86.60-93.37). The accuracy of the SONOBREAST model is identical to that found with BI-RADS when the same parameters are used with respect to the cut-off point at which malignancy is suspected. Regarding the continuous probability of malignancy with BI-RADS categories 3, 4 and 5, SONOBREAST permits a more precise and individualized evaluation. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

The sensitivity of the human breast to cancer induction by ionizing radiation

International Nuclear Information System (INIS)

Mole, R.H.

1978-01-01

Available evidence for the induction of cancer in the human breast by small doses of radiation is reviewed. A comparison is made of risk estimates for the frequency of breast cancer in excess of controls, per rad of ionizing radiation, resulting from multiple fluoroscopy, radiotherapy of non-malignant diseases of the breast, or the exposure of Japanese bomb survivors. The significance of the age at exposure is discussed, and consideration is given to the application of the evidence to practical problems in radiography, radiotherapy, screening by mammography, and radiological protection for occupational exposure. (U.K.)

Increased interreader agreement in diagnosis of hepatocellular carcinoma using an adapted LI-RADS algorithm

Energy Technology Data Exchange (ETDEWEB)

Becker, Anton S., E-mail: anton.becker@usz.ch; Barth, Borna K.; Marquez, Paulo H.; Donati, Olivio F.; Ulbrich, Erika J.; Karlo, Christoph; Reiner, Cäcilia S.; Fischer, Michael A.

2017-01-15

Purpose: To evaluate a simplified Liver Imaging Reporting and Data System (LI-RADS) algorithm to improve interreader agreement while maintaining diagnostic performance for HCC. Materials and methods: MRI scans of 84 cirrhotic patients with 104 distinct liver observations were retrospectively selected to equivocally match each of the LI-RADS grades (LR1-5) using histopathology and imaging follow up as standard of reference. Four independent radiologists categorized all observations as benign (LR1-2) or potentially malignant (LR3-5) and determined LI-RADS based imaging features including observation size, arterial phase hyperenhancement, washout, capsule appearance and threshold growth for LR3-5 observations and timed their readouts. LR3-5 observations were categorized according to the LI-RADS v2014 algorithm and according to a modified LI-RADS (mLI-RADS) version. Diagnostic performance and Interreader agreement were determined for LI-RADS and mLI-RADS using receiver operating characteristics (ROC) and Fleiss’ and Cohen’s Kappa analysis respectively. Results: ROC analysis revealed equal diagnostic performance for LI-RADS and mLI-RADS (area under the ROC curve = 0.91). Interreader agreement was higher using mLI-RADS as compared to current LI-RADS showing an improved overall (κ = 0.53 ± 0.04 vs. 0.45 ± 0.04), and pair-wise agreement between most readers (κ range 0.44-0.62 vs. 0.35-0.60) at a reduced median evaluation time (51 vs. 62 s per observation, p < 0.0001). Conclusion: Focusing on observation size and washout criteria using a modified, stepwise LI-RADS decision tree for LR3-5 observations results in higher interobserver reliability and faster categorization while maintaining diagnostic accuracy.

Temperature-sensitive defects of the GSP1gene, yeast Ran homologue, activate the Tel1-dependent pathway

International Nuclear Information System (INIS)

Hayashi, Naoyuki; Murakami, Seishi; Tsurusaki, Susumu; Nagaura, Zen-ichiro; Oki, Masaya; Nishitani, Hideo; Kobayashi, Masahiko; Shimizu, Hiroko; Yamamoto, Ken-ichi; Nishimoto, Takeharu

2007-01-01

RanGTPase is involved in many cellular processes. It functions in nuclear-cytosolic transport and centrosome formation. Ran also localizes to chromatin as RCC1 does, its guanine nucleotide exchange factor, but Ran's function on chromatin is not known. We found that gsp1, a temperature-sensitive mutant of GSP1, a Saccharomyces cerevisiae Ran homologue, suppressed the hydroxyurea (HU) and ultra violet (UV) sensitivities of the mec1 mutant. In UV-irradiated mec1 gsp1 cells, Rad53 was phosphorylated despite the lack of Mec1. This suppression depended on the TEL1 gene, given that the triple mutant, mec1 gsp1 tel1, was unable to grow. The gsp1 mutations also suppressed the HU sensitivity of the rad9 mutant in a Tel1-dependent manner, but not the HU sensitivity of the rad53 mutant. These results indicated that Rad53 was activated by the Tel1 pathway in mec1 gsp1 cells, suggesting that Gsp1 helps regulate the role switching the ATM family kinases Mec1 and Tel1

Structure of a hexameric form of RadA recombinase from Methanococcus voltae

International Nuclear Information System (INIS)

Du, Liqin; Luo, Yu

2012-01-01

Hexameric rings of RadA recombinase from M. voltae have been crystallized. Structural comparisons suggest that homologues of RadA tend to form double-ringed assemblies. Archaeal RadA proteins are close homologues of eukaryal Rad51 and DMC1 proteins and are remote homologues of bacterial RecA proteins. For the repair of double-stranded breaks in DNA, these recombinases promote a pivotal strand-exchange reaction between homologous single-stranded and double-stranded DNA substrates. This DNA-repair function also plays a key role in the resistance of cancer cells to chemotherapy and radiotherapy and in the resistance of bacterial cells to antibiotics. A hexameric form of a truncated Methanococcus voltae RadA protein devoid of its small N-terminal domain has been crystallized. The RadA hexamers further assemble into two-ringed assemblies. Similar assemblies can be observed in the crystals of Pyrococcus furiosus RadA and Homo sapiens DMC1. In all of these two-ringed assemblies the DNA-interacting L1 region of each protomer points inward towards the centre, creating a highly positively charged locus. The electrostatic characteristics of the central channels can be utilized in the design of novel recombinase inhibitors

Chromosome aberrations in human lymphocytes after irradiation with NIRS-cyclotron fast neutrons in vitro

International Nuclear Information System (INIS)

Muramatsu, Susumu; Maruyama, Takashi

1977-01-01

The dose-response relationships for inducing chromosome aberrations (dicentrics) in human lymphocytes were studied by whole-blood microculture following in vitro exposures at various doses either 200 kVp x-rays or NIRS-cyclotron fast neutrons. The yields of dicentrics induced were dependent on the exposure dose of two types of radiations between 48 to 384 rad and 25 to 400 rad by x-rays and fast neutrons, respectively. The dicentrics yields gave the best fit to the linear quadratic function Y=αD + βD 2 ; namely Y sub(X)=3.66 x 10 -4 D + 8.01 x 10 -6 D 2 for x-rays and Y sub(N)=28.90 x 10 -4 D + 4.04 x 10 -6 D 2 for fast neutrons. The RBE value of NIRS-cyclotron fast neutrons versus 200 kVP x-rays decreased with increasing neutron doses, for example from 2.3 at 50 rad to 1.2 at doses up to 300 rad. (auth.)

Characterisation of the novel deleterious RAD51C p.Arg312Trp variant and prioritisation criteria for functional analysis of RAD51C missense changes.

Science.gov (United States)

Gayarre, Javier; Martín-Gimeno, Paloma; Osorio, Ana; Paumard, Beatriz; Barroso, Alicia; Fernández, Victoria; de la Hoya, Miguel; Rojo, Alejandro; Caldés, Trinidad; Palacios, José; Urioste, Miguel; Benítez, Javier; García, María J

2017-09-26

Despite a high prevalence of deleterious missense variants, most studies of RAD51C ovarian cancer susceptibility gene only provide in silico pathogenicity predictions of missense changes. We identified a novel deleterious RAD51C missense variant (p.Arg312Trp) in a high-risk family, and propose a criteria to prioritise RAD51C missense changes qualifying for functional analysis. To evaluate pathogenicity of p.Arg312Trp variant we used sequence homology, loss of heterozygosity (LOH) and segregation analysis, and a comprehensive functional characterisation. To define a functional-analysis prioritisation criteria, we used outputs for the known functionally confirmed deleterious and benign RAD51C missense changes from nine pathogenicity prediction algorithms. The p.Arg312Trp variant failed to correct mitomycin and olaparib hypersensitivity and to complement abnormal RAD51C foci formation according to functional assays, which altogether with LOH and segregation data demonstrated deleteriousness. Prioritisation criteria were based on the number of predictors providing a deleterious output, with a minimum of 5 to qualify for testing and a PredictProtein score greater than 33 to assign high-priority indication. Our study points to a non-negligible number of RAD51C missense variants likely to impair protein function, provides a guideline to prioritise and encourage their selection for functional analysis and anticipates that reference laboratories should have available resources to conduct such assays.

γ radiation dosimetry in Mega rad range using sugar solution

International Nuclear Information System (INIS)

Venkataramani, R.; Mehta, S.K.; Soman, S.D.

1976-01-01

The formation of malonaldehyde under γ irradiation of solid sucrose and aqueous sucrose, fructose and arabinose solutions has been studied in the Mega rad range. Malonaldehyde (MA) concentration was estimated spectrophotometrically after complexing with 2-thio-barbituric acid. The effect of free radical scavengers (KI and N 2 O) on the yield of MA was investigated. Of the systems studied a 5% aqueous sucrose solution gave a proportional response of MA formation with dose in 0.2 to 5 Mega rad range. A 5% aqueous solution of sucrose prepared from sucrose irradiated in solid state also gave a smooth response of MA yield with dose from 8 to 30 Mega rad. The aqueous and solid sucrose systems together can be conveniently used for dosimetry in the range of 0.2 30 Mega rad. (author)

gamma. radiation dosimetry in Mega rad range using sugar solution

Energy Technology Data Exchange (ETDEWEB)

Venkataramani, R; Mehta, S K; Soman, S D [Bhabha Atomic Research Centre, Bombay (India). Health Physics Div.

1976-09-01

The formation of malonaldehyde under ..gamma.. irradiation of solid sucrose and aqueous sucrose, fructose and arabinose solutions has been studied in the Mega rad range. Malonaldehyde (MA) concentration was estimated spectrophotometrically after complexing with 2-thio-barbituric acid. The effect of free radical scavengers (KI and N/sub 2/O) on the yield of MA was investigated. Of the systems studied a 5% aqueous sucrose solution gave a proportional response of MA formation with dose in 0.2 to 5 Mega rad range. A 5% aqueous solution of sucrose prepared from sucrose irradiated in solid state also gave a smooth response of MA yield with dose from 8 to 30 Mega rad. The aqueous and solid sucrose systems together can be conveniently used for dosimetry in the range of 0.2 30 Mega rad.

Breast imaging reporting and data system (BI-RADS) lexicon for breast MRI: Interobserver variability in the description and assignment of BI-RADS category

International Nuclear Information System (INIS)

El Khoury, Mona; Lalonde, Lucie; David, Julie; Labelle, Maude; Mesurolle, Benoit; Trop, Isabelle

2015-01-01

Highlights: • The use of BI-RADS lexicon in interpreting breast MRI examinations is beneficial. • Our study shows: (a) moderate to substantial agreement between observers and (b) better agreement in interpreting mass than non-mass enhancement (NME). • Careful analysis of the NME should be done to help detect cancer as early as possible. - Abstract: Purpose: To retrospectively evaluate interobserver variability between breast radiologists when describing abnormal enhancement on breast MR examinations and assigning a BI-RADS category using the Breast Imaging Reporting and Data System (BI-RADS) terminology. Materials and methods: Five breast radiologists blinded to patients’ medical history and pathologic results retrospectively and independently reviewed 257 abnormal areas of enhancement on breast MRI performed in 173 women. Each radiologist described the focal enhancement using BI-RADS terminology and assigned a final BI-RADS category. Krippendorff's α coefficient of agreement was used to asses interobserver variability. Results: All radiologists agreed on the morphology of enhancement in 183/257 (71%) lesions, yielding a substantial agreement (Krippendorff's α = 0.71). Moderate agreement was obtained for mass descriptors – shape, margins and internal enhancement – (α = 0.55, 0.51 and 0.45 respectively) and NME (non-mass enhancement) descriptors – distribution and internal enhancement – (α = 0.54 and 0.43). Overall substantial agreement was obtained for BI-RADS category assignment (α = 0.71). It was however only moderate (α = 0.38) for NME compared to mass (α = 0.80). Conclusion: Our study shows good agreement in describing mass and NME on a breast MR examination but a better agreement in predicting malignancy for mass than NME

Breast imaging reporting and data system (BI-RADS) lexicon for breast MRI: Interobserver variability in the description and assignment of BI-RADS category

Energy Technology Data Exchange (ETDEWEB)

El Khoury, Mona, E-mail: monelkhoury@gmail.com [Centre Hospitalier Universitaire de Montréal, Breast Centre, Radiology Department, 3840 Rue Saint Urbain, Montréal, QC H2W1T8 (Canada); Lalonde, Lucie; David, Julie; Labelle, Maude [Centre Hospitalier Universitaire de Montréal, Breast Centre, Radiology Department, 3840 Rue Saint Urbain, Montréal, QC H2W1T8 (Canada); Mesurolle, Benoit [Centre Hospitalier Universitaire de McGill, Cedar Breast Centre, Radiology Department, 687 Pine Avenue West, Montreal, QC H3A1A1 (Canada); Trop, Isabelle [Centre Hospitalier Universitaire de Montréal, Breast Centre, Radiology Department, 3840 Rue Saint Urbain, Montréal, QC H2W1T8 (Canada)

2015-01-15

Highlights: • The use of BI-RADS lexicon in interpreting breast MRI examinations is beneficial. • Our study shows: (a) moderate to substantial agreement between observers and (b) better agreement in interpreting mass than non-mass enhancement (NME). • Careful analysis of the NME should be done to help detect cancer as early as possible. - Abstract: Purpose: To retrospectively evaluate interobserver variability between breast radiologists when describing abnormal enhancement on breast MR examinations and assigning a BI-RADS category using the Breast Imaging Reporting and Data System (BI-RADS) terminology. Materials and methods: Five breast radiologists blinded to patients’ medical history and pathologic results retrospectively and independently reviewed 257 abnormal areas of enhancement on breast MRI performed in 173 women. Each radiologist described the focal enhancement using BI-RADS terminology and assigned a final BI-RADS category. Krippendorff's α coefficient of agreement was used to asses interobserver variability. Results: All radiologists agreed on the morphology of enhancement in 183/257 (71%) lesions, yielding a substantial agreement (Krippendorff's α = 0.71). Moderate agreement was obtained for mass descriptors – shape, margins and internal enhancement – (α = 0.55, 0.51 and 0.45 respectively) and NME (non-mass enhancement) descriptors – distribution and internal enhancement – (α = 0.54 and 0.43). Overall substantial agreement was obtained for BI-RADS category assignment (α = 0.71). It was however only moderate (α = 0.38) for NME compared to mass (α = 0.80). Conclusion: Our study shows good agreement in describing mass and NME on a breast MR examination but a better agreement in predicting malignancy for mass than NME.

The rem mutations in the ATP-binding groove of the Rad3/XPD helicase lead to Xeroderma pigmentosum-Cockayne syndrome-like phenotypes.

Science.gov (United States)

Herrera-Moyano, Emilia; Moriel-Carretero, María; Montelone, Beth A; Aguilera, Andrés

2014-12-01

The eukaryotic TFIIH complex is involved in Nucleotide Excision Repair and transcription initiation. We analyzed three yeast mutations of the Rad3/XPD helicase of TFIIH known as rem (recombination and mutation phenotypes). We found that, in these mutants, incomplete NER reactions lead to replication fork breaking and the subsequent engagement of the homologous recombination machinery to restore them. Nevertheless, the penetrance varies among mutants, giving rise to a phenotype gradient. Interestingly, the mutations analyzed reside at the ATP-binding groove of Rad3 and in vivo experiments reveal a gain of DNA affinity upon damage of the mutant Rad3 proteins. Since mutations at the ATP-binding groove of XPD in humans are present in the Xeroderma pigmentosum-Cockayne Syndrome (XP-CS), we recreated rem mutations in human cells, and found that these are XP-CS-like. We propose that the balance between the loss of helicase activity and the gain of DNA affinity controls the capacity of TFIIH to open DNA during NER, and its persistence at both DNA lesions and promoters. This conditions NER efficiency and transcription resumption after damage, which in human cells would explain the XP-CS phenotype, opening new perspectives to understand the molecular basis of the role of XPD in human disease.

Evidence for a Rad18-independent frameshift mutagenesis pathway in human cell-free extracts.

Directory of Open Access Journals (Sweden)

Régine Janel-Bintz

Full Text Available Bypass of replication blocks by specialized DNA polymerases is crucial for cell survival but may promote mutagenesis and genome instability. To gain insight into mutagenic sub-pathways that coexist in mammalian cells, we examined N-2-acetylaminofluorene (AAF-induced frameshift mutagenesis by means of SV40-based shuttle vectors containing a single adduct. We found that in mammalian cells, as previously observed in E. coli, modification of the third guanine of two target sequences, 5'-GGG-3' (3G and 5'-GGCGCC-3' (NarI site, induces -1 and -2 frameshift mutations, respectively. Using an in vitro assay for translesion synthesis, we investigated the biochemical control of these events. We showed that Pol eta, but neither Pol iota nor Pol zeta, plays a major role in the frameshift bypass of the AAF adduct located in the 3G sequence. By complementing PCNA-depleted extracts with either a wild-type or a non-ubiquitinatable form of PCNA, we found that this Pol eta-mediated pathway requires Rad18 and ubiquitination of PCNA. In contrast, when the AAF adduct is located within the NarI site, TLS is only partially dependent upon Pol eta and Rad18, unravelling the existence of alternative pathways that concurrently bypass this lesion.

Predictive values of BI-RADS{sup ®} magnetic resonance imaging (MRI) in the detection of breast ductal carcinoma in situ (DCIS)

Energy Technology Data Exchange (ETDEWEB)

Badan, Gustavo Machado, E-mail: gustavobadan@hotmail.com [Breast Imaging Service of Radiology Depatment—Irmandade da Santa Casa de Misericórdia de São Paulo, São Paulo, SP (Brazil); Piato, Sebastião [Mastology Division—Gynecology and Obstetrics Department (Brazil); Roveda, Décio; Faria Castro Fleury, Eduardo de [Breast Imaging Service of Radiology Depatment—Irmandade da Santa Casa de Misericórdia de São Paulo, São Paulo, SP (Brazil)

2016-10-15

Purpose: The purpose of this study was to evaluate BI-RADS indicators in the detection of DCIS by MRI. Materials and methods: Prospective observational study that started in 2014 and lasted 24 months. A total of 110 consecutive patients were evaluated, who presented with suspicious or highly suspicious microcalcifications on screening mammography (BI-RADS categories 4 and 5) and underwent stereotactic-guided breast biopsy, having had an MRI scan performed prior to biopsy. Results: Altogether, 38 cases were characterized as positive for malignancy, of which 25 were DCIS and 13 were invasive ductal carcinoma cases. MRI had a sensitivity of 96%; specificity of 75.67%; positive predictive value (PPV) for DCIS detection of 57.14%; negative predictive value (NPV) in the detection of DCIS of 98.24%; and an accuracy of 80.80%. Conclusion: BI-RADS as a tool for the detection of DCIS by MRI is a powerful instrument whose sensitivity was higher when compared to that observed for mammography in the literature. Likewise, the PPV obtained by MRI was higher than that observed in the present study for mammography, and the high NPV obtained on MRI scans can provide early evidence to discourage breast biopsy in selected cases.

Characterization of the interaction between the cohesin subunits Rad21 and SA1/2.

Directory of Open Access Journals (Sweden)

Nenggang Zhang

Full Text Available The cohesin complex is responsible for the fidelity of chromosomal segregation during mitosis. It consists of four core subunits, namely Rad21/Mcd1/Scc1, Smc1, Smc3, and one of the yeast Scc3 orthologs SA1 or SA2. Sister chromatid cohesion is generated during DNA replication and maintained until the onset of anaphase. Among the many proposed models of the cohesin complex, the 'core' cohesin subunits Smc1, Smc3, and Rad21 are almost universally displayed as tripartite ring. However, other than its supportive role in the cohesin ring, little is known about the fourth core subunit SA1/SA2. To gain deeper insight into the function of SA1/SA2 in the cohesin complex, we have mapped the interactive regions of SA2 and Rad21 in vitro and ex vivo. Whereas SA2 interacts with Rad21 through a broad region (301-750 aa, Rad21 binds to SA proteins through two SA-binding motifs on Rad21, namely N-terminal (NT and middle part (MP SA-binding motif, located at 60-81 aa of the N-terminus and 383-392 aa of the MP of Rad21, respectively. The MP SA-binding motif is a 10 amino acid, α-helical motif. Deletion of these 10 amino acids or mutation of three conserved amino acids (L(385, F(389, and T(390 in this α-helical motif significantly hinders Rad21 from physically interacting with SA1/2. Besides the MP SA-binding motif, the NT SA-binding motif is also important for SA1/2 interaction. Although mutations on both SA-binding motifs disrupt Rad21-SA1/2 interaction, they had no apparent effect on the Smc1-Smc3-Rad21 interaction. However, the Rad21-Rad21 dimerization was reduced by the mutations, indicating potential involvement of the two SA-binding motifs in the formation of the two-ring handcuff for chromosomal cohesion. Furthermore, mutant Rad21 proteins failed to significantly rescue precocious chromosome separation caused by depletion of endogenous Rad21 in mitotic cells, further indicating the physiological significance of the two SA-binding motifs of Rad21.

Mammalian RAD52 Functions in Break-Induced Replication Repair of Collapsed DNA Replication Forks

DEFF Research Database (Denmark)

Sotiriou, Sotirios K; Kamileri, Irene; Lugli, Natalia

2016-01-01

Human cancers are characterized by the presence of oncogene-induced DNA replication stress (DRS), making them dependent on repair pathways such as break-induced replication (BIR) for damaged DNA replication forks. To better understand BIR, we performed a targeted siRNA screen for genes whose...... RAD52 facilitates repair of collapsed DNA replication forks in cancer cells....

A uniform system for mammographic reporting BI-RADS

International Nuclear Information System (INIS)

Masroor, I.; Ahmad, M. N.; Sheikh, M. Y.

2001-01-01

Breast image reporting and data system (BI-RADS) is a new system of categorizing and reporting mammographs and mammographic findings recommended by American College of Radiology. The importance of BI-RADS and final assessment categories are discussed. The purpose is to introduce the above-mentioned mammographic reporting system so that it becomes a standard terminology among the medical personnel, involved in the diagnosis and management of breast diseases. (author)

The single-strand DNA binding activity of human PC4 preventsmutagenesis and killing by oxidative DNA damage

Energy Technology Data Exchange (ETDEWEB)

Wang, Jen-Yeu; Sarker, Altaf Hossain; Cooper, Priscilla K.; Volkert, Michael R.

2004-02-01

Human positive cofactor 4 (PC4) is a transcriptional coactivator with a highly conserved single-strand DNA (ssDNA) binding domain of unknown function. We identified PC4 as a suppressor of the oxidative mutator phenotype of the Escherichia coli fpg mutY mutant and demonstrate that this suppression requires its ssDNA binding activity. Yeast mutants lacking their PC4 ortholog Sub1 are sensitive to hydrogen peroxide and exhibit spontaneous and peroxide induced hypermutability. PC4 expression suppresses the peroxide sensitivity of the yeast sub l{Delta} mutant, suggesting that the human protein has a similar function. A role for yeast and human proteins in DNA repair is suggested by the demonstration that Sub1 acts in a peroxide-resistance pathway involving Rad2 and by the physical interaction of PC4 with the human Rad2 homolog XPG. We show XPG recruits PC4 to a bubble-containing DNA substrate with resulting displacement of XPG and formation of a PC4-DNA complex. We discuss the possible requirement for PC4 in either global or transcription-coupled repair of oxidative DNA damage to mediate the release of XPG bound to its substrate.

Sensitization of a transplantable murine fibrosarcoma by partial synchronization with hydroxyurea

International Nuclear Information System (INIS)

Kummermehr, J.; Trott, K.R.; Gesellschaft fuer Strahlen- und Umweltforschung m.b.H., Neuherberg/Muenchen

1977-01-01

A C3H fibrosarcoma was synchronized by an injection schedule of hydroxyurea adjusted to its proliferation kinetics. By imposing an 8 h block, 70% of the proliferating non-S-phase cells were accumulated and entered the S-phase synchronously between 2 and 3 h after the last injection. Progression of S-phase cells exposed to hydroxyurea was severely disturbed whereas progression of the synchronized population was nearly normal. Tumours were given a local irradiation with single doses of 300kV X-rays either 2 h after the last hydroxyurea injection, when the synchronized population was still at the G 1 /S-border, or 6 h after the last injection, when cells had proceeded into mid S-phase. Doses ranged from 600 rad to 2400 rad and were given under ambient or hypoxic conditions. The tumour volume was measured at regular intervals. The median regrowth delay of tumours irradiated in air without hydroxyurea displayed a typical biphasic dose/response curve. Tumours irradiated 6 h after hydroxyurea injection showed the same response. For tumours irradiated 2 h after hydroxyurea injection, a significant increase in delay time was found after 600 rad had been given in air, but not after higher doses. A similar sensitizing effect could be detected after 2400 rad had been given under hypoxic conditions. The sensitizing effect of synchronization could be repeated 2 days after a first dose of 600 rad but not after 3 or 4 days. Repeating the synchronization and 600 rad irradiation schedule three times was less effective than irradiating with 3 fractions of 600 rad in 4 days. (author)

RAD51 Is a Selective DNA Repair Target to Radiosensitize Glioma Stem Cells.

Science.gov (United States)

King, Harry O; Brend, Tim; Payne, Helen L; Wright, Alexander; Ward, Thomas A; Patel, Karan; Egnuni, Teklu; Stead, Lucy F; Patel, Anjana; Wurdak, Heiko; Short, Susan C

2017-01-10

Patients with glioblastoma die from local relapse despite surgery and high-dose radiotherapy. Resistance to radiotherapy is thought to be due to efficient DNA double-strand break (DSB) repair in stem-like cells able to survive DNA damage and repopulate the tumor. We used clinical samples and patient-derived glioblastoma stem cells (GSCs) to confirm that the DSB repair protein RAD51 is highly expressed in GSCs, which are reliant on RAD51-dependent DSB repair after radiation. RAD51 expression and RAD51 foci numbers fall when these cells move toward astrocytic differentiation. In GSCs, the small-molecule RAD51 inhibitors RI-1 and B02 prevent RAD51 focus formation, reduce DNA DSB repair, and cause significant radiosensitization. We further demonstrate that treatment with these agents combined with radiation promotes loss of stem cells defined by SOX2 expression. This indicates that RAD51-dependent repair represents an effective and specific target in GSCs. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Extracting BI-RADS Features from Portuguese Clinical Texts.

Science.gov (United States)

Nassif, Houssam; Cunha, Filipe; Moreira, Inês C; Cruz-Correia, Ricardo; Sousa, Eliana; Page, David; Burnside, Elizabeth; Dutra, Inês

2012-01-01

In this work we build the first BI-RADS parser for Portuguese free texts, modeled after existing approaches to extract BI-RADS features from English medical records. Our concept finder uses a semantic grammar based on the BIRADS lexicon and on iterative transferred expert knowledge. We compare the performance of our algorithm to manual annotation by a specialist in mammography. Our results show that our parser's performance is comparable to the manual method.

El radón: ¿riesgo para la salud?

Directory of Open Access Journals (Sweden)

Juan Miguel Barros Dios

2011-12-01

Full Text Available El radón (Rn222 es un gas noble radiactivo que procede directamente del radio (Ra226 cuando este emite una partícula alfa (dos protones y dos neutrones o núcleo de helio, y que a su vez se transforma en otro elemento radiactivo (Po218 al desprenderse de otra partícula alfa. Desde hace varias décadas se conoce su efecto como factor de riesgo del cáncer primario pulmonar, primero en mineros del uranio y posteriormente en la población general expuesta al radón residencial en hogares construidos sobre suelos de rocas ricas en uranio (U238, elemento inicial de la cadena de degradación radiactiva de la que procede el radón. Áreas geológicamente constituidas por granitos o pizarras, como son las de gran parte de Galicia y todo el noroeste y oeste de la península ibérica, han sido catalogadas como de alto riesgo de exhalación de radón al interior de edificios y domicilios. En numerosos países de América y Europa existen desde hace varios lustros, políticas de prevención del cáncer pulmonar en aquellas zonas de riesgo basadas en programas de reducción de radón en los domicilios y edificios públicos. Desde finales de los años 80, la radiación alfa procedente del radón y sus descen- dientes de vida media corta han sido clasificados como agentes cancerígenos por la Internacional Agency of Research on Cancer (Lyon, 1988 y el Nacional Research Council (BEIR IV, 1988, constituyendo la segunda causa de cáncer pulmonar después del tabaco, y responsable del 10 al 15 % de todas las muertes por esa neoplasia. Estudios realizados en Galicia confirman esta evidencia, con riesgos de 2 a 3 en expuestos a concentraciones del gas en domicilios y la responsabilidad directa del 9% de todos los casos de cáncer pulmonar del área estudiada y una interacción radón/tabaco que multiplica por 45 el riesgo.

Location of RAD51-like protein during meiotic prophase in Eimeria tenella.

Science.gov (United States)

Del Cacho, Emilio; Gallego, Margarita; Pagés, Marc; Barbero, José Luís; Monteagudo, Luís; Sánchez-Acedo, Caridad

2011-05-31

This study focuses on reporting events in Eimeria tenella oocysts from early to late prophase I in terms of RAD51 protein in association with the synaptonemal complex formed between homologous chromosomes. The aim of the study was the sequential localization of RAD51 protein, which is involved in the repair of double-strand breaks (DSBs) on the eimerian chromosomes as they synapse and desynapse. Structural Maintenance of Chromosome protein SMC3, which plays a role in synaptonemal complex formation, was labeled to identify initiation and progress of chromosome synapsis and desynapsis in parallel with the appearance and disappearance of RAD51 foci. Antibodies directed against RAD51 and cohesin subunit SMC3 proteins were labeled with either fluorescence or colloidal gold to visualize RAD51 protein foci and synaptonemal complexes. RAD51 protein localization during prophase I was studied on meiotic chromosomes spreads obtained from oocysts at different points in time after the start of sporulation. The present findings showed that foci detected with the antibody directed against RAD51 protein first appeared at the pre-leptotene stage before homologous chromosomes began pairing. Subsequently, the foci were detected in association with the lateral elements at the precise sites where synapsis were in progress. These findings lead us to suggest that in E. tenella, homologous chromosome pairing was a DSB-dependent mechanism and reinforced the participation of RAD51 protein in meiotic homology search, alignment and pairing of chromosomes. Copyright © 2010 Elsevier B.V. All rights reserved.

Effects of oxygen and TMPN on the initial part of the dose-effect curves of human cells in culture

International Nuclear Information System (INIS)

Pettersen, E.O.; Wibe, E.; Lovhaug, D.; Oftebro, R.; Brustad, T.

1975-01-01

Human cells of the established cell line NHIK 3025 have been irradiated under various conditions of oxygen and TMPN concentrations. Complete survival curves are presented for each concentration of both oxygen and TMPN. The survival curves for extremely hypoxic cells in the absence of TMPN were found to be strictly exponential in the dose range below about 2300 rad, irrespective of the technique used. Oxygen at a concentration of 37 ppm was found to protect the cells at least above the dose range up to 2500 rad, while 250 ppm of oxygen exerted a protective effect in the dose range below 1200 rad and a sensitizing effect (OER = 1.43) for higher doses. However, the protective effect below 700 rad was found to be higher in the presence of 250 ppm O 2 , than 37 ppm O 2 , indicating that the degree of protection in this low-dose range is optimal for an oxygen concentration higher than 37 ppm. TMPN provides a protective and a sensitizing effect in about the same way as oxygen does, but TMPN is less effective. When the TMPN concentration is increased from 0.5 to 10 mM the maximum dose for which TMPN exerts a protective effect on the hypoxic cells decreases from 700 to 400 rad. However the degree of protection in the dose range below 300 rad is higher for TMPN concentrations of 1 mM and 3 mM than for 0.5 mM and 10 mM. Results indicate that the degree of protection is optimal in the low-dose range (< 300 rad) for a TMPN concentration somewhere between 0.5 mM and 3 mM. (author)

RBE/absorbed dose relationship of d(50)-Be neutrons determined for early intestinal tolerance in mice

International Nuclear Information System (INIS)

Gueulette, J.; Wambersie, A.

1978-01-01

RBE/absorbed dose relationship of d(50)-Be neutrons (ref.: 60 Co) was determined using intestinal tolerance in mice (LD50) after single and fractionated irradiation. RBE is 1.8 for a single fraction (about 1000 rad 60 Co dose); it increases when decreasing dose and reaches the plateau value of 2.8 for a 60 Co dose of about 200 rad. This RBE value is used for the clinical applications with the cyclotron 'Cyclone' at Louvain-la-Neuve [fr

Evaluation of the ESUR PI-RADS scoring system for multiparametric MRI of the prostate with targeted MR/TRUS fusion-guided biopsy at 3.0 Tesla.

Science.gov (United States)

Roethke, M C; Kuru, T H; Schultze, S; Tichy, D; Kopp-Schneider, A; Fenchel, M; Schlemmer, H-P; Hadaschik, B A

2014-02-01

To evaluate the Prostate Imaging Reporting and Data System (PI-RADS) proposed by the European Society of Urogenital Radiology (ESUR) for detection of prostate cancer (PCa) by multiparametric magnetic resonance imaging (mpMRI) in a consecutive cohort of patients with magnetic resonance/transrectal ultrasound (MR/TRUS) fusion-guided biopsy. Suspicious lesions on mpMRI at 3.0 T were scored according to the PI-RADS system before MR/TRUS fusion-guided biopsy and correlated to histopathology results. Statistical correlation was obtained by a Mann-Whitney U test. Receiver operating characteristics (ROC) and optimal thresholds were calculated. In 64 patients, 128/445 positive biopsy cores were obtained out of 95 suspicious regions of interest (ROIs). PCa was present in 27/64 (42%) of the patients. ROC results for the aggregated PI-RADS scores exhibited higher areas under the curve compared to those of the Likert score. Sensitivity/Specificity for the following thresholds were calculated: 85 %/73 % and 67 %/92 % for PI-RADS scores of 9 and 10, respectively; 85 %/60 % and 56 %/97 % for Likert scores of 3 and 4, respectively [corrected. The standardised ESUR PI-RADS system is beneficial to indicate the likelihood of PCa of suspicious lesions on mpMRI. It is also valuable to identify locations to be targeted with biopsy. The aggregated PI-RADS score achieved better results compared to the single five-point Likert score. • The ESUR PI-RADS scoring system was evaluated using multiparametric 3.0-T MRI. • To investigate suspicious findings, transperineal MR/TRUS fusion-guided biopsy was used. • PI-RADS can guide biopsy locations and improve detection of clinically significant cancer. • Biopsy procedures can be optimised, reducing unnecessary negative biopsies for patients. • The PI-RADS scoring system may contribute to more effective prostate MRI.

A real-time sub-μrad laser beam tracking system

Science.gov (United States)

Buske, Ivo; Schragner, Ralph; Riede, Wolfgang

2007-10-01

We present a rugged and reliable real-time laser beam tracking system operating with a high speed, high resolution piezo-electric tip/tilt mirror. Characteristics of the piezo mirror and position sensor are investigated. An industrial programmable automation controller is used to develop a real-time digital PID controller. The controller provides a one million field programmable gate array (FPGA) to realize a high closed-loop frequency of 50 kHz. Beam tracking with a root-mean-squared accuracy better than 0.15 μrad has been laboratory confirmed. The system is intended as an add-on module for established mechanical mrad tracking systems.

RAD21L, a novel cohesin subunit implicated in linking homologous chromosomes in mammalian meiosis.

Science.gov (United States)

Lee, Jibak; Hirano, Tatsuya

2011-01-24

Cohesins are multi-subunit protein complexes that regulate sister chromatid cohesion during mitosis and meiosis. Here we identified a novel kleisin subunit of cohesins, RAD21L, which is conserved among vertebrates. In mice, RAD21L is expressed exclusively in early meiosis: it apparently replaces RAD21 in premeiotic S phase, becomes detectable on the axial elements in leptotene, and stays on the axial/lateral elements until mid pachytene. RAD21L then disappears, and is replaced with RAD21. This behavior of RAD21L is unique and distinct from that of REC8, another meiosis-specific kleisin subunit. Remarkably, the disappearance of RAD21L at mid pachytene correlates with the completion of DNA double-strand break repair and the formation of crossovers as judged by colabeling with molecular markers, γ-H2AX, MSH4, and MLH1. RAD21L associates with SMC3, STAG3, and either SMC1α or SMC1β. Our results suggest that cohesin complexes containing RAD21L may be involved in synapsis initiation and crossover recombination between homologous chromosomes.

Multivariate Models for Prediction of Human Skin Sensitization ...

Science.gov (United States)

One of the lnteragency Coordinating Committee on the Validation of Alternative Method's (ICCVAM) top priorities is the development and evaluation of non-animal approaches to identify potential skin sensitizers. The complexity of biological events necessary to produce skin sensitization suggests that no single alternative method will replace the currently accepted animal tests. ICCVAM is evaluating an integrated approach to testing and assessment based on the adverse outcome pathway for skin sensitization that uses machine learning approaches to predict human skin sensitization hazard. We combined data from three in chemico or in vitro assays - the direct peptide reactivity assay (DPRA), human cell line activation test (h-CLAT) and KeratinoSens TM assay - six physicochemical properties and an in silico read-across prediction of skin sensitization hazard into 12 variable groups. The variable groups were evaluated using two machine learning approaches , logistic regression and support vector machine, to predict human skin sensitization hazard. Models were trained on 72 substances and tested on an external set of 24 substances. The six models (three logistic regression and three support vector machine) with the highest accuracy (92%) used: (1) DPRA, h-CLAT and read-across; (2) DPRA, h-CLAT, read-across and KeratinoSens; or (3) DPRA, h-CLAT, read-across, KeratinoSens and log P. The models performed better at predicting human skin sensitization hazard than the murine

Radiomic modeling of BI-RADS density categories

Science.gov (United States)

Wei, Jun; Chan, Heang-Ping; Helvie, Mark A.; Roubidoux, Marilyn A.; Zhou, Chuan; Hadjiiski, Lubomir

2017-03-01

Screening mammography is the most effective and low-cost method to date for early cancer detection. Mammographic breast density has been shown to be highly correlated with breast cancer risk. We are developing a radiomic model for BI-RADS density categorization on digital mammography (FFDM) with a supervised machine learning approach. With IRB approval, we retrospectively collected 478 FFDMs from 478 women. As a gold standard, breast density was assessed by an MQSA radiologist based on BI-RADS categories. The raw FFDMs were used for computerized density assessment. The raw FFDM first underwent log-transform to approximate the x-ray sensitometric response, followed by multiscale processing to enhance the fibroglandular densities and parenchymal patterns. Three ROIs were automatically identified based on the keypoint distribution, where the keypoints were obtained as the extrema in the image Gaussian scale-space. A total of 73 features, including intensity and texture features that describe the density and the parenchymal pattern, were extracted from each breast. Our BI-RADS density estimator was constructed by using a random forest classifier. We used a 10-fold cross validation resampling approach to estimate the errors. With the random forest classifier, computerized density categories for 412 of the 478 cases agree with radiologist's assessment (weighted kappa = 0.93). The machine learning method with radiomic features as predictors demonstrated a high accuracy in classifying FFDMs into BI-RADS density categories. Further work is underway to improve our system performance as well as to perform an independent testing using a large unseen FFDM set.

RadCon: Parameter report focusing on Tropical and Subtropical environments in Australia

International Nuclear Information System (INIS)

Domel, R.U.; Crawford, J; Harris, F.; Twining, J.

2000-09-01

Models to simulate the transfer of radionuclides through air, water and terrestrial ecosystems have been developed and used regularly over the last 20 years. RadCon was developed as a simple model to assess the radiological consequences, as dose, to humans of short-term depositions of radionuclides. Internal exposure via inhalation and ingestion are included in this model as well as external exposure from the passing cloud (cloud shine) and from radioactivity deposited on the ground (ground shine).Initially, the RadCon model will deal with the Australian and South East Asian region but flexibility has been incorporated into the design to allow application in other regions. In a manner similar to a geographic information system, the display of input and output data allows quick access to the results, both numerically and graphically. Coloured concentration gradients, stepping through time, are superimposed on the area of interest to present atmospheric and ground concentrations of the radionuclides and, after the calculations, human dose. The model has portability across computer platforms.This report summarises the parameters and some of the transfer factors underlying the calculations. While the focus was on the tropical and subtropical regions in Australia, for many parameters the values may only have been available for temperate regions, in which case this has been used as the default value. The parameter flexibility is a major aspect of this model and a report to describe the editor has been written (Crawford and Domel, ANSTO/M-129). The aim of this document is to chronologically expand on the formulae and parameter tables presented in the Technical Guide (Crawford et al., ANSTO/E-744, May 2000). The two documents should be read together with the Technical Guide presenting the mathematical computations and this report presenting some of the input values used to calculate the end-point results from the computations. A User Guide to assist in the implementation

Effect of irradiation on human T-cell proliferation: low dose irradiation stimulates mitogen-induced proliferation and function of the suppressor/cytotoxic T-cell subset

International Nuclear Information System (INIS)

Gualde, N.; Goodwin, J.S.

1984-01-01

Unfractionated human T cells exposed to 10-50 rad of X irradiation incorporated less [ 3 H]thymidine than nonirradiated T cells when subsequently cultured with PHA or Con A. The cytotoxic/suppressor T-cell subset, isolated as either OKT8(+) or OKT4(-) cells, demonstrated significantly enhanced [ 3 H]thymidine incorporation in PHA- or Con A-stimulated cultures after exposure to 10-50 rad, compared to unirradiated cells, while the proliferation of the OKT4(+) helper/inducer subset was inhibited by low dose irradiation. It has been previously reported that approximately 30% of the cytotoxic/suppressor subset also stains with OKM1. When the cytotoxic/suppressor subset was further subdivided into OKT4(-), OKM1(+), and OKT4(-), OKM1(-) cells, proliferation of the OKT4(-), OKM1(+) population was inhibited by exposure to 25 rad while proliferation of the OKT4(-), OKM1(-) population was stimulated. The increase in proliferation of the cytotoxic/suppressor T-cell subset after low dose irradiation is paralleled by an increase in suppressor activity of these cells. T cells exposed to 25 rad and then cultured with Con A for 48 hr caused greater inhibition of IgG production when added to fresh autologous lymphocytes stimulated by pokeweed mitogen than did unirradiated cells. Thus, low dose irradiation enhances both the proliferation and function of the human suppressor T-cell subset

RadNet Air Quality (Deployable) Data

Data.gov (United States)

U.S. Environmental Protection Agency — RadNet Deployable Monitoring is designed to collect radiological and meteorological information and data asset needed to establish the impact of radiation levels on...

The AtRAD21.1 and AtRAD21.3 Arabidopsis cohesins play a synergistic role in somatic DNA double strand break damage repair

Czech Academy of Sciences Publication Activity Database

da Costa-Nunes, J.A.; Capitao, C.; Kozák, Jaroslav; Costa-Nunes, P.; Ducasa, G.M.; Pontes, O.; Angelis, Karel

2014-01-01

Roč. 14, DEC 16 2014 (2014) ISSN 1471-2229 R&D Projects: GA MŠk(CZ) LD13006; GA ČR GA13-06595S Institutional support: RVO:61389030 Keywords : Arabidopsis * AtRAD21.1 * AtRAD21.3 Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.813, year: 2014

The DNA translocase RAD5A acts independently of the other main DNA repair pathways, and requires both its ATPase and RING domain for activity in Arabidopsis thaliana.

Science.gov (United States)

Klemm, Tobias; Mannuß, Anja; Kobbe, Daniela; Knoll, Alexander; Trapp, Oliver; Dorn, Annika; Puchta, Holger

2017-08-01

Multiple pathways exist to repair DNA damage induced by methylating and crosslinking agents in Arabidopsis thaliana. The SWI2/SNF2 translocase RAD5A, the functional homolog of budding yeast Rad5 that is required for the error-free branch of post-replicative repair, plays a surprisingly prominent role in the repair of both kinds of lesions in Arabidopsis. Here we show that both the ATPase domain and the ubiquitination function of the RING domain of the Arabidopsis protein are essential for the cellular response to different forms of DNA damage. To define the exact role of RAD5A within the complex network of DNA repair pathways, we crossed the rad5a mutant line with mutants of different known repair factors of Arabidopsis. We had previously shown that RAD5A acts independently of two main pathways of replication-associated DNA repair defined by the helicase RECQ4A and the endonuclease MUS81. The enhanced sensitivity of all double mutants tested in this study indicates that the repair of damaged DNA by RAD5A also occurs independently of nucleotide excision repair (AtRAD1), single-strand break repair (AtPARP1), as well as microhomology-mediated double-strand break repair (AtTEB). Moreover, RAD5A can partially complement for a deficient AtATM-mediated DNA damage response in plants, as the double mutant shows phenotypic growth defects. © 2017 The Authors The Plant Journal © 2017 John Wiley & Sons Ltd.

Tsuruga: 1 ton, some 10 mCi of rad-liquid leaks out to the sea, no environmental and human costs

International Nuclear Information System (INIS)

1981-01-01

In the Tsuruga Nuclear Power Station of Japan Atomic Power Co., the leakage of radioactivity from the site into the sea occurred, as follows. Due to a valve being left open on March 8, 1981, the overflow of liquid waste from the filter sludge storage tank into the laundry waste filtering room took place. A part of it leaked through the floor into the general underground waterway. The amount was estimated to be one ton with some 10 mCi. The incident is reviewed with the following topics: nobody expected rad-material in the waterway with the leakage from a filter sludge tank; construction, human and management mistakes were revealed in the survey; no environmental impact, with the defect peculiar to Tsuruga; JAPCO executives assume the responsibility; JAPCO and regulatory authorities need review. (Mori, K.)

Mek1 Down Regulates Rad51 Activity during Yeast Meiosis by Phosphorylation of Hed1.

Science.gov (United States)

Callender, Tracy L; Laureau, Raphaelle; Wan, Lihong; Chen, Xiangyu; Sandhu, Rima; Laljee, Saif; Zhou, Sai; Suhandynata, Ray T; Prugar, Evelyn; Gaines, William A; Kwon, YoungHo; Börner, G Valentin; Nicolas, Alain; Neiman, Aaron M; Hollingsworth, Nancy M

2016-08-01

During meiosis, programmed double strand breaks (DSBs) are repaired preferentially between homologs to generate crossovers that promote proper chromosome segregation at Meiosis I. In many organisms, there are two strand exchange proteins, Rad51 and the meiosis-specific Dmc1, required for interhomolog (IH) bias. This bias requires the presence, but not the strand exchange activity of Rad51, while Dmc1 is responsible for the bulk of meiotic recombination. How these activities are regulated is less well established. In dmc1Δ mutants, Rad51 is actively inhibited, thereby resulting in prophase arrest due to unrepaired DSBs triggering the meiotic recombination checkpoint. This inhibition is dependent upon the meiosis-specific kinase Mek1 and occurs through two different mechanisms that prevent complex formation with the Rad51 accessory factor Rad54: (i) phosphorylation of Rad54 by Mek1 and (ii) binding of Rad51 by the meiosis-specific protein Hed1. An open question has been why inhibition of Mek1 affects Hed1 repression of Rad51. This work shows that Hed1 is a direct substrate of Mek1. Phosphorylation of Hed1 at threonine 40 helps suppress Rad51 activity in dmc1Δ mutants by promoting Hed1 protein stability. Rad51-mediated recombination occurring in the absence of Hed1 phosphorylation results in a significant increase in non-exchange chromosomes despite wild-type levels of crossovers, confirming previous results indicating a defect in crossover assurance. We propose that Rad51 function in meiosis is regulated in part by the coordinated phosphorylation of Rad54 and Hed1 by Mek1.

Mek1 Down Regulates Rad51 Activity during Yeast Meiosis by Phosphorylation of Hed1.

Directory of Open Access Journals (Sweden)

Tracy L Callender

2016-08-01

Full Text Available During meiosis, programmed double strand breaks (DSBs are repaired preferentially between homologs to generate crossovers that promote proper chromosome segregation at Meiosis I. In many organisms, there are two strand exchange proteins, Rad51 and the meiosis-specific Dmc1, required for interhomolog (IH bias. This bias requires the presence, but not the strand exchange activity of Rad51, while Dmc1 is responsible for the bulk of meiotic recombination. How these activities are regulated is less well established. In dmc1Δ mutants, Rad51 is actively inhibited, thereby resulting in prophase arrest due to unrepaired DSBs triggering the meiotic recombination checkpoint. This inhibition is dependent upon the meiosis-specific kinase Mek1 and occurs through two different mechanisms that prevent complex formation with the Rad51 accessory factor Rad54: (i phosphorylation of Rad54 by Mek1 and (ii binding of Rad51 by the meiosis-specific protein Hed1. An open question has been why inhibition of Mek1 affects Hed1 repression of Rad51. This work shows that Hed1 is a direct substrate of Mek1. Phosphorylation of Hed1 at threonine 40 helps suppress Rad51 activity in dmc1Δ mutants by promoting Hed1 protein stability. Rad51-mediated recombination occurring in the absence of Hed1 phosphorylation results in a significant increase in non-exchange chromosomes despite wild-type levels of crossovers, confirming previous results indicating a defect in crossover assurance. We propose that Rad51 function in meiosis is regulated in part by the coordinated phosphorylation of Rad54 and Hed1 by Mek1.

Studies of DNA repair in Saccharomyces cerevisiae. I. Characterization of a new allele of RAD6. II. Investigation of events in the first cell cycle after DNA damage

International Nuclear Information System (INIS)

Dolthwright-Fasse, J.A.

1980-01-01

Studies in two independent, but related, areas of DNA repair have been carried out in the eucaryotic yeast, Saccharomyces cerevisiae. The first is the characterization of a new allele in the RAD6 gene suggesting that the gene is multifunctional. The second is the utilization of photoreactivation as a probe of events occurring during the first cell cycle after DNA damage. Strains carrying the new allele, designated rad6-4, of the RAD6 locus are about as sensitive to uv and ionizing radiation as those carrying rad6-1 or rad6-3. Although rad6-4 may well be a missense mutation, the data suggest that the RAD6 gene is multifunctional. One function is necessary to recover from DNA damage in an error-free manner, and the other is concerned with mutagenic processes and sporulation. The loss of photoreversibility (LOP) of ultraviolet induced mutations to arginine independence in an excision defective strain carrying arg4-17 examines the events occurring in the first cell cycle. The post uv protein synthesis causes pyrimidine dimmers to become inaccessible to the photoreactivating enzyme in some unknown manner. There is no evidence indicating whether the normal function of the protein is involved in excision repair, or in one of the two repair processes believed to be inducible; induced mutagenesis or recombinational repair

Hypoxia Potentiates the Radiation-Sensitizing Effect of Olaparib in Human Non-Small Cell Lung Cancer Xenografts by Contextual Synthetic Lethality

Energy Technology Data Exchange (ETDEWEB)

Jiang, Yanyan; Verbiest, Tom; Devery, Aoife M.; Bokobza, Sivan M.; Weber, Anika M.; Leszczynska, Katarzyna B.; Hammond, Ester M.; Ryan, Anderson J., E-mail: anderson.ryan@oncology.ox.ac.uk

2016-06-01

Purpose: Poly(ADP-ribose) polymerase (PARP) inhibitors potentiate radiation therapy in preclinical models of human non-small cell lung cancer (NSCLC) and other types of cancer. However, the mechanisms underlying radiosensitization in vivo are incompletely understood. Herein, we investigated the impact of hypoxia on radiosensitization by the PARP inhibitor olaparib in human NSCLC xenograft models. Methods and Materials: NSCLC Calu-6 and Calu-3 cells were irradiated in the presence of olaparib or vehicle under normoxic (21% O{sub 2}) or hypoxic (1% O{sub 2}) conditions. In vitro radiosensitivity was assessed by clonogenic survival assay and γH2AX foci assay. Established Calu-6 and Calu-3 subcutaneous xenografts were treated with olaparib (50 mg/kg, daily for 3 days), radiation (10 Gy), or both. Tumors (n=3/group) were collected 24 or 72 hours after the first treatment. Immunohistochemistry was performed to assess hypoxia (carbonic anhydrase IX [CA9]), vessels (CD31), DNA double strand breaks (DSB) (γH2AX), and apoptosis (cleaved caspase 3 [CC3]). The remaining xenografts (n=6/group) were monitored for tumor growth. Results: In vitro, olaparib showed a greater radiation-sensitizing effect in Calu-3 and Calu-6 cells in hypoxic conditions (1% O{sub 2}). In vivo, Calu-3 tumors were well-oxygenated, whereas Calu-6 tumors had extensive regions of hypoxia associated with down-regulation of the homologous recombination protein RAD51. Olaparib treatment increased unrepaired DNA DSB (P<.001) and apoptosis (P<.001) in hypoxic cells of Calu-6 tumors following radiation, whereas it had no significant effect on radiation-induced DNA damage response in nonhypoxic cells of Calu-6 tumors or in the tumor cells of well-oxygenated Calu-3 tumors. Consequently, olaparib significantly increased radiation-induced growth inhibition in Calu-6 tumors (P<.001) but not in Calu-3 tumors. Conclusions: Our data suggest that hypoxia potentiates the radiation-sensitizing effects of

RadNet: Open network protocol for radiation data

International Nuclear Information System (INIS)

Rees, B.; Olson, K.; Beckes-Talcott, J.; Kadner, S.; Wenderlich, T.; Hoy, M.; Doyle, W.; Koskelo, M.

1998-01-01

Safeguards instrumentation is increasingly being incorporated into remote monitoring applications. In the past, vendors of radiation monitoring instruments typically provided the tools for uploading the monitoring data to a host. However, the proprietary nature of communication protocols lends itself to increased computer support needs and increased installation expenses. As a result, a working group of suppliers and customers of radiation monitoring instruments defined an open network protocol for transferring packets on a local area network from radiation monitoring equipment to network hosts. The protocol was termed RadNet. While it is now primarily used for health physics instruments, RadNet's flexibility and strength make it ideal for remote monitoring of nuclear materials. The incorporation of standard, open protocols ensures that future work will not render present work obsolete; because RadNet utilizes standard Internet protocols, and is itself a non-proprietary standard. The use of industry standards also simplifies the development and implementation of ancillary services, e.g. E-main generation or even pager systems

Dose-rate models for human survival after exposure to ionizing radiation

International Nuclear Information System (INIS)

Jones, T.D.; Morris, M.D.; Young, R.W.

1987-01-01

This paper reviews new estimates of the LD 50 in man by Mole and by Rotblat, the biological processes contributing to hematologic death, the collection of animal experiments dealing with hematologic death, and the use of regression analysis to make new estimates of human mortality based on all relevant animal studies. Regression analysis of animal mortality data has shown that mortality is dependent strongly on dose rate, species, body weight, and time interval over which the exposure is delivered. The model has predicted human LD 50 s of 194, 250, 310, and 360 rad to marrow when the exposure time is a minute, an hour, a day, and a week, respectively

Dose-rate models for human survival after exposure to ionizing radiation

International Nuclear Information System (INIS)

Jones, T.D.; Morris, M.D.; Young, R.W.

1986-01-01

This paper reviews new estimates of the L 50 in man by Mole and by Rotblat, the biological processes contributing to hematologic death, the collection of animal experiments dealing with hematologic death, and the use of regression analysis to make new estimates of human mortality based on all relevant animal studies. Regression analysis of animal mortality data has shown that mortality is dependent strongly on dose rate, species, body weight, and time interval over which the exposure is delivered. The model has predicted human LD 50 s of 194, 250, 310, and 360 rad to marrow when the exposure time is a minute, an hour, a day, and a week, respectively

Rapid diagnosis of equine influenza by highly sensitive silver amplification immunochromatography system.

Science.gov (United States)

Yamanaka, Takashi; Nemoto, Manabu; Bannai, Hiroshi; Tsujimura, Koji; Kondo, Takashi; Matsumura, Tomio; Fu, Tao Qi Huang; Fernandez, Charlene Judith; Gildea, Sarah; Cullinane, Ann

2017-06-16

Equine influenza (EI) is a respiratory disease caused by equine influenza A virus (EIV, H3N8) infection. Rapid diagnosis is essential to limit the disease spread. We previously reported that some rapid antigen detection (RAD) tests are fit for diagnosing EI although their sensitivity is not optimal. Here, we evaluated the performance of the newly developed RAD test using silver amplification immunochromatography (Quick Chaser Auto Flu A, B: QCA) to diagnose EI. The detection limits of QCA for EIVs were five-fold lower than the conventional RAD tests. The duration of virus antigen detection in the infected horses was longer than the conventional RAD tests. We conclude that QCA could be a valuable diagnostic method for EI.

21 CFR 170.50 - Glycine (aminoacetic acid) in food for human consumption.

Science.gov (United States)

2010-04-01

... consumption. 170.50 Section 170.50 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION (CONTINUED) FOOD ADDITIVES Specific Administrative Rulings and Decisions § 170.50 Glycine (aminoacetic acid) in food for human consumption. (a) Heretofore, the...

The rad-hard readout system of the BaBar silicon vertex tracker

Science.gov (United States)

Re, V.; DeWitt, J.; Dow, S.; Frey, A.; Johnson, R. P.; Kroeger, W.; Kipnis, I.; Leona, A.; Luo, L.; Mandelli, E.; Manfredi, P. F.; Nyman, M.; Pedrali-Noy, M.; Poplevin, P.; Perazzo, A.; Roe, N.; Spencer, N.

1998-02-01

This paper discusses the behaviour of a prototype rad-hard version of the chip developed for the readout of the BaBar silicon vertex tracker. A previous version of the chip, implemented in the 0.8 μm HP rad-soft version has been thoroughly tested in the recent times. It featured outstanding noise characteristics and showed that the specifications assumed as target for the tracker readout were met to a very good extent. The next step was the realization of a chip prototype in the rad-hard process that will be employed in the actual chip production. Such a prototype is structurally and functionally identical to its rad-soft predecessor. However, the process parameters being different, and not fully mastered at the time of design, some deviations in the behaviour were to be expected. The reasons for such deviations have been identified and some of them were removed by acting on the points that were left accessible on the chip. Other required small circuit modifications that will not affect the production schedule. The tests done so far on the rad-hard chip have shown that the noise behaviour is very close to that of the rad-soft version, that is fully adequate for the vertex detector readout.

Estimation of percentage breast tissue density: comparison between digital mammography (2D full field digital mammography) and digital breast tomosynthesis according to different BI-RADS categories.

Science.gov (United States)

Tagliafico, A S; Tagliafico, G; Cavagnetto, F; Calabrese, M; Houssami, N

2013-11-01

To compare breast density estimated from two-dimensional full-field digital mammography (2D FFDM) and from digital breast tomosynthesis (DBT) according to different Breast Imaging-Reporting and Data System (BI-RADS) categories, using automated software. Institutional review board approval and written informed patient consent were obtained. DBT and 2D FFDM were performed in the same patients to allow within-patient comparison. A total of 160 consecutive patients (mean age: 50±14 years; mean body mass index: 22±3) were included to create paired data sets of 40 patients for each BI-RADS category. Automatic software (MedDensity(©), developed by Giulio Tagliafico) was used to compare the percentage breast density between DBT and 2D FFDM. The estimated breast percentage density obtained using DBT and 2D FFDM was examined for correlation with the radiologists' visual BI-RADS density classification. The 2D FFDM differed from DBT by 16.0% in BI-RADS Category 1, by 11.9% in Category 2, by 3.5% in Category 3 and by 18.1% in Category 4. These differences were highly significant (pBI-RADS categories and the density evaluated using 2D FFDM and DBT (r=0.56, pBI-RADS categories. These data are relevant for clinical practice and research studies using density in determining the risk. On DBT, breast density values were lower than with 2D FFDM, with a non-linear relationship across the classical BI-RADS categories.

Studies of DNA repair in saccharomyces cerevisiae. I. Characterization of a new allele of RAD6. II. Investigation of events in the first cell cycle after DNA damage

International Nuclear Information System (INIS)

Douthwright-Fasse, J.A.

1979-01-01

Studies in two independent, but related, areas of DNA repair have been carried out in Saccharomyces cerevisiae; characterization of a new allele in the RAD6 gene which suggests that the gene is multifunctional, and utilization of photoreactivation as a probe of events occurring during the first cell cycle after DNA damage. Strains carrying the new allele, designated rad6-4, are as sensitive to uv and ionizing radiation as those carrying rad6-1 or rad6-3 but, unlike them, are capable of induced mutagenesis and sporulation. Although rad6-4 may well be a missense mutation, the evidence shows that it is unlikely that this phenotype is due to leakiness. Instead, the data suggest that the RAD6 gene is multifunctional. One function is necessary to recover from DNA damage in an error-free manner, and the other is concerned with mutagenic processes and sporulation. Rad6-1 and rad6-3 strains are deficient in both of these functions, while rad6-4 strains are deficient only in the error-free function. The loss of photoreversibility (LOP) of ultraviolet induced mutations to arginine independence in an excision defective strain carrying arg4-17 examines the events occurring in the first cell cycle after DNA damage. LOP is dependent upon de novo protein synthesis. LOP begins immediately after UV irradiation, before semiconservative DNA synthesis takes place, and is complete after four hours in growth medium.There is no evidence indicating whether the normal function of the protein is involved in excision repair, or in one of the two repair processes believed to be inducible; induced mutagenesis or recombinational repair

Radiosensitivity of T and B lymphocytes. V. Effects of whole-body irradiation on numbers of recirculating T cells and sensitization to primary skin grafts in mice

International Nuclear Information System (INIS)

Anderson, R.E.; Williams, W.L.

1977-01-01

Whole-body exposure of mice to 50, 100, 300, or 500 rads results in an acute dose-related decrease in the number of viable recirculating T cells. The magnitude of this decrement becomes more pronounced with the passage of time. The dose-response relationship over this range of dosages appears to consist of three components: a steep drop between 0 and 50 rads, a plateau between 50 and 500 rads, and a second drop between 300 and 500 rads. The residual radioresistant cells are able to recognize a histoincompatible skin graft during the initial 5 days after irradiation. Low to moderate doses (50 to 300 rads) abrogate the partial tolerance noted in nonirradiated recipients exposed to the skin graft for 5 days and then regrafted from the same donor source 25 days after complete removal of the primary graft. A large (500 rads) dose results in prolonged graft survival in comparison with the nonirradiated group. It is suggested that the subpopulation of recirculating T cells which develops partial tolerance during a 5-day exposure to a homograft is more radiosensitive than the effector subpopulation which is involved in graft rejection

In vitro radiation and chemotherapy sensitivity of established cell lines of human small cell lung cancer and its large cell morphological variants

International Nuclear Information System (INIS)

Carney, D.N.; Mitchell, J.B.; Kinsella, T.J.

1983-01-01

The in vitro response to radiation and chemotherapeutic drugs of cell lines established from 7 patients with small cell (SC) lung cancer were tested using a soft agarose clonogenic assay. Five cell lines retained the typical morphological and biochemical amine precursor uptake decarboxylation characteristics of SC, while two cell lines had undergone ''transformation'' to large cell (LC) morphological variants with loss of amine precursor uptake decarboxylation cell characteristics of SC. The radiation survival curves for the SC lines were characterized by D0 values ranging from 51 to 140 rads and extrapolation values (n) ranging from 1.0 to 3.3. While the D0 values of the radiation survival curves of the LC variants were similar (91 and 80 rads), the extrapolation values were 5.6 and 11.1 In vitro chemosensitivity testing of the cell lines revealed an excellent correlation between prior treatment status of the patient and in vitro sensitivity or resistance. No correlation was observed between in vitro chemosensitivity and radiation response. These data suggest that transformation of SC to LC with loss of amine precursor uptake and decarboxylation characteristics is associated with a marked increase in radiation resistance (n) in vitro. The observation of a 2- to 5-fold increase in survival of the LC compared to the SC lines following 200 rads suggests that the use of larger daily radiation fractions and/or radiation-sensitizing drugs might lead to a significantly greater clinical response in patients with LC morphology. This clinical approach may have a major impact on patient response and survival

Co-design of RAD and ETHICS methodologies: a combination of information system development methods

Science.gov (United States)

Nasehi, Arezo; Shahriyari, Salman

2011-12-01

Co-design is a new trend in the social world which tries to capture different ideas in order to use the most appropriate features for a system. In this paper, co-design of two information system methodologies is regarded; rapid application development (RAD) and effective technical and human implementation of computer-based systems (ETHICS). We tried to consider the characteristics of these methodologies to see the possibility of having a co-design or combination of them for developing an information system. To reach this purpose, four different aspects of them are analyzed: social or technical approach, user participation and user involvement, job satisfaction, and overcoming change resistance. Finally, a case study using the quantitative method is analyzed in order to examine the possibility of co-design using these factors. The paper concludes that RAD and ETHICS are appropriate to be co-designed and brings some suggestions for the co-design.

Multivariate Models for Prediction of Human Skin Sensitization Hazard

Science.gov (United States)

Strickland, Judy; Zang, Qingda; Paris, Michael; Lehmann, David M.; Allen, David; Choksi, Neepa; Matheson, Joanna; Jacobs, Abigail; Casey, Warren; Kleinstreuer, Nicole

2016-01-01

One of ICCVAM’s top priorities is the development and evaluation of non-animal approaches to identify potential skin sensitizers. The complexity of biological events necessary to produce skin sensitization suggests that no single alternative method will replace the currently accepted animal tests. ICCVAM is evaluating an integrated approach to testing and assessment based on the adverse outcome pathway for skin sensitization that uses machine learning approaches to predict human skin sensitization hazard. We combined data from three in chemico or in vitro assays—the direct peptide reactivity assay (DPRA), human cell line activation test (h-CLAT), and KeratinoSens™ assay—six physicochemical properties, and an in silico read-across prediction of skin sensitization hazard into 12 variable groups. The variable groups were evaluated using two machine learning approaches, logistic regression (LR) and support vector machine (SVM), to predict human skin sensitization hazard. Models were trained on 72 substances and tested on an external set of 24 substances. The six models (three LR and three SVM) with the highest accuracy (92%) used: (1) DPRA, h-CLAT, and read-across; (2) DPRA, h-CLAT, read-across, and KeratinoSens; or (3) DPRA, h-CLAT, read-across, KeratinoSens, and log P. The models performed better at predicting human skin sensitization hazard than the murine local lymph node assay (accuracy = 88%), any of the alternative methods alone (accuracy = 63–79%), or test batteries combining data from the individual methods (accuracy = 75%). These results suggest that computational methods are promising tools to effectively identify potential human skin sensitizers without animal testing. PMID:27480324

Substantial differences in bias between single-digest and double-digest RAD-seq libraries: A case study.

Science.gov (United States)

Flanagan, Sarah P; Jones, Adam G

2018-03-01

The trade-offs of using single-digest vs. double-digest restriction site-associated DNA sequencing (RAD-seq) protocols have been widely discussed. However, no direct empirical comparisons of the two methods have been conducted. Here, we sampled a single population of Gulf pipefish (Syngnathus scovelli) and genotyped 444 individuals using RAD-seq. Sixty individuals were subjected to single-digest RAD-seq (sdRAD-seq), and the remaining 384 individuals were genotyped using a double-digest RAD-seq (ddRAD-seq) protocol. We analysed the resulting Illumina sequencing data and compared the two genotyping methods when reads were analysed either together or separately. Coverage statistics, observed heterozygosity, and allele frequencies differed significantly between the two protocols, as did the results of selection components analysis. We also performed an in silico digestion of the Gulf pipefish genome and modelled five major sources of bias: PCR duplicates, polymorphic restriction sites, shearing bias, asymmetric sampling (i.e., genotyping fewer individuals with sdRAD-seq than with ddRAD-seq) and higher major allele frequencies. This combination of approaches allowed us to determine that polymorphic restriction sites, an asymmetric sampling scheme, mean allele frequencies and to some extent PCR duplicates all contribute to different estimates of allele frequencies between samples genotyped using sdRAD-seq versus ddRAD-seq. Our finding that sdRAD-seq and ddRAD-seq can result in different allele frequencies has implications for comparisons across studies and techniques that endeavour to identify genomewide signatures of evolutionary processes in natural populations. © 2017 John Wiley & Sons Ltd.

Stratification of mammographic computerized analysis by BI-RADS categories

International Nuclear Information System (INIS)

Lederman, Richard; Leichter, Isaac; Buchbinder, Shalom; Novak, Boris; Bamberger, Philippe; Fields, Scott

2003-01-01

The Breast Imaging Reporting and Data System (BI-RADS) was implemented to standardize characterization of mammographic findings. The purpose of the present study was to evaluate in which BI-RADS categories the changes recommended by computerized mammographic analysis are most beneficial. Archival cases including, 170 masses (101 malignant, 69 benign) and 63 clusters of microcalcifications (MCs; 36 malignant, 27 benign), were evaluated retrospectively, using the BI-RADS categories, by several radiologists, blinded to the pathology results. A computerized system then automatically extracted from the digitized mammogram features characterizing mammographic lesions, which were used to classify the lesions. The results of the computerized classification scheme were compared, by receiver operating characteristics (ROC) analysis, to the conventional interpretation. In the ''low probability of malignancy group'' (excluding BI-RADS categories 4 and 5), computerized analysis improved the A z of the ROC curve significantly, from 0.57 to 0.89. In the ''high probability of malignancy group'' (mostly category 5) the computerized analysis yielded an ROC curve with an A z of 0.99. In the ''intermediate probability of malignancy group'' computerized analysis improved the A z significantly, from 0.66 for to 0.83. Pair-wise analysis showed that in the latter group the modifications resulting from computerized analysis were correct in 83% of cases. Computerized analysis has the ability to improve the performance of the radiologists exactly in the BI-RADS categories with the greatest difficulties in arriving at a correct diagnosis. It increased the performance significantly in the problematic group of ''intermediate probability of malignancy'' and pinpointed all the cases with missed cancers in the ''low probability'' group. (orig.)

An in vitro human skin test for assessing sensitization potential.

Science.gov (United States)

Ahmed, S S; Wang, X N; Fielding, M; Kerry, A; Dickinson, I; Munuswamy, R; Kimber, I; Dickinson, A M

2016-05-01

Sensitization to chemicals resulting in an allergy is an important health issue. The current gold-standard method for identification and characterization of skin-sensitizing chemicals was the mouse local lymph node assay (LLNA). However, for a number of reasons there has been an increasing imperative to develop alternative approaches to hazard identification that do not require the use of animals. Here we describe a human in-vitro skin explant test for identification of sensitization hazards and the assessment of relative skin sensitizing potency. This method measures histological damage in human skin as a readout of the immune response induced by the test material. Using this approach we have measured responses to 44 chemicals including skin sensitizers, pre/pro-haptens, respiratory sensitizers, non-sensitizing chemicals (including skin-irritants) and previously misclassified compounds. Based on comparisons with the LLNA, the skin explant test gave 95% specificity, 95% sensitivity, 95% concordance with a correlation coefficient of 0.9. The same specificity and sensitivity were achieved for comparison of results with published human sensitization data with a correlation coefficient of 0.91. The test also successfully identified nickel sulphate as a human skin sensitizer, which was misclassified as negative in the LLNA. In addition, sensitizers and non-sensitizers identified as positive or negative by the skin explant test have induced high/low T cell proliferation and IFNγ production, respectively. Collectively, the data suggests the human in-vitro skin explant test could provide the basis for a novel approach for characterization of the sensitizing activity as a first step in the risk assessment process. Copyright © 2015 John Wiley & Sons, Ltd.

Simulation of aerosol radiative properties with the ORISAM-RAD model during a pollution event (ESCOMPTE 2001)

Science.gov (United States)

Mallet, M.; Pont, V.; Liousse, C.; Roger, J. C.; Dubuisson, P.

The aim of this study is to present the organic and inorganic spectral aerosol module-radiative (ORISAM-RAD) module, allowing the 3D distribution of aerosol radiative properties (aerosol optical depth, single scattering albedo and asymmetry parameter) from the ORISAM module. In this work, we test ORISAM-RAD for one selected day (24th June) during the ESCOMPTE (expérience sur site pour contraindre les modèles de pollution atmosphérique et de transport d'emissions) experiment for an urban/industrial aerosol type. The particle radiative properties obtained from in situ and AERONET observations are used to validate our simulations. In a first time, simulations obtained from ORISAM-RAD indicate high aerosol optical depth (AOD)˜0.50-0.70±0.02 (at 440 nm) in the aerosol pollution plume, slightly lower (˜10-20%) than AERONET retrievals. In a second time, simulations of the single scattering albedo ( ωo) have been found to well reproduce the high spatial heterogeneities observed over this domain. Concerning the asymmetry parameter ( g), ORISAM-RAD simulations reveal quite uniform values over the whole ESCOMPTE domain, comprised between 0.61±0.01 and 0.65±0.01 (at 440 nm), in excellent agreement with ground based in situ measurements and AERONET retrievals. Finally, the outputs of ORISAM-RAD have been used in a radiative transfer model in order to simulate the diurnal direct radiative forcing at different locations (urban, industrial and rural). We show that anthropogenic aerosols strongly decrease surface solar radiation, with diurnal mean surface forcings comprised between -29.0±2.9 and -38.6±3.9 W m -2, depending on the sites. This decrease is due to the reflection of solar radiations back to space (-7.3±0.8<Δ FTOA<-12.3±1.2 W m -2) and to its absorption into the aerosol layer (21.1±2.1<Δ FATM<26.3±2.6 W m -2). These values are found to be consistent with those measured at local scale.

A meta-analysis of use of Prostate Imaging Reporting and Data System Version 2 (PI-RADS V2) with multiparametric MR imaging for the detection of prostate cancer

Energy Technology Data Exchange (ETDEWEB)

Zhang, Li; Chen, Sipan [Fourth Military Medical University, Department of Radiology, Xijing Hospital, Xi' an, Shaanxi (China); Shaanxi Provincial People' s Hospital, Department of MRI, Xi' an, Shaanxi (China); Tang, Min; Lei, Xiaoyan; Zhang, Xiaoling [Shaanxi Provincial People' s Hospital, Department of MRI, Xi' an, Shaanxi (China); Huan, Yi [Fourth Military Medical University, Department of Radiology, Xijing Hospital, Xi' an, Shaanxi (China)

2017-12-15

This meta-analysis was undertaken to review the diagnostic accuracy of PI-RADS V2 for prostate cancer (PCa) detection with multiparametric MR (mp-MR). A comprehensive literature search of electronic databases was performed by two observers independently. Inclusion criteria were original research using the PI-RADS V2 system in reporting prostate MRI. The methodological quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Data necessary to complete 2 x 2 contingency tables were obtained from the included studies. Thirteen studies (2,049 patients) were analysed. This is an initial meta-analysis of PI-RADs V2 and the overall diagnostic accuracy in diagnosing PCa was as follows: pooled sensitivity, 0.85 (0.78-0.91); pooled specificity, 0.71 (0.60-0.80); pooled positive likelihood ratio (LR+), 2.92 (2.09-4.09); pooled negative likelihood ratio (LR-), 0.21 (0.14-0.31); pooled diagnostic odds ratio (DOR), 14.08 (7.93-25.01), respectively. Positive predictive values ranged from 0.54 to 0.97 and negative predictive values ranged from 0.26 to 0.92. Currently available evidence indicates that PI-RADS V2 appears to have good diagnostic accuracy in patients with PCa lesions with high sensitivity and moderate specificity. However, no recommendation regarding the best threshold can be provided because of heterogeneity. (orig.)

Yeast DNA-repair gene RAD14 encodes a zinc metalloprotein with affinity for ultraviolet-damaged DNA

International Nuclear Information System (INIS)

Guzder, S.N.; Sung, P.; Prakash, S.; Prakash, L.

1993-01-01

Xeroderma pigmentosum (XP) patients suffer from a high incidence of skin cancers due to a defect in excision repair of UV light-damaged DNA. Of the seven XP complementation groups, A--G, group A represents a severe and frequent form of the disease. The Saccharomyces cerevisiae RAD14 gene is a homolog of the XP-A correcting (XPAC) gene. Like XP-A cells, rad14-null mutants are defective in the incision step of excision repair of UV-damaged DNA. The authors have purified RAD14 protein to homogeneity from extract of a yeast strain genetically tailored to overexpress RAD14. As determined by atomic emission spectroscopy, RAD14 contains one zinc atom. They also show in vitro that RAD14 binds zinc but does not bind other divalent metal ions. In DNA mobility-shift assays, RAD14 binds specifically to UV-damaged DNA. Removal of cyclobutane pyrimidine dimers from damaged DNA by enzymatic photoreactivation has no effect on binding, strongly suggesting that RAD14 recognizes pyrimidine(6-4)pyrimidone photoproduct sites. These findings indicate that RAD14 functions in damage recognition during excision repair. 37 refs., 4 figs

Low morbidity following 9,000-rad intracavitary endocurietherapy (ECT) using the Kumar cervical applicator and external-beam radiotherapy (EXRT) in the management of carcinoma of the uterine cervix

International Nuclear Information System (INIS)

Kumar, P.P.; Good, R.R.; Scott, J.C.; Jones, E.O.; Lynch, G.; McCaul, G.F.

1988-01-01

The Kumar Cervical Applicator minimizes patient discomfort and improves patient mobility while reducing the tendency of the applicator to rotate during the 40 to 50 hours of uterine intracavitary endocurietherapy. Patients with previously untreated invasive carcinoma of the uterine cervix, F.I.G.O. stages IB-IVA, were treated with two Kumar intracavitary endocurietherapy (ECT) applications of 2,500 rad each to point ''A,'' and 4,000 rad external-beam radiotherapy (EXRT) to midplane, for a total dose of 9,000 rad. The major complication rate was 2.7 %, and the local control rate was 85 % (22/26 patients) for stage I and II, and 91 % (10/11 patients) for stage III and IVA. (author)

Reconfigurable, Bi-Directional Flexfet Level Shifter for Low-Power, Rad-Hard Integration

Science.gov (United States)

DeGregorio, Kelly; Wilson, Dale G.

2009-01-01

Two prototype Reconfigurable, Bi-directional Flexfet Level Shifters (ReBiLS) have been developed, where one version is a stand-alone component designed to interface between external low voltage and high voltage, and the other version is an embedded integrated circuit (IC) for interface between internal low-voltage logic and external high-voltage components. Targeting stand-alone and embedded circuits separately allows optimization for these distinct applications. Both ReBiLS designs use the commercially available 180-nm Flex fet Independently Double-Gated (IDG) SOI CMOS (silicon on insulator, complementary metal oxide semiconductor) technology. Embedded ReBiLS circuits were integrated with a Reed-Solomon (RS) encoder using CMOS Ultra-Low-Power Radiation Tolerant (CULPRiT) double-gated digital logic circuits. The scope of the project includes: creation of a new high-voltage process, development of ReBiLS circuit designs, and adjustment of the designs to maximize performance through simulation, layout, and manufacture of prototypes. The primary technical objectives were to develop a high-voltage, thick oxide option for the 180-nm Flexfet process, and to develop a stand-alone ReBiLS IC with two 8-channel I/O busses, 1.8 2.5 I/O on the low-voltage pins, 5.0-V-tolerant input and 3.3-V output I/O on the high-voltage pins, and 100-MHz minimum operation with 10-pF external loads. Another objective was to develop an embedded, rad-hard ReBiLS I/O cell with 0.5-V low-voltage operation for interface with core logic, 5.0-V-tolerant input and 3.3-V output I/O pins, and 100-MHz minimum operation with 10- pF external loads. A third objective was to develop a 0.5- V Reed-Solomon Encoder with embedded ReBilS I/O: Transfer the existing CULPRiT RS encoder from a 0.35-micron bulk-CMOS process to the ASI 180-nm Flexfet, rad-hard SOI Process. 0.5-V low-voltage core logic. 5.0-V-tolerant input and 3.3-V output I/O pins. 100-MHz minimum operation with 10- pF external loads. The stand

Rad52 forms DMA repair and recombination centers during S phase

DEFF Research Database (Denmark)

Lisby, M.; Rothstein, R.; Mortensen, Uffe Hasbro

2001-01-01

fluorescent protein (GFP) is fully functional in DNA repair and recombination. After induction of DNA double-strand breaks by gamma -irradiation, meiosis, or the HO endonuclease, Rad52-GFP relocalizes from a diffuse nuclear distribution to distinct foci. Interestingly, Rad52 foci are formed almost exclusively...

RadNet (Environmental Radiation Ambient Monitoring System)

Data.gov (United States)

U.S. Environmental Protection Agency — RadNet, formerly Environmental Radiation Ambient Monitoring System (ERAMS), is a national network of monitoring stations that regularly collect air, precipitation,...

VirRAD - The virtual radiopharmacy - a virtual learning community in radiopharmacy

International Nuclear Information System (INIS)

Mather, S.J.

2002-01-01

VirRAD is a new research project funded by the Information Society Technologies programme of the Fifth RTD Framework Programme of the European Union. The aim of VirRAD is to develop an Internet-based virtual learning environment for Radiopharmacy which will facilitate learning and understanding in the speciality at all levels both within and outside the radiopharmaceutical community. The final structure of VirRAD is yet to be decided and will be determined by the needs and desires of its ultimate participants, however it is expected to include multimedia teaching modules for distance learning applications, 3-D simulations of specialised equipment and complex techniques used in radiopharmaceutical preparation and research as well as improved systems of peer-to-peer and student-to-tutor communication and information retrieval. To be as useful and effective as possible VirRAD needs ideas and suggestions from the Nuclear Medicine community. A mechanism for obtaining such input and feedback will be an integral part of the development process

Stratification of mammographic computerized analysis by BI-RADS categories

Energy Technology Data Exchange (ETDEWEB)

Lederman, Richard [Department of Radiology, Hadassah University Hospital, Ein Kerem, Jerusalem (Israel); Leichter, Isaac [Department of Electro-Optics, Jerusalem College of Technology, P.O.B. 16031, Jerusalem (Israel); Buchbinder, Shalom [Department of Radiology of The Montefiore Medical Center, The University Hospital for the Albert Einstein College of Medicine, Bronx, New York (United States); Novak, Boris [Department of Applied Mathematics, Jerusalem College of Technology, P.O.B. 16031, Jerusalem 91160 (Israel); Bamberger, Philippe [Department of Electronics, Jerusalem College of Technology, POB 16031, Jerusalem (Israel); Fields, Scott [Department of Radiology, Hadassah University Hospital, Mt. Scopus, Jerusalem (Israel)

2003-02-01

The Breast Imaging Reporting and Data System (BI-RADS) was implemented to standardize characterization of mammographic findings. The purpose of the present study was to evaluate in which BI-RADS categories the changes recommended by computerized mammographic analysis are most beneficial. Archival cases including, 170 masses (101 malignant, 69 benign) and 63 clusters of microcalcifications (MCs; 36 malignant, 27 benign), were evaluated retrospectively, using the BI-RADS categories, by several radiologists, blinded to the pathology results. A computerized system then automatically extracted from the digitized mammogram features characterizing mammographic lesions, which were used to classify the lesions. The results of the computerized classification scheme were compared, by receiver operating characteristics (ROC) analysis, to the conventional interpretation. In the ''low probability of malignancy group'' (excluding BI-RADS categories 4 and 5), computerized analysis improved the A{sub z}of the ROC curve significantly, from 0.57 to 0.89. In the ''high probability of malignancy group'' (mostly category 5) the computerized analysis yielded an ROC curve with an A {sub z}of 0.99. In the ''intermediate probability of malignancy group'' computerized analysis improved the A {sub z}significantly, from 0.66 for to 0.83. Pair-wise analysis showed that in the latter group the modifications resulting from computerized analysis were correct in 83% of cases. Computerized analysis has the ability to improve the performance of the radiologists exactly in the BI-RADS categories with the greatest difficulties in arriving at a correct diagnosis. It increased the performance significantly in the problematic group of ''intermediate probability of malignancy'' and pinpointed all the cases with missed cancers in the ''low probability'' group. (orig.)

A comparison between rad-hard float zone silicon diodes as gamma dosimeter in radiation processing

Energy Technology Data Exchange (ETDEWEB)

Camargo, Fábio de [Amazônia Azul Tecnologias de Defesa S.A. (AMAZUL), São Paulo, SP (Brazil); Gonçalves, Josemary A.C.; Bueno, Carmen C., E-mail: dcamargo@gmail.com, E-mail: ccbueno@ipen.br [Instituto de Pesquisas Energeticas e Nucleares (IPEN-CNEN/SP), Sao Paulo, SP (Brazil)

2017-07-01

In this work, we report on the results obtained with rad-hard Standard Float Zone (STFZ) and Diffused Oxygenated Float Zone (DOFZ) silicon diodes in radiation processing dosimetry. The dosimetric probes were designed to operate in the direct current mode, as on-line radiation dosimeter. The irradiation of the samples was performed using a {sup 60}Co source with a dose rate of almost 2.4 kGy/h. The current response of each diode was measured as a function of the exposure time in steps from 5 kGy up to 50 kGy to achieve a total absorbed dose of 275 kGy. In this dose range it is observed a significant decrease in the photocurrent generated in both devices due to gamma radiation defects produced in their active volumes. To mitigate this effect, the samples were pre-irradiated with {sup 60}Co gamma rays at 700 kGy. Despite of being less sensitive, these devices presented stable and reproducible current signals with a relative sensitivity decrease of about 19% within the whole range of dose studied. The dose-response curves of the pre-irradiated diodes showed quadratic behavior with correlation coefficient higher than 0.9999 for total absorbed dose up to 275 kGy. The comparison of the FZ and DOFZ responses evidenced that the latter was slightly superior to the first. However, it is important to note that all pre-irradiated diodes can be used as gamma dosimeters in radiation processing applications. (author)

A comparison between rad-hard float zone silicon diodes as gamma dosimeter in radiation processing

International Nuclear Information System (INIS)

Camargo, Fábio de; Gonçalves, Josemary A.C.; Bueno, Carmen C.

2017-01-01

In this work, we report on the results obtained with rad-hard Standard Float Zone (STFZ) and Diffused Oxygenated Float Zone (DOFZ) silicon diodes in radiation processing dosimetry. The dosimetric probes were designed to operate in the direct current mode, as on-line radiation dosimeter. The irradiation of the samples was performed using a 60 Co source with a dose rate of almost 2.4 kGy/h. The current response of each diode was measured as a function of the exposure time in steps from 5 kGy up to 50 kGy to achieve a total absorbed dose of 275 kGy. In this dose range it is observed a significant decrease in the photocurrent generated in both devices due to gamma radiation defects produced in their active volumes. To mitigate this effect, the samples were pre-irradiated with 60 Co gamma rays at 700 kGy. Despite of being less sensitive, these devices presented stable and reproducible current signals with a relative sensitivity decrease of about 19% within the whole range of dose studied. The dose-response curves of the pre-irradiated diodes showed quadratic behavior with correlation coefficient higher than 0.9999 for total absorbed dose up to 275 kGy. The comparison of the FZ and DOFZ responses evidenced that the latter was slightly superior to the first. However, it is important to note that all pre-irradiated diodes can be used as gamma dosimeters in radiation processing applications. (author)

Dose-rate models for human survival after exposure to ionizing radiation

Energy Technology Data Exchange (ETDEWEB)

Jones, T.D.; Morris, M.D.; Young, R.W.

1986-01-01

This paper reviews new estimates of the L/sub 50/ in man by Mole and by Rotblat, the biological processes contributing to hematologic death, the collection of animal experiments dealing with hematologic death, and the use of regression analysis to make new estimates of human mortality based on all relevant animal studies. Regression analysis of animal mortality data has shown that mortality is dependent strongly on dose rate, species, body weight, and time interval over which the exposure is delivered. The model has predicted human LD/sub 50/s of 194, 250, 310, and 360 rad to marrow when the exposure time is a minute, an hour, a day, and a week, respectively.

Resolving RAD51C function in late stages of homologous recombination

Directory of Open Access Journals (Sweden)

Kuznetsov Sergey G

2007-06-01

Full Text Available Abstract DNA double strand breaks are efficiently repaired by homologous recombination. One of the last steps of this process is resolution of Holliday junctions that are formed at the sites of genetic exchange between homologous DNA. Although various resolvases with Holliday junctions processing activity have been identified in bacteriophages, bacteria and archaebacteria, eukaryotic resolvases have been elusive. Recent biochemical evidence has revealed that RAD51C and XRCC3, members of the RAD51-like protein family, are involved in Holliday junction resolution in mammalian cells. However, purified recombinant RAD51C and XRCC3 proteins have not shown any Holliday junction resolution activity. In addition, these proteins did not reveal the presence of a nuclease domain, which raises doubts about their ability to function as a resolvase. Furthermore, oocytes from infertile Rad51C mutant mice exhibit precocious separation of sister chromatids at metaphase II, a phenotype that reflects a defect in sister chromatid cohesion, not a lack of Holliday junction resolution. Here we discuss a model to explain how a Holliday junction resolution defect can lead to sister chromatid separation in mouse oocytes. We also describe other recent in vitro and in vivo evidence supporting a late role for RAD51C in homologous recombination in mammalian cells, which is likely to be resolution of the Holliday junction.

Suspicious breast calcifications undergoing stereotactic biopsy in women ages 70 and over: Breast cancer incidence by BI-RADS descriptors.

Science.gov (United States)

Grimm, Lars J; Johnson, David Y; Johnson, Karen S; Baker, Jay A; Soo, Mary Scott; Hwang, E Shelley; Ghate, Sujata V

2017-06-01

To determine the malignancy rate overall and for specific BI-RADS descriptors in women ≥70 years who undergo stereotactic biopsy for calcifications. We retrospectively reviewed 14,577 consecutive mammogram reports in 6839 women ≥70 years to collect 231 stereotactic biopsies of calcifications in 215 women. Cases with missing images or histopathology and calcifications associated with masses, distortion, or asymmetries were excluded. Three breast radiologists determined BI-RADS descriptors by majority. Histology, hormone receptor status, and lymph node status were correlated with BI-RADS descriptors. There were 131 (57 %) benign, 22 (10 %) atypia/lobular carcinomas in situ, 55 (24 %) ductal carcinomas in situ (DCIS), and 23 (10 %) invasive diagnoses. Twenty-seven (51 %) DCIS cases were high-grade. Five (22 %) invasive cases were high-grade, two (9 %) were triple-negative, and three (12 %) were node-positive. Malignancy was found in 49 % (50/103) of fine pleomorphic, 50 % (14/28) of fine linear, 25 % (10/40) of amorphous, 20 % (3/15) of round, 3 % (1/36) of coarse heterogeneous, and 0 % (0/9) of dystrophic calcifications. Among women ≥70 years that underwent stereotactic biopsy for calcifications only, we observed a high rate of malignancy. Additionally, coarse heterogeneous calcifications may warrant a probable benign designation. • Cancer rates of biopsied calcifications in women ≥70 years are high • Radiologists should not dismiss suspicious calcifications in older women • Coarse heterogeneous calcifications may warrant a probable benign designation.

NeuRad detector prototype pulse shape study

Science.gov (United States)

Muzalevsky, I.; Chudoba, V.; Belogurov, S.; Kiselev, O.; Bezbakh, A.; Fomichev, A.; Krupko, S.; Slepnev, R.; Kostyleva, D.; Gorshkov, A.; Ovcharenko, E.; Schetinin, V.

2018-04-01

The EXPERT setup located at the Super-FRS facility, the part of the FAIR complex in Darmstadt, Germany, is intended for investigation of properties of light exotic nuclei. One of its modules, the high granularity neutron detector NeuRad assembled from a large number of the scintillating fiber is intended for registration of neutrons emitted by investigated nuclei in low-energy decays. Feasibility of the detector strongly depends on its timing properties defined by the spatial distribution of ionization, light propagation inside the fibers, light emission kinetics and transition time jitter in the multi-anode photomultiplier tube. The first attempt of understanding the pulse formation in the prototype of the NeuRad detector by comparing experimental results and Monte Carlo (MC) simulations is reported in this paper.

QSAR models of human data can enrich or replace LLNA testing for human skin sensitization

Science.gov (United States)

Alves, Vinicius M.; Capuzzi, Stephen J.; Muratov, Eugene; Braga, Rodolpho C.; Thornton, Thomas; Fourches, Denis; Strickland, Judy; Kleinstreuer, Nicole; Andrade, Carolina H.; Tropsha, Alexander

2016-01-01

Skin sensitization is a major environmental and occupational health hazard. Although many chemicals have been evaluated in humans, there have been no efforts to model these data to date. We have compiled, curated, analyzed, and compared the available human and LLNA data. Using these data, we have developed reliable computational models and applied them for virtual screening of chemical libraries to identify putative skin sensitizers. The overall concordance between murine LLNA and human skin sensitization responses for a set of 135 unique chemicals was low (R = 28-43%), although several chemical classes had high concordance. We have succeeded to develop predictive QSAR models of all available human data with the external correct classification rate of 71%. A consensus model integrating concordant QSAR predictions and LLNA results afforded a higher CCR of 82% but at the expense of the reduced external dataset coverage (52%). We used the developed QSAR models for virtual screening of CosIng database and identified 1061 putative skin sensitizers; for seventeen of these compounds, we found published evidence of their skin sensitization effects. Models reported herein provide more accurate alternative to LLNA testing for human skin sensitization assessment across diverse chemical data. In addition, they can also be used to guide the structural optimization of toxic compounds to reduce their skin sensitization potential. PMID:28630595

Time-dependent biodistribution and transgene expression of a recombinant human adenovirus serotype 5-luciferase vector as a surrogate agent for rAd5-FMDV vaccines in cattle

Science.gov (United States)

Replication-defective recombinant adenovirus 5 (rAd5) vectors carrying foot-and-mouth disease virus (FMDV) transgenes elicit a robust immune response to FMDV challenge in cattle; however vaccine function mechanisms are incompletely understood. Recent efforts addressing critical interactions of rAd5 ...

Development of high integrity containers for rad-waste treatment

Energy Technology Data Exchange (ETDEWEB)

Song, Yung Chul; Cho, Myung Sug; Jung, Yun Sub [Korea Electric Power Corp. (KEPCO), Taejon (Korea, Republic of). Research Center

1995-12-31

Nuclear power plants are generating rad waste such as solid wastes, concentrated liquid wastes, spent resins and spent filters, and various types of imported containers which have different specifications and material properties are employed to handle the rad wastes according to facility characteristics of the plants or the type of wastes. These containers are stored at the intermediate storage facilities at the plant site due to the construction delay of permanent disposal site, and the additional construction of storage and disposal sites become more difficult with increase of the numbers and the operation time of the plants. In order to solve these difficulties, rad wastes volume reduction facilities such as High Pressure Compression Facility or Drying Facility are being installed and use of High Integrity Containers(HIC) are increasing. Therefore, we decide quality and technology standards required for the HIC, and then develop the HIC which satisfies the standards with new composite material called Steel Fiber Polymer Impregnated Concrete(SFPIC) (author). 84 refs., 118 figs.

Development of high integrity containers for rad-waste treatment

Energy Technology Data Exchange (ETDEWEB)

Song, Yung Chul; Cho, Myung Sug; Jung, Yun Sub [Korea Electric Power Corp. (KEPCO), Taejon (Korea, Republic of). Research Center

1996-12-31

Nuclear power plants are generating rad waste such as solid wastes, concentrated liquid wastes, spent resins and spent filters, and various types of imported containers which have different specifications and material properties are employed to handle the rad wastes according to facility characteristics of the plants or the type of wastes. These containers are stored at the intermediate storage facilities at the plant site due to the construction delay of permanent disposal site, and the additional construction of storage and disposal sites become more difficult with increase of the numbers and the operation time of the plants. In order to solve these difficulties, rad wastes volume reduction facilities such as High Pressure Compression Facility or Drying Facility are being installed and use of High Integrity Containers(HIC) are increasing. Therefore, we decide quality and technology standards required for the HIC, and then develop the HIC which satisfies the standards with new composite material called Steel Fiber Polymer Impregnated Concrete(SFPIC) (author). 84 refs., 118 figs.

Alpha-particle doses to human organs and tissues from internally-deposited 226Ra and 228Ra

International Nuclear Information System (INIS)

Keane, A.T.; Schlenker, R.A.

1981-01-01

Estimation of radiation doses to the soft tissues from internally-deposited 226 Ra and 228 Ra is relevant to an investigation of soft-tissue malignancies in radium-exposed persons being conducted at the Center for Human Radiobiology. Alpha-particle doses in a 50-year period following a single injection of 226 Ra or 228 Ra are presented for 31 soft tissues and organs of the adult human. The dose estimates were derived from the ICRP alkaline earth model fitted to data on retention of 226 Ra in soft tissues and bone, combined with reported ratios of 226 Ra to Ca in soft tissue and bone at natural levels and the distribution of Ca in the tissues of Reference Man (ICRP23). The median of the 31 organ and tissue doses from the α-particles of 226 Ra itself is 0.08 rad per injected μCi. An additional average dose of 0.01 rad per μCi 226 Ra daughter products produced in soft tissue or transferred from bone to soft tissue. Soft-tissue doses from α-particles of the 228 Ra decay series are about six times those from 226 Ra α-particles for equal injected activities of 228 Ra and 226 Ra, with the assumption that 228 Ra daughter products do not transfer from the organ in which they are produced. The 50-year dose to the red marrow of bone from α-particles originating in bone is 0.55 rad per μCi 226 Ra injected and 1.0 rad per μCi 228 Ra injected. For ingestion by dial painters of luminous compound containg 226 Ra or 228 Ra with a daughter-to-parent activity ratio of 0.5, the dose to the mucosal alyer of the lower large intestine from α-particles originating in the gut contents is about 0.1 rad per μCi systemic intake of 226 Ra or 228 Ra

Rad GTPase is essential for the regulation of bone density and bone marrow adipose tissue in mice.

Science.gov (United States)

Withers, Catherine N; Brown, Drew M; Byiringiro, Innocent; Allen, Matthew R; Condon, Keith W; Satin, Jonathan; Andres, Douglas A

2017-10-01

The small GTP-binding protein Rad (RRAD, Ras associated with diabetes) is the founding member of the RGK (Rad, Rem, Rem2, and Gem/Kir) family that regulates cardiac voltage-gated Ca 2+ channel function. However, its cellular and physiological functions outside of the heart remain to be elucidated. Here we report that Rad GTPase function is required for normal bone homeostasis in mice, as Rad deletion results in significantly lower bone mass and higher bone marrow adipose tissue (BMAT) levels. Dynamic histomorphometry in vivo and primary calvarial osteoblast assays in vitro demonstrate that bone formation and osteoblast mineralization rates are depressed, while in vitro osteoclast differentiation is increased, in the absence of Rad. Microarray analysis revealed that canonical osteogenic gene expression (Runx2, osterix, etc.) is not altered in Rad -/- calvarial osteoblasts; instead robust up-regulation of matrix Gla protein (MGP, +11-fold), an inhibitor of extracellular matrix mineralization and a protein secreted during adipocyte differentiation, was observed. Strikingly, Rad deficiency also resulted in significantly higher marrow adipose tissue levels in vivo and promoted spontaneous in vitro adipogenesis of primary calvarial osteoblasts. Adipogenic differentiation of wildtype calvarial osteoblasts resulted in the loss of endogenous Rad protein, further supporting a role for Rad in the control of BMAT levels. These findings reveal a novel in vivo function for Rad and establish a role for Rad signaling in the complex physiological control of skeletal homeostasis and bone marrow adiposity. Copyright © 2017 Elsevier Inc. All rights reserved.

RAD6 gene of Saccharomyces cerevisiae encodes a protein containing a tract of 13 consecutive aspartates

International Nuclear Information System (INIS)

Reynolds, P.; Weber, S.; Prakash, L.

1985-01-01

The RAD6 gene of Saccharomyces cerevisiae is required for postreplication repair of UV-damaged DNA, for induced mutagenesis, and for sporulation. The authors have mapped the transcripts and determined the nucleotide sequence of the cloned RAD6 gene. The RAD6 gene encodes two transcripts of 0.98 and 0.86 kilobases which differ only in their 3' termini. The transcribed region contains an open reading frame of 516 nucleotides. The rad6-1 and rad6-3 mutant alleles, which the authors have cloned and sequenced, introduce amber and ochre nonsense mutations, respectively into the open reading frame, proving that it encodes the RAD6 protein. The RAD6 protein predicted by the nucleotide sequence is 172 amino acids long, has a molecular weight of 19,704, and contains 23.3% acidic and 11.6% basic residues. Its most striking feature is the highly acidic carboxyl terminus: 20 of the 23 terminal amino acids are acidic, including 13 consecutive aspartates. RAD6 protein thus resembles high mobility group proteins HMG-1 and HMG-2, which each contain a carboxyl-proximal tract of acidic amino acids. 48 references, 6 figures

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 ...

RadCon: A radiological consequences model. Technical guide - Version 2.0

International Nuclear Information System (INIS)

Crawford, J; Domel, R.U.; Harris, F.F.; Twining, J.R.

2000-05-01

A Radiological Consequence model (RadCon) is being developed at ANSTO to assess the radiological consequences, after an incident, in any climate, using appropriate meteorological and radiological transfer parameters. The major areas of interest to the developers are tropical and subtropical climates. This is particularly so given that it is anticipated that nuclear energy will become a mainstay for economies in these regions within the foreseeable future. Therefore, data acquisition and use of parameter values have been concentrated primarily on these climate types. Atmospheric dispersion and deposition for Australia can be modelled and supplied by the Regional Specialised Meteorological Centre (RSMC, one of five in the world) which is part of the Bureau of Meteorology Research Centre (BMRC), Puri et al. (1992). RadCon combines these data (i.e. the time dependent air and ground concentration generated by the dispersion model or measured quantities in the case of an actual incident) with specific regional parameter values to determine the dose to people via the major pathways of external and internal irradiation. For the external irradiation calculations, data are needed on lifestyle information such as the time spent indoors/outdoors, the high/low physical activity rates for different groups of people (especially critical groups) and shielding factors for housing types. For the internal irradiation calculations, data are needed on food consumption, effect of food processing, transfer parameters (soil to plant, plant to animal) and interception values appropriate for the region under study. Where the relevant data are not available default temperate data are currently used. The results of a wide ranging literature search has highlighted where specific research will be initiated to determine the information required for tropical and sub-tropical regions. The user is able to initiate sensitivity analyses within RadCon. This allows the parameters to be ranked in

Arabidopsis rad23-4 gene is required for pollen development under ...

African Journals Online (AJOL)

Nucleotide excision repair (NER) is a highly conserved DNA repair pathway for correcting DNA lesions that cause distortion of the double helical structure. The protein heterodimer Rad23 is involved in recognition and binding to such lesions. Here, we showed that rad23-4 (AT5g38470) was expressed in the roots, mature ...

The efficacy of hyperbaric oxygen in modifying the response of tissue to irradiation in doses of 200-400 rad per fraction

International Nuclear Information System (INIS)

Suit, D.D.; Orsi, L.

1975-01-01

The efficacy of respiration of O 2 at 30 psi in modifying the response of normal and tumour tissue to irradiation administered at 200 to 400 rad per fraction to anaesthetized mice has been evaluated. End-points have been delay in growth and TCD 50 for an early generation iso-transplant of a C 3 H mouse mammary carcinoma, and the acute reaction of skin of the C 3 H/Sed mouse. Results showed that the ratios of dose (air)/dose (O 2 30 psi) to elicit these end points were in the range 1.2 to 1.4. In earlier work using the same end points but doses per fraction 430 to 2100 rad, the ratios were 1.6 to 1.8. That is, for these tissue responses, respiration of O 2 at 30 psi increases the response of both normal and tumour tissue to all radiation doses tested. It is of greater effectiveness when combined with large doses per fraction, eg. greater than 430 rad. (author)

Malignancy risk estimation of screen-detected nodules at baseline CT: comparison of the PanCan model, Lung-RADS and NCCN guidelines

Energy Technology Data Exchange (ETDEWEB)

Riel, Sarah J. van; Ciompi, Francesco; Jacobs, Colin; Scholten, Ernst T.; Prokop, Mathias; Ginneken, Bram van [Radboud University Nijmegen Medical Center, Department of Radiology and Nuclear Medicine, Nijmegen (Netherlands); Winkler Wille, Mathilde M.; Naqibullah, Matiullah [University of Copenhagen, Department of Pulmonology Gentofte Hospital, Hellerup (Denmark); Lam, Stephen [British Columbia Cancer Agency, Department of Integrative Oncology, Vancouver, British Columbia (Canada); Schaefer-Prokop, Cornelia [Radboud University Nijmegen Medical Center, Department of Radiology and Nuclear Medicine, Nijmegen (Netherlands); Meander Medical Center, Department of Radiology, Amersfoort (Netherlands)

2017-10-15

To compare the PanCan model, Lung-RADS and the 1.2016 National Comprehensive Cancer Network (NCCN) guidelines for discriminating malignant from benign pulmonary nodules on baseline screening CT scans and the impact diameter measurement methods have on performances. From the Danish Lung Cancer Screening Trial database, 64 CTs with malignant nodules and 549 baseline CTs with benign nodules were included. Performance of the systems was evaluated applying the system's original diameter definitions: D{sup longest-C} (PanCan), D{sup meanAxial} (NCCN), both obtained from axial sections, and D{sup mean3D} (Lung-RADS). Subsequently all diameter definitions were applied uniformly to all systems. Areas under the ROC curves (AUC) were used to evaluate risk discrimination. PanCan performed superiorly to Lung-RADS and NCCN (AUC 0.874 vs. 0.813, p = 0.003; 0.874 vs. 0.836, p = 0.010), using the original diameter specifications. When uniformly applying D{sup longest-C}, D{sup mean3D} and D{sup meanAxial}, PanCan remained superior to Lung-RADS (p < 0.001 - p = 0.001) and NCCN (p < 0.001 - p = 0.016). Diameter definition significantly influenced NCCN's performance with D{sup longest-C} being the worst (D{sup longest-C} vs. D{sup mean3D}, p = 0.005; D{sup longest-C} vs. D{sup meanAxial}, p = 0.016). Without follow-up information, the PanCan model performs significantly superiorly to Lung-RADS and the 1.2016 NCCN guidelines for discriminating benign from malignant nodules. The NCCN guidelines are most sensitive to nodule size definition. (orig.)

NARAC Dispersion Model Product Integration With RadResponder

Energy Technology Data Exchange (ETDEWEB)

Aluzzi, Fernando [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

2015-09-30

Work on enhanced cooperation and interoperability of Nuclear Incident Response Teams (NIRT) is a joint effort between DHS/FEMA, DOE/NNSA and EPA. One such effort was the integration between the RadResponder Network, a resource sponsored by FEMA for the management of radiological data during an emergency, and the National Atmospheric Advisory Center (NARAC), a DOE/NNSA modeling resource whose predictions are used to aid radiological emergency preparedness and response. Working together under a FEMA-sponsored project these two radiological response assets developed a capability to read and display plume model prediction results from the NARAC computer system in the RadResponder software tool. As a result of this effort, RadResponder users have been provided with NARAC modeling predictions of contamination areas, radiological dose levels, and protective action areas (e.g., areas warranting worker protection or sheltering/evacuation) to help guide protective action decisions and field monitoring surveys, and gain key situation awareness following a radiological/nuclear accident or incident (e.g., nuclear power plant accident, radiological dispersal device incident, or improvised nuclear detonation incident). This document describes the details of this integration effort.

RadNet-Air Near Real Time Data

Data.gov (United States)

U.S. Environmental Protection Agency — RadNet-Air is a national network of air monitoring stations that regularly collect air samples for near real time analysis of radioactivity. The data is transmitted...

Validity of the breast imaging reporting and data system BI-RADS{sup TM} for clinical mammography in men; Anwendbarkeit des Breast Imaging Reporting and Data System (BI-RADS{sup TM}) auf die klinische Mammographie des Mannes

Energy Technology Data Exchange (ETDEWEB)

Bock, K.; Duda, V.F.; Bonwetsch, C.; Hadji, P.; Schulz, K.D. [Marburg Univ. (Germany). Klinik fuer Gynaekologie, Gynaekologische Endokrinologie und Onkologie; Iwinska-Zelder, J.; Klose, K.J. [Marburg Univ. (Germany). Klinik fuer Diagnostische Radiologie; Rode, G. [Diagnostische Gemeinschaftspraxis Marburg (Germany)

2001-11-01

Aim: The implementation of diagnostic standards enhances quality assurance. The American College of Radiology's breast imaging-reporting and data system (BI-RADS{sup TM}) is intended to standardize terminology in the mammography report, the assessment of the findings, and the recommendation af action to be taken. The purpose of this study was to assess the value of the standardized system for clinically apparent male breast tumors. Do the special male anatomy and physiology limit the applicability of an evaluation system designed for female screening mammograms? Methods: 4 investigators with different degrees of experience retrospectively evaluated 160 male mammograms. Our study was based on the 36 cases which could be correlated to histopathological findings: gynecomastia in the majority of cases, but also 4 invasive ductal carcinoma, 1 leiomyosarcoma and 1 ductal carcinoma in situ. Results: Assessment of the mammograms by BI-RADS{sup TM} (3{sup rd} Edition 1998) correctly placed all cases of malignancy into categories 4 and 5 without respect to the investigators's level of experience. Conclusion: Therefore, we conclude that the BI-RADS{sup TM}-classification can successfully be used to classify male mammograms with a high positive predictive value for malignancy. Knowledge of gender-specific imaging characteristics increases the specificity at a constant high level of sensitivity. (orig.) [German] Ziel: In der apparativen Diagnostik dient die Einfuehrung von Standards der Qualitaetssicherung. Das breast imaging-reporting and data system (BI-RADS{sup TM}) des American College of Radiology standardisiert den Sprachgebrauch in der Befundbeschreibung, die Befundbewertung und die resultierenden Empfehlungen in der Mammographie. Unser Interesse galt der Frage, inwieweit dieses System der Kategorisierung von Screening-Mammographien der Frau uebertragbar ist auf klinische Mammographien des Mannes. Begrenzen Anatomie und Physiologie der maennlichen Brustdruese

How and how much does RAD-seq bias genetic diversity estimates?

Science.gov (United States)

Cariou, Marie; Duret, Laurent; Charlat, Sylvain

2016-11-08

RAD-seq is a powerful tool, increasingly used in population genomics. However, earlier studies have raised red flags regarding possible biases associated with this technique. In particular, polymorphism on restriction sites results in preferential sampling of closely related haplotypes, so that RAD data tends to underestimate genetic diversity. Here we (1) clarify the theoretical basis of this bias, highlighting the potential confounding effects of population structure and selection, (2) confront predictions to real data from in silico digestion of full genomes and (3) provide a proof of concept toward an ABC-based correction of the RAD-seq bias. Under a neutral and panmictic model, we confirm the previously established relationship between the true polymorphism and its RAD-based estimation, showing a more pronounced bias when polymorphism is high. Using more elaborate models, we show that selection, resulting in heterogeneous levels of polymorphism along the genome, exacerbates the bias and leads to a more pronounced underestimation. On the contrary, spatial genetic structure tends to reduce the bias. We confront the neutral and panmictic model to "ideal" empirical data (in silico RAD-sequencing) using full genomes from natural populations of the fruit fly Drosophila melanogaster and the fungus Shizophyllum commune, harbouring respectively moderate and high genetic diversity. In D. melanogaster, predictions fit the model, but the small difference between the true and RAD polymorphism makes this comparison insensitive to deviations from the model. In the highly polymorphic fungus, the model captures a large part of the bias but makes inaccurate predictions. Accordingly, ABC corrections based on this model improve the estimations, albeit with some imprecisions. The RAD-seq underestimation of genetic diversity associated with polymorphism in restriction sites becomes more pronounced when polymorphism is high. In practice, this means that in many systems where

The TCD50 and regrowth delay assay in human tumor xenografts: Differences and implications

International Nuclear Information System (INIS)

Budach, W.; Budach, V.; Stuschke, M.; Dinges, S.; Sack, H.

1993-01-01

The response to irradiation of five human xenograft cell lines - a malignant paraganglioma, a neurogenic sarcoma, a malignant histiocytoma, a primary lymphoma of the brain, and a squamous cell carcinoma - were tested in nude mice. All mice underwent 5 Gy whole body irradiation prior to xenotransplantation to minimize the residual immune response. The subcutaneous tumors were irradiated at a tumor volume of 120 mm 3 under acutely hypoxic conditions with single doses between 8 Gy and 80 Gy depending on the expected radiation sensitivity of the tumor line. Endpoints of the study were the tumor control dose 50% (TCD 50 ) and the regrowth delay endpoints growth delay, specific growth delay, and the tumor bed effect corrected specific growth delay. Specific growth delay and corrected specific growth delay at 76% of the TCD 50 was used in order to compare the data to previously published data from spheroids. The lowest TCD 50 was found in the lymphoma with 24.9 Gy, whereas the TCD 50 of the soft tissue sarcomas and the squamous cell carcinoma ranged from 57.8 Gy to 65.6 Gy. The isoeffective dose levels for the induction of 30 days growth delay, a specific growth delay of 3, and a corrected specific growth delay of 3 ranged from 15.5 Gy (ECL1) to 37.1 Gy (FADU), from 7.2 Gy (ENE2) to 45.6 Gy (EPG1) and from 9.2 Gy (ENE2) to 37.6 Gy (EPG1), respectively. The corrected specific growth delay at 76% of the TCD 50 was correlated with the number of tumor rescue units per 100 cells in spheroids, which was available for three tumor lines, and with the tumor doubling time in xenografts (n = 5). The TCD 50 values corresponded better to the clinical experience than the regrowth delay data. There was no correlation between TCD 50 and any of the regrowth delay endpoints. This missing correlation was most likely a result of large differences in the number of tumor rescue units in human xenografts of the same size

Performance and precision of double digestion RAD (ddRAD) genotyping in large multiplexed datasets of marine fish species

DEFF Research Database (Denmark)

Maroso, F.; Hillen, J E J; Pardo, B. G.

2018-01-01

; (ii) the discrepancy between expected and observed tag length and coverage; (iii) the performances of reference based vs. de novo approaches; (iv) the sources of potential genotyping errors of the library preparation/bioinformatics protocol, by comparing technical replicates. Our results showed use...... a standardized protocol. A common bioinformatics pipeline based on STACKS was established, with and without the use of a reference genome. We performed analyses throughout the production and analysis of ddRAD data in order to explore (i) the loss of information due to heterogeneous raw read number across samples...... of downstream analysis carried out with ddRAD vs single SNP allele specific assay genotypes provided information about the levels of genotyping imprecision that can have a significant impact on allele frequency estimations and population assignment. The results and insights presented here will help to select...

Homologous Recombination Repair Signaling in Chemical Carcinogenesis: Prolonged Particulate Hexavalent Chromium Exposure Suppresses the Rad51 Response in Human Lung Cells

Science.gov (United States)

Qin, Qin; Xie, Hong; Wise, Sandra S.; Browning, Cynthia L.; Thompson, Kelsey N.; Holmes, Amie L.; Wise, John Pierce

2014-01-01

The aim of this study was to focus on hexavalent chromium, [Cr(VI)], a chemical carcinogen and major public health concern, and consider its ability to impact DNA double strand break repair. We further focused on particulate Cr(VI), because it is the more potent carcinogenic form of Cr(VI). DNA double strand break repair serves to protect cells against the detrimental effects of DNA double strand breaks. For particulate Cr(VI), data show DNA double strand break repair must be overcome for neoplastic transformation to occur. Acute Cr(VI) exposures reveal a robust DNA double strand break repair response, however, longer exposures have not been considered. Using the comet assay, we found longer exposures to particulate zinc chromate induced concentration-dependent increases in DNA double strand breaks indicating breaks were occurring throughout the exposure time. Acute (24 h) exposure induced DNA double strand break repair signaling by inducing Mre11 foci formation, ATM phosphorylation and phosphorylated ATM foci formation, Rad51 protein levels and Rad51 foci formation. However, longer exposures reduced the Rad51 response. These data indicate a major chemical carcinogen can simultaneously induce DNA double strand breaks and alter their repair and describe a new and important aspect of the carcinogenic mechanism for Cr(VI). PMID:25173789

Rad52 multimerization is important for its nuclear localization in Saccharomyces cerevisiae

DEFF Research Database (Denmark)

Plate, Iben; Albertsen, Line; Lisby, Michael

2008-01-01

Rad52 is essential for all homologous recombination and DNA double strand break repair events in Saccharomyces cerevisiae. This protein is multifunctional and contains several domains that allow it to interact with DNA as well as with different repair proteins. However, it has been unclear how Rad...

Effects of extracellular plaque components on the chlorhexidine sensitivity of strains of Streptococcus mutans and human dental plaque

International Nuclear Information System (INIS)

Wolinsky, L.E.; Hume, W.R.

1985-01-01

An in vitro study was undertaken to determine the effects of sucrose-derived extracellular plaque components on the sensitivity of selected oral bacteria to chlorhexidine (CX). Cultures of Streptococcus mutans HS-6, OMZ-176, Ingbritt C, 6715-wt13, and pooled human plaque were grown in trypticase soy media with or without 1% sucrose. The sensitivity to CX of bacteria grown in each medium was determined by fixed-time exposure to CX and subsequent measurement of 3 H-thymidine uptake. One-hour exposure to CX at concentrations of 10(-4) M (0.01% w/v) or greater substantially inhibited subsequent cellular division among all the S. mutans strains and human plaque samples tested. An IC50 (the CX concentration which depressed 3 H-thymidine incorporation to 50% of control level) of close to 10(-4) M was noted for S. mutans strains HS-6, OMZ-176, and 6715-wt13 when grown in the presence of sucrose. The same strains grown in cultures without added sucrose showed about a ten-fold greater sensitivity to CX (IC50 close to 10(-5) M). A three-fold difference was noted for S. mutans Ingbritt C. Only a slight increase in the IC50 was noted for the plaque samples cultured in sucrose-containing media, but their threshold for depression of 3 H-thymidine uptake by CX was lower than that for the sucrose-free plaque samples. The study showed that extracellular products confer some protection against CX to the bacteria examined, and provided an explanation for the disparity between clinically-recommended concentrations for plaque suppression and data on in vitro susceptibility

Radiation sensitivity of food decay fungi

International Nuclear Information System (INIS)

Chang, H.G.; Lee, B.H.

1980-01-01

Five species of food decay fungi, Aspergillus flavus, Asp. uiger, Penicillium sp., Botrytis cinerea and Rhizopus stolonifer, were examined for their radiosensitivity in several suspension media. Asp. flavus, Asp. niger and Penicillium sp. have almost the same sensitivity toward gamma rays, with D value in the range of 30 to 35 K rad, whereas Botrytis cinerea has a D value of approximately 55 K rad and Rhizopus stolonifer, the most resistant fungus studied, has a D value of approximately 100 K rad. Dry spores of Asp. flavus showed a considerable increase in their radioresistance when compared with spores irradiated in water. Asp. flavus and Penicillium sp. spores irradiated in citrate buffer at pH 3-7 showed almost no change in their radiosensitivity with pH, but Botrytis cinerea spores showed a distinct decrease in their radioresistance at pH 6 and 7. Penicillium sp. spores irradiated in sucrose solutions showed no significant change in their radioresistance. Botrytis cinerea spores displayed a higher radioresistance when they were irradiated in sucrose solution than in water. (author)

Management for BI-RADS category 3 lesions detected in preoperative breast MR imaging of breast cancer patients

Energy Technology Data Exchange (ETDEWEB)

Gweon, Hye Mi [Seoul National University College of Medicine, Seoul National University Hospital, Department of Radiology, Seoul (Korea, Republic of); Gangnam Severance Hospital, Yonsei University College of Medicine, Department of Radiology, Seoul (Korea, Republic of); Cho, Nariya; Kim, Soo-Yeon [Seoul National University College of Medicine, Seoul National University Hospital, Department of Radiology, Seoul (Korea, Republic of); Koo, Hye Ryoung [Hanyang University College of Medicine, Department of Radiology, Seoul (Korea, Republic of); Seo, Mirinae [Kyung Hee University College of Medicine, Department of Radiology, Seoul (Korea, Republic of); Chu, Ajung [Seoul National University College of Medicine, Boramae Medical Center, Department of Radiology, Seoul (Korea, Republic of); Son, Eun Ju [Gangnam Severance Hospital, Yonsei University College of Medicine, Department of Radiology, Seoul (Korea, Republic of)

2017-08-15

To retrospectively evaluate characteristics of and determine appropriate follow-up recommendations for BI-RADS category 3 lesions detected in preoperative MRI of breast cancer patients. BI-RADS category 3 assessments were identified from the breast MRI database for 5,110 consecutive breast cancer patients who had undergone preoperative MRI and surgery. Patient and lesion characteristics, malignancy rate, and interval between lesion detection and cancer diagnosis were analysed. Histopathological results or imaging at or after 2-year follow-up were used as reference standards. Of the 626 lesions, morphological features included a single focus in 26.5% (n = 166), multiple foci in 47.1% (n = 295), mass in 21.7% (n = 136) and non-mass enhancement in 4.6% (n = 29). Cancer was found in 0.8% (5/626) at a median interval of 50 months (range, 29-66 months). Malignancy rate according to morphological feature was: 1.8% (3/166) in a single focus, 0.7% (1/136) in mass and 3.4% (1/29) in non-mass enhancement. All detected cancers were stage 0 or IA. Annual follow-up might be adequate for BI-RADS category 3 lesions detected at preoperative MRI because of the 0.8% (5/626) malignancy rate, long interval between lesion detection and cancer diagnosis, and early stage of diagnosed cancers. (orig.)

Radiation sensitivity of human malignant lymphocytes

International Nuclear Information System (INIS)

Seshadri, R.; Matthews, C.; Morley, A.A.

1985-01-01

A simple and rapid in vitro technique to assess the sensitivity of human malignant lymphocytes to roentgen irradiation is described. A variety of established malignant lymphocyte cell lines were cloned in microwells and clone survival was used as the end-point. The survival of the clonogenic malignant lymphocyte down to a fraction of approximately 0.001 could be measured accurately. Except for a T-cell line, the radiation sensitivities of the cell lines were similar to that of normal T-lymphocytes. (orig.)

Simultaneous ATM/BRCA1/RAD51 expression variations associated with prognostic factors in Iranian sporadic breast cancer patients.

Science.gov (United States)

Hallajian, Zeinab; Mahjoubi, Frouzandeh; Nafissi, Nahid

2017-07-01

DNA double-strand breaks (DSBs) as a serious lesion are repaired by non-homologous end-joining and homologous recombination pathways. ATM, BRCA1, RAD51 genes are involved in HR pathways. While some studies have revealed individual expression changes of these genes in different types of cancer, there are limited studies attempting to evaluate correlation of expression variations of these genes in breast cancer pathogenesis. This study aimed to determine RAD51, ATM and BRCA1 gene expression level and its association with clinicopathological factors in fresh breast cancer tissues. Moreover, this study evaluates potential correlations among expression levels of these genes. 50 breast cancer tissues were collected and examined for BRCA1, RAD51 and ATM gene expression by Real Time PCR. Expression changes were analyzed with REST software version 2009. mRNA expression was reduced in all these three genes when compared with β-Actin as a control gene (P value  ATM, BRCA1 and RAD51 gene down expression (P value  ATM with stage (P value  < 0.05), necrosis (P value  < 0.05), perineural invasion (P value  < 0.05), vascular invasion (P value  < 0.01), malignancy (P value  ≤ 0.001), PR (P value  < 0.05) and ER status (P value  < 0.01). In addition, there was a significant association between down expression of BRCA1 with Ki67 (P value  ≤ 0.001). Moreover, there was a significant association between down expression of RAD51 with lymph node involvement (P value  < 0.01), auxiliary lymph node metastasis (P value  = 0.01), age (P = 0.001), grade (P value  < 0.05) and PR status (P value  < 0.05). This study suggests association between expression changes in several DSB repair genes in a common functional pathway in breast cancer and the significant association between abnormal expression of these genes and important clinical prognostic factors.

Genetic Interactions Between the Meiosis-Specific Cohesin Components, STAG3, REC8, and RAD21L.

Science.gov (United States)

Ward, Ayobami; Hopkins, Jessica; Mckay, Matthew; Murray, Steve; Jordan, Philip W

2016-06-01

Cohesin is an essential structural component of chromosomes that ensures accurate chromosome segregation during mitosis and meiosis. Previous studies have shown that there are cohesin complexes specific to meiosis, required to mediate homologous chromosome pairing, synapsis, recombination, and segregation. Meiosis-specific cohesin complexes consist of two structural maintenance of chromosomes proteins (SMC1α/SMC1β and SMC3), an α-kleisin protein (RAD21, RAD21L, or REC8), and a stromal antigen protein (STAG1, 2, or 3). STAG3 is exclusively expressed during meiosis, and is the predominant STAG protein component of cohesin complexes in primary spermatocytes from mouse, interacting directly with each α-kleisin subunit. REC8 and RAD21L are also meiosis-specific cohesin components. Stag3 mutant spermatocytes arrest in early prophase ("zygotene-like" stage), displaying failed homolog synapsis and persistent DNA damage, as a result of unstable loading of cohesin onto the chromosome axes. Interestingly, Rec8, Rad21L double mutants resulted in an earlier "leptotene-like" arrest, accompanied by complete absence of STAG3 loading. To assess genetic interactions between STAG3 and α-kleisin subunits RAD21L and REC8, our lab generated Stag3, Rad21L, and Stag3, Rec8 double knockout mice, and compared them to the Rec8, Rad21L double mutant. These double mutants are phenotypically distinct from one another, and more severe than each single knockout mutant with regards to chromosome axis formation, cohesin loading, and sister chromatid cohesion. The Stag3, Rad21L, and Stag3, Rec8 double mutants both progress further into prophase I than the Rec8, Rad21L double mutant. Our genetic analysis demonstrates that cohesins containing STAG3 and REC8 are the main complex required for centromeric cohesion, and RAD21L cohesins are required for normal clustering of pericentromeric heterochromatin. Furthermore, the STAG3/REC8 and STAG3/RAD21L cohesins are the primary cohesins required for

RAD51 and RTEL1 compensate telomere loss in the absence of telomerase.

Science.gov (United States)

Olivier, Margaux; Charbonnel, Cyril; Amiard, Simon; White, Charles I; Gallego, Maria E

2018-03-16

Replicative erosion of telomeres is naturally compensated by telomerase and studies in yeast and vertebrates show that homologous recombination can compensate for the absence of telomerase. We show that RAD51 protein, which catalyzes the key strand-invasion step of homologous recombination, is localized at Arabidopsis telomeres in absence of telomerase. Blocking the strand-transfer activity of the RAD51 in telomerase mutant plants results in a strikingly earlier onset of developmental defects, accompanied by increased numbers of end-to-end chromosome fusions. Imposing replication stress through knockout of RNaseH2 increases numbers of chromosome fusions and reduces the survival of these plants deficient for telomerase and homologous recombination. This finding suggests that RAD51-dependent homologous recombination acts as an essential backup to the telomerase for compensation of replicative telomere loss to ensure genome stability. Furthermore, we show that this positive role of RAD51 in telomere stability is dependent on the RTEL1 helicase. We propose that a RAD51 dependent break-induced replication process is activated in cells lacking telomerase activity, with RTEL1 responsible for D-loop dissolution after telomere replication.

A non-human primate model for gluten sensitivity.

Directory of Open Access Journals (Sweden)

Michael T Bethune

2008-02-01

Full Text Available Gluten sensitivity is widespread among humans. For example, in celiac disease patients, an inflammatory response to dietary gluten leads to enteropathy, malabsorption, circulating antibodies against gluten and transglutaminase 2, and clinical symptoms such as diarrhea. There is a growing need in fundamental and translational research for animal models that exhibit aspects of human gluten sensitivity.Using ELISA-based antibody assays, we screened a population of captive rhesus macaques with chronic diarrhea of non-infectious origin to estimate the incidence of gluten sensitivity. A selected animal with elevated anti-gliadin antibodies and a matched control were extensively studied through alternating periods of gluten-free diet and gluten challenge. Blinded clinical and histological evaluations were conducted to seek evidence for gluten sensitivity.When fed with a gluten-containing diet, gluten-sensitive macaques showed signs and symptoms of celiac disease including chronic diarrhea, malabsorptive steatorrhea, intestinal lesions and anti-gliadin antibodies. A gluten-free diet reversed these clinical, histological and serological features, while reintroduction of dietary gluten caused rapid relapse.Gluten-sensitive rhesus macaques may be an attractive resource for investigating both the pathogenesis and the treatment of celiac disease.

Rad-hard embedded computers for nuclear robotics

International Nuclear Information System (INIS)

Giraud, A.; Joffre, F.; Marceau, M.; Robiolle, M.; Brunet, J.P.; Mijuin, D.

1993-01-01

For requirements of nuclear industries, it is necessary to use robots with embedded rad hard electronics and high level safety. The computer developed for french research program SYROCO is presented in this paper. (authors). 8 refs., 5 figs

Mutations in LRRC50 predispose zebrafish and humans to seminomas.

Directory of Open Access Journals (Sweden)

Sander G Basten

2013-04-01

Full Text Available Seminoma is a subclass of human testicular germ cell tumors (TGCT, the most frequently observed cancer in young men with a rising incidence. Here we describe the identification of a novel gene predisposing specifically to seminoma formation in a vertebrate model organism. Zebrafish carrying a heterozygous nonsense mutation in Leucine-Rich Repeat Containing protein 50 (lrrc50 also called dnaaf1, associated previously with ciliary function, are found to be highly susceptible to the formation of seminomas. Genotyping of these zebrafish tumors shows loss of heterozygosity (LOH of the wild-type lrrc50 allele in 44.4% of tumor samples, correlating with tumor progression. In humans we identified heterozygous germline LRRC50 mutations in two different pedigrees with a family history of seminomas, resulting in a nonsense Arg488* change and a missense Thr590Met change, which show reduced expression of the wild-type allele in seminomas. Zebrafish in vivo complementation studies indicate the Thr590Met to be a loss-of-function mutation. Moreover, we show that a pathogenic Gln307Glu change is significantly enriched in individuals with seminoma tumors (13% of our cohort. Together, our study introduces an animal model for seminoma and suggests LRRC50 to be a novel tumor suppressor implicated in human seminoma pathogenesis.

Activation of human B lymphocytes. 8. Differential radiosensitivity of subpopulations of lymphoid cells involved in the polyclonally-induced PFC responses of peripheral blood B lymphocytes

Energy Technology Data Exchange (ETDEWEB)

Fauci, A S; Pratt, K R; Whalen, G [National Inst. of Allergy and Infectious Diseases, Bethesda, MD (USA)

1978-11-01

The differential effect of various doses of irradiation on subpopulations of human peripheral blood lymphoid cells involved in the pokeweed mitogen induced PFC response against sheep red blood cells was studied. The plaque forming B cells were quite sensitive to low doses of irradiation with complete suppression of responses at 300 to 500 rad. On the contrary, helper T-cell function was resistant to 2000 rad. Co-culture of irradiated T cells with autologous or allogeneic B cells resulted in marked enhancement of PFC responses consistent with the suppression of naturally occurring suppressor cells with a resulting pure helper effect. Irradiated T-cell-depleted suspensions failed to produce this effect as did heat killed T cells, whereas mitomycin C treated T cells gave effects similar to irradiated T cells. These findings are consistent with a lack of requirement of cell division for a T-cell helper effect and a requirement of mitosis or another irradiation sensitive, mitomycin C sensitive process for a T-suppressor cell effect. These studies have potential relevance in the evaluation of subpopulations of human lymphoid cells involved in antibody production in normal individuals and in disease states.

A comparison of the radiosensitivity of stationary, exponential and G1 phase wild type and repair deficient yeast cultures: supporting evidence for stationary phase yeast cells being in G0

International Nuclear Information System (INIS)

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

1982-01-01

The main points to emerge from this comparison of the radiosensitivity of stationary, exponential and G 1 phase yeast cultures were: (1) In wild type yeast cultures, G 1 cells were the most sensitive to the lethal effects of X-rays, exponential phase cells were the most resistant and stationary phase cells were intermediate in sensitivity. (2) With the excision-repair-defective strain D61-3 (rad 3) stationary phase cells were more resistant than exponential cells with G 1 cells again being most sensitive. (3) The rad 50 gene present in JD50 had a marked effect on the X-ray inactivation response of this strain. In the presence of the defective rad 50 allele, exponential phase cells were as sensitive as G 1 phase cells, with stationary phase cells being more resistant than either. (4) There were marked differences in sensitivity between stationary phase and G 1 phase cells. These differences, along with other physiological differences reported by other workers, lead the authors to suggest that stationary phase cells can be better described as being in G 0 phase, i.e. a stage which is outside the normal mitotic cell cycle of an exponential culture. (author)

Use of BI-RADS-MRI descriptors for differentiation between mucinous carcinoma and fibroadenoma.

Science.gov (United States)

Igarashi, Takao; Ashida, Hirokazu; Morikawa, Kazuhiko; Motohashi, Kenji; Fukuda, Kunihiko

2016-06-01

We evaluated the latest breast imaging reporting and data system (BI-RADS) magnetic resonance imaging (MRI) (5th edition) descriptors and non BI-RADS MRI factors that contribute to differentiation between mucinous carcinomas (MCs) and fibroadenomas (FAs). This retrospective study included 27 patients with P-MCs or M-MCs similar to P-MCs and 22 patients with FAs who underwent breast MRI between October 2008 and July 2014 at our institution. Definitive histopathological diagnoses were made for all of the MCs and FAs. The latest BI-RADS MRI descriptors for abnormal enhancement, including maximum diameter, shape (irregular or round/oval), margin (irregular or circumscribed), rim enhancement (present or absent), dark internal septation (absent or present), delayed internal enhancement (heterogeneous or homogeneous), and the time-intensity curve pattern (not persistent or persistent) were evaluated. As additional non BI-RADS MRI factors related to differentiation between MC and FA, age, signal intensity in the T2-weighted image (high or not high), extent of lobulation (strong or weak), enhancing internal septation (present or absent), and the apparent diffusion coefficient value were also evaluated. One radiologist retrospectively evaluated interpreted MR findings and analyzed the findings. Statistically significant findings were identified through univariate and multivariate analyses. Then, three blinded radiologists reviewed the MR images where MR findings had shown a significant association with outcomes during univariate analyses. Independently, the three blinded readers reviewed the MR images for the evaluation of inter-observer variability, and then arrived at a consensus for the evaluation of observer performance. Observer performance and inter-observer variability were determined via a receiver-operating-characteristic curve analysis and weighted k statistics. The sensitivity, specificity, and accuracy of each of the MR findings were calculated. Univariate

Comparison of Danish dichotomous and BI-RADS classifications of mammographic density

DEFF Research Database (Denmark)

Hodge, Rebecca; Hellmann, Sophie Sell; von Euler-Chelpin, My

2014-01-01

BACKGROUND: In the Copenhagen mammography screening program from 1991 to 2001, mammographic density was classified either as fatty or mixed/dense. This dichotomous mammographic density classification system is unique internationally, and has not been validated before. PURPOSE: To compare the Danish...... dichotomous mammographic density classification system from 1991 to 2001 with the density BI-RADS classifications, in an attempt to validate the Danish classification system. MATERIAL AND METHODS: The study sample consisted of 120 mammograms taken in Copenhagen in 1991-2001, which tested false positive......, and which were in 2012 re-assessed and classified according to the BI-RADS classification system. We calculated inter-rater agreement between the Danish dichotomous mammographic classification as fatty or mixed/dense and the four-level BI-RADS classification by the linear weighted Kappa statistic. RESULTS...

Fast neutron background characterization with the Radiological Multi-sensor Analysis Platform (RadMAP)

Energy Technology Data Exchange (ETDEWEB)

Davis, John R., E-mail: john.davis@usma.edu [Lawrence Berkeley National Laboratory, Berkeley, CA (United States); The United States Military Academy, West Point, NY (United States); Brubaker, Erik [Sandia National Laboratories, Livermore, CA (United States); Vetter, Kai [Lawrence Berkeley National Laboratory, Berkeley, CA (United States)

2017-06-21

In an effort to characterize the fast neutron radiation background, 16 EJ-309 liquid scintillator cells were installed in the Radiological Multi-sensor Analysis Platform (RadMAP) to collect data in the San Francisco Bay Area. Each fast neutron event was associated with specific weather metrics (pressure, temperature, absolute humidity) and GPS coordinates. The expected exponential dependence of the fast neutron count rate on atmospheric pressure was demonstrated and event rates were subsequently adjusted given the measured pressure at the time of detection. Pressure adjusted data was also used to investigate the influence of other environmental conditions on the neutron background rate. Using National Oceanic and Atmospheric Administration (NOAA) coastal area lidar data, an algorithm was implemented to approximate sky-view factors (the total fraction of visible sky) for points along RadMAPs route. Three areas analyzed in San Francisco, Downtown Oakland, and Berkeley all demonstrated a suppression in the background rate of over 50% for the range of sky-view factors measured. This effect, which is due to the shielding of cosmic-ray produced neutrons by surrounding buildings, was comparable to the pressure influence which yielded a 32% suppression in the count rate over the range of pressures measured.

High-sensitivity simultaneous liquid chromatography-tandem mass spectrometry assay of ethinyl estradiol and levonorgestrel in human plasma

Institute of Scientific and Technical Information of China (English)

Abhishek Gandhi; Swati Guttikar; Priti Trivedi

2015-01-01

A sensitive and simultaneous liquid chromatography-tandem mass spectrometry method was developed and validated for quantification of ethinyl estradiol and levonorgestrel. The analytes were extracted with methyl-tert-butyl ether: n-hexane (50:50, v/v) solvent mixture, followed by dansyl derivatization. The chromatographic separation was performed on a Kinetex C18 (50 mm × 4.6 mm, 2.6μm) column with a mobile phase of 0.1% (v/v) formic acid in water and acetonitrile in gradient composition. The mass transitions were monitored in electrospray positive ionization mode. The assay exhibited a linear range of 0.100-20.0 ng/mL for levonorgestrel and 4.00-500 pg/mL for ethinyl estradiol in human plasma. A run time of 9.0 min for each sample made it possible to analyze a throughput of more than 100 samples per day. The validated method has been successfully used to analyze human plasma samples for application in pharmacokinetic and bioequivalence studies.

Sensitivity of species to chemicals: dose-response characteristics for various test types (LC(50), LR(50) and LD(50)) and modes of action.

Science.gov (United States)

Hendriks, A Jan; Awkerman, Jill A; de Zwart, Dick; Huijbregts, Mark A J

2013-11-01

While variable sensitivity of model species to common toxicants has been addressed in previous studies, a systematic analysis of inter-species variability for different test types, modes of action and species is as of yet lacking. Hence, the aim of the present study was to identify similarities and differences in contaminant levels affecting cold-blooded and warm-blooded species administered via different routes. To that end, data on lethal water concentrations LC50, tissue residues LR50 and oral doses LD50 were collected from databases, each representing the largest of its kind. LC50 data were multiplied by a bioconcentration factor (BCF) to convert them to internal concentrations that allow for comparison among species. For each endpoint data set, we calculated the mean and standard deviation of species' lethal level per compound. Next, the means and standard deviations were averaged by mode of action. Both the means and standard deviations calculated depended on the number of species tested, which is at odds with quality standard setting procedures. Means calculated from (BCF) LC50, LR50 and LD50 were largely similar, suggesting that different administration routes roughly yield similar internal levels. Levels for compounds interfering biochemically with elementary life processes were about one order of magnitude below that of narcotics disturbing membranes, and neurotoxic pesticides and dioxins induced death in even lower amounts. Standard deviations for LD50 data were similar across modes of action, while variability of LC50 values was lower for narcotics than for substances with a specific mode of action. The study indicates several directions to go for efficient use of available data in risk assessment and reduction of species testing. Copyright © 2013 Elsevier Inc. All rights reserved.

Roles of Rad51 protein in homologous recombination in mammalian cells: relation with repair, replication and cell cycle

International Nuclear Information System (INIS)

Lambert, S.

2001-01-01

Homologous recombination (HR) is a fundamental process, allowing a faithful repair. In mammalian, MmRAD51, which is the homologue of Saccharomyces cerevisiae ScRAD51 key protein for HR, is an essential gene. This work is based on the characterisation of viable hyper and hypo-recombinant cell lines specifically affected in the Rad51 pathway. By expressing wild type and dominant negative forms of MmRad51, we demonstrated that Rad51 pathway participates to the repair by HR to induced DNA damages. However, inhibition of the Rad 51 pathway does not affect cell viability, spontaneously or after irradiation, whereas, radiation induced HR is inhibited. In the presence of DNA damages during late S and G2/M phase, inhibition of Rad51 pathway induced chromosomal aberrations, leading to a transient arrest in mitosis. This arrest is associated with an increased of cell death. However, a fraction of cells can escape from this transient arrest by forming tetraploid cells, associated with an absence of chromalid separation. Thus, in response to impaired Rad51 pathway, mitotic checkpoints seems to play an essential role. In line with this, we showed that the essential function of Rad51 is p53-dependent, which is in agreement with the role of p53 in tetraploidy inhibition. Our results suggest that the Rad51 protein could participate to the control of mitotic checkpoints and thus to the maintenance of genetic stability. This function could involve other Rad51 partners such as the tumour suppressors BRCA1, BRCA2 and p53. (author) [fr

Lysine residue 185 of Rad1 is a topological but not a functional counterpart of lysine residue 164 of PCNA.

Directory of Open Access Journals (Sweden)

Niek Wit

Full Text Available Monoubiquitylation of the homotrimeric DNA sliding clamp PCNA at lysine residue 164 (PCNA(K164 is a highly conserved, DNA damage-inducible process that is mediated by the E2/E3 complex Rad6/Rad18. This ubiquitylation event recruits translesion synthesis (TLS polymerases capable of replicating across damaged DNA templates. Besides PCNA, the Rad6/Rad18 complex was recently shown in yeast to ubiquitylate also 9-1-1, a heterotrimeric DNA sliding clamp composed of Rad9, Rad1, and Hus1 in a DNA damage-inducible manner. Based on the highly similar crystal structures of PCNA and 9-1-1, K185 of Rad1 (Rad1(K185 was identified as the only topological equivalent of PCNA(K164. To investigate a potential role of posttranslational modifications of Rad1(K185 in DNA damage management, we here generated a mouse model with a conditional deletable Rad1(K185R allele. The Rad1(K185 residue was found to be dispensable for Chk1 activation, DNA damage survival, and class switch recombination of immunoglobulin genes as well as recruitment of TLS polymerases during somatic hypermutation of immunoglobulin genes. Our data indicate that Rad1(K185 is not a functional counterpart of PCNA(K164.

Contribution of a caffeine-sensitive recombinational repair pathway to survival and mutagenesis in UV-irradiated Schizosaccharomyces pombe

International Nuclear Information System (INIS)

Gentner, N.E.; Werner, M.M.; Hannan, M.A.; Nasim, A.

1978-01-01

Cells of wild-type Schizosacharomyces pombe exposed to UV radiation in either G1 or G2 phase show enhanced inactivation of colony-forming ability if plated in the presence of caffeine. This UV-sensitization by caffeine is abolished in both G1 an G2 phase cells by the radlmutation; since both caffeine and the radl mutation markedly reduce recombinational events, this suggests that a recombinational repair process is active in cells irradiated either in G1 or G2 phase. Caffeine-sensitive repair begins immediately and is completed before resumption of DNA synthesis. Caffeine-sensitive repair of UV-damage in G1 cells displays a considerable lag and then occurs concomitantly with DNA synthesis. UV-induced mutagenesis was examined in wild-type and rad mutants using a forward mutation system. Rad mutants which show higher UV-induced mutation rates than wild-type retain the recombinational mechanism. In contrast, rad strains which are relatively UV-immutable compared to wild-type do not possess the caffeine-sensitive UV-repair process. The recombinational process therefore may be the major pathway responsible for UV-induced mutation. (orig./AJ) [de

Stage sensitivity and dose response of meiotic chromosomes of pollen mother cells of Tradescantia to X-rays

Energy Technology Data Exchange (ETDEWEB)

Ma, T H; Kontos, Jr, G J; Anderson, V A [Western Illinois Univ., Macomb (USA). Dept. of Biological Sciences

1980-05-01

Chromosome damage induced by physical and chemical mutagens can be quantitated by the frequencies of micronuclei (MCN) produced in tetrads of the meiotic pollen mother cells of Tradescantia, i.e. the 'MCN-in-Tetrad' test. The stage sensitivity and dose response of these meiocytes to low exposures of X-rays was studied to improve the efficiency and reliability of this test. Stage sensitivity was determined by observing, at 3 hr intervals, the frequencies of X-ray (35 rads)-induced MCN in tetrads from a series of 16 fixations of tetrad-containing inflorescences. Late stages of meiosis (3-9 hr post-irradiation fixation groups) were insensitive (5-14 MCN/100 tetrads). Relatively high sensitivity was exhibited in the early stages of meiosis. The first and second sensitive peaks (62 and 61 MCN/100 tetrads) centered around the 21 and 39 hr post-irradiation fixation groups respectively. Control groups yielded around 3-4 MCN/100 tetrads. A dose-response relation for MCN was determined by treating early stages of meiotic pollen mother cells with X-ray exposures ranging from 9.5 to 57.5 rads. A linear regression line was established with about 20 MCN/100 tetrads per 10 rad increment.

Isolation of cell cycle-dependent gamma ray-sensitive Chinese hamster ovary cell

International Nuclear Information System (INIS)

Stamato, T.D.; Weinstein, R.; Giaccia, A.; Mackenzie, L.

1983-01-01

A technique for the isolation of gamma ray-sensitive Chinese hamster ovary (CHO) cell mutants is described, which uses nylon cloth replica plating and photography with dark-field illumination to directly monitor colonies for growth after gamma irradiation. Two gamma ray-sensitive mutants were isolated using this method. One of these cells (XR-1) had a two-slope survival curve: an initial steep slope and then a flattening of the curve at about 10% survival. Subsequently, it was found that this cell is sensitive to gamma irradiation in G1, early S, and late G2 phases of the cell cycle, whereas in the resistant phase (late S phase) its survival approaches that of the parental cells. The D37 in the sensitive G1 period is approximately 30 rads, compared with 300 rads of the parental cell. This mutant cell is also sensitive to killing by the DNA breaking agent, bleomycin, but is relatively insensitive to UV light and ethyl methane sulfonate, suggesting that the defect is specific for agents that produce DNA strand breakage

Conservatism in SRS Criticality Alarm System 12 Rad Zone Calculations - How Much is Enough?

International Nuclear Information System (INIS)

Yates, K.R.

2002-01-01

Savannah River Site (SRS) uses two methods (i.e., Approximate Method and MCNP) of calculating the 12-rad zone. The reasons for the two-tier approach are described in Ref. 1 and 2. Lately, there have been occasions in which the use of either the Approximate Method (AM) or MCNP3 calculations indicated potential facility impacts. For example, one or both methods may indicate that a 12-rad zone extends outside of relatively thick shielding, or extends to the roof of a facility, or extends through shielding to part of a stairwell. In such cases, a criticality alarm system may have to be installed to protect workers in a small, localized area from a potential dose that is not substantially greater than 12 rad in air. But, is the potential dose really greater than 12 rad in air? A subcommittee was appointed to look into the two 12-rad zone calculation methods for the purpose of identifying items contributing to over-conservatism and under-conservatism, and to recommend a path forward

Checkpoint Kinase Rad53 Couples Leading- and Lagging-Strand DNA Synthesis under Replication Stress.

Science.gov (United States)

Gan, Haiyun; Yu, Chuanhe; Devbhandari, Sujan; Sharma, Sushma; Han, Junhong; Chabes, Andrei; Remus, Dirk; Zhang, Zhiguo

2017-10-19

The checkpoint kinase Rad53 is activated during replication stress to prevent fork collapse, an essential but poorly understood process. Here we show that Rad53 couples leading- and lagging-strand synthesis under replication stress. In rad53-1 cells stressed by dNTP depletion, the replicative DNA helicase, MCM, and the leading-strand DNA polymerase, Pol ε, move beyond the site of DNA synthesis, likely unwinding template DNA. Remarkably, DNA synthesis progresses further along the lagging strand than the leading strand, resulting in the exposure of long stretches of single-stranded leading-strand template. The asymmetric DNA synthesis in rad53-1 cells is suppressed by elevated levels of dNTPs in vivo, and the activity of Pol ε is compromised more than lagging-strand polymerase Pol δ at low dNTP concentrations in vitro. Therefore, we propose that Rad53 prevents the generation of excessive ssDNA under replication stress by coordinating DNA unwinding with synthesis of both strands. Copyright © 2017 Elsevier Inc. All rights reserved.

Breast Imaging Reporting and Data System (BI-RADS) breast composition descriptors: Automated measurement development for full field digital mammography

International Nuclear Information System (INIS)

Fowler, E. E.; Sellers, T. A.; Lu, B.; Heine, J. J.

2013-01-01

Purpose: The Breast Imaging Reporting and Data System (BI-RADS) breast composition descriptors are used for standardized mammographic reporting and are assessed visually. This reporting is clinically relevant because breast composition can impact mammographic sensitivity and is a breast cancer risk factor. New techniques are presented and evaluated for generating automated BI-RADS breast composition descriptors using both raw and calibrated full field digital mammography (FFDM) image data.Methods: A matched case-control dataset with FFDM images was used to develop three automated measures for the BI-RADS breast composition descriptors. Histograms of each calibrated mammogram in the percent glandular (pg) representation were processed to create the new BR pg measure. Two previously validated measures of breast density derived from calibrated and raw mammograms were converted to the new BR vc and BR vr measures, respectively. These three measures were compared with the radiologist-reported BI-RADS compositions assessments from the patient records. The authors used two optimization strategies with differential evolution to create these measures: method-1 used breast cancer status; and method-2 matched the reported BI-RADS descriptors. Weighted kappa (κ) analysis was used to assess the agreement between the new measures and the reported measures. Each measure's association with breast cancer was evaluated with odds ratios (ORs) adjusted for body mass index, breast area, and menopausal status. ORs were estimated as per unit increase with 95% confidence intervals.Results: The three BI-RADS measures generated by method-1 had κ between 0.25–0.34. These measures were significantly associated with breast cancer status in the adjusted models: (a) OR = 1.87 (1.34, 2.59) for BR pg ; (b) OR = 1.93 (1.36, 2.74) for BR vc ; and (c) OR = 1.37 (1.05, 1.80) for BR vr . The measures generated by method-2 had κ between 0.42–0.45. Two of these measures were significantly

The USP1-UAF1 complex interacts with RAD51AP1 to promote homologous recombination repair.

Science.gov (United States)

Cukras, Scott; Lee, Euiho; Palumbo, Emily; Benavidez, Pamela; Moldovan, George-Lucian; Kee, Younghoon

2016-10-01

USP1 deubiquitinating enzyme and its stoichiometric binding partner UAF1 play an essential role in promoting DNA homologous recombination (HR) repair in response to various types of DNA damaging agents. Deubiquitination of FANCD2 may be attributed to the key role of USP1-UAF1 complex in regulating HR repair, however whether USP1-UAF1 promotes HR repair independently of FANCD2 deubiquitination is not known. Here we show evidence that the USP1-UAF1 complex has a FANCD2-independent function in promoting HR repair. Proteomic search of UAF1-interacting proteins revealed that UAF1 associates with RAD51AP1, a RAD51-interacting protein implicated in HR repair. We show that UAF1 mediates the interaction between USP1 and RAD51AP1, and that depletion of USP1 or UAF1 led to a decreased stability of RAD51AP1. Protein interaction mapping analysis identified some key residues within RAD51AP1 required for interacting with the USP1-UAF1 complex. Cells expressing the UAF1 interaction-deficient mutant of RAD51AP1 show increased chromosomal aberrations in response to Mitomycin C treatment. Moreover, similar to the RAD51AP1 depleted cells, the cells expressing UAF1-interaction deficient RAD51AP1 display persistent RAD51 foci following DNA damage exposure, indicating that these factors regulate a later step during the HR repair. These data altogether suggest that the USP1-UAF1 complex promotes HR repair via multiple mechanisms: through FANCD2 deubiquitination, as well as by interacting with RAD51AP1.

RadNet Real-Time Monitoring Spectrometry Data Inventory

Data.gov (United States)

U.S. Environmental Protection Agency — The RadNet Real-Time Monitoring Spectrometry Data Inventory contains measured data used to identify and measure specific radioactive materials in the atmosphere at...

QSAR models of human data can enrich or replace LLNA testing for human skin sensitization

OpenAIRE

Alves, Vinicius M.; Capuzzi, Stephen J.; Muratov, Eugene; Braga, Rodolpho C.; Thornton, Thomas; Fourches, Denis; Strickland, Judy; Kleinstreuer, Nicole; Andrade, Carolina H.; Tropsha, Alexander

2016-01-01

Skin sensitization is a major environmental and occupational health hazard. Although many chemicals have been evaluated in humans, there have been no efforts to model these data to date. We have compiled, curated, analyzed, and compared the available human and LLNA data. Using these data, we have developed reliable computational models and applied them for virtual screening of chemical libraries to identify putative skin sensitizers. The overall concordance between murine LLNA and human skin ...

Sensitization of human cancer cells to gemcitabine by the Chk1 inhibitor MK-8776: cell cycle perturbation and impact of administration schedule in vitro and in vivo

International Nuclear Information System (INIS)

Montano, Ryan; Thompson, Ruth; Chung, Injae; Hou, Huagang; Khan, Nadeem; Eastman, Alan

2013-01-01

Chk1 inhibitors have emerged as promising anticancer therapeutic agents particularly when combined with antimetabolites such as gemcitabine, cytarabine or hydroxyurea. Here, we address the importance of appropriate drug scheduling when gemcitabine is combined with the Chk1 inhibitor MK-8776, and the mechanisms involved in the schedule dependence. Growth inhibition induced by gemcitabine plus MK-8776 was assessed across multiple cancer cell lines. Experiments used clinically relevant “bolus” administration of both drugs rather than continuous drug exposures. We assessed the effect of different treatment schedules on cell cycle perturbation and tumor cell growth in vitro and in xenograft tumor models. MK-8776 induced an average 7-fold sensitization to gemcitabine in 16 cancer cell lines. The time of MK-8776 administration significantly affected the response of tumor cells to gemcitabine. Although gemcitabine induced rapid cell cycle arrest, the stalled replication forks were not initially dependent on Chk1 for stability. By 18 h, RAD51 was loaded onto DNA indicative of homologous recombination. Inhibition of Chk1 at 18 h rapidly dissociated RAD51 leading to the collapse of replication forks and cell death. Addition of MK-8776 from 18–24 h after a 6-h incubation with gemcitabine induced much greater sensitization than if the two drugs were incubated concurrently for 6 h. The ability of this short incubation with MK-8776 to sensitize cells is critical because of the short half-life of MK-8776 in patients’ plasma. Cell cycle perturbation was also assessed in human pancreas tumor xenografts in mice. There was a dramatic accumulation of cells in S/G 2 phase 18 h after gemcitabine administration, but cells had started to recover by 42 h. Administration of MK-8776 18 h after gemcitabine caused significantly delayed tumor growth compared to either drug alone, or when the two drugs were administered with only a 30 min interval. There are two reasons why delayed

A new parameterization for ice cloud optical properties used in BCC-RAD and its radiative impact

International Nuclear Information System (INIS)

Zhang, Hua; Chen, Qi; Xie, Bing

2015-01-01

A new parameterization of the solar and infrared optical properties of ice clouds that considers the multiple habits of ice particles was developed on the basis of a prescribed dataset. First, the fitting formulae of the bulk extinction coefficient, single-scatter albedo, asymmetry factor, and δ-function forward-peak factor at the given 65 wavelengths as a function of effective radius were created for common scenarios, which consider a greater number of wavelengths and are more accurate than those used previously. Then, the band-averaged volume extinction and absorption coefficients, asymmetry factor and forward-peak factor of ice cloud were derived for the BCC-RAD (Beijing Climate Center radiative transfer model) using a parameter reference table. Finally, the newly developed and the original schemes in the BCC-RAD and the commonly used Fu Scheme of ice cloud were all applied to the BCC-RAD. Their influences on radiation calculations were compared using the mid-latitude summer atmospheric profile with ice clouds under no-aerosol conditions, and produced a maximum difference of approximately 30.0 W/m 2 for the radiative flux, and 4.0 K/d for the heating rate. Additionally, a sensitivity test was performed to investigate the impact of the ice crystal density on radiation calculations using the three schemes. The results showed that the maximum difference was 68.1 W/m 2 for the shortwave downward radiative flux (for the case of perpendicular solar insolation), and 4.2 K/d for the longwave heating rate, indicating that the ice crystal density exerts a significant effect on radiation calculations for a cloudy atmosphere. - Highlights: • A new parameterization of the radiative properties of ice cloud was obtained. • More accurate fitting formulae of them were created for common scenarios. • The band-averaged of them were derived for our radiation model of BCC-RAD. • We found that there exist large differences of results among different ice schemes. • We found

Performance evaluation of the Bio-Rad Laboratories GS HIV Combo Ag/Ab EIA, a 4th generation HIV assay for the simultaneous detection of HIV p24 antigen and antibodies to HIV-1 (groups M and O) and HIV-2 in human serum or plasma.

Science.gov (United States)

Bentsen, Christopher; McLaughlin, Lisa; Mitchell, Elizabeth; Ferrera, Carol; Liska, Sally; Myers, Robert; Peel, Sheila; Swenson, Paul; Gadelle, Stephane; Shriver, M Kathleen

2011-12-01

A multi-center study was conducted to evaluate the Bio-Rad GS HIV Combo Ag/Ab EIA, a 4th generation HIV-1/HIV-2 assay for the simultaneous detection of HIV p24 antigen and antibodies to HIV-1 (groups M and O) and HIV-2 in human serum or plasma in adult and pediatric populations. The objectives of the study were to assess assay performance for the detection of acute HIV infections; sensitivity in known HIV positive samples; percent agreement with HIV status; specificity in low and high risk individuals of unknown HIV status; and to compare assay performance to a 3rd generation HIV assay. The evaluation included testing 9150 samples at four U.S. clinical trial sites, using three kit lots. Unlinked samples were from routine testing, repositories or purchased from vendors. GS HIV Combo Ag/Ab EIA detection in samples from individuals in two separate populations with acute HIV infection was 95.2% (20/21) and 86.4% (38/44). Sensitivity was 100% (1603/1603) in known antibody positive [HIV-1 Groups M and O, and HIV-2] samples. HIV p24 antigen detection was 100% (53/53) in HIV-1 culture supernatants. HIV-1 seroconversion panel detection improved by a range of 0-20 days compared to a 3rd generation HIV test. Specificity was 99.9% (5989/5996) in low risk, 99.9% (959/960) in high risk and 100% (100/100) in pediatric populations. The GS HIV Combo Ag/Ab EIA significantly reduced the diagnostic window when compared to the 3rd generation screening assay, enabling earlier diagnosis of HIV infection. The performance parameters of the Bio-Rad GS HIV Combo Ag/Ab EIA are well suited for use in HIV diagnostic settings. Copyright © 2011 Elsevier B.V. All rights reserved.

High energy density physics effects predicted in simulations of the CERN HiRadMat beam-target interaction experiments

Science.gov (United States)

Tahir, N. A.; Burkart, F.; Schmidt, R.; Shutov, A.; Wollmann, D.; Piriz, A. R.

2016-12-01

Experiments have been done at the CERN HiRadMat (High Radiation to Materials) facility in which large cylindrical copper targets were irradiated with 440 GeV proton beam generated by the Super Proton Synchrotron (SPS). The primary purpose of these experiments was to confirm the existence of hydrodynamic tunneling of ultra-relativistic protons and their hadronic shower in solid materials, that was predicted by previous numerical simulations. The experimental measurements have shown very good agreement with the simulation results. This provides confidence in our simulations of the interaction of the 7 TeV LHC (Large Hadron Collider) protons and the 50 TeV Future Circular Collider (FCC) protons with solid materials, respectively. This work is important from the machine protection point of view. The numerical simulations have also shown that in the HiRadMat experiments, a significant part of thetarget material is be converted into different phases of High Energy Density (HED) matter, including two-phase solid-liquid mixture, expanded as well as compressed hot liquid phases, two-phase liquid-gas mixture and gaseous state. The HiRadMat facility is therefore a unique ion beam facility worldwide that is currently available for studying the thermophysical properties of HED matter. In the present paper we discuss the numerical simulation results and present a comparison with the experimental measurements.

Environmental radon with RAD7 detector; Radon ambiental con detector RAD7

Energy Technology Data Exchange (ETDEWEB)

Lopez M, A.; Balcazar, M. [ININ, Carretera Mexico-Toluca s/n, 52750 Ocoyoacac, Estado de Mexico (Mexico); Fernandez G, I. M.; Capote F, E., E-mail: arturo.lopez@inin.gob.mx [Centro de Proteccion e Higiene de las Radiaciones, Carretera La Victoria II Km 2.5 e/ Monumental y Final, Guanabacoa, La Habana (Cuba)

2016-09-15

Experimental results of the radon detection with the equipment RAD7 are presented. The use of a solid state detector placed in a semi-spherical chamber with an electric field allows a high sensitivity of 0.4 cpm/P Ci/l. Radon detection is achieved by the spectroscopy of its decay products. In accordance with a table of errors for various ranges of counts and radon concentrations, reported by the manufacturer, an equation was obtained that allows establishing operation criteria of the equipment. For radon detection at ambient concentrations as low as 30 Bq m{sup -3}, is shown that short counts of 10 minutes are good enough to make decisions on radiation protection matter. In places where concentrations are close to 200 Bq m{sup -3}, counting intervals of the order of 0.5 hours will have an acceptable counting error of the order of 20%. The determination of radon in soil was, according to the expected, on the order of 10 kBq m{sup -3}, and was found that even with the recommended counting times of 5 minutes, there is a risk of increased humidity inside the detector above 20% Rh, with associated reduction of detection efficiency, if the desiccant is not used properly. The equipment was subjected to a radon exposure in air of 13, 373 Bq m{sup -3} ± 3.7%, contained within a controlled chamber, with a variation in temperature of (19-21) degrees Celsius and in the relative humidity of (5-7) %, the good stability of the chamber allows to propose calibration processes of these equipment s by assessing the concentration by means of a Ge (Hp) detector. (Author)

Dosimetry of a Deep-Space (Mars) Mission using Measurements from RAD on the Mars Science Laboratory

Science.gov (United States)

Hassler, D.; Zeitlin, C.; Ehresmann, B.; Wimmer-Schweingruber, R. F.; Guo, J.; Matthiae, D.; Reitz, G.

2017-12-01

The space radiation environment is one of the outstanding challenges of a manned deep-space mission to Mars. To improve our understanding and take us one step closer to enabling a human Mars to mission, the Radiation Assessment Detector (RAD) on the Mars Science Laboratory (MSL) has been characterizing the radiation environment, both during cruise and on the surface of Mars for the past 5 years. Perhaps the most significant difference between space radiation and radiation exposures from terrestrial exposures is that space radiation includes a significant component of heavy ions from Galactic Cosmic Rays (GCRs). Acute exposures from Solar Energetic Particles (SEPs) are possible during and around solar maximum, but the energies from SEPs are generally lower and more easily shielded. Thus the greater concern for long duration deep-space missions is the GCR exposure. In this presentation, I will review the the past 5 years of MSL RAD observations and discuss current approaches to radiation risk estimation used by NASA and other space agencies.

Development of an in vitro skin sensitization test using human cell lines; human Cell Line Activation Test (h-CLAT). II. An inter-laboratory study of the h-CLAT.

Science.gov (United States)

Sakaguchi, H; Ashikaga, T; Miyazawa, M; Yoshida, Y; Ito, Y; Yoneyama, K; Hirota, M; Itagaki, H; Toyoda, H; Suzuki, H

2006-08-01

Recent regulatory changes have placed a major emphasis on in vitro safety testing and alternative models. In regard to skin sensitization tests, dendritic cells (DCs) derived from human peripheral blood have been considered in the development of new in vitro alternatives. Human cell lines have been also reported recently. In our previous study, we suggested that measuring CD86 and/or CD54 expression on THP-1 cells (human monocytic leukemia cell line) could be used as an in vitro skin sensitization method. An inter-laboratory study among two laboratories was undertaken in Japan in order to further develop an in vitro skin sensitization model. In the present study, we used two human cell lines: THP-1 and U-937 (human histiocytic lymphoma cell line). First we optimized our test protocol (refer to the related paper entitled "optimization of the h-CLAT protocol" within this journal) and then we did an inter-laboratory validation with nine chemicals using the optimized protocol. We measured the expression of CD86 and CD54 on the above cells using flow cytometry after a 24h and 48h exposure to six known allergens (e.g., DNCB, pPD, NiSO(4)) and three non-allergens (e.g., SLS, tween 80). For the sample test concentration, four doses (0.1x, 0.5x, 1x, and 2x of the 50% inhibitory concentration (IC(50))) were evaluated. IC(50) was calculated using MTT assay. We found that allergens/non-allergens were better predicted using THP-1 cells compared to U-937 cells following a 24 h and a 48 h exposure. We also found that the 24h treatment time tended to have a better accuracy than the 48 h treatment time for THP-1 cells. Expression of CD86 and CD54 were good predictive markers for THP-1 cells, but for U-937 cells, expression of CD86 was a better predictor than CD54, at the 24h and the 48 h treatment time. The accuracy also improved when both markers (CD86 and CD54) were used as compared with a single marker for THP-1 cells. Both laboratories gave a good prediction of allergen

PI-RADS v2 and ADC values: is there room for improvement?

Science.gov (United States)

Jordan, Eric J; Fiske, Charles; Zagoria, Ronald; Westphalen, Antonio C

2018-03-17

To determine the diagnostic accuracy of ADC values in combination with PI-RADS v2 for the diagnosis of clinically significant prostate cancer (CS-PCa) compared to PI-RADS v2 alone. This retrospective study included 155 men whom underwent 3-Tesla prostate MRI and subsequent MR/US fusion biopsies at a single non-academic center from 11/2014 to 3/2016. All scans were performed with a surface coil and included T2, diffusion-weighted, and dynamic contrast-enhanced sequences. Suspicious findings were classified using Prostate Imaging Reporting and Data System (PI-RADS) v2 and targeted using MR/US fusion biopsies. Mixed-effect logistic regression analyses were used to determine the ability of PIRADS v2 alone and combined with ADC values to predict CS-PCa. As ADC categories are more practical in clinical situations than numeric values, an additional model with ADC categories of ≤ 800 and > 800 was performed. A total of 243 suspicious lesions were included, 69 of which were CS-PCa, 34 were Gleason score 3+3 PCa, and 140 were negative. The overall PIRADS v2 score, ADC values, and ADC categories are independent statistically significant predictors of CS-PCa (p values or categories is better discrimination of PI-RADS v2 4 lesions. ADC values and categories help to diagnose CS-PCa when lesions are assigned a PI-RADS v2 score of 4.

Proto-jet configurations in RADs orbiting a Kerr SMBH: symmetries and limiting surfaces

Science.gov (United States)

Pugliese, D.; Stuchlík, Z.

2018-05-01

Ringed accretion disks (RADs) are agglomerations of perfect-fluid tori orbiting around a single central attractor that could arise during complex matter inflows in active galactic nuclei. We focus our analysis to axi-symmetric accretion tori orbiting in the equatorial plane of a supermassive Kerr black hole; equilibrium configurations, possible instabilities, and evolutionary sequences of RADs were discussed in our previous works. In the present work we discuss special instabilities related to open equipotential surfaces governing the material funnels emerging at various regions of the RADs, being located between two or more individual toroidal configurations of the agglomerate. These open structures could be associated to proto-jets. Boundary limiting surfaces are highlighted, connecting the emergency of the jet-like instabilities with the black hole dimensionless spin. These instabilities are observationally significant for active galactic nuclei, being related to outflows of matter in jets emerging from more than one torus of RADs orbiting around supermassive black holes.

Oak Ridge Reservation Environmental Protection Rad Neshaps Radionuclide Inventory Web Database and Rad Neshaps Source and Dose Database.

Science.gov (United States)

Scofield, Patricia A; Smith, Linda L; Johnson, David N

2017-07-01

The U.S. Environmental Protection Agency promulgated national emission standards for emissions of radionuclides other than radon from US Department of Energy facilities in Chapter 40 of the Code of Federal Regulations (CFR) 61, Subpart H. This regulatory standard limits the annual effective dose that any member of the public can receive from Department of Energy facilities to 0.1 mSv. As defined in the preamble of the final rule, all of the facilities on the Oak Ridge Reservation, i.e., the Y-12 National Security Complex, Oak Ridge National Laboratory, East Tennessee Technology Park, and any other U.S. Department of Energy operations on Oak Ridge Reservation, combined, must meet the annual dose limit of 0.1 mSv. At Oak Ridge National Laboratory, there are monitored sources and numerous unmonitored sources. To maintain radiological source and inventory information for these unmonitored sources, e.g., laboratory hoods, equipment exhausts, and room exhausts not currently venting to monitored stacks on the Oak Ridge National Laboratory campus, the Environmental Protection Rad NESHAPs Inventory Web Database was developed. This database is updated annually and is used to compile emissions data for the annual Radionuclide National Emission Standards for Hazardous Air Pollutants (Rad NESHAPs) report required by 40 CFR 61.94. It also provides supporting documentation for facility compliance audits. In addition, a Rad NESHAPs source and dose database was developed to import the source and dose summary data from Clean Air Act Assessment Package-1988 computer model files. This database provides Oak Ridge Reservation and facility-specific source inventory; doses associated with each source and facility; and total doses for the Oak Ridge Reservation dose.

Rad10 exhibits lesion-dependent genetic requirements for recruitment to DNA double-strand breaks in Saccharomyces cerevisiae

DEFF Research Database (Denmark)

Moore, Destaye M; Karlin, Justin; González-Barrera, Sergio

2009-01-01

In the yeast Saccharomyces cerevisiae, the Rad1-Rad10 protein complex participates in nucleotide excision repair (NER) and homologous recombination (HR). During HR, the Rad1-Rad10 endonuclease cleaves 3' branches of DNA and aberrant 3' DNA ends that are refractory to other 3' processing enzymes. ...

Breast Density Estimation with Fully Automated Volumetric Method: Comparison to Radiologists' Assessment by BI-RADS Categories.

Science.gov (United States)

Singh, Tulika; Sharma, Madhurima; Singla, Veenu; Khandelwal, Niranjan

2016-01-01

The objective of our study was to calculate mammographic breast density with a fully automated volumetric breast density measurement method and to compare it to breast imaging reporting and data system (BI-RADS) breast density categories assigned by two radiologists. A total of 476 full-field digital mammography examinations with standard mediolateral oblique and craniocaudal views were evaluated by two blinded radiologists and BI-RADS density categories were assigned. Using a fully automated software, mean fibroglandular tissue volume, mean breast volume, and mean volumetric breast density were calculated. Based on percentage volumetric breast density, a volumetric density grade was assigned from 1 to 4. The weighted overall kappa was 0.895 (almost perfect agreement) for the two radiologists' BI-RADS density estimates. A statistically significant difference was seen in mean volumetric breast density among the BI-RADS density categories. With increased BI-RADS density category, increase in mean volumetric breast density was also seen (P BI-RADS categories and volumetric density grading by fully automated software (ρ = 0.728, P BI-RADS density category by two observers showed fair agreement (κ = 0.398 and 0.388, respectively). In our study, a good correlation was seen between density grading using fully automated volumetric method and density grading using BI-RADS density categories assigned by the two radiologists. Thus, the fully automated volumetric method may be used to quantify breast density on routine mammography. Copyright © 2016 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.

Diagnostic sensitivity of two radio receptor assays (TRAK Assay and TRAK Dyno human) for the detection of TSH receptor antibodies

International Nuclear Information System (INIS)

Paunkovic, N.; Paunkovic, J.

2003-01-01

Radio receptor assays for the detection of TSH receptor antibodies in serum are typically based on binding the competition of TSH-R antibodies and 125I -labelled-TSH for membrane preparation of thyrocytes (TBII tests). The sensitivity of the available tests utilizing porcine cell membranes was found to be around 80%. A new test (TRAK Dyno human, BRAHMS) utilizes human recombinant TSH receptor and human standard material that is supposed to improve the performance of the test. We have compared the results of these two assays. The sensitivity of the TRAK Assay tested in 356 patients with untreated Grave's disease was found to be 85%, and 97.5% for TRAK Dyno human in 111 newly diagnosed patients. Both tests were performed from the same serum specimen for 60 of the investigated patients. The TRAK Assay was positive in 50 patients (83.2%) and TRAK Dyno human in 59 patients (98.3%). The specificity of the new radio receptor assay was also improved. (author)

Predictive values of Bi-Rads categories 3, 4 and 5 in non-palpable breast masses evaluated by mammography, ultrasound and magnetic resonance imaging; Valores preditivos das categorias 3, 4 e 5 do sistema Bi-Rads em lesoes mamarias nodulares nao-palpaveis avaliadas por mamografia, ultra-sonografia e ressonancia magnetica

Energy Technology Data Exchange (ETDEWEB)

Roveda Junior, Decio; Fleury, Eduardo de Castro Faria [Santa Casa de Misericordia de Sao Paulo, SP (Brazil). Faculdade de Ciencias Medicas. Servico de Diagnostico por Imagem]. E-mail: decio.jr@uol.com.br; Piato, Sebastiao [Santa Casa de Misericordia de Sao Paulo, SP (Brazil). Dept. de Obstetricia e Ginecologia. Clinica Ginecologica; Oliveira, Vilmar Marques de [Santa Casa de Misericordia de Sao Paulo, SP (Brazil). Dept. de Obstetricia e Ginecologia. Ginecologia Geral; Rinaldi, Jose Francisco [Santa Casa de Misericordia de Sao Paulo, SP (Brazil). Dept. de Obstetricia e Ginecologia. Clinica de Mastologia; Ferreira, Carlos Alberto Pecci [Santa Casa de Misericordia de Sao Paulo, SP (Brazil). Faculdade de Ciencias Medicas. Dept. de Clinica Medica. Servico de Imagenologia Mamaria

2007-03-15

Objective: To evaluate the predictive value of BI-RADS{sup TM} categories 3, 4 and 5 in non-palpable breast masses assessed by mammography, ultrasound and magnetic resonance imaging. Materials And Methods: Twenty-nine patients with BI-RADS categories 3, 4 and 5 non-palpable breast masses identified by mammograms were submitted to complementary ultrasound and magnetic resonance imaging studies, besides excisional biopsy. In total, 30 biopsies were performed. The lesions as well as their respective BI-RADS classification into 3, 4 and 5 were correlated with the histopathological results. The predictive values calculation was made by means of specific mathematical equations. Results: Negative predictive values for category 3 were: mammography, 69.23%; ultrasound, 70.58%; and magnetic resonance imaging, 100%. Positive predictive values for category 4 were: mammography, 63.63%; ultrasound, 50%; and magnetic resonance imaging, 30.76%. For category 5, positive predictive values were: mammography and ultrasound, 100%; and magnetic resonance imaging, 92.85%. Conclusion: For category 3, the negative predictive value of magnetic resonance imaging was high, and for categories 4 and 5, the positive predictive values of the three modalities were moderate. (author)

Role of teh Rad52 Amino-terminal DNA Binding Activity in DNA Strand Capture in Homologous Recombination

DEFF Research Database (Denmark)

Shi, Idina; Hallwyl, Swee Chuang Lim; Seong, Changhyun

2009-01-01

Saccharomyces cerevisiae Rad52 protein promotes homologous recombination by nucleating the Rad51 recombinase onto replication protein A-coated single-stranded DNA strands and also by directly annealing such strands. We show that the purified rad52-R70A mutant protein, with a compromised amino-ter...

Diagnostic value of breast ultrasound in mammography BI-RADS 0 and clinically indeterminate or suspicious of malignancy breast lesions

Directory of Open Access Journals (Sweden)

Dobrosavljević Aleksandar

2016-01-01

Full Text Available Background/Aim. Not only that ultrasound makes the difference between cystic and solid changes in breast tissue, as it was the case at the beginning of its use, but it also makes the differential diagnosis in terms of benign-malignant. The aim of this study was to assess the role of sonography in the diagnosis of palpable breast masses according to the American College of Radiology Ultrasonographic Breast Imaging Reporting and Data System (BI-RADS and to correlate the BI-RADS 4 and BI-RADS 5 category with pathohistological findings. Methods. A retrospective study was conducted with the breast sonograms of 30 women presented with palpable breast masses found to be mammography category BI-RADS 0 and ultrasonographic BI-RADS categories 4 and 5. The sonographic categories were correlated with pathohistological findings. Results. Surgical biopsy in 30 masses revealed: malignancy (56.7%, fibroadenoma (26.7%, fibrocystic dysplasia with/without atypia (10%, lipoma (3.3% and intramammary lymph node (3.3%. Correlation between BI-RADS categories and pathohistological findings was found (p < 0.05. All BI-RADS 5 masses were malignant, while in BI-RADS 4A category fibroadenomas dominated. A total of 53.8% of all benign lesions were found in women 49 years of age or younger as compared with 35.3% of all malignancies in this group (p < 0.05. Conclusion. Ultrasonography BI-RADS improved classification of breast masses. The ultrasound BI-RADS 4 (A, B, C and BI-RADS 5 lesions should be worked-up with biopsy.

Yugoslav central disposal system or rad waste materials: necessity and justification of construction

International Nuclear Information System (INIS)

Peric, A.; Plecas, I.; Pavlovic, R.

1995-01-01

Decision on searching for the location and the choice of appropriate type of system for final disposal of low and intermediate level rad waste materials should be made urgently in Yugoslavia. capacities for further storing of such waste materials on the site of the Vinca Institute will be full in the next few years, following the trend of present rad waste generation and delivery. Selection of the location and type of the disposal system in Yugoslavia is of crucial importance from the point of view of conservation of environment quality level and enabling permanent control of disposed immobilized rad waste materials and its impact on the environment. (author)

Evaluation of BICRON NE MCP DXT-RAD passive extremity dosemeter

CERN Document Server

Yuen, P S; Frketich, G; Rotunda, J

1999-01-01

Passive extremity dosemeters currently used in dosimetry communities worldwide have shortcomings. In general, an extremity dosemeter has too thick a detector element, and the dosemeter response is highly energy dependent for beta rays with energies ranging from 200 keV to 2 MeV. It often does not have dosemeter identification, causing problems in the chain of custody. It is often read manually, rendering reading/packing operations very labour intensive. As a result of collaboration between AECL and BICRON NE, a new extremity dosemeter, incorporating a highly sensitive LiF:Mg,Cu,P TLD and tentatively code named MCP DXT-RAD, was developed. It has been evaluated for radiological performance against an ISO draft standard for extremity dosemeters in twelve categories: homogeneity, detection threshold, beta ray energy response, beta angular response, photon energy response, photon angular response, reproducibility, stability under various climatic conditions, linearity, residue, self irradiation, and effect of ligh...

Relation between cell cycle and yield of aberrations observed in irradiated human lymphocytes

International Nuclear Information System (INIS)

Leonard, A.; Decat, G.

1979-01-01

The bromodeoxyuridine-Giemsa technique has been used to study systematically the incidence of cells in first or subsequent mitoses at differrent fixation times of human lymphocyte control cultures as well as the influence of ionizing radiations on cell kinetics. Second divisions appear (3%) in cultures harvested 48 h after initiation. In 72 h cultures 40% of the dividing cells are in second and 33% in third division. Administration of 200 rads of X-rays before PHA stimulation results in a mitotic delay but does not increase the incidence of SCE. The yield of dicentrics after an exposure to 200 rads was the same for all cells in first mitosis regardless of fixation time. These results demonstrate that there is no evidence for the existence of sensitive subpopulations that could be distinguished by the time of the first mitotic division following stimulation. (author)

Breast imaging reporting and data system (BI-RADS) or French 'classification ACR'

International Nuclear Information System (INIS)

Dilhuydy, Marie Helene

2007-01-01

Summary: The American College of Radiology Task Force on Breast Cancer published in 2003 Fourth edition of BI-RADS for Mammography. It is a lexicon of mammography terms including illustrations of each feature described, followed by a reporting format with assessment categories according to the degree of concern. The aim is to reduce inconsistencies in mammography reports and recommendations for assessment, to facilitate outcome monitoring and to allow each radiologist to audit his own mammography practice. In France, the Societe Francaise de Radiologie acquired the rights to translate BI-RADS, word for word and without adaptation or influence. The last edition was published in 2004. Simultaneously, French Haute Autorite de Sante and National Committee for Breast Cancer Screening proposed to all community practice mammography facilities a classification of detected abnormalities stating more clearly than BI-RADS do which feature has to be included in such and such assessment category and how to manage it. This 'classification ACR' is adapted from BI-RADS but strongly influenced by the context of the French nationwide screening programme, and by European recommendations to limitate undesirable risks of screening such as false positive and overdiagnosis. The differences between the two systems are discussed

The use of sonographic subjective tumor assessment, IOTA logistic regression model 1, IOTA Simple Rules and GI-RADS system in the preoperative prediction of malignancy in women with adnexal masses.

Science.gov (United States)

Koneczny, Jarosław; Czekierdowski, Artur; Florczak, Marek; Poziemski, Paweł; Stachowicz, Norbert; Borowski, Dariusz

2017-01-01

Sonography based methods with various tumor markers are currently used to discriminate the type of adnexal masses. To compare the predictive value of selected sonography-based models along with subjective assessment in ovarian cancer prediction. We analyzed data of 271 women operated because of adnexal masses. All masses were verified by histological examination. Preoperative sonography was performed in all patients and various predictive models includ¬ing IOTA group logistic regression model LR1 (LR1), IOTA simple ultrasound-based rules by IOTA (SR), GI-RADS and risk of malignancy index (RMI3) were used. ROC curves were constructed and respective AUC's with 95% CI's were compared. Of 271 masses 78 proved to be malignant including 6 borderline tumors. LR1 had sensitivity of 91.0%, specificity of 91.2%, AUC = 0.95 (95% CI: 0.92-0.98). Sensitivity for GI-RADS for 271 patients was 88.5% with specificity of 85% and AUC = 0.91 (95% CI: 0.88-0.95). Subjective assessment yielded sensitivity and specificity of 85.9% and 96.9%, respectively with AUC = 0.97 (95% CI: 0.94-0.99). SR were applicable in 236 masses and had sensitivity of 90.6% with specificity of 95.3% and AUC = 0.93 (95% CI 0.89-0.97). RMI3 was calculated only in 104 women who had CA125 available and had sensitivity of 55.3%, specificity of 94% and AUC = 0.85 (95% CI: 0.77-0.93). Although subjective assessment by the ultrasound expert remains the best current method of adnexal tumors preoperative discrimination, the simplicity and high predictive value favor the IOTA SR method, and when not applicable, the IOTA LR1 or GI-RADS models to be primarily and effectively used.

Lingering single-strand breaks trigger Rad51-independent homology-directed repair of collapsed replication forks in the polynucleotide kinase/phosphatase mutant of fission yeast.

Directory of Open Access Journals (Sweden)

Arancha Sanchez

2017-09-01

Full Text Available The DNA repair enzyme polynucleotide kinase/phosphatase (PNKP protects genome integrity by restoring ligatable 5'-phosphate and 3'-hydroxyl termini at single-strand breaks (SSBs. In humans, PNKP mutations underlie the neurological disease known as MCSZ, but these individuals are not predisposed for cancer, implying effective alternative repair pathways in dividing cells. Homology-directed repair (HDR of collapsed replication forks was proposed to repair SSBs in PNKP-deficient cells, but the critical HDR protein Rad51 is not required in PNKP-null (pnk1Δ cells of Schizosaccharomyces pombe. Here, we report that pnk1Δ cells have enhanced requirements for Rad3 (ATR/Mec1 and Chk1 checkpoint kinases, and the multi-BRCT domain protein Brc1 that binds phospho-histone H2A (γH2A at damaged replication forks. The viability of pnk1Δ cells depends on Mre11 and Ctp1 (CtIP/Sae2 double-strand break (DSB resection proteins, Rad52 DNA strand annealing protein, Mus81-Eme1 Holliday junction resolvase, and Rqh1 (BLM/WRN/Sgs1 DNA helicase. Coupled with increased sister chromatid recombination and Rad52 repair foci in pnk1Δ cells, these findings indicate that lingering SSBs in pnk1Δ cells trigger Rad51-independent homology-directed repair of collapsed replication forks. From these data, we propose models for HDR-mediated tolerance of persistent SSBs with 3' phosphate in pnk1Δ cells.

Effect of low dose x-irradiation on alloantigen sensitized and unsensitized lymphocytes

Energy Technology Data Exchange (ETDEWEB)

Dohi, Kiyohiko; Yahata, Hiroshi; Fukuda, Yasuhiko; Asahara, Toshimasa; Ono, Eiji; Ezaki, Haruo

1984-12-01

The effect of local graft irradiation on immune response in allograft in which acute rejection occurs was studied using an in vitro model. Unidirectional mixed lymphocyte culture (MLC) was used as the in vitro model of acute rejection. 150 and 300 rad x-irradiation suppressed mixed lymphocyte reaction (MLR) but did not cell-mediated-lympholysis (CML) of unsensitized lymphocytes. X-irradiated alloantigen sensitized cells (ASC) generated in 6-day MLC suppressed MLR and CML of unsensitized lymphocytes. Suppressive effects of x-irradiated ASC were of the same degree by x-irradiation doses of 150-500 rad. Suppressive effect of x-irradiation was maintained for only a short period after x-irradiation. Potential function of suppressor precursor cells among unsensitized lymphocytes was abolished by x-irradiation of 300 rad. (author).

Quantitative relationship between the local lymph node assay and human skin sensitization assays.

Science.gov (United States)

Schneider, K; Akkan, Z

2004-06-01

The local lymph node assay (LLNA) is a new test method which allows for the quantitative assessment of sensitizing potency in the mouse. Here, we investigate the quantitative correlation between results from the LLNA and two human sensitization tests--specifically, human repeat insult patch tests (HRIPTs) and human maximization tests (HMTs). Data for 57 substances were evaluated, of which 46 showed skin sensitizing properties in human tests, whereas 11 yielded negative results in humans. For better comparability data from mouse and human tests were transformed to applied doses per skin area, which ranged over four orders of magnitude for the substances considered. Regression analysis for the 46 human sensitizing substances revealed a significant positive correlation between the LLNA and human tests. The correlation was better between LLNA and HRIPT data (n=23; r=0.77) than between LLNA and HMT data (n=38; r=0.65). The observed scattering of data points is related to various uncertainties, in part associated with insufficiencies of data from older HMT studies. Predominantly negative results in the LLNA for another 11 substances which showed no skin sensitizing activity in human maximization tests further corroborate the correspondence between LLNA and human tests. Based on this analysis, the LLNA can be considered a reliable basis for relative potency assessments for skin sensitizers. Proposals are made for the regulatory exploitation of the LLNA: four potency groups can be established, and assignment of substances to these groups according to the outcome of the LLNA can be used to characterize skin sensitizing potency in substance-specific assessments. Moreover, based on these potency groups, a more adequate consideration of sensitizing substances in preparations becomes possible. It is proposed to replace the current single concentration limit for skin sensitizers in preparations, which leads to an all or nothing classification of a preparation as sensitizing to

FBH1 helicase disrupts RAD51 filaments in vitro and modulates homologous recombination in mammalian cells

DEFF Research Database (Denmark)

Simandlova, Jitka; Zagelbaum, Jennifer; Payne, Miranda J

2013-01-01

Efficient repair of DNA double strand breaks and interstrand cross-links requires the homologous recombination (HR) pathway, a potentially error-free process that utilizes a homologous sequence as a repair template. A key player in HR is RAD51, the eukaryotic ortholog of bacterial RecA protein. RAD......51 can polymerize on DNA to form a nucleoprotein filament that facilitates both the search for the homologous DNA sequences and the subsequent DNA strand invasion required to initiate HR. Because of its pivotal role in HR, RAD51 is subject to numerous positive and negative regulatory influences...... filaments on DNA through its ssDNA translocase function. Consistent with this, a mutant mouse embryonic stem cell line with a deletion in the FBH1 helicase domain fails to limit RAD51 chromatin association and shows hyper-recombination. Our data are consistent with FBH1 restraining RAD51 DNA binding under...

Sensitivity of risk parameters to human errors for a PWR

International Nuclear Information System (INIS)

Samanta, P.; Hall, R.E.; Kerr, W.

1980-01-01

Sensitivities of the risk parameters, emergency safety system unavailabilities, accident sequence probabilities, release category probabilities and core melt probability were investigated for changes in the human error rates within the general methodological framework of the Reactor Safety Study for a Pressurized Water Reactor (PWR). Impact of individual human errors were assessed both in terms of their structural importance to core melt and reliability importance on core melt probability. The Human Error Sensitivity Assessment of a PWR (HESAP) computer code was written for the purpose of this study

Significance and Application of Digital Breast Tomosynthesis for the BI-RADS Classification of Breast Cancer.

Science.gov (United States)

Cai, Si-Qing; Yan, Jian-Xiang; Chen, Qing-Shi; Huang, Mei-Ling; Cai, Dong-Lu

2015-01-01

Full-field digital mammography (FFDM) with dense breasts has a high rate of missed diagnosis, and digital breast tomosynthesis (DBT) could reduce organization overlapping and provide more reliable images for BI-RADS classification. This study aims to explore application of COMBO (FFDM+DBT) for effect and significance of BI-RADS classification of breast cancer. In this study, we selected 832 patients who had been treated from May 2013 to November 2013. Classify FFDM and COMBO examination according to BI-RADS separately and compare the differences for glands in the image of the same patient in judgment, mass characteristics display and indirect signs. Employ Paired Wilcoxon rank sum test was used in 79 breast cancer patients to find differences between two examine methods. The results indicated that COMBO pattern is able to observe more details in distribution of glands when estimating content. Paired Wilcoxon rank sum test showed that overall classification level of COMBO is higher significantly compared to FFDM to BI-RADS diagnosis and classification of breast (PBI-RADS classification in breast cancer in clinical.

The Over-expression of the β2 Catalytic Subunit of the Proteasome Decreases Homologous Recombination and Impairs DNA Double-Strand Break Repair in Human Cells

Directory of Open Access Journals (Sweden)

Anita Collavoli

2011-01-01

Full Text Available By a human cDNA library screening, we have previously identified two sequences coding two different catalytic subunits of the proteasome which increase homologous recombination (HR when overexpressed in the yeast Saccharomyces cerevisiae. Here, we investigated the effect of proteasome on spontaneous HR and DNA repair in human cells. To determine if the proteasome has a role in the occurrence of spontaneous HR in human cells, we overexpressed the β2 subunit of the proteasome in HeLa cells and determined the effect on intrachromosomal HR. Results showed that the overexpression of β2 subunit decreased HR in human cells without altering the cell proteasome activity and the Rad51p level. Moreover, exposure to MG132 that inhibits the proteasome activity reduced HR in human cells. We also found that the expression of the β2 subunit increases the sensitivity to the camptothecin that induces DNA double-strand break (DSB. This suggests that the β2 subunit has an active role in HR and DSB repair but does not alter the intracellular level of the Rad51p.

The Molecular Basis of Double-Strand DNA Break Repair: The Critical Structure of the RAD52/RPA Complex

National Research Council Canada - National Science Library

Jackson, Dobra

2001-01-01

.... RAD52 has specific interactions with RAD51, RPA and DNA (1,2,3). The binding of RAD52 to ends of double-strand breaks has been found to be a key initiation step to DNA repair by homologous recombination...

Cloning, sequencing, disruption and phenotypic analysis of uvsC, an Aspergillus nidulans homologue of yeast RAD51.

Science.gov (United States)

van Heemst, D; Swart, K; Holub, E F; van Dijk, R; Offenberg, H H; Goosen, T; van den Broek, H W; Heyting, C

1997-05-01

We have cloned the uvsC gene of Aspergillus nidulans by complementation of the A. nidulans uvsC114 mutant. The predicted protein UVSC shows 67.4% sequence identity to the Saccharomyces cerevisiae Rad51 protein and 27.4% sequence identity to the Escherichia coli RecA protein. Transcription of uvsC is induced by methyl-methane sulphonate (MMS), as is transcription of RAD51 of yeast. Similar levels of uvsC transcription were observed after MMS induction in a uvsC+ strain and the uvsC114 mutant. The coding sequence of the uvsC114 allele has a deletion of 6 bp, which results in deletion of two amino acids and replacement of one amino acid in the translation product. In order to gain more insight into the biological function of the uvsC gene, a uvsC null mutant was constructed, in which the entire uvsC coding sequence was replaced by a selectable marker gene. Meiotic and mitotic phenotypes of a uvsC+ strain, the uvsC114 mutant and the uvsC null mutant were compared. The uvsC null mutant was more sensitive to both UV and MMS than the uvsC114 mutant. The uvsC114 mutant arrested in meiotic prophase-I. The uvsC null mutant arrested at an earlier stage, before the onset of meiosis. One possible interpretation of these meiotic phenotypes is that the A. nidulans homologue of Rad51 of yeast has a role both in the specialized processes preceding meiosis and in meiotic prophase I.

Stage sensitivity and dose response of meiotic chromosomes of pollen mother cells of Tradescantia to X-rays

International Nuclear Information System (INIS)

Ma, T.-H.; Kontos, G.J. Jr.; Anderson, V.A.

1980-01-01

Chromosome damage induced by physical and chemical mutagens can be quantitated by the frequencies of micronuclei (MCN) produced in tetrads of the meiotic pollen mother cells of Tradescantia, i.e. the 'MCN-in-Tetrad' test. The stage sensitivity and dose response of these meiocytes to low exposures of X-rays was studied to improve the efficiency and reliability of this test. Stage sensitivity was determined by observing, at 3 hr intervals, the frequencies of X-ray (35 rads)-induced MCN in tetrads from a series of 16 fixations of tetrad-containing inflorescences. Late stages of meiosis (3-9 hr post-irradiation fixation groups) were insensitive (5-14 MCN/100 tetrads). Relatively high sensitivity was exhibited in the early stages of meiosis. The first and second sensitive peaks (62 and 61 MCN/100 tetrads) centered around the 21 and 39 hr post-irradiation fixation groups respectively. Control groups yielded around 3-4 MCN/100 tetrads. A dose-response relation for MCN was determined by treating early stages of meiotic pollen mother cells with X-ray exposures ranging from 9.5 to 57.5 rads. A linear regression line was established with about 20 MCN/100 tetrads per 10 rad increment. (author)

Lysophosphatidylcholine hydrolases of human erythrocytes, lymphocytes, and brain: Sensitive targets of conserved specificity for organophosphorus delayed neurotoxicants

International Nuclear Information System (INIS)

Vose, Sarah C.; Holland, Nina T.; Eskenazi, Brenda; Casida, John E.

2007-01-01

Brain neuropathy target esterase (NTE), associated with organophosphorus (OP)-induced delayed neuropathy, has the same OP inhibitor sensitivity and specificity profiles assayed in the classical way (paraoxon-resistant, mipafox-sensitive hydrolysis of phenyl valerate) or with lysophosphatidylcholine (LysoPC) as the substrate. Extending our earlier observation with mice, we now examine human erythrocyte, lymphocyte, and brain LysoPC hydrolases as possible sensitive targets for OP delayed neurotoxicants and insecticides. Inhibitor profiling of human erythrocytes and lymphocytes gave the surprising result of essentially the same pattern as with brain. Human erythrocyte LysoPC hydrolases are highly sensitive to OP delayed neurotoxicants, with in vitro IC 50 values of 0.13-85 nM for longer alkyl analogs, and poorly sensitive to the current OP insecticides. In agricultural workers, erythrocyte LysoPC hydrolyzing activities are similar for newborn children and their mothers and do not vary with paraoxonase status but have high intersample variation that limits their use as a biomarker. Mouse erythrocyte LysoPC hydrolase activity is also of low sensitivity in vitro and in vivo to the OP insecticides whereas the delayed neurotoxicant ethyl n-octylphosphonyl fluoride inhibits activity in vivo at 1-3 mg/kg. Overall, inhibition of blood LysoPC hydrolases is as good as inhibition of brain NTE as a predictor of OP inducers of delayed neuropathy. NTE and lysophospholipases (LysoPLAs) both hydrolyze LysoPC, yet they are in distinct enzyme families with no sequence homology and very different catalytic sites. The relative contributions of NTE and LysoPLAs to LysoPC hydrolysis and clearance from erythrocytes, lymphocytes, and brain remain to be defined

Genetic control of yeast cell radiosensitivity modification by oxygen and hypoxic sensitizers

International Nuclear Information System (INIS)

Zhuranovskaya, G.P.; Petin, V.G.

1984-01-01

Diploid yeast cells Saccharomyces cerevisiae ''of the wild type'', individual mutants, homozygous in rad 2 and rad 54 and double mutants, containing both these loci in homozygous state are considered to prove genetic determination of radiosensitivity modification of hypoxic cells by oxygen and electron acceptor compounds previously demonstrated on yeast cells of other genotypes. It is shown that both ''oxygen effect'' and the effect of hypoxic sensitizers depend on the activity of repair systems. The possible mechanism of participation of post-radiation restoration processes in the modification of cell radiosensitivity, is discussed

Food Irradiation Is Done in Grays, not Rads

International Nuclear Information System (INIS)

Strom, Daniel J.

2002-01-01

One federal agency has chosen to use exclusively modern SI units of radiation dose in its regulations: the FDA. While not exactly hot news, this bold move by a U.S. government agency on November 26, 1997, should be noted by those who wish to encourage the switch from curies, working level months, rads, rems, and roentgens to becquerels, joule hours per cubic meter, grays, sieverts, and coulombs per kilogram. The regulation is 21 CFR 179, Irradiation in the Production, Processing, and Handling of Food. Specifically, 21 CFR 179.26 (b) 8. permits meat irradiation up to 4.5 kGy for refrigerated meat and 7.0 kGy for frozen meat. Prior to the 1997 addition, radiation doses had been quoted in grays (kGy) with rad (Mrad) values in parentheses. In the 1997 addition, the Mrads disappeared

A trial of ACNU and radiation therapy with sensitizing agents for malignant gliomas

Energy Technology Data Exchange (ETDEWEB)

Kawano, Hirokazu; Hayashi, Minoru; Satoh, Kazufumi; Ishii, Hisamasa; Nakatsugawa, Shigekazu; Ishii, Yasushi (Fukui Medical School, Yoshida, Fukui (Japan))

1989-11-01

Twelve cases of malignant gliomas (anaplastic astrocytoma 4, glioblatoma 8, recurrent 3, primary 9) were treated with ACNU and radiation with sensitizing agents after the surgical removal of the tumor. BUdR, Vidarabine (Ara-A), Aciclovir (ACV) were applied for sensitizing agents. BUdR was administrated intraarterially prior to radiation (380 rad, two times a week), and Ara-A and ACV intravenously during and after the radiation. Total dosage of the radiation was 50-60 Grey for each case. All recurrent and eight primary patients died. The mean survival time of the recurrent patients was 17.7 months, while that of the primary patients was 13.4 months. One of the primary patients was glioblastoma and is still surviving more than 24 months by now. The complete response (CR) rate of the primary tumor patients observed by computerized tomography (CT) scan was 5/9. We can expect the availability of this trial for malignant gliomas because of high CR rate in primary tumor cases. (author).

The KYxxL motif in Rad17 protein is essential for the interaction with the 9–1–1 complex

Energy Technology Data Exchange (ETDEWEB)

Fukumoto, Yasunori, E-mail: fukumoto@faculty.chiba-u.jp [Laboratory of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675 (Japan); Ikeuchi, Masayoshi; Nakayama, Yuji [Department of Biochemistry & Molecular Biology, Kyoto Pharmaceutical University, Kyoto 607-8414 (Japan); Yamaguchi, Naoto, E-mail: nyama@faculty.chiba-u.jp [Laboratory of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675 (Japan)

2016-09-02

ATR-dependent DNA damage checkpoint is the major DNA damage checkpoint against UV irradiation and DNA replication stress. The Rad17–RFC and Rad9–Rad1–Hus1 (9–1–1) complexes interact with each other to contribute to ATR signaling, however, the precise regulatory mechanism of the interaction has not been established. Here, we identified a conserved sequence motif, KYxxL, in the AAA+ domain of Rad17 protein, and demonstrated that this motif is essential for the interaction with the 9–1–1 complex. We also show that UV-induced Rad17 phosphorylation is increased in the Rad17 KYxxL mutants. These data indicate that the interaction with the 9–1–1 complex is not required for Rad17 protein to be an efficient substrate for the UV-induced phosphorylation. Our data also raise the possibility that the 9–1–1 complex plays a negative regulatory role in the Rad17 phosphorylation. We also show that the nucleotide-binding activity of Rad17 is required for its nuclear localization. - Highlights: • We have identified a conserved KYxxL motif in Rad17 protein. • The KYxxL motif is crucial for the interaction with the 9–1–1 complex. • The KYxxL motif is dispensable or inhibitory for UV-induced Rad17 phosphorylation. • Nucleotide binding of Rad17 is required for its nuclear localization.

Mutation of cysteine-88 in the Saccharomyces cerevisiae RAD6 protein abolishes its ubiquitin-conjugating activity and its various biological functions

International Nuclear Information System (INIS)

Sung, P.; Prakash, S.; Prakash, L.

1990-01-01

The RAD6 gene of Saccharomyces cerevisiae is required for DNA repair, DNA damage-induced mutagenesis, and sporulation. RAD6 protein is a ubiquitin-conjugating enzyme (E2) that has been shown to attach multiple molecules of ubiquitin to histones H2A and H2B. We have now examined whether the E2 activity of RAD6 is involved in its various biological functions. Since the formation of a thioester adduct between E2 and ubiquitin is necessary for E2 activity, the single cysteine residue (Cys-88) present in RAD6 was changed to alanine or valine. The mutant proteins were overproduced in yeast cells and purified to near homogeneity. We show that the rad6 Ala-88 and rad6 Val-88 mutant proteins lack the capacity for thioester formation with ubiquitin and, as a consequence, are totally devoid of any E2 activity. The rad6 Ala-88 and rad6 Val-88 mutations confer a defect in DNA repair, mutagenesis, and sporulation equivalent to that in the rad6 null allele. We suggest that the biological functions of RAD6 require its E2 activity. (author)

Investigations of the regulation of cerebral circulation by means of functional changes observed on unanaesthetized rabbits during hypoxia, paradoxical sleep and after whole-body γ-exposure (850-150 rad dose range)

International Nuclear Information System (INIS)

Dufour, Raymond.

1977-01-01

Both the general effects and the effects on cerebral circulation of whole-body exposure were studied at doses of 850, 650, 450, 250 and 150 rads. Early functional changes following exposure demonstrated two juxtaposed mechanisms, a central one and a peripheral one. The central process, slightly sensitive to the dose-effect, occurred earlier and should be at the origin of hyperthermia, hyperventilation, tachycardia, skin vasoconstruction and a slight increase of arterial pressure. The peripheral mechanisms, occurring slightly later should be more sensitive to the dose-effect and might be at the origin of hypothermic effects and cardiovascular depression. The increase of cerebral blood flow occurring at the 450 rad dose should be best explained by the presence of vasotropic substances. A twofold component of cerebral vasotonicity should be assumed that would depend on the autonomous nervous system and myogenous autoregulation [fr

222Rn Determination In Drinking Waters - RAD7 And LSC Technique Comparison

International Nuclear Information System (INIS)

Todorovic, N.; Stojkovic, I.; Nikolov, J.; Tenjovic, B.

2015-01-01

A procedure for the determination of 222Rn in environmental water samples using liquid scintillation counting (LSC) was applied and optimized. For radon determination in drinking water from groundwater and surface water sources by LSC, the EPA Method 913.0 was used. A minimum detectable activity of 0.029 Bq L-1 in a 20 mL glass vial (10 mL water sample mixed with 10 mL of liquid scintillation cocktail) has been achieved during 300 minutes of measurement time. The procedure was compared with RAD7 radon detector measurements. Factors that affect the measurement accuracy and precision of RAD7 radon detector are the sampling technique, sample concentration, sample size, counting time, temperature, relative humidity and background effects. The minimal detectable activity (MDA) for RAD7 technique was found to be 0.1 Bq/L. From obtained results of 222Rn measurements in 15 water samples with different 222Rn activities, correlation between the two techniques applied for measurements of 222Rn in water samples (A less than 400 Bq/L) was determined. There is reasonable agreement (within statistical uncertainties) between the various techniques in most cases, while disagreements most likely come from systematic uncertainties associated with sampling procedures. Discrepancy in determined activities between the two techniques becomes more evident with increased 222Rn activities in water. LSC technique gives in general higher activity concentrations for about 30 percent than RAD7 spectrometer. The interpretation of shown results could be that RAD7 is not properly calibrated for higher activities, since USA reference level of 222Rn concentrations in water is only 11.1 Bq/L (US EPA, Proposed Radon in Drinking Water Regulation). (author).

The role of Rad 51 protein in radioresistance of spheroid model of Du 145 prostate carcinoma cell line

International Nuclear Information System (INIS)

Taghizadeh, M.; Khoei, S.; Nikoofar, A. R.; Ghamsari, L.; Goliaei, B.

2009-01-01

Rad 51 is a protein with critical role in double strand break repair. Down-regulation of this protein has a significant effect in radiosensitivity of some cell lines like prostate carcinoma. Compared to monolayer cell culture model, the spheroids are more resistant to radiation. The aim of the current study was to determine the Rad 51 protein level in Du 145 spheroids, and monolayer cells before and after exposure to gamma irradiation. Materials and Methods: In the present study, western blot was used to determine the level of Rad 51 protein in Du 145 cell line grown as monolayer and spheroid. Results: Western blot analysis showed that in the spheroid cells, Rad 51 had an elevated level before and after radiation in comparison with monolayer cells. Higher doses of radiation induced elevated expression of Rad 51 protein in both culture models.The level of at protein after exposure to gamma rays had been time-dependent. Conclusion: Rad 51 might act as a mediator of radiation resistance in tumor cells. Repression of Rad 51 activity could be a prominent strategy to overcome radiation resistance of tumors.

Dancing on damaged chromatin. Functions of ATM and the RAD50/MRE11/NBS1 complex in cellular responses to DNA damage

International Nuclear Information System (INIS)

Iijima, Kenta; Ohara, Maki; Seki, Ryota; Tauchi, Hiroshi

2008-01-01

In order to preserve and protect genetic information, eukaryotic cells have developed a signaling or communications network to help the cell respond to DNA damage, and ATM and NBS1 are key players in this network. ATM is a protein kinase which is activated immediately after a DNA double strand break (DSB) is formed, and the resulting signal cascade generated in response to cellular DSBs is regulated by post-translational protein modifications such as phosphorylation and acetylation. In addition, to ensure the efficient functioning of DNA repair and cell cycle checkpoints, the highly ordered structure of eukaryotic chromatin must be appropriately altered to permit access of repair-related factors to DNA. These alterations are termed chromatin remodeling, and are executed by a specific remodeling complex in conjunction with histone modifications. Current advances in the molecular analysis of DNA damage responses have shown that the auto-phosphorylation of ATM and the interaction between ATM and NBS1 are key steps for ATM activation, and that the association of ATM and NBS1 is involved in chromatin remodeling. Identification of novel factors which function in ubiquitination (RNF8, Ubc13, Rap80, etc.) has also enabled us to understand more details of the early stages in DNA repair pathways which respond to DSBs. In this review, the focus is on the role of ATM and the RAD50/MRE11/NBS1 complex in DSB response pathways, and their role in DSB repair and in the regulation of chromatin remodeling. (author)

Predictive values of Bi-Rads categories 3, 4 and 5 in non-palpable breast masses evaluated by mammography, ultrasound and magnetic resonance imaging

International Nuclear Information System (INIS)

Roveda Junior, Decio; Fleury, Eduardo de Castro Faria; Piato, Sebastiao; Oliveira, Vilmar Marques de; Rinaldi, Jose Francisco; Ferreira, Carlos Alberto Pecci

2007-01-01

Objective: To evaluate the predictive value of BI-RADS TM categories 3, 4 and 5 in non-palpable breast masses assessed by mammography, ultrasound and magnetic resonance imaging. Materials And Methods: Twenty-nine patients with BI-RADS categories 3, 4 and 5 non-palpable breast masses identified by mammograms were submitted to complementary ultrasound and magnetic resonance imaging studies, besides excisional biopsy. In total, 30 biopsies were performed. The lesions as well as their respective BI-RADS classification into 3, 4 and 5 were correlated with the histopathological results. The predictive values calculation was made by means of specific mathematical equations. Results: Negative predictive values for category 3 were: mammography, 69.23%; ultrasound, 70.58%; and magnetic resonance imaging, 100%. Positive predictive values for category 4 were: mammography, 63.63%; ultrasound, 50%; and magnetic resonance imaging, 30.76%. For category 5, positive predictive values were: mammography and ultrasound, 100%; and magnetic resonance imaging, 92.85%. Conclusion: For category 3, the negative predictive value of magnetic resonance imaging was high, and for categories 4 and 5, the positive predictive values of the three modalities were moderate. (author)

The recovery of the human organism after radiation exposure

International Nuclear Information System (INIS)

Gerber, G.B.

1976-01-01

The repair of radiation damage in the human organism is reviewed. A distinction is made between the single repair steps, first the molecular repair of sublethal damage during the periods of 30 min to 2 h and several days to months, second the substitution of the whole cells during a period of reproduction which is specific for the kind and persistence of the cells. One example is the radiosensitive stem cell with a reproduction rate of 40% and a redoublication time of 10 d at 100 rads and the very low reproduction rate of 1% with redoublication time of 7 d after a dose of 400 rads. 5 rads seems to be acceptable for systems with recovery and repeated exposure, single doses normally should not exceed 25 rads, not 100 rads/d for to save human life, and not a total dose of 500 rads. About 20% of irradiation damage is not repaired and leads to late effects, for example the induction of tumors, the shortening of life span and an increase in embryonic mortality. The author recommends the acceptance of a radiation dose leading to 20 additional cases of leucemia in the whole population of Germany and an increase of tumor frequency of 1%. The shortening of life span should not exceed 0,5%. The equivalent residual dose (ERD) can be calculated by the following equation: ERD = last effective dose minus 5 rads x number of days. (AJ) [de

Comparing Visually Assessed BI-RADS Breast Density and Automated Volumetric Breast Density Software: A Cross-Sectional Study in a Breast Cancer Screening Setting.

Science.gov (United States)

van der Waal, Daniëlle; den Heeten, Gerard J; Pijnappel, Ruud M; Schuur, Klaas H; Timmers, Johanna M H; Verbeek, André L M; Broeders, Mireille J M

2015-01-01

The objective of this study is to compare different methods for measuring breast density, both visual assessments and automated volumetric density, in a breast cancer screening setting. These measures could potentially be implemented in future screening programmes, in the context of personalised screening or screening evaluation. Digital mammographic exams (N = 992) of women participating in the Dutch breast cancer screening programme (age 50-75y) in 2013 were included. Breast density was measured in three different ways: BI-RADS density (5th edition) and with two commercially available automated software programs (Quantra and Volpara volumetric density). BI-RADS density (ordinal scale) was assessed by three radiologists. Quantra (v1.3) and Volpara (v1.5.0) provide continuous estimates. Different comparison methods were used, including Bland-Altman plots and correlation coefficients (e.g., intraclass correlation coefficient [ICC]). Based on the BI-RADS classification, 40.8% of the women had 'heterogeneously or extremely dense' breasts. The median volumetric percent density was 12.1% (IQR: 9.6-16.5) for Quantra, which was higher than the Volpara estimate (median 6.6%, IQR: 4.4-10.9). The mean difference between Quantra and Volpara was 5.19% (95% CI: 5.04-5.34) (ICC: 0.64). There was a clear increase in volumetric percent dense volume as BI-RADS density increased. The highest accuracy for predicting the presence of BI-RADS c+d (heterogeneously or extremely dense) was observed with a cut-off value of 8.0% for Volpara and 13.8% for Quantra. Although there was no perfect agreement, there appeared to be a strong association between all three measures. Both volumetric density measures seem to be usable in breast cancer screening programmes, provided that the required data flow can be realized.